![Page 1: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/1.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
STATISTICAL ANALYSIS PLAN
Study: SP0982 Product: Lacosamide
A double-blind, randomized, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of lacosamide as adjunctive therapy for uncontrolled primary generalized
tonic-clonic seizures in subjects with idiopathic generalized epilepsy
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019
Confidentiality Statement
Confidential This document is the property of UCB and may not – in full or in part – be passed on,
reproduced, published, or otherwise used without the express permission of UCB.
REDACTED COPY
09 Aug 2016
REDACTED COPY
09 Aug 201624 Feb 2017
REDACTED COPY
24 Feb 201714 Mar 2017REDACTED C
OPY
14 Mar 2017201R
EDACTED COPY
201
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
group, multicenter study to evaluate
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
group, multicenter study to evaluate the efficacy and safety of lacosamide as adjunctive therapy for uncontrolled primary generalized
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
the efficacy and safety of lacosamide as adjunctive therapy for uncontrolled primary generalized clonic seizures in subjects with idiopathic generalized epilepsy
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
clonic seizures in subjects with idiopathic generalized epilepsy
14 Mar 2017
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
14 Mar 2017
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
201
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
2019
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
9Mar 2019
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Mar 2019
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
![Page 2: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/2.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
TABLE OF CONTENTS
LIST OF ABBREVIATIONS .................................................................................................... 8 1 INTRODUCTION ........................................................................................................... 10 2 PROTOCOL SUMMARY ............................................................................................... 10 2.1 Study objectives ........................................................................................................... 10
2.1.1 Primary objective ................................................................................................. 10 2.1.2 Secondary objective ............................................................................................. 10
2.2 Study variables ............................................................................................................. 10 2.2.1 Efficacy variables ................................................................................................ 10
2.2.1.1 Primary efficacy variable .......................................................................... 10 2.2.1.2 Secondary efficacy variables ..................................................................... 10 2.2.1.3 Other efficacy variables ............................................................................. 10
2.2.2 Safety variables .................................................................................................... 12 2.2.2.1 Other safety variables ................................................................................ 12
2.2.3 Pharmacokinetic variables ................................................................................... 12 2.3 Study design and conduct ............................................................................................ 12
2.3.1 Study description ................................................................................................. 12 2.3.2 Rationale for study design ................................................................................... 14
2.4 Determination of sample size ....................................................................................... 15 3 DATA ANALYSIS CONSIDERATIONS ...................................................................... 15 3.1 General presentation of summaries and analyses ........................................................ 15 3.2 General study level definitions .................................................................................... 16
3.2.1 Analysis time points ............................................................................................ 16 3.2.2 Seizure cluster ...................................................................................................... 17 3.2.3 Event .................................................................................................................... 17 3.2.4 Censoring ............................................................................................................. 17 3.2.5 AEDs and benzodiazepines ................................................................................. 18
3.2.5.1 Prohibited concomitant treatments (medications and therapies) ............... 18 3.2.6 Relative day ......................................................................................................... 19 3.2.7 Last Visit .............................................................................................................. 19 3.2.8 Month ................................................................................................................... 19
3.3 Definition of Baseline values ....................................................................................... 19 3.4 Protocol deviations....................................................................................................... 19 3.5 Analysis sets................................................................................................................. 20
3.5.1 Screened Set ......................................................................................................... 20 3.5.2 Randomized Set ................................................................................................... 20 3.5.3 Safety Set ............................................................................................................. 20 3.5.4 Full Analysis Set .................................................................................................. 20
REDACTED COPY ................................
REDACTED COPY ................................
................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................
REDACTED COPY
................................ERATIONS
REDACTED COPY
ERATIONSGeneral presentation of summaries and analyses
REDACTED COPY
General presentation of summaries and analysesGeneral study level definitionsREDACTED C
OPY
General study level definitions
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
10
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
10.............
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
............. 10
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
10................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................ 10
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
10................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
..........................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
..........................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................General presentation of summaries and analyses
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
General presentation of summaries and analyses................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................AEDs and benzodiazepines
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
AEDs and benzodiazepinesProhibited concomitant treatments (medications and therapies)
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Prohibited concomitant treatments (medications and therapies)Relative day
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Relative dayLast Visit
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Last VisitMonth
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
MonthDefinition of Base
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Definition of Base3.4
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
3.4 Protocol deviations
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Protocol deviations
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
3.5
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
3.5
![Page 3: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/3.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
3.5.5 Per Protocol Set ................................................................................................... 20 3.6 Treatment assignment and treatment groups ............................................................... 20 3.7 Center pooling strategy ................................................................................................ 21 3.8 Coding dictionaries ...................................................................................................... 21 3.9 Changes to protocol-defined analyses ......................................................................... 21 4 STATISTICAL/ANALYTICAL ISSUES ....................................................................... 21 4.1 Adjustments for covariates .......................................................................................... 21 4.2 Handling of dropouts or missing data .......................................................................... 21
4.2.1 Missing seizure diary days ................................................................................... 21 4.2.2 Incomplete dates for first epilepsy diagnosis ....................................................... 22 4.2.3 Incomplete dates for adverse events and concomitant medications .................... 22 4.2.4 Incomplete date for the last administration of study medication ......................... 23 4.2.5 Missing adverse event intensity ........................................................................... 24 4.2.6 Missing adverse event relationship to study medication ..................................... 24
4.3 Interim analyses and data monitoring .......................................................................... 24 4.4 Multicenter studies ....................................................................................................... 24 4.5 Multiple comparisons/multiplicity ............................................................................... 24 4.6 Use of an efficacy subset of subjects ........................................................................... 24 4.7 Active-control studies intended to show equivalence .................................................. 25 4.8 Examination of subgroups ........................................................................................... 25 4.9 Stratum Pooling ........................................................................................................... 26 5 STUDY POPULATION CHARACTERISTICS ............................................................. 26 5.1 Subject disposition ....................................................................................................... 26 5.2 Protocol deviations....................................................................................................... 27 6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 27 6.1 Demographics .............................................................................................................. 27
6.1.1 Derivation of demographics variables ................................................................. 27 6.1.1.1 BMI ........................................................................................................... 27
6.1.2 Analysis of demographics variables .................................................................... 28 6.2 Other Baseline characteristics ...................................................................................... 28
6.2.1 Derivation of other Baseline characteristics ........................................................ 28 6.2.1.1 Time since first diagnosis .......................................................................... 28 6.2.1.2 Age at diagnosis ........................................................................................ 28
6.2.2 Analysis of other Baseline characteristics ........................................................... 28 6.3 Subgroups .................................................................................................................... 28 6.4 Medical history and concomitant diseases ................................................................... 29 6.5 Procedure history ......................................................................................................... 29 6.6 Prior and concomitant medications .............................................................................. 29
REDACTED COPY ................................
REDACTED COPY ................................
................................
REDACTED COPY
................................control studies intended to show equivalence
REDACTED COPY
control studies intended to show equivalence................................
REDACTED COPY
................................................................
REDACTED COPY
................................RACTERISTICSREDACTED C
OPY
RACTERISTICS
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
..........
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.......... 21
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
21...................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................... 21
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
21.......................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
...........................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.............................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.........................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................control studies intended to show equivalence
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
control studies intended to show equivalence................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................RACTERISTICS
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
RACTERISTICS................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................
................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................DEMOGRAPHICS AND OTH
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
DEMOGRAPHICS AND OTHER BASELINE CHARACTE
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
ER BASELINE CHARACTE................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................Derivation of demographics variables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Derivation of demographics variablesBMI
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
BMI ................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Analysis of demographics variables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Analysis of demographics variablesOther Baseline characteristics
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Other Baseline characteristicsDerivation of other Baseline characteristics
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Derivation of other Baseline characteristics6.2.1.1
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
6.2.1.16.2.1.2
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
6.2.1.26.2.2
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
6.2.26.3
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
6.3
![Page 4: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/4.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
7 MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 29 8 EFFICACY ANALYSES ................................................................................................ 30 8.1 Statistical analysis of the primary efficacy variable .................................................... 30
8.1.1 Derivations of primary efficacy variable ............................................................. 30 8.1.2 Primary analysis of the primary efficacy variable ............................................... 30 8.1.3 Secondary analyses of the primary efficacy variable .......................................... 31 8.1.4 Supportive and sensitivity analyses of the primary efficacy variable ................. 31
8.2 Statistical analysis of the secondary efficacy variables ............................................... 31 8.2.1 Derivations of secondary efficacy variables ........................................................ 32
8.2.1.1 Variable: Seizure freedom for PGTCS for the 166-day Treatment Period 32 8.2.1.2 Variable: Time to first PGTCS during the 166-day Treatment Period ..... 32
8.2.2 Analysis of secondary efficacy variables............................................................. 32 8.2.2.1 Analysis: Seizure freedom for PGTCS for the 166-day Treatment Period32 8.2.2.2 Analysis: Time to first PGTCS during the 166-day Treatment Period ..... 33
8.3 Analysis of seizure related other efficacy variables .................................................... 34 8.3.1 Derivations of seizure related other efficacy variables ........................................ 34
8.3.1.1 Variable: PGTCS frequency per 28 days .................................................. 34 8.3.1.2 Variable: Days with seizures per 28 days ................................................. 35 8.3.1.3 Variable: Seizure-free status ..................................................................... 35 8.3.1.4 Variable: Responder status – reduction in PGTCS frequency .................. 35 8.3.1.5 Variable: PGTCS frequency - worsening .................................................. 36 8.3.1.6 Variable: Responder status – reduction in days with absence seizures ..... 36 8.3.1.7 Variable: Responder status – reduction in days with myoclonic seizures 36 8.3.1.8 Variable: Days with absence and myoclonic seizures – worsening .......... 36 8.3.1.9 Variable: Absence and myoclonic seizure frequencies per 28 days ......... 36 8.3.1.10 Variable: Responder status – reduction in absence and myoclonic seizure
frequencies ................................................................................................. 37 8.3.1.11 Variable: Absence and myoclonic seizure frequency - worsening ........... 37
8.3.2 Analysis of seizure related other efficacy variables ............................................ 37 8.3.2.1 Analysis: Percent change in PGTCS frequency per 28 days from
Combined Baseline .................................................................................... 37 8.3.2.2 Analysis: Reduction in days with seizures per 28 days ............................. 37 8.3.2.3 Analysis: Seizure-free status ..................................................................... 38 8.3.2.4 Analysis: Responder status – reduction in PGTCS frequency .................. 38 8.3.2.5 Analysis: Responder status – reduction in days with absence seizures..... 39 8.3.2.6 Analysis: Responder status – reduction in days with myoclonic seizures 39 8.3.2.7 Analysis: Percent change in absence and myoclonic seizure frequency per
28 days from Prospective Baseline............................................................ 40
REDACTED COPY Variable: PGTCS frequency per 28 days
REDACTED COPY Variable: PGTCS frequency per 28 days
Variable: Days with seizures per 28 days
REDACTED COPY
Variable: Days with seizures per 28 daysfree status
REDACTED COPY
free status ................................
REDACTED COPY
................................Variable: Responder status
REDACTED COPY
Variable: Responder status –
REDACTED COPY
–Variable: PGTCS frequency
REDACTED COPY
Variable: PGTCS frequency Variable: Responder status REDACTED C
OPY
Variable: Responder status
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
...............
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
............... 31
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
31........................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
........................ 32
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
32day Treatment Period
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
day Treatment Periodday Treatment Period
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
day Treatment Period.............................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.............................day Treatment Period
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
day Treatment Periodday Treatment Period
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
day Treatment Period................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................Derivations of seizure related other efficacy variables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Derivations of seizure related other efficacy variables................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................Variable: PGTCS frequency per 28 days
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: PGTCS frequency per 28 days ................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................Variable: Days with seizures per 28 days
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Days with seizures per 28 days................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................reduction
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
reductionVariable: PGTCS frequency
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: PGTCS frequency -
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
- worsening
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
worseningVariable: Responder status
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Responder status Variable: Responder status
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Responder status Variable: Days with absence and myoclonic seizures
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Days with absence and myoclonic seizures
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Absence and myoclonic seizure frequencies per
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Absence and myoclonic seizure frequencies per Variable: Responder status
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Responder status frequencies
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
frequenciesVariable: Absence and myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Variable: Absence and myoclonic seizure frequency Analysis of seizure related other efficacy variables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Analysis of seizure related other efficacy variablesAnalysis: Percent change in PGTCS frequency per 28 days from
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Analysis: Percent change in PGTCS frequency per 28 days from
8.3.2.2
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
8.3.2.28.3.2.3
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
8.3.2.38.3.2.4
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
8.3.2.4
![Page 5: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/5.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
8.3.2.8 Analysis: Responder status – reduction in absence and myoclonic seizure frequency ................................................................................................... 40
8.4 Analysis of health outcome other efficacy variables ................................................... 41 8.4.1 Derivations of health outcome other efficacy variables ...................................... 41
8.4.1.1 QOLIE-31-P variables ............................................................................... 41 8.4.1.2 PedsQL variables ....................................................................................... 42 8.4.1.3 EQ-5D-3L quality of life variables ........................................................... 42 8.4.1.4 Hospital stays ............................................................................................ 42
8.4.2 Analysis of health outcome other efficacy variables ........................................... 43 8.4.2.1 QOLIE-31-P variables ............................................................................... 43 8.4.2.2 PedsQL variables ....................................................................................... 43 8.4.2.3 EQ-5D-3L quality of life variables ........................................................... 43 8.4.2.4 Concomitant medical procedures .............................................................. 44 8.4.2.5 Healthcare provider consultations ............................................................. 44 8.4.2.6 Hospital stays ............................................................................................ 44 8.4.2.7 Number of working or school days lost due to epilepsy ........................... 44 8.4.2.8 Number of days with help from a paid caregiver due to epilepsy ............. 44 8.4.2.9 Socio-professional data ............................................................................. 44
9 PHARMACOKINETICS ................................................................................................. 44 10 SAFETY ANALYSES ..................................................................................................... 45 10.1 Extent of exposure ....................................................................................................... 45
10.1.1 Derivation of exposure variables ......................................................................... 45 10.1.2 Analysis of exposure variables ............................................................................ 45
10.2 Adverse events ............................................................................................................. 45 10.3 Clinical laboratory evaluations .................................................................................... 47 10.4 Vital signs, physical findings, and other observations related to safety ...................... 48
10.4.1 Vital signs ............................................................................................................ 48 10.4.2 Electrocardiograms .............................................................................................. 48
10.4.2.1 Derivation of corrected QT values ............................................................ 48 10.4.2.2 Analysis of ECG parameters ..................................................................... 49
10.4.3 Physical examination ........................................................................................... 49 10.4.4 Safety Seizure Information .................................................................................. 49
10.4.4.1 New Seizure Type ..................................................................................... 49 10.4.4.2 Increase in days with absence seizures ...................................................... 50 10.4.4.3 Increase in days with myoclonic seizures ................................................. 50 10.4.4.4 Increase in absence seizure frequency ....................................................... 50 10.4.4.5 Increase in myoclonic seizure frequency .................................................. 50
10.4.5 Tanner stage assessment ...................................................................................... 50
REDACTED COPY Number of days with help from a paid caregiver due to epilepsy
REDACTED COPY Number of days with help from a paid caregiver due to epilepsy
................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................
REDACTED COPY
................................ivation of exposure variablesREDACTED C
OPY
ivation of exposure variables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
42
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
42...........
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
........... 43
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
43...............
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
......................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
..................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.........................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
..............................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.............................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.............................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................Number of working or school days lost due to epilepsy
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Number of working or school days lost due to epilepsyNumber of days with help from a paid caregiver due to epilepsy
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Number of days with help from a paid caregiver due to epilepsy................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................ivation of exposure variables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
ivation of exposure variables ................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................Analysis of exposure variables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Analysis of exposure variables................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................laboratory evaluations
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
laboratory evaluationsVital signs, physical findings, and other observations related to safety
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Vital signs, physical findings, and other observations related to safety................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................Electrocardiograms
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
ElectrocardiogramsDerivation of corrected QT values
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Derivation of corrected QT values10.4.2.2
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
10.4.2.2 Analysis of ECG parameters
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Analysis of ECG parametersPhysical examination
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Physical examination10.4.4
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
10.4.4 Safety Seizure Information
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Safety Seizure Information10.4.4.1
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
10.4.4.1
![Page 6: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/6.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
10.4.6 Neurological examination .................................................................................... 51 10.4.7 Assessment of suicidality .................................................................................... 51 10.4.8 Achenbach Child Behavior Checklist .................................................................. 51
10.4.8.1 Derivation of Achenbach variables ........................................................... 51 10.4.8.2 Analysis of Achenbach variables .............................................................. 52
10.4.9 BRIEF-P and BRIEF assessment ......................................................................... 53 10.4.9.1 BRIEF-P scores ......................................................................................... 53 10.4.9.2 BRIEF scores ............................................................................................. 54
10.4.10 Vagus nerve stimulation ...................................................................................... 55 10.4.11 Ketogenic diet ...................................................................................................... 56
11 REFERENCES ................................................................................................................ 57 12 APPENDICES ................................................................................................................. 58 12.1 Appendix 1: QOLIE-31-P total and subscale score calculations ................................. 58 12.2 Appendix 2: Adverse Events ....................................................................................... 62
12.2.1 Other Significant AEs .......................................................................................... 62 12.2.2 List of AEs for Potentially Drug Induced Liver Injury (PDILI).......................... 64
12.3 Appendix 3: Markedly abnormal values ...................................................................... 67 12.3.1 Hematology .......................................................................................................... 67 12.3.2 Chemistry ............................................................................................................. 68 12.3.3 Vital signs ............................................................................................................ 70 12.3.4 ECGs .................................................................................................................... 72
12.4 Appendix 4: NCI CTC ................................................................................................. 73 12.5 Appendix 5: Registry Required Tables ........................................................................ 75 12.6 Additional Subgroups to be programmed in ADSL .................................................... 76 13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 77 13.1 Amendment 1 ............................................................................................................... 77
13.1.1 Rationale for the amendment ............................................................................... 77 13.1.2 Modification and changes .................................................................................... 77
13.1.2.1 Specific changes ........................................................................................ 77 13.2 Amendment 2 ............................................................................................................... 80
13.2.1 Rationale for the amendment ............................................................................... 80 13.2.2 Modification and changes .................................................................................... 81
13.2.2.1 Specific changes ........................................................................................ 81 13.3 Amendment 3 ............................................................................................................... 82
13.3.1 Rationale for the amendment ............................................................................... 82 13.3.2 Modification and changes .................................................................................... 82
13.3.2.1 Specific changes ........................................................................................ 82 13.4 Amendment 4 ............................................................................................................. 114
REDACTED COPY ................................
REDACTED COPY ................................
................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................
REDACTED COPY
................................................................REDACTED C
OPY
................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.............................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
............................. 54
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
54......................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
...................... 55
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
55................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
......................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
......................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................List of AEs for Potentially Drug Induced Liver Injury (PDILI)
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
List of AEs for Potentially Drug Induced Liver Injury (PDILI)................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................endix 5: Registry Required Tables
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
endix 5: Registry Required TablesAdditional Subgroups to be programmed in ADSL
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Additional Subgroups to be programmed in ADSLAMENDMENT(S) TO THE
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
AMENDMENT(S) TO THE STATISTICAL ANALYSIS
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
STATISTICAL ANALYSIS................................
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
................................for the amendment
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
for the amendmentModification and changes
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Modification and changesSpecific changes
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Specific changes
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
ndment 2
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
ndment 2Rationale for the amendment
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
Rationale for the amendment13.2.2
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
13.2.213
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
13.2.2.1
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
.2.2.1
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
13.3
This do
cumen
t can
not b
e use
d to su
pport
any m
arketi
ng au
thoriz
ation
appli
catio
n and
any e
xtens
ions o
r vari
ation
s the
reof.
13.3
![Page 7: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/7.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
13.4.1 Rationale for the amendment ............................................................................. 114 13.4.2 Modification and changes .................................................................................. 114
13.4.2.1 Specific changes ...................................................................................... 115 STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 126
LIST OF TABLES
Table 1: Number of PGTC Seizures for Study Entry .................................................... 13
Table 2: CBCL/1½-5 ...................................................................................................... 51
Table 3: CBCL/6-18 ....................................................................................................... 52
Table 4: BRIEF-P questionnaire scoring ....................................................................... 53
Table 5: BRIEF questionnaire scoring ........................................................................... 54
Table 6: Other Significant AEs ...................................................................................... 62
Table 7: AEs for PDILI .................................................................................................. 64
Table 8: Hematology - Markedly Abnormal Values ...................................................... 67
Table 9: Chemistry: Markedly Abnormal Values .......................................................... 68
Table 10: Vital Signs - Abnormality Criteria ................................................................... 70
Table 11: ECGs - Abnormality Criteria ........................................................................... 72
Table 12: NCI CTC .......................................................................................................... 73
REDACTED C
OPY Chemistry: Markedly Abnormal Values
REDACTED COPY
Chemistry: Markedly Abnormal Values ................................
REDACTED COPY
................................
Abnormality Criteria
REDACTED COPY
Abnormality Criteria................................
REDACTED COPY
................................
................................
REDACTED COPY
................................
................................
REDACTED COPY
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
13
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
13
......
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
...... 51
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
51
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
.......................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
.......
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
................................
![Page 8: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/8.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
LIST OF ABBREVIATIONS
AE adverse event
AED antiepileptic drug
ALT Alanine aminotransferase
AST Aspartate aminotransferase
ATC Anatomic Therapeutic Chemical
BMI body mass index
BP Blood pressure
BRI Behavioral Regulation index
BRIEF® Behavior Rating Inventory of Executive Function®
BRIEF®-P Behavior Rating Inventory of Executive Function®-Preschool version
CB combined baseline
CBCL Child Behavior Checklist
CRF case report form
C-SSRS Columbia-Suicide Severity Rating Scale
ECG Electrocardiogram
ET Early Termination
EQ-5D-3L 3-Level EuroQol-5 Dimension Quality of Life Assessment
FAS Full Analysis Set
GEC Global Executive Composite
GGT Gamma glutamyl transferase
HR hazard ratio
HRQoL health-related quality of life
IDMC independent data monitoring committee
IGE idiopathic generalized epilepsy
II Generalized seizures
IIA Absence seizures
IIB Myoclonic seizures
IIC Clonic seizures
IID Tonic seizures
IIE (primary generalized) tonic-clonic seizures
IIF Atonic seizures
REDACTED COPY
Suicide Severity Rating Scale
REDACTED COPY
Suicide Severity Rating Scale
lectrocardiogram
REDACTED COPY
lectrocardiogram
Early Termination
REDACTED COPY
Early Termination
-REDACTED C
OPY
-Level REDACTED C
OPY
Level AssessmentREDACTED C
OPY
Assessment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Behavior Rating Inventory of Executive Function
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Behavior Rating Inventory of Executive Function®
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
®
Behavior Rating Inventory of Executive
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Behavior Rating Inventory of Executive
Suicide Severity Rating Scale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Suicide Severity Rating Scale
lectrocardiogram
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lectrocardiogram
Early Termination
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Early Termination
Level
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Level EuroQol
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
EuroQolAssessment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Assessment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Full Analysis Set
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Full Analysis Set
Global Executive Composite
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Global Executive Composite
IIA
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IIA
IIB
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IIB
IIC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IIC
![Page 9: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/9.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
III Unclassified seizures
ILAE International League Against Epilepsy
IRT Interactive response technology
KM Kaplan-Meier
LCM Lacosamide
LLN lower limit of normal
MedDRA Medical Dictionary for Regulatory Activities
MI Metacognition Index
NCI CTC National Cancer Institute Common Terminology Criteria for Adverse Events
PCH percent change
PedsQL Pediatric Quality of Life Inventory
PGTC primary generalized tonic-clonic
PGTCS Primary generalized tonic-clonic seizure
PH proportional hazard
PHREG proportional hazards regression
PPS Per-Protocol Set
PT preferred term
QOLIE-31-P Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31
QTcB Bazett corrected QT
QTcF Fridericia corrected QT
RS Randomized Set
SAP Statistical Analysis Plan
SAS® Statistical analysis software
ScS Screened Set
SF seizure frequency SOC system organ class SS Safety Set
TEAE treatment emergent adverse event
TEMA treatment emergent markedly abnormal
ULN upper limit of normal
VAS visual analog scale
VNS vagus nerve stimulation
WHO-DD World Health Organization Drug Dictionary
REDACTED COPY
proportional hazards regression
REDACTED COPY
proportional hazards regression
Protocol Set
REDACTED COPY
Protocol Set
preferred term
REDACTED COPY
preferred term
Patient
REDACTED COPY
Patient-
REDACTED COPY
-Weighted Quality of Life in Epilepsy
REDACTED COPY
Weighted Quality of Life in Epilepsy InventoryREDACTED C
OPY
Inventory
Bazett corrected QTREDACTED COPY
Bazett corrected QT
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
National Cancer Institute Common Terminology Criteria
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
National Cancer Institute Common Terminology Criteria
clonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
clonic seizure
proportional hazards regression
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
proportional hazards regression
preferred term
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
preferred term
Weighted Quality of Life in Epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Weighted Quality of Life in Epilepsy Inventory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Inventory-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-Form 31
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Form 31
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Bazett corrected QT
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Bazett corrected QT
Fridericia corrected QT
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Fridericia corrected QT
Randomized Set
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Randomized Set
TEAE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
TEAE
TEMA
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
TEMA
ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ULN
![Page 10: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/10.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
1 INTRODUCTION
The purpose of the statistical analysis plan (SAP) is to describe the analyses of study SP0982.
2 PROTOCOL SUMMARY
2.1 Study objectives
2.1.1 Primary objective
The primary study objective is to demonstrate the efficacy of oral lacosamide (LCM) vs placebo as adjunctive therapy for uncontrolled primary generalized tonic-clonic seizures (PGTCS) in subjects with idiopathic generalized epilepsy (IGE) currently taking 1 to 3 concomitant antiepileptic drugs (AEDs) independent of the number of prior failed AEDs.
2.1.2 Secondary objective
The secondary study objective is to assess the safety and tolerability of LCM in subjects with IGE with uncontrolled PGTCS.
2.2 Study variables
2.2.1 Efficacy variables
2.2.1.1 Primary efficacy variable
The primary efficacy variable is the time to the second PGTCS during the 24-week Treatment Period.
2.2.1.2 Secondary efficacy variables
The key secondary efficacy variable is:
Seizure freedom for PGTCS during the 24-week Treatment Period, estimated using Kaplan-Meier analysis
The other secondary efficacy variable is:
Time to first seizure during the 24-week Treatment Period
2.2.1.3 Other efficacy variables
Other efficacy variables are:
The percent change in PGTCS frequency per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Combined Baseline Period (combined 12-week Historical and 4-week Prospective Baseline Periods)
The percent change in PGTCS frequency per 28 days during the first 12 weeks of the Treatment Period relative to the Combined Baseline Period
The percent change in PGTCS frequency per 28 days during the Treatment Period relative to the Combined Baseline Period
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
REDACTED COPY
he time to the second PGTCS during the 24
REDACTED COPY
he time to the second PGTCS during the 24
Secondary efficacy variables
REDACTED COPY
Secondary efficacy variables
Seizure freedom for PGTCS during the 24REDACTED COPY
Seizure freedom for PGTCS during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(LCM) vs placebo
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(LCM) vs placebo clonic seizures (PGTCS) in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
clonic seizures (PGTCS) in
The secondary study objective is to assess the safety and tolerability of LCM in subjects with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The secondary study objective is to assess the safety and tolerability of LCM in subjects with
he time to the second PGTCS during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
he time to the second PGTCS during the 24
Secondary efficacy variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Secondary efficacy variables
Seizure freedom for PGTCS during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure freedom for PGTCS during the 24 week Treatment Period, estimated using Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period, estimated using Kaplan
efficacy variable is:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
efficacy variable is:
Time to first seizure during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Time to first seizure during the 24
Other efficacy variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Other efficacy variables
Other efficacy variables are:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Other efficacy variables are:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change in PGTCS frequency per 28 days during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change in PGTCS frequency per 28 days during the first 6 weeks of the Treatment Period (Titration Period) re
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period (Titration Period) reweek Historical and 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Historical and 4
The percent change in PGTCS frequency per 28 days during the first 12 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change in PGTCS frequency per 28 days during the first 12 weeks of the Treatment Period relative to the Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period relative to the Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The pe
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The pe
![Page 11: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/11.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percent change in days with absence seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline Period
Percent change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
Percentage of subjects with at least a 50% reduction in absence seizure days compared to Prospective Baseline Period
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline Period
Percent change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to Prospective Baseline Period
Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Titration Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Treatment Period compared to Combined Baseline Period
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment Period
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total scores in subjects <18 years of age
Change from Baseline to end of treatment or early termination (ET) in the 3-Level EuroQol-5 Dimension Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and change in utility as converted from the 5 dimensions (for subjects ≥12 years of age)
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
Number of working or school days lost by subject due to epilepsy
REDACTED COPY week Treatment Period
REDACTED COPY week Treatment Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the
REDACTED COPY
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Titration Period compared to Combined Baseline Period
REDACTED COPY
Titration Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% re
REDACTED COPY
Percentage of subjects with at least a 50% reweeks of the Treatment Period compared to Combined Baseline Period
REDACTED COPY
weeks of the Treatment Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the REDACTED COPY
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the
Percent change in days with myoclonic seizures per 28 days during the Treatment P
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 days during the Treatment P
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to
for the first 12 weeks of the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for the first 12 weeks of the Treatment Period
week Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Titration Period compared to Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Titration Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% re
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
duction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks of the Treatment Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Treatment Period compared to Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to Combined Baseline Period
free status (yes, no) for all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for all generalized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
generalized
free status (yes, no) for all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for all
Change from Baseline in Patient
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change from Baseline in PatientP) subscale (Seizure Worry, Daily Activities/Social Functioning,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P) subscale (Seizure Worry, Daily Activities/Social Functioning, Energy/Fatigue, Emotional Well
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Energy/Fatigue, Emotional WellQuality of Life and Medication Effects) and total scores in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Quality of Life and Medication Effects) and total scores in change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total scores in subjects <18 years of age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores in subjects <18 years of age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change fr
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change fr
![Page 12: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/12.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Number of days with help from a caregiver due to epilepsy
2.2.2 Safety variables
The safety variable is:
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed by the investigator
2.2.2.1 Other safety variables
Other safety variables are:
Subject withdrawal due to AEs
Incidence of new seizure types during the Treatment Period
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
Changes in 12-lead electrocardiograms (ECGs)
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body weight and height) and physical and neurological examination findings
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½-5 or CBCL/6-18)
Cognitive function assessment (Behavior Rating Inventory of Executive Function®-Preschool Version [BRIEF-P] or Behavior Rating Inventory of Executive Function® [BRIEF]) for pediatric subjects only
2.2.3 Pharmacokinetic variables
The plasma concentrations of LCM will be assessed.
2.3 Study design and conduct
2.3.1 Study description
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study designed to assess the efficacy of oral LCM vs placebo as adjunctive therapy for uncontrolled PGTCS in subjects ≥4 years of age with IGE currently taking 1 to 3 concomitant AEDs independent of the number of prior failed AEDs.
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible extension to other countries and regions, are planned to be randomized in this study to see 125 events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of study medication administration is 28 weeks. The study will last a maximum of 36 weeks per subject.
REDACTED COPY
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
REDACTED COPY
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
lead electrocardiograms (ECGs)
REDACTED COPY
lead electrocardiograms (ECGs)
measurements (ie, blood pressure [BP] and pulse rate) (including body
REDACTED COPY
measurements (ie, blood pressure [BP] and pulse rate) (including body weight and height) and physical and neurological examination findings
REDACTED COPY
weight and height) and physical and neurological examination findings
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½REDACTED COPY
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
cts with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
cts with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with absence seizures per 28 days during the Treatment Period relative to the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with absence seizures per 28 days during the Treatment Period relative to the Prospective
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
measurements (ie, blood pressure [BP] and pulse rate) (including body
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
measurements (ie, blood pressure [BP] and pulse rate) (including body weight and height) and physical and neurological examination findings
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weight and height) and physical and neurological examination findings
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½
ehavior Rating Inventory of Executive Function
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ehavior Rating Inventory of Executive FunctionP] or Behavior Rating Inventory of Executive Function
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P] or Behavior Rating Inventory of Executive Function
Pharmacokinetic variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Pharmacokinetic variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The plasma concentrations of LCM will be assessed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The plasma concentrations of LCM will be assessed.
Study design a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Study design a
Study description
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Study description
SP0982 is a double
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SP0982 is a doubledesigned to assess the efficacy of oral LCM vs placebo as adjunctive therapy for uncontrolled
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
designed to assess the efficacy of oral LCM vs placebo as adjunctive therapy for uncontrolled PGTCS in subjects ≥4 years of age with IG
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS in subjects ≥4 years of age with IGindependent of the number of prior failed AEDs.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
independent of the number of prior failed AEDs.
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible extension to other countries and regions, are planned to be randomi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
extension to other countries and regions, are planned to be randomi
![Page 13: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/13.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Eligibility to enter SP0982 will be based on a 12-week Historical Baseline prior to screening at Visit 1. In rare cases where there is a gap between consenting and Visit 1 procedures, the 12-week Historical Baseline will be calculated from the date of Informed Consent/Assent.
Prior to randomization, the following 3 criteria concerning PGTCS frequency must be met:
The subject must have experience at least 3 PGTCS during the 16-week Combined Baseline Period,
The subject must have experienced at least 2 PGTCS during the 12-week Historical Baseline Period,
Of the above seizures, at least 1 PGTCS should have occurred during the first 8 weeks and at least 1 PGTC seizure should have occurred during the second 8 weeks of the 16-week Combined Baseline Period.
Examples of different scenarios and the subjects’ eligibility in terms of Baseline Period PGTCS are presented in Table 1 . Seizures reported on the Historical Seizure Count CRF with incomplete dates will be assumed to have occurred with the 12-week Historical Baseline Period when checking eligibility for the study and inclusion in baseline PGTCS frequency per 28 days.
Table 1: Number of PGTC Seizures for Study Entry
Number of PGTCS for Study Entry Subject Eligible for Study? Historical Baseline
Weeks -16 to -9 Historical Baseline
Weeks -8 to -5 Prospective Baseline
Weeks -4 to 0 (Visit 1 to Visit 2)
2 1 0 Yes
3 0 0 No
1 1 1 Yes
0 2 1 No
1 2 0 Yes
2 0 1 Yes
1 0 2 No
1 1 0 No
The study consists of a 4-week Prospective Baseline Period and a 6-week (minimum) to 24-week (maximum) Treatment Period, which includes a 6-week Titration Period and an 18-week (maximum) Maintenance Period. Eligible subjects who choose to enter the open-label extension study (EP0012) after the completion of Visit 10 (Week 24) or the ET Visit will complete a 4-week blinded transition. Subjects who choose not to continue in EP0012 must complete an up to 4-week blinded taper followed by a 30-day Safety Follow-up Period.
At the end of the 4-week Prospective Baseline (Visit 2), eligible subjects will be randomized to receive LCM or placebo in a 1:1 fashion (active:placebo) and stratified by Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 16 week Combined Baseline Period prior to randomization) and by age at informed consent (≥4 to <12 years of age vs ≥12 to <18 years of
REDACTED COPY Number of PGTCS for Study Entry
REDACTED COPY Number of PGTCS for Study Entry
REDACTED COPY
Prospective Baseline
REDACTED COPY
Prospective Baseline
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
line
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
line
Of the above seizures, at least 1 PGTCS should have occurred during the first 8 weeks and at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Of the above seizures, at least 1 PGTCS should have occurred during the first 8 weeks and at least 1 PGTC seizure should have occurred during the second 8 weeks of the 16
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
least 1 PGTC seizure should have occurred during the second 8 weeks of the 16-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-week
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week
ubjects’ eligibility in terms of Baseline Period PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ubjects’ eligibility in terms of Baseline Period PGTCS Seizures reported on the Historical Seizure Count CRF with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizures reported on the Historical Seizure Count CRF with week Historical Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Historical Baseline Period when checking eligibility for the study and inclusion in baseline PGTCS frequency per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
when checking eligibility for the study and inclusion in baseline PGTCS frequency per 28 days.
Number of PGTC Seizures for Study Entry
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of PGTC Seizures for Study Entry
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective BaselineWeeks
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Weeks (Visit 1 to Visit 2)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(Visit 1 to Visit 2)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The study consists of a 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The study consists of a 4(maximum) Treatment Period, which includes a 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(maximum) Treatment Period, which includes a 6(maximum) Maintenance Period. Eligible subjects who choose to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(maximum) Maintenance Period. Eligible subjects who choose to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
study (EP0012) after the completion of Visit 10 (Week 24) or the ET Visit will complete a 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
study (EP0012) after the completion of Visit 10 (Week 24) or the ET Visit will complete a 4week blinded transition. Subjects who choose not to continue in EP0012 must complete an up to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week blinded transition. Subjects who choose not to continue in EP0012 must complete an up to 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
4 week blinded taper followed by a 30
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week blinded taper followed by a 30
![Page 14: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/14.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
age, and ≥18 years of age). The Treatment Period starts at the time of the Randomization Visit (Visit 2).
The Treatment Period continues until 1 of the following occurs (whichever occurs first):
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTCS
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTCS
Occurrence of the 125th event (an event is each subject’s 2nd second PGTCS).
Subjects will be required to exit the study and complete the ET Visit if either of the following events occur:
Subject completes the first 6 weeks of the Treatment Period (after randomization) and experiences ≥2 PGTCS during that time
Subject experiences a second PGTCS after the first 6 weeks of the Treatment Period
If the 125th event occurs while the subject is still participating in the study, the subject can:
Complete the Visit 10 (Week 24) or ET Visit (if the next scheduled visit is not Visit 10) and choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic Visit.
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next scheduled visit is not Visit 10) and an up to 4-week blinded taper followed by an End of Taper visit.
The study design is discussed in more detail in Section 5 of the protocol.
2.3.2 Rationale for study design
Clinical experience has shown that up to 30% of patients with PGTCS who are treated with currently available AEDs have insufficient PGTCS control or unacceptable drug tolerability. Thus, there is a significant unmet medical need for new treatment options in this patient population.
The primary efficacy variable, the time to the second PGTCS, has several advantages from a clinical and methodological perspective. In traditional adjunctive study designs, the primary endpoint is percent reduction in PGTCS frequency over the entire Treatment Period; which requires a higher frequency of PGTCS at entry. Using the time to second PGTCS, the frequency of Baseline PGTCS and the duration of the Prospective Baseline can be reduced as the endpoint is time to reach an event (second PGTCS), rather than a percentage decrease in the number of events (PGTCS). This expands the patient population under study and allows for enrollment of subjects more representative of the broader PGTCS population. Furthermore, subjects are treated for up to 24 weeks in a traditional adjunctive design, depending upon the titration schedule of the active treatment. Subjects must remain on treatment as they continue to experience PGTCS. In the time to nth seizure design, subjects are required to remain in the study for a minimum of 6 weeks. If a subject experiences ≥2 PGTCS while on treatment, then after 6 weeks the subject exits the study, rather than continuing to have PGTCS, while remaining eligible to receive LCM in the open-label extension study (EP0012).
REDACTED COPY
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next
REDACTED COPY
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next week blinded taper followed by an End of
REDACTED COPY
week blinded taper followed by an End of
The study design is discussed in more detail in Section 5 of the protocol.
REDACTED COPY
The study design is discussed in more detail in Section 5 of the protocol.
Rationale for study design
REDACTED COPY
Rationale for study design
Clinical experience has shown that up to 30% of patients with PREDACTED COPY
Clinical experience has shown that up to 30% of patients with P
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects will be required to exit the study and complete the ET Visit if either of the following
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects will be required to exit the study and complete the ET Visit if either of the following
Subject completes the first 6 weeks of the Treatment Period (after randomization) and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subject completes the first 6 weeks of the Treatment Period (after randomization) and
Subject experiences a second PGTCS after the first 6 weeks of the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subject experiences a second PGTCS after the first 6 weeks of the Treatment Period
event occurs while the subject is still participating in the study, the subject can:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event occurs while the subject is still participating in the study, the subject can:
Visit (if the next scheduled visit is not Visit 10) and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit (if the next scheduled visit is not Visit 10) and choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next week blinded taper followed by an End of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week blinded taper followed by an End of
The study design is discussed in more detail in Section 5 of the protocol.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The study design is discussed in more detail in Section 5 of the protocol.
Rationale for study design
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Rationale for study design
Clinical experience has shown that up to 30% of patients with P
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Clinical experience has shown that up to 30% of patients with Pcurrently available AEDs have insufficient PGTCS control or unacceptable drug tolerability.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
currently available AEDs have insufficient PGTCS control or unacceptable drug tolerability. Thus, there is a significant unmet medical need for new treatment options in this patient
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Thus, there is a significant unmet medical need for new treatment options in this patient
The primary efficacy variable, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The primary efficacy variable, theclinical and methodological perspective. In traditional adjunctive study designs, the primary
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
clinical and methodological perspective. In traditional adjunctive study designs, the primary endpoint is percent reduction in PGTCS frequency over the entire Treatment Period; which
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
endpoint is percent reduction in PGTCS frequency over the entire Treatment Period; which r frequency of PGTCS at entry. Using the time to second PGTCS, the frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
r frequency of PGTCS at entry. Using the time to second PGTCS, the frequency of Baseline PGTCS and the duration of the Prospective Baseline can be reduced as the endpoint
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of Baseline PGTCS and the duration of the Prospective Baseline can be reduced as the endpoint is time to reach an event (second PGTCS), rather than a percentage decrease in the nu
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is time to reach an event (second PGTCS), rather than a percentage decrease in the nuevents (PGTCS). This expands the patient population under study and allows for enrollment of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
events (PGTCS). This expands the patient population under study and allows for enrollment of subjects more representative of the broader PGTCS population. Furthermore, subjects are treated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects more representative of the broader PGTCS population. Furthermore, subjects are treated for up to 24 weeks in a traditional adjunctive design, depe
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for up to 24 weeks in a traditional adjunctive design, depe
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
active treatment. Subjects must remain on treatment as they continue to experience PGTCS. In
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
active treatment. Subjects must remain on treatment as they continue to experience PGTCS. In the time to nth seizure design, subjects are required to remain in the study for a minimum of 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the time to nth seizure design, subjects are required to remain in the study for a minimum of 6 weeks. If a subject experi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks. If a subject experi
![Page 15: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/15.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The rationale for time to second PGTCS was established by using data from an adjunctive study in subjects with PGTCS, using an 8-week Baseline, 7-week Titration, and 12-week Maintenance Period comparing lamotrigine and placebo (French et al, 2007). This post-hoc analysis using a Cox proportional hazards model revealed that time to third PGTCS was statistically significant with a hazard ratio of 0.533 (lamotrigine 48.2%, placebo 25.4%). Lamotrigine requires a long Titration Period, where a minimally effective dose is not reached until the fifth week of the Titration Period (100mg/day). Lacosamide, by comparison, reaches a minimally effective dose in the second week (200mg/day) for a majority of trial subjects. Since a majority of the events in the lamotrigine study occurred before Day 21, it is likely that fewer events would occur using LCM as it reaches an effective dose earlier; therefore, time to second PGTCS was chosen as a reasonable endpoint from a clinical and statistical perspective.
2.4 Determination of sample size
Observing 125 events (subjects who had a second PGTCS during the 24-week Treatment Period) will provide 90% power to observe a hazard ratio of 0.56 at the 2-sided 5% level, assuming a dropout rate of 15%. The observed hazard ratio was based on a 25.4% survival rate for placebo and 48.2% for lamotrigine from a previous study comparing lamotrigine and placebo (French et al, 2007). The observed hazard ratio in the lamotrigine study was 0.533; however, in order to account for the possibility of an increased placebo response, as has been documented in recent clinical studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a sample size for this study. The rationale for the increase in the hazard ratio included the following considerations: different active compounds (LCM and lamotrigine) and a choice of time to second PGTCS as the primary efficacy endpoint (in the lamotrigine study, percent change in PGTCS frequency was the primary endpoint).
This is an event-driven study. Enrollment in the study will continue up to 125 events occurring or a maximum of 250 subjects randomized, whichever comes first.
3 DATA ANALYSIS CONSIDERATIONS
3.1 General presentation of summaries and analyses
Statistical analysis and generation of tables, figures, subject data listings, and statistical output will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier New font size 9.
Descriptive statistics will be used to provide an overview of the primary, secondary, and other variable results. For categorical parameters, the number and percentage of subjects in each category will be presented. The denominator for percentages will be based on the number of subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will be displayed for zero counts, and no decimal will be presented when the percentage is 100%. For continuous parameters, descriptive statistics will include number of subjects, mean, standard deviation, median, minimum, and maximum.
Decimal places for descriptive statistics will always apply the following rules:
“n” will be an integer
Mean, SD and median will use 1 additional decimal place compared to the original data.
Minimum and maximum will have the same number of decimal places as the original value.
REDACTED COPY clinical studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a sample
REDACTED COPY clinical studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a sample
size for this study. The rationale for the increase in the hazard ratio included the following
REDACTED COPY
size for this study. The rationale for the increase in the hazard ratio included the following considerations: different active compounds (LCM and lamotr
REDACTED COPY
considerations: different active compounds (LCM and lamotrsecond PGTCS as the primary efficacy endpoint (in the lamotrigine study, percent change in
REDACTED COPY
second PGTCS as the primary efficacy endpoint (in the lamotrigine study, percent change in PGTCS frequency was the primary endpoint).
REDACTED COPY
PGTCS frequency was the primary endpoint).
driven study. Enrollment in the study will continue up to 125 events occuREDACTED C
OPY
driven study. Enrollment in the study will continue up to 125 events occuor a maximum of 250 subjects randomized, whichever comes first. REDACTED C
OPY
or a maximum of 250 subjects randomized, whichever comes first.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
itration Period (100mg/day). Lacosamide, by comparison, reaches a minimally effective dose in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
itration Period (100mg/day). Lacosamide, by comparison, reaches a minimally effective dose in
wer events would occur using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
wer events would occur using LCM as it reaches an effective dose earlier; therefore, time to second PGTCS was chosen as a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
LCM as it reaches an effective dose earlier; therefore, time to second PGTCS was chosen as a
week Treatment Period)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period) sided 5% level, assuming a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
sided 5% level, assuming a dropout rate of 15%. The observed hazard ratio was based on a 25.4% survival rate for placebo
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dropout rate of 15%. The observed hazard ratio was based on a 25.4% survival rate for placebo trigine from a previous study comparing lamotrigine and placebo (French et
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
trigine from a previous study comparing lamotrigine and placebo (French et al, 2007). The observed hazard ratio in the lamotrigine study was 0.533; however, in order to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
al, 2007). The observed hazard ratio in the lamotrigine study was 0.533; however, in order to account for the possibility of an increased placebo response, as has been documented in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
account for the possibility of an increased placebo response, as has been documented inclinical studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a sample
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
clinical studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a sample size for this study. The rationale for the increase in the hazard ratio included the following
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
size for this study. The rationale for the increase in the hazard ratio included the following considerations: different active compounds (LCM and lamotr
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
considerations: different active compounds (LCM and lamotrsecond PGTCS as the primary efficacy endpoint (in the lamotrigine study, percent change in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
second PGTCS as the primary efficacy endpoint (in the lamotrigine study, percent change in
driven study. Enrollment in the study will continue up to 125 events occu
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
driven study. Enrollment in the study will continue up to 125 events occuor a maximum of 250 subjects randomized, whichever comes first.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or a maximum of 250 subjects randomized, whichever comes first.
DATA ANALYSIS CONSID
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
DATA ANALYSIS CONSID
General presentation of summaries and analyses
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
General presentation of summaries and analyses
Statistical analysis and generation of tables, figures, subject data listings, and statistical output
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Statistical analysis and generation of tables, figures, subject data listings, and statistical output performed using SAS® Version 9.4 or higher. All tables and listings will use Courier
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
performed using SAS® Version 9.4 or higher. All tables and listings will use Courier
Descriptive statistics will be used to provide an overview of the primary, secondary, and other
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics will be used to provide an overview of the primary, secondary, and other variable results. For categorical parameters, the number
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
variable results. For categorical parameters, the number category will be presented. The denominator for percentages will be based on the number of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
category will be presented. The denominator for percentages will be based on the number of subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be displayed to 1 decimal place
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be presented when the percentage is 100%. For continuous parameters, descriptive statistics
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be presented when the percentage is 100%. For continuous parameters, descriptive statistics will include number of subjects, mean, standard deviation, median, minimum, and maximum.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will include number of subjects, mean, standard deviation, median, minimum, and maximum.
Dec
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Dec
![Page 16: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/16.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
By-visit summaries will not include data from unscheduled clinic visits unless otherwise stated. Data provided at these visits will be included in subject data listings. A complete set of data listings containing all documented data and all calculated data (eg, change from Baseline) will be generated.
3.2 General study level definitions
3.2.1 Analysis time points
The following study periods will be defined for analyses:
Historical Baseline Period: This period starts 84 days prior to Visit 1 and ends the day before Visit 1. This is expected to be 12 weeks in duration.
Prospective Baseline Period: This period starts the date of Visit 1 and ends the day before Visit 2. This is expected to be 4 weeks in duration.
Combined Baseline Period: combined Historical and Prospective Baseline Periods. This Period starts 84 days prior to Visit 1 and ends the day before Visit 2. This is expected to be 16 weeks in duration.
Treatment Period: 24-week period following the 4-week Prospective Baseline. The Treatment Period is composed of the Titration Period and the Maintenance Period.
Titration Period: 6-week period following the 4-week Prospective Baseline. The Titration Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before Visit 5 (or the date of the Early Termination (ET) visit in the situation where a subject discontinues prior to the last visit in the Titration Period).
Maintenance Period: 18-week period following the 6-week Titration Period. The Maintenance Period starts on the day of Visit 5 and continues until 1 of the following occurs (whichever occurs first):
◦ Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures and completion of the ET Visit
◦ Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of 2 PGTC seizures.
First 12 weeks: this is defined as the Titration Period + the first 6 weeks of the Maintenance Period.
Transition Period: up to 4-week period after the completion of Visit 10 (Week 24) or the ET Visit for subjects who choose to enter EP0012. The Transition Period starts the day after Visit 10 (Week 24) or the ET Visit and continues until 1 of the following occurs (whichever occurs first):
◦ On the day before the first date that there is a dose decrease (subject enters Taper period)
◦ On the date of the Final Clinic Visit (also date of EP0012 Visit 1).
Taper Period: up to 4-week period following either the Treatment Period for subjects who discontinue from the study at any time and are not eligible or choose not to enter EP0012 or
REDACTED COPY eriod is composed of the Titration Period and the Maintenance Period.
REDACTED COPY eriod is composed of the Titration Period and the Maintenance Period.
week period following the 4
REDACTED COPY
week period following the 4-
REDACTED COPY
-week Prospective Baseline. The Titration
REDACTED COPY
week Prospective Baseline. The Titration Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before
REDACTED COPY
Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before (or the date of the Early Termination (ET) visit in the situation where a subject
REDACTED COPY
(or the date of the Early Termination (ET) visit in the situation where a subject discontinues prior to the last visit in the Titration Period).
REDACTED COPY
discontinues prior to the last visit in the Titration Period).
REDACTED COPY
week period following the 6REDACTED C
OPY
week period following the 6Maintenance Period starts on theREDACTED C
OPY
Maintenance Period starts on the day of Visit 5 and continues until 1 of the following REDACTED COPY
day of Visit 5 and continues until 1 of the following
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ends the day before
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ends the day before
Prospective Baseline Period: This period starts the date of Visit 1 and ends the day before
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline Period: This period starts the date of Visit 1 and ends the day before
storical and Prospective Baseline Periods. This
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
storical and Prospective Baseline Periods. This Period starts 84 days prior to Visit 1 and ends the day before Visit 2. This is expected to be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period starts 84 days prior to Visit 1 and ends the day before Visit 2. This is expected to be
week Prospective Baseline. The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Prospective Baseline. The eriod is composed of the Titration Period and the Maintenance Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
eriod is composed of the Titration Period and the Maintenance Period.
week Prospective Baseline. The Titration
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Prospective Baseline. The Titration Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before (or the date of the Early Termination (ET) visit in the situation where a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(or the date of the Early Termination (ET) visit in the situation where a subject discontinues prior to the last visit in the Titration Period).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
discontinues prior to the last visit in the Titration Period).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week period following the 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week period following the 6day of Visit 5 and continues until 1 of the following
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day of Visit 5 and continues until 1 of the following occurs (whichever occurs first):
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
occurs (whichever occurs first):
Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures and completion of the ET Visit
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and completion of the ET Visit
Completion of 18 weeks (Visit 10) of the Maintenance Perio
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completion of 18 weeks (Visit 10) of the Maintenance Perio2 PGTC seizures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2 PGTC seizures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
First 12 weeks: this is defined as the Titration Period + the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
First 12 weeks: this is defined as the Titration Period + the first 6 weeks of the Maintenance Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Maintenance Period.
Transition Period: up to 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Transition Period: up to 4Visit for subjects w
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit for subjects w
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit 10 (Week 24) or the ET Visit and continues until 1 of the following occurs (whichever
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit 10 (Week 24) or the ET Visit and continues until 1 of the following occurs (whichever occurs first):
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
occurs first):
![Page 17: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/17.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
following the Transition Period for subjects that discontinue from the study during the Transition Period. The Taper Period starts the first date that there is a dose decrease or the day after the ET Visit for subjects that choose not to enter EP0012 and continues until the date of last dose of study medication.
Safety Follow-up Period: period following the Taper Period for subjects who complete the Taper Period. The Safety Follow-up Period starts the day after the last dose of study medication and continues until the Final Clinic Visit date or the Safety Follow-up telephone contact date, whichever is later.
3.2.2 Seizure cluster
If a seizure cluster is reported, it will be assigned to the International League Against Epilepsy (ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters reported.
3.2.3 Event
In the primary efficacy analysis, an event for analysis purposes is:
The 2nd PGTCS
While keeping in mind the definition of seizure clusters in Section 3.2.2.
For the primary and secondary efficacy analyses, these endpoints will be assessed using the at most the first 166 days, which is the 24-week Treatment Period minus a protocol-allowed 2 day window. For all other efficacy parameters, all data reported during the Treatment Period will be used in the analysis.
The primary efficacy endpoint, time to event, is defined as the “stop date” - the date of first dose of study drug + 1 day where the “stop date” is the first of the following to occur:
date of the event,
date of the premature discontinuation,
date of last dose of study medication in the Treatment Period,
date of the completion of the Treatment Period,
date of the 125th event,
Day 166
The same algorithm applies for the other secondary endpoint, where time to event, is replaced by time to 1st PGTCS.
3.2.4 Censoring
For the primary and secondary efficacy analyses, a Treatment Period of 166 days will be utilized. The censoring for the primary efficacy analysis will be as follows:
Subjects who complete the Treatment Period without having an event during the Treatment Period will be censored as of Day 167.
REDACTED COPY
these endpoints will be assessed using the at
REDACTED COPY
these endpoints will be assessed using the at week Treatment Period minus a protocol
REDACTED COPY
week Treatment Period minus a protocolFor all other efficacy parameters, all data report
REDACTED COPY
For all other efficacy parameters, all data report
The primary efficacy endpoint, time to event, is defined as the “stop date”
REDACTED COPY
The primary efficacy endpoint, time to event, is defined as the “stop date” of study drug + 1 day where the “stop date” is the first of the following to occur:REDACTED C
OPY
of study drug + 1 day where the “stop date” is the first of the following to occur:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
up telephone
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
up telephone
If a seizure cluster is reported, it will be assigned to the International League Against Epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If a seizure cluster is reported, it will be assigned to the International League Against Epilepsy (ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters
in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in Section 3.2.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3.2.2
these endpoints will be assessed using the at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
these endpoints will be assessed using the at week Treatment Period minus a protocol
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period minus a protocolFor all other efficacy parameters, all data report
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For all other efficacy parameters, all data reported during the Treatment Period will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ed during the Treatment Period will be
The primary efficacy endpoint, time to event, is defined as the “stop date”
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The primary efficacy endpoint, time to event, is defined as the “stop date” of study drug + 1 day where the “stop date” is the first of the following to occur:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of study drug + 1 day where the “stop date” is the first of the following to occur:
date of the premature discontinuation,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of the premature discontinuation,
ose of study medication in the T
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ose of study medication in the T
date of the completion of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of the completion of the
event,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The same algorithm applies for the other secondary
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The same algorithm applies for the other secondaryPGTCS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS.
3.2.4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3.2.4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the primary and secondary efficacy analyses, a Treatment Period of 166 days will be utilized.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the primary and secondary efficacy analyses, a Treatment Period of 166 days will be utilized. The censoring for the primary efficacy analysis will be as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The censoring for the primary efficacy analysis will be as follows:
![Page 18: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/18.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
If the subject’s Treatment Period participation is less than or equal to 166 days (premature discontinuation), their PGTCS information will be censored on the date after the last dose of study drug.
If the subject’s Treatment Period participation is greater than 166 days, their PGTCS information will be censored as of Day 167.
For the subjects who are ongoing in the study when the 125th event occurs, their PGTCS information for the primary efficacy endpoint analysis will be censored as of the day after the 125th event, even if the subjects experience an event after the date of the 125th event but before 166 days of treatment is completed.
Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on the same date in reporting the 125th event, the first event reported to IRT will be deemed the 125th event. Data after the 125th event will be censored.
Censoring for time to 1st PGTCS will be calculated in a similar manner, except using the date of the 1st PGTCS instead of the date of the event. For subjects who are ongoing in the study when the 125th event occurs, the time to 1st PGTCS information will be censored in the same manner as the time to event information (ie., censor all PGTCS information beyond the date of the 125th event).
3.2.5 AEDs and benzodiazepines
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant and prior medication case report form (CRF) for AEDs. At study entry, a subject should be taking a stable dose of 1 to 2 non-benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1 of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for at least 28 days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline and the Treatment Period with or without additional concurrent stable VNS. Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the Treatment Period.
AEDs at study entry are defined as AEDs where the start date is on or before 28 days prior to Visit 1 and the medication was still ongoing on the date of Visit 1. Lifetime AEDs are defined as AEDs taken in the subject’s history and stopped at least 28 days prior to Visit 1.
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the CRF, although rescue AEDs will also be identified programmatically as any AED taken intermittently for 1 or 2 days, at any frequency, with an epilepsy or seizure related indication. Rescue medication is defined as the intermittent use of benzodiazepines (limited to 2 doses per 28 days) for epilepsy indications if established at least 28 days prior to Visit 1. Lifetime benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at least 28 days prior to Visit 1.
3.2.5.1 Prohibited concomitant treatments (medications and therapies)
The following medications/therapies are prohibited during the Treatment Period:
Clozapine
REDACTED COPY
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant
REDACTED COPY
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant tion case report form (CRF) for AEDs. At study entry, a subject should be
REDACTED COPY
tion case report form (CRF) for AEDs. At study entry, a subject should be benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1
REDACTED COPY
benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1 of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for at
REDACTED COPY
of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for atdays prior to Visit 1. The subject must maintain this AED dosing regimen throughout the
REDACTED COPY
days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline and the Treatment Period with or without additional concurrent stable REDACTED C
OPY
Prospective Baseline and the Treatment Period with or without additional concurrent stable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be censored as of the day after the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be censored as of the day after the
125 events will be included in the primary efficacy endpoint analyses. In case of ties on
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
125 events will be included in the primary efficacy endpoint analyses. In case of ties on event, the first event reported to IRT will be deemed the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event, the first event reported to IRT will be deemed the
will be calculated in a similar manner, except using the date of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be calculated in a similar manner, except using the date of For subjects who are ongoing in the study when
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For subjects who are ongoing in the study when PGTCS information will be censored i
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS information will be censored ias the time to event information (ie., censor all PGTCS information beyond the date of the 125
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as the time to event information (ie., censor all PGTCS information beyond the date of the 125
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant tion case report form (CRF) for AEDs. At study entry, a subject should be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tion case report form (CRF) for AEDs. At study entry, a subject should be benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1 of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for atdays prior to Visit 1. The subject must maintain this AED dosing regimen throughout the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline and the Treatment Period with or without additional concurrent stable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline and the Treatment Period with or without additional concurrent stable VNS. Vagus nerve stimulation must have been in place for at least 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
VNS. Vagus nerve stimulation must have been in place for at least 6constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the
AEDs at study entry are defined as AEDs where the start date is on or before 28 days prior to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
AEDs at study entry are defined as AEDs where the start date is on or before 28 days prior to ation was still ongoing on the date of Visit 1. Lifetime AEDs are defined as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ation was still ongoing on the date of Visit 1. Lifetime AEDs are defined as AEDs taken in the subject’s history and stopped at least 28 days prior to Visit 1.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
AEDs taken in the subject’s history and stopped at least 28 days prior to Visit 1.
Benzodiazepines
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Benzodiazepines taken for rescue
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
taken for rescue F, although rescue
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
F, although rescue intermittently for 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
intermittently for 1 Rescue medication is defined as the intermittent use of benzodiazepines (lim
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Rescue medication is defined as the intermittent use of benzodiazepines (lim28 days) for epilepsy indications if established at least 28 days prior to Visit 1. Lifetime
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
28 days) for epilepsy indications if established at least 28 days prior to Visit 1. Lifetime benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at least 28 days prior to Visit 1.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
least 28 days prior to Visit 1.
3.2.5.1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3.2.5.1
![Page 19: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/19.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Any MAO inhibitors
Barbiturates (except as antiepileptic medications)
Unstable dosing of non-benzodiazepine anxiolytics or once-daily hypnotics
Herbal medicines for epilepsy
The study physician will review the concomitant medications and flag prohibited medications.
3.2.6 Relative day
Relative day will be presented in most subject data listings. Relative day will be calculated as follows:
If the start/stop date occurred prior to the first dose of study medication, the relative day is calculated as start/stop date minus first study medication dose date. In subject data listings, relative days based on this situation will be preceded by a ‘-’.
If the start/stop date occurred on or after the first dose of study medication but prior to the last dose of study medication, the relative day is calculated as start/stop date minus first study medication dose date + 1.
If the start/stop date occurred after the date of last dose of study medication, the relative day is calculated as start/stop date minus date of last dose of study medication. In subject data listings, relative days based on this situation will be preceded by a ‘+’.
Subjects with missing or incomplete dates will also have a missing relative day.
3.2.7 Last Visit
Last Visit is defined as the last post-Baseline non-missing visit (including unscheduled visits) during the Treatment Period.
3.2.8 Month
A month is defined as 28 days.
3.3 Definition of Baseline values
Data collected at Visit 2 prior to the first dose of study medication (physical examination, neurological examination, ECG, vital signs, laboratory tests) will be used as Baseline values. Data collected on the date of first dose of study medication will be assumed to be prior to the first dose. For quantitative ECG assessments, if repeat measurements pre-dose, then the average value is used as the Baseline value. For data not collected at Visit 2 prior to the first dose of study medication, the last data collected prior to the first dose of study medication will be used as Baseline values.
For PGTCS efficacy analyses, the data used for Baseline calculations come from the Combined Baseline Period. For absence and myoclonic seizure analyses, the data used for Baseline calculations come from the Prospective Baseline Period only.
3.4 Protocol deviations
Important protocol deviations are deviations from the protocol which potentially could have a meaningful impact on either primary efficacy outcome or key safety outcomes for an individual
REDACTED COPY ccurred after the date of last dose of study medication, the relative day
REDACTED COPY ccurred after the date of last dose of study medication, the relative day
is calculated as start/stop date minus date of last dose of study medication. In subject data
REDACTED COPY is calculated as start/stop date minus date of last dose of study medication. In subject data
listings, relative days based on this situation will be preceded by a ‘+’.
REDACTED COPY
listings, relative days based on this situation will be preceded by a ‘+’.
missing or incomplete dates will also have a missing relative day.
REDACTED COPY
missing or incomplete dates will also have a missing relative day.
Baseline nonREDACTED C
OPY
Baseline non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Relative day will be presented in most subject data listings. Relative day will be calculated as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Relative day will be presented in most subject data listings. Relative day will be calculated as
If the start/stop date occurred prior to the first dose of study medication, the relative day is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the start/stop date occurred prior to the first dose of study medication, the relative day is calculated as start/stop date minus first study medication dose date. In subject data listings,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
calculated as start/stop date minus first study medication dose date. In subject data listings,
If the start/stop date occurred on or after the first dose of study medication but prior to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the start/stop date occurred on or after the first dose of study medication but prior to the last dose of study medication, the relative day is calculated as start/stop date minus first study
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
last dose of study medication, the relative day is calculated as start/stop date minus first study
ccurred after the date of last dose of study medication, the relative day
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ccurred after the date of last dose of study medication, the relative day is calculated as start/stop date minus date of last dose of study medication. In subject data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is calculated as start/stop date minus date of last dose of study medication. In subject data listings, relative days based on this situation will be preceded by a ‘+’.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
listings, relative days based on this situation will be preceded by a ‘+’.
missing or incomplete dates will also have a missing relative day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
missing or incomplete dates will also have a missing relative day.
Baseline non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline non
Definition of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Definition of Baseline values
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values
Data collected at Visit 2 prior to the first dose of study medication (physical examination,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Data collected at Visit 2 prior to the first dose of study medication (physical examination, neurological examination, ECG, vital signs, laboratory tests) will be used as Baseline values.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
neurological examination, ECG, vital signs, laboratory tests) will be used as Baseline values.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Data collected on the date of first dose of study m
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Data collected on the date of first dose of study mfirst dose. For quantitative ECG assessments, if repeat measurements pre
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first dose. For quantitative ECG assessments, if repeat measurements prevalue is used as the Baseline value. For data not collected at Visit 2 prior to the first dose of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
value is used as the Baseline value. For data not collected at Visit 2 prior to the first dose of study medication,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
study medication,Baseline values.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values.
For PGTCS efficacy analyses, the data used for Baseline calculations come from the Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For PGTCS efficacy analyses, the data used for Baseline calculations come from the Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period. For absence and myoclonic seizure analyses,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period. For absence and myoclonic seizure analyses, calculations come from the Prospective Baseline Period only.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
calculations come from the Prospective Baseline Period only.
![Page 20: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/20.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
subject. The criteria for identifying important protocol deviations and the classification of important protocol deviations will be defined within the project Data Cleaning Plan. To the extent feasible, rules for identifying protocol deviations will be defined without review of the data and without consideration of the frequency of occurrence of such deviations. Whenever possible, criteria for identifying important protocol deviations will be implemented algorithmically to ensure consistency in the classification of important protocol deviations across all subjects.
Important protocol deviations will be reviewed in a blinded manner as part of the ongoing data cleaning process prior to database lock to confirm exclusion from the Per Protocol Set (PPS).
3.5 Analysis sets
The Safety Set (SS) will serve as the primary population for assessing safety endpoints. The Full Analysis Set (FAS) will serve as the primary population for assessing efficacy endpoints.
3.5.1 Screened Set
The Screened Set (ScS) consists of all subjects who have entered screening at Visit 1, have a signed Informed Consent/Assent Form, and have at least basic demographic data available.
3.5.2 Randomized Set
The Randomized Set (RS) is a subset of the ScS and consists of all subjects who were randomized at the Randomization Visit (Visit 2).
3.5.3 Safety Set
The SS is a subset of the RS and consists of all subjects who have been treated with at least 1 dose of study drug, either LCM or placebo. This population will serve as the primary population for assessing safety endpoints.
3.5.4 Full Analysis Set
The FAS is a subset of the SS consisting of all subjects with at least 1 seizure diary assessment during the Treatment Period. This population will serve as the primary population for assessing efficacy endpoints.
3.5.5 Per Protocol Set
The PPS is a subset of the FAS excluding subjects who completed fewer than 6 weeks of treatment or subjects with important protocol deviations affecting the interpretation of the primary efficacy analysis. Important protocol deviations will be determined prior to database lock and unblinding.
3.6 Treatment assignment and treatment groups
Safety data summaries will be presented by randomized treatment and sometimes by overall, while efficacy data summaries will be presented by randomized treatment. Treatments will be reported as LCM and placebo, and in some cases, by all subjects.
If a subject receives a treatment other than the randomized treatment, an evaluation of the mis-treatment will be made to determine if the subject should be summarized under a different treatment arm for safety assessments. Data obtained from subjects who receive an incorrect kit
REDACTED COPY The Randomized Set (RS) is a subset of the ScS and consists of a
REDACTED COPY The Randomized Set (RS) is a subset of the ScS and consists of a
The SS is a subset of the RS and consists of all subjects who have been treated with at least 1
REDACTED COPY
The SS is a subset of the RS and consists of all subjects who have been treated with at least 1 dose of study drug, either LCM or placebo. This population will serve as the pr
REDACTED COPY
dose of study drug, either LCM or placebo. This population will serve as the pr
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Important protocol deviations will be reviewed in a blinded manner as part of the ongoing data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Important protocol deviations will be reviewed in a blinded manner as part of the ongoing data n from the Per Protocol Set (PPS).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
n from the Per Protocol Set (PPS).
The Safety Set (SS) will serve as the primary population for assessing safety endpoints. The Full
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The Safety Set (SS) will serve as the primary population for assessing safety endpoints. The Full Analysis Set (FAS) will serve as the primary population for assessing efficacy endpoints.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis Set (FAS) will serve as the primary population for assessing efficacy endpoints.
reened Set (ScS) consists of all subjects who have entered screening at Visit 1, have a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reened Set (ScS) consists of all subjects who have entered screening at Visit 1, have a signed Informed Consent/Assent Form, and have at least basic demographic data available.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
signed Informed Consent/Assent Form, and have at least basic demographic data available.
The Randomized Set (RS) is a subset of the ScS and consists of a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The Randomized Set (RS) is a subset of the ScS and consists of all subjects who were
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ll subjects who were
The SS is a subset of the RS and consists of all subjects who have been treated with at least 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The SS is a subset of the RS and consists of all subjects who have been treated with at least 1 dose of study drug, either LCM or placebo. This population will serve as the pr
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dose of study drug, either LCM or placebo. This population will serve as the pr
The FAS is a subset of the SS consisting of all subjects with at least 1 seizure diary assessment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The FAS is a subset of the SS consisting of all subjects with at least 1 seizure diary assessment during the Treatment Period. This population will serve as the primary population for asses
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the Treatment Period. This population will serve as the primary population for asses
Per Protocol Set
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Per Protocol Set
The PPS is a subset of the FAS excluding subjects who completed fewer than 6 weeks of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The PPS is a subset of the FAS excluding subjects who completed fewer than 6 weeks of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment or subjects with important protocol deviations affecting the interpretation of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment or subjects with important protocol deviations affecting the interpretation of the primary efficacy analysis.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
primary efficacy analysis. lock and unblinding.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lock and unblinding.
afety data summaries will be presented by randomized treatment and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
afety data summaries will be presented by randomized treatment andwhile efficacy data summaries will b
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
while efficacy data summaries will breported as LCM
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reported as LCM
![Page 21: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/21.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
will be reviewed and the study team will determine how to handle such cases in the statistical analyses prior to database lock and unblinding.
3.7 Center pooling strategy
Refer to Section 4.4.
3.8 Coding dictionaries
Adverse events and medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD, SEP/2013). All coding will be completed prior to database lock and unblinding.
3.9 Changes to protocol-defined analyses
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis. Also, Protocol Section 13.3.2.1 states that the key secondary efficacy variable will be analyzed in the same manner as the primary endpoint using the FAS and that the percentage of seizure-free subjects at 24 weeks will be estimated from the KM estimates of time to first seizure. The analysis of the key secondary endpoint has been clarified to assess the seizure-free rate at 24 weeks using an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates within each stratum. The extended Mantel-Haenszel technique is a randomization-based nonparametric method that provides a more robust method to assess seizure freedom. Thus, the key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy endpoint; the other secondary efficacy variable, time to first PGTCS, will be analyzed in the same manner as the primary efficacy endpoint.
4 STATISTICAL/ANALYTICAL ISSUES
4.1 Adjustments for covariates
Analyses of the primary efficacy variable and several other efficacy variables will be adjusted for the stratification variables Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 16 week Combined Baseline Period prior to randomization) and age at informed consent (≥4 to <12 years of age vs ≥12 to <18 years of age, and ≥18 years of age). Stratification factors recorded at randomization in the interactive response technology (IRT) will be used.
4.2 Handling of dropouts or missing data
4.2.1 Missing seizure diary days
For evaluations based on seizure diary data, imputation for missing data will not be performed.
For the purpose of the derivation of the primary efficacy endpoint, secondary efficacy endpoints and for PGTC seizure-free status, if there are PGTCS counts reported as “not done” on a specific day, then the PGTCS count will be assumed to be zero on that date.
The calculation of average 28-day PGTCS frequency accounts for missing data by only evaluating days for which data are available.
REDACTED COPY Haenszel technique which combines Kaplan
REDACTED COPY Haenszel technique which combines Kaplan
Haenszel technique is a randomization
REDACTED COPY
Haenszel technique is a randomizationnonparametric method that provides a more robust method to assess seizure freedom.
REDACTED COPY
nonparametric method that provides a more robust method to assess seizure freedom.key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy
REDACTED COPY
key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy endpoint; the other secondary efficacy variable, time to first
REDACTED COPY
endpoint; the other secondary efficacy variable, time to first same manner as the primary efficacy endpoint.
REDACTED COPY
same manner as the primary efficacy endpoint.
STATISTICAL/ANALYTICREDACTED COPY
STATISTICAL/ANALYTIC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
using the Medical Dictionary for Regulatory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
using the Medical Dictionary for Regulatory
DD, SEP/2013). All coding will be completed prior to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
DD, SEP/2013). All coding will be completed prior to
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for week Treatment Period, will be estimated using Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period, will be estimated using Kaplan-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-Meier analysis.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Meier analysis. that the key secondary efficacy variable will be analyzed in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
that the key secondary efficacy variable will be analyzed in the same manner as the primary endpoint using the FAS and that the percentage of seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the same manner as the primary endpoint using the FAS and that the percentage of seizureom the KM estimates of time to first seizure.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
om the KM estimates of time to first seizure. of the key secondary endpoint has been clarified to assess the seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the key secondary endpoint has been clarified to assess the seizureHaenszel technique which combines Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Haenszel technique which combines KaplanHaenszel technique is a randomization
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Haenszel technique is a randomizationnonparametric method that provides a more robust method to assess seizure freedom.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nonparametric method that provides a more robust method to assess seizure freedom.key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy endpoint; the other secondary efficacy variable, time to first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
endpoint; the other secondary efficacy variable, time to first same manner as the primary efficacy endpoint.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
same manner as the primary efficacy endpoint.
STATISTICAL/ANALYTIC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
STATISTICAL/ANALYTIC
Adjustments for covariates
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Adjustments for covariates
Analyses of the primary efficacy variable and several other efficacy variables will be adjusted for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analyses of the primary efficacy variable and several other efficacy variables will be adjusted for iables Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
iables Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 16 week Combined Baseline Period prior to randomization) and age at informed consent (≥4 to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
16 week Combined Baseline Period prior to randomization) and age at informed consent (≥4 to <12 years of age vs ≥12 to <18 years of age, and ≥18 years of age). Stratification factors
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<12 years of age vs ≥12 to <18 years of age, and ≥18 years of age). Stratification factorsrecorded at randomization in the interactive response technology (IRT) will be used.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
recorded at randomization in the interactive response technology (IRT) will be used.
Handling of dropouts or missing data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Handling of dropouts or missing data
Missing seizure diary days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Missing seizure diary days
For evaluations based on seizure diary data, imputation for missing data will not be performed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For evaluations based on seizure diary data, imputation for missing data will not be performed.
For the pu
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the pu
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and for PGTC seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and for PGTC seizureday, then the PGTCS count will be assumed to be zero on that date.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day, then the PGTCS count will be assumed to be zero on that date.
The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The
![Page 22: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/22.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
4.2.2 Incomplete dates for first epilepsy diagnosis
To calculate the time since first epilepsy diagnosis, a complete date will be imputed for partially missing first diagnosis date. First diagnosis dates will be displayed as reported in the subject data listings (ie, no imputed values will be displayed in data listing).
Missing the day, but month and year present:
Assign the 1st day of the month or the subject’s birthday (imputing 1st for the day if only month and year are collected), whichever is later.
Missing the day and month, but year present:
Assign January 1st of the year or the subject’s birthday, whichever is later.
Missing the day, month and year:
No imputation will be done.
4.2.3 Incomplete dates for adverse events and concomitant medications
The following rules are applied to impute partial start and stop dates for medications. The date as recorded on the CRF should be presented in subject data listings (no imputed dates should be included in subject data listings).
Imputation of Partial Start Dates
If only the month and year are specified and the month and year of first dose is not the same as the month and year of the start date, then use the first day of the month.
If only the month and year are specified and the month and year of first dose is the same as the month and year of the start, then use the date of first dose.
If only the year is specified, and the year of first dose is not the same as the year of the start date, then use January 1st of the year of the start date.
If only the year is specified, and the year of first dose is the same as the year of the start date, then use the date of first dose.
If the start date is completely unknown and the stop date is unknown or not prior to the date of first dose, then use the date of first dose.
Imputation of Partial Stop Dates
If only the month and year are specified, then use the last day of the month.
If only the year is specified, then the end day and month will be set to the maximum of the date of study termination or the date equivalent to 30 days after the last intake of LCM. However, if the study termination year and year for the date which is 30 days after last intake of LCM are greater than the concomitant medication year, then the day and month are to be set to December 31st.
If the stop date is completely unknown, do not impute the stop date.
In the event of ambiguity or incomplete data which makes it impossible to determine whether a medication was concomitant or not, the medication will be considered as concomitant.
REDACTED COPY
If only the month and year are specified and the month and year of first dose is not the same
REDACTED COPY
If only the month and year are specified and the month and year of first dose is not the same then use the first day of the month.
REDACTED COPY
then use the first day of the month.
If only the month and year are specified and the month and year of first dose is the same as
REDACTED COPY
If only the month and year are specified and the month and year of first dose is the same as the month and year of the start, then use the date of first dose.
REDACTED COPY
the month and year of the start, then use the date of first dose.
If only the year is specified, and the year of first dose isREDACTED COPY
If only the year is specified, and the year of first dose is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incomplete dates for adverse events and concomitant medications
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incomplete dates for adverse events and concomitant medications
The following rules are applied to impute partial start and stop dates for medications. The date as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following rules are applied to impute partial start and stop dates for medications. The date as bject data listings (no imputed dates should be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
bject data listings (no imputed dates should be
If only the month and year are specified and the month and year of first dose is not the same
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the month and year are specified and the month and year of first dose is not the same then use the first day of the month.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
then use the first day of the month.
If only the month and year are specified and the month and year of first dose is the same as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the month and year are specified and the month and year of first dose is the same as the month and year of the start, then use the date of first dose.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the month and year of the start, then use the date of first dose.
If only the year is specified, and the year of first dose is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the year is specified, and the year of first dose isof the year of the start date.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the year of the start date.
If only the year is specified, and the year of first dose is the same as the year of the start date,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the year is specified, and the year of first dose is the same as the year of the start date, then use the date of first dose.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
then use the date of first dose.
If the start date is comp
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the start date is completely unknown and the stop date is unknown or not prior to the date
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
letely unknown and the stop date is unknown or not prior to the date
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of first dose, then use the date of first dose.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of first dose, then use the date of first dose.
Imputation of Partial Stop Dates
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Imputation of Partial Stop Dates
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the month and year are specified, then use the last day of the month.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the month and year are specified, then use the last day of the month.
If only the year is specifie
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the year is specifiedate of study termination or the date equivalent to 30 days after the last intake of LCM.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of study termination or the date equivalent to 30 days after the last intake of LCM. However, if the study termination year and year for the date which is 30 days after last intake
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
However, if the study termination year and year for the date which is 30 days after last intake of LCM
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of LCMset to December 31
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
set to December 31
![Page 23: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/23.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The following rules are applied to impute partial onset and resolution dates for AEs. AEs with partial onset date are classified as either non-treatment- or treatment-emergent based on the imputed onset date.
Imputation of Partial Onset Dates
If only the month and year are specified and the month and year of first dose is not the same as the month and year of onset, then use the first day of the month.
If only the month and year are specified and the month and year of first dose is the same as the month and year of onset, then use the date of first dose.
If only the year is specified, and the year of first dose is not the same as the year of onset, then use January 1st of the year of onset.
If only the year is specified, and the year of first dose is the same as the year of onset, then use the date of first dose.
If the AE onset date is completely unknown, then use the date of first dose.
Imputation of Partial Resolution Dates
If only the month and year are specified, then use the last day of the month.
If only the year is specified, then the end day and month will be set to the maximum of the date of study termination or the date equivalent to 30 days after the last intake of LCM. However, if the study termination year and year for the date which is 30 days after last intake of LCM are greater than the event year, then the day and month are to be set to December 31st.
If the AE resolved and the resolution date is completely unknown, then do not impute the resolution date.
4.2.4 Incomplete date for the last administration of study medication
No imputation should be performed for missing study medication start dates. This field on the CRF should not be partial or missing.
For partial or missing date of last dose of study medication, the following imputation rules will be applied for the purpose of calculating overall exposure:
If the day is missing (but month and year available), impute the last dose date as the minimum of the last day of the month or the date of last contact reported on the Study Termination CRF; if day and month are both missing (only year available), impute the last dose date as the minimum of the last day of the year or the date of last contact on the Study Termination CRF.
If a subject died and has a partial or missing last administration date, the date is set to the date of death. If there is a partial date of last dose and the month/year are prior to the month and year of the date of death, follow partial date imputation rules.
If the last dose date is completely missing and no information could be obtained from data cleaning exercises, the last dose date should be imputed as the date of last contact according to the Study Termination CRF. A review of the data for subjects with completely missing last
REDACTED COPY If only the year is specified, then the end day and month will be set to the maximum of the
REDACTED COPY If only the year is specified, then the end day and month will be set to the maximum of the
date of study termination or the date equivalent to 30 days after the
REDACTED COPY
date of study termination or the date equivalent to 30 days after theHowever, if the study termination year and year for the date which is 30 days after last intake
REDACTED COPY
However, if the study termination year and year for the date which is 30 days after last intake of LCM are greater than the event year, then the day and month are to be set to December
REDACTED COPY
of LCM are greater than the event year, then the day and month are to be set to December
If the AE resolved and the resolution date iREDACTED C
OPY
If the AE resolved and the resolution date i
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the month and year are specified and the month and year of first dose is the same as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the month and year are specified and the month and year of first dose is the same as
If only the year is specified, and the year of first dose is not the same as the year of onset,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the year is specified, and the year of first dose is not the same as the year of onset,
If only the year is specified, and the year of first dose is the same as the year of onset, then
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the year is specified, and the year of first dose is the same as the year of onset, then
If the AE onset date is completely unknown, then use the date of first dose.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the AE onset date is completely unknown, then use the date of first dose.
If only the month and year are specified, then use the last day of the month.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the month and year are specified, then use the last day of the month.
If only the year is specified, then the end day and month will be set to the maximum of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If only the year is specified, then the end day and month will be set to the maximum of the date of study termination or the date equivalent to 30 days after the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of study termination or the date equivalent to 30 days after theHowever, if the study termination year and year for the date which is 30 days after last intake
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
However, if the study termination year and year for the date which is 30 days after last intake of LCM are greater than the event year, then the day and month are to be set to December
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of LCM are greater than the event year, then the day and month are to be set to December
If the AE resolved and the resolution date i
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the AE resolved and the resolution date is completely unknown, then do not impute the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
s completely unknown, then do not impute the
Incomplete date for the last administration of study medication
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incomplete date for the last administration of study medication
No imputation should be performed for missing study medication start dates. This field on the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
No imputation should be performed for missing study medication start dates. This field on the CRF should not be partial or missing
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
CRF should not be partial or missing
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For partial or missing date of last dose of study medication, the following imputation rules will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For partial or missing date of last dose of study medication, the following imputation rules will be applied for the purpose of calculating overall exposure:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be applied for the purpose of calculating overall exposure:
If the day is missing (but month and year available), impute the last dose date as the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the day is missing (but month and year available), impute the last dose date as the minimum o
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
minimum of the last day of the month or the date of last contact reported on the Study
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
f the last day of the month or the date of last contact reported on the Study Termination CRF; if day and month are both missing (only year available), impute the last
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Termination CRF; if day and month are both missing (only year available), impute the last
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dose date as the minimum of the last day of the year or the date of last contact on the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dose date as the minimum of the last day of the year or the date of last contact on the Termination CRF.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Termination CRF.
If a subject died and has a partial or missing last administration date, the date is set to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If a subject died and has a partial or missing last administration date, the date is set to the date of death. If there is a partial date of last dose and the month/year are prior to the month
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of death. If there is a partial date of last dose and the month/year are prior to the month
![Page 24: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/24.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
dose dates should be performed to ensure that the imputation does not result in an unrealistic value for duration of exposure.
Imputed date of last dose dates should only be used for calculation of the duration of exposure. The date as recorded on the CRF should be presented in subject data listings (no imputed dates should be included in subject data listings).
4.2.5 Missing adverse event intensity
If the intensity of an AE is missing then it will be counted as severe for analysis purposes.
4.2.6 Missing adverse event relationship to study medication
If the AE relationship to study medication is missing then it will be counted as related for analysis purposes.
4.3 Interim analyses and data monitoring
To enhance safety monitoring, 3 interim analyses are planned when 25%, 50%, and 75% of subjects experience an event (31, 62, and 93 events, respectively) or 24 weeks after 50, 100, and 150 subjects have been randomized, respectively, whichever comes first. An event is defined as the occurrence of the second PGTCS during the Treatment Period.
These interim reviews for safety will be performed using an Independent Data Monitoring Committee (IDMC), with a single futility assessment planned at the second interim analysis. The IDMC will oversee the safety of the study by reviewing safety data periodically. Details are provided in an IDMC charter. Both safety and futility will be assessed in a manner that ensures that blinding is not compromised for individuals involved with operational aspects of the study, nor individuals involved with the planning and conduct of the final statistical analyses. Analysis of the primary efficacy endpoint (time to second PGTCS) will only be examined at the planned futility assessment; an unblinded, descriptive review of safety and seizure data will be provided for all IDMC meetings.
No consideration will be made for stopping due to early demonstration of efficacy; however, the significance level will be set using a Haybittle-Peto boundary at alpha=0.0001 so as to require only a nominal alpha adjustment for the final analysis. Full details of the interim analysis are described in the Interim Analysis Statistical Analysis Plan.
4.4 Multicenter studies
Due to the small number of subjects per site, all sites will be pooled together for analysis. There will be no planned analyses for multi-center effects.
4.5 Multiple comparisons/multiplicity
A gatekeeping strategy (Marcus et al, 1996) will be used to test the key secondary efficacy variable provided that the primary efficacy endpoint is statistically significant (See Section 8.2.1 for additional details). No additional adjustments for multiplicity are required as all additional inferences will be hypothesis-generating only.
4.6 Use of an efficacy subset of subjects
The PPS will be used to evaluate subjects who completed at least 6 weeks of treatment and have no important protocol deviations related to the primary efficacy variable. This analysis set will
REDACTED COPY These interim reviews for safety will be performed using an Independent Data Monitoring
REDACTED COPY These interim reviews for safety will be performed using an Independent Data Monitoring
Committee (IDMC), with a single futility assessment planned at the second interim analysis. The
REDACTED COPY
Committee (IDMC), with a single futility assessment planned at the second interim analysis. The C will oversee the safety of the study by reviewing safety data periodically. Details are
REDACTED COPY
C will oversee the safety of the study by reviewing safety data periodically. Details are provided in an IDMC charter. Both safety and futility will be assessed in a manner that ensures
REDACTED COPY
provided in an IDMC charter. Both safety and futility will be assessed in a manner that ensures that blinding is not compromised for individuals involved with operati
REDACTED COPY
that blinding is not compromised for individuals involved with operatinor individuals involved with the planning and conduct of the final statistical analyses. Analysis
REDACTED COPY
nor individuals involved with the planning and conduct of the final statistical analyses. Analysis of the primary efficacy endpoint (time to second PGTCS) will only be examined at the planned
REDACTED COPY
of the primary efficacy endpoint (time to second PGTCS) will only be examined at the planned scriptive review of safety and seizure data will be provided REDACTED C
OPY
scriptive review of safety and seizure data will be provided
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the AE relationship to study medication is missing then it will be counted as related for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the AE relationship to study medication is missing then it will be counted as related for
onitoring, 3 interim analyses are planned when 25%, 50%, and 75% of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
onitoring, 3 interim analyses are planned when 25%, 50%, and 75% of subjects experience an event (31, 62, and 93 events, respectively) or 24 weeks after 50, 100,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects experience an event (31, 62, and 93 events, respectively) or 24 weeks after 50, 100, 150 subjects have been randomized, respectively, whichever comes first. An event is define
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
150 subjects have been randomized, respectively, whichever comes first. An event is defineas the occurrence of the second PGTCS during the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as the occurrence of the second PGTCS during the Treatment Period.
These interim reviews for safety will be performed using an Independent Data Monitoring
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
These interim reviews for safety will be performed using an Independent Data Monitoring Committee (IDMC), with a single futility assessment planned at the second interim analysis. The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Committee (IDMC), with a single futility assessment planned at the second interim analysis. The C will oversee the safety of the study by reviewing safety data periodically. Details are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
C will oversee the safety of the study by reviewing safety data periodically. Details are provided in an IDMC charter. Both safety and futility will be assessed in a manner that ensures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
provided in an IDMC charter. Both safety and futility will be assessed in a manner that ensures that blinding is not compromised for individuals involved with operati
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
that blinding is not compromised for individuals involved with operatinor individuals involved with the planning and conduct of the final statistical analyses. Analysis
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nor individuals involved with the planning and conduct of the final statistical analyses. Analysis of the primary efficacy endpoint (time to second PGTCS) will only be examined at the planned
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the primary efficacy endpoint (time to second PGTCS) will only be examined at the planned scriptive review of safety and seizure data will be provided
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scriptive review of safety and seizure data will be provided
No consideration will be made for stopping due to early demonstration of efficacy; however, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
No consideration will be made for stopping due to early demonstration of efficacy; however, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
significance level will be set using a Haybittle
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
significance level will be set using a Haybittleonly a nominal alpha adjustment for the final analysis. Full details of the interim analysis are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
only a nominal alpha adjustment for the final analysis. Full details of the interim analysis are described in the Interim Analysis Statistical Analysis Plan.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
described in the Interim Analysis Statistical Analysis Plan.
Multicenter studies
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Multicenter studies
Due to the small number of subjects per site, all sites wi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Due to the small number of subjects per site, all sites wiwill be no planned analyses for multi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be no planned analyses for multi
Multiple comparisons/multiplicity
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Multiple comparisons/multiplicity
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A gatekeeping strategy (Marcus et al, 1996) will be used to test the key secondary efficacy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A gatekeeping strategy (Marcus et al, 1996) will be used to test the key secondary efficacy variable provided that the primary
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
variable provided that the primaryfor additional details). No additional adjustments for multiplicity are required
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for additional details). No additional adjustments for multiplicity are required inferences will be hypothesis
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
inferences will be hypothesis
![Page 25: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/25.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
provide additional information on the analysis of the primary efficacy variable and will describe findings in a subset of subjects who more closely followed the intentions of the study protocol.
Other than the planned analyses based on the PPS, no other efficacy subsets are defined for statistical analyses.
4.7 Active-control studies intended to show equivalence
This section is not applicable for this study.
4.8 Examination of subgroups
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the FAS. Disposition will be presented by age subgroup for the SS and FAS. Exposure will be presented by age and region subgroups for the SS. Overall TEAE incidence will be presented by age subgroup for the SS. Selected disposition and safety analyses will be presented by Development for the purpose of addressing requirements set in Article 46 of the European Pediatric Regulation (see Section 12.5 for further details).
The subgroups to be examined include:
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
Development (Pediatric [≥4 to < 18 years old], Adult [≥18 years old])
Racial group (white, non-white)
Gender (male, female)
Region
North America: United States, Puerto Rico
Latin America: Brazil, Mexico
Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland, Portugal, Slovakia, Spain
Eastern Europe: Bulgaria, Romania, Russia, Turkey
Asia/Pacific/Other: Australia, China, Israel, Japan, South Korea, Taiwan
Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baseline Period)
Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the subject is taking when enrolled into the study (1, 2, 3).
Separate age sub-groupings are used for the purpose of summarizing the following scales:
PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years)
Achenbach CBCL (4 to 5 years, 6 to 18 years)
BRIEF-P/BRIEF (4 to <5 years, ≥5 years).
REDACTED COPY ediatric [≥4 to < 18 years old], Adult [≥18 years old])
REDACTED COPY ediatric [≥4 to < 18 years old], Adult [≥18 years old])
North America: United States, Puerto RicoREDACTED C
OPY
North America: United States, Puerto Rico
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the FAS. Disposition will be presented by age subgroup for the SS and FAS. Exposure will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
FAS. Disposition will be presented by age subgroup for the SS and FAS. Exposure will be cidence will be presented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
cidence will be presented by age subgroup for the SS. Selected disposition and safety analyses will be presented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
age subgroup for the SS. Selected disposition and safety analyses will be presented by Development for the purpose of addressing requirements set in Article 46 of the European
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Development for the purpose of addressing requirements set in Article 46 of the European
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
ediatric [≥4 to < 18 years old], Adult [≥18 years old])
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ediatric [≥4 to < 18 years old], Adult [≥18 years old])
North America: United States, Puerto Rico
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
North America: United States, Puerto Rico
Western/Central Europe: Belgium, Czech Republic, France, Germany,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Western/Central Europe: Belgium, Czech Republic, France, Germany, Poland, Portugal, Slovakia, Spain
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Poland, Portugal, Slovakia, Spain
Eastern Europe: Bulgaria, Romania, Russia,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Eastern Europe: Bulgaria, Romania, Russia,
Asia/Pacific/Other: Australia, China, Israel, Japan, South Korea, Taiwan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Asia/Pacific/Other: Australia, China, Israel, Japan, South Korea, Taiwan
Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baselin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baselin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the subject is taking when enrolled into the study (1, 2, 3).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subject is taking when enrolled into the study (1, 2, 3).
Separate age sub
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Separate age sub
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PedsQL (4 yea
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PedsQL (4 yea
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 26: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/26.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
4.9 Stratum Pooling
The stratification factors for this study are Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analyses will use the stratification factors from IRT.
To determine if strata pooling should occur for time to event (2nd PGTCS) analysis:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age at informed consent categories will be summed. For categories with < 3 total events, the combining should occur as follows:
If 2 of the age at informed consent categories combined have < 3 total events, then all age categories are combined for the analysis.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
If ≥18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the strata with the 2nd smallest number of events.
Repeat the algorithm for combining strata for the subjects who did not have events if there are categories with < 3 total non-events.
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to determine stratum pooling for both events and non-events.
For each primary efficacy endpoint sensitivity analysis which uses stratum pooling, the pooling of the strata should be reassessed since the event distribution for the specific sensitivity may be different than the distribution in the primary efficacy endpoint analysis.
Time to 1st PGTCS analyses:
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that “events” will now be in reference to subjects having only 1 PGTCS.
Seizure freedom analyses:
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that “events” will now be in reference to subjects having 0 PGTCS.
5 STUDY POPULATION CHARACTERISTICS
5.1 Subject disposition
The number of subjects screened and the number and percentage of screen failures will be summarized overall. Screen failures are those subjects who are in the ScS and either met an exclusion criterion or did not meet an inclusion criterion. The reason for screen failure will be presented. The number and percentage of baseline failures due to PGTCS frequency during the Combined Baseline Period will also be summarized. The study eligibility criteria and those
REDACTED COPY events or less, it should be combined with the strata with the 2
REDACTED COPY events or less, it should be combined with the strata with the 2
Repeat the algorithm for combining strata for the
REDACTED COPY
Repeat the algorithm for combining strata for the subjects
REDACTED COPY
subjects
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to
REDACTED COPY
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to for both events and non
REDACTED COPY
for both events and non
acy endpoint sensitivity analysiREDACTED COPY
acy endpoint sensitivity analysi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
of the age at informed consent categories combined have < 3 total events, then all age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the age at informed consent categories combined have < 3 total events, then all age
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with the ≥12 and <18 years of age category.
If ≥18 years of age is the category with the smallest number of events that are 2 events or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
less, it should be combined with the ≥12 and <18 years of age category.
the smallest number of events that are 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the smallest number of events that are 2 events or less, it should be combined with the strata with the 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
events or less, it should be combined with the strata with the 2
subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who did
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
who did
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to for both events and non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for both events and non
acy endpoint sensitivity analysi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
acy endpoint sensitivity analysi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the strata should be reassessed since
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the strata should be reassessed since the event distribution
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the event distribution different than the distribution in the pri
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
different than the distribution in the primary efficacy endpoint analysis.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mary efficacy endpoint analysis.
The prior algorithm for stratum pooling will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The prior algorithm for stratum pooling will“events” will now be in reference to subjects having only 1 PGTCS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
“events” will now be in reference to subjects having only 1 PGTCS.
Seizure freedom analyses:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure freedom analyses:
The prior algorithm for stratum pooling will be used
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The prior algorithm for stratum pooling will be used
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
“events” will now
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
“events” will now
5.1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5.1
The number of subjects screened and the number and percentage of screen failures will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number of subjects screened and the number and percentage of screen failures will be summarized overall. Screen failures are those subjects who are in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
summarized overall. Screen failures are those subjects who are in the
![Page 27: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/27.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
subjects who did not meet it will be listed. All disposition data for the ScS will be presented in subject data listings.
The number of subjects in the ScS, Randomized Set (RS), SS, FAS, and PPS will be presented by investigator; the date of first subject in and date of last subject out will also be included in this summary. The subject populations will be listed.
The overall number and percentage of subjects who completed and discontinued from the study will be presented for the SS, FAS, and PPS including number and percentages for each reason for discontinuation. The completion of the study is defined as meeting any of the predetermined exit criteria (including when the 125th event has occurred) or experiencing <2 PGTCS within the 24-week treatment period. Discontinuation is defined as the completion of the ET Visit in all other cases. This summary will be repeated for specific subgroups as detailed in Section 4.8 for the SS and FAS. The study termination information will be presented in the subject data listings.
A by-subject listing will be presented to show all visit dates and the associated relative day.
5.2 Protocol deviations
The number and percentage of subjects without any important protocol deviations and with at least 1 important protocol deviation in each of the categories defined in the prior to database lock and unblinding will be summarized overall for the RS.
All important protocol deviations for subjects in the RS will be listed by site, subject number, and protocol deviation category.
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Unless otherwise specified, demographics and baseline characteristics will be summarized by treatment group and overall.
6.1 Demographics
6.1.1 Derivation of demographics variables
6.1.1.1 BMI
The body mass index (BMI) will be derived at Baseline only, from the Baseline height and weight values. BMI will be calculated using the following formula:
2
2
(cm)height (kg)weight *10000)(kg/m BMI
REDACTED COPY
All important protocol deviations for subjects in the RS will be listed by site, subject number,
REDACTED COPY
All important protocol deviations for subjects in the RS will be listed by site, subject number,
DEMOGRAPHICS AND OTH
REDACTED COPY
DEMOGRAPHICS AND OTH
REDACTED COPY
CHARACTERISTICS
REDACTED COPY
CHARACTERISTICS
Unless otherwise specified, demographics and baselineREDACTED COPY
Unless otherwise specified, demographics and baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for discontinuation. The completion of the study is defined as meeting any of the predetermined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for discontinuation. The completion of the study is defined as meeting any of the predetermined iencing <2 PGTCS within the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
iencing <2 PGTCS within the week treatment period. Discontinuation is defined as the completion of the ET Visit
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week treatment period. Discontinuation is defined as the completion of the ET Visit in all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in all Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 4.8
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
4.8the SS and FAS. The study termination information will be presented in the subject data listings.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the SS and FAS. The study termination information will be presented in the subject data listings.
subject listing will be presented to show all visit dates and the associated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subject listing will be presented to show all visit dates and the associated relative day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
relative day.
The number and percentage of subjects without any important protocol deviations and with at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects without any important protocol deviations and with at least 1 important protocol deviation in each of the categories defined in the prior to database lock
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
least 1 important protocol deviation in each of the categories defined in the prior to database lock
All important protocol deviations for subjects in the RS will be listed by site, subject number,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All important protocol deviations for subjects in the RS will be listed by site, subject number,
DEMOGRAPHICS AND OTH
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
DEMOGRAPHICS AND OTH
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ER BASELINE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ER BASELINE
Unless otherwise specified, demographics and baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Unless otherwise specified, demographics and baseline
Derivation of demographics variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Derivation of demographics variables
The body mass index (BMI) will be derived at Baseline only, from the Baseline height and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The body mass index (BMI) will be derived at Baseline only, from the Baseline height and weight values. BMI will be calculated using t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weight values. BMI will be calculated using t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
*10000)(kg/m BMI
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
*10000)(kg/m BMI
![Page 28: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/28.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
6.1.2 Analysis of demographics variables
Baseline demographics will be summarized for the SS and include gender, race, ethnicity, age, age category, age strata from IRT, height (cm), weight (kg), BMI (kg/m2). Note age from the CRF will be summarized.
Demographics will be listed for all subjects screened.
6.2 Other Baseline characteristics
6.2.1 Derivation of other Baseline characteristics
6.2.1.1 Time since first diagnosis
The time since first diagnosis of epilepsy is calculated as follows:
the date of informed consent – the date of first epilepsy diagnosis/365.25.
Imputation for partial dates of first epilepsy diagnosis will be imputed as described in Section 4.2.2.
6.2.1.2 Age at diagnosis
Age at diagnosis of epilepsy will be calculated using the first epilepsy diagnosis date and the date of birth. Imputation for partial dates of first epilepsy diagnosis will be imputed as described in Section 4.2.2.
6.2.2 Analysis of other Baseline characteristics
Combined Baseline PGTCS frequency, 12-week Historical Baseline PGTCS frequency, and 4-week Prospective Baseline PGTCS frequency derived as frequencies per 28 days will be summarized as continuous data. Combined Baseline PGTCS frequency will also be summarized as categorical data (≤2 per 28 days and >2 per 28 days) from the CRF and IRT at randomization.
The following Baseline characteristics will also be presented:
Time since first diagnosis at date of consent
Age at diagnosis of epilepsy
Number of lifetime AEDs and Benzodiazepines (0, 1-3, 4-6, ≥7)
Concomitant benzodiazepine use at study entry (yes, no)
ILAE (1989) Seizure classification history
Classification of epileptic syndrome
Etiology of epilepsy
All Baseline characteristics will be presented in data listings. All reproductive potential and birth control information will be presented in data listings.
6.3 Subgroups
All subgroups detailed in Section 4.8 will be summarized in a table for the SS and FAS. Subgroup identification will also be listed.
REDACTED COPY of birth. Imputation for partial dates of first epilepsy diagnosis will be imputed as described in
REDACTED COPY of birth. Imputation for partial dates of first epilepsy diagnosis will be imputed as described in
Analysis of other Baseline characteristics
REDACTED COPY
Analysis of other Baseline characteristics
week Historical Baseline PGTCS frequency, and 4
REDACTED COPY
week Historical Baseline PGTCS frequency, and 4week Prospective Baseline PGTCS frequency derived as frequenc
REDACTED COPY
week Prospective Baseline PGTCS frequency derived as frequencsummarized as continuous data. Combined Baseline PGTCS frequency will also be summarized
REDACTED COPY
summarized as continuous data. Combined Baseline PGTCS frequency will also be summarized as categorical data (≤2 per 28 days and >2 per 28 days) from the CRF and IRT at randomization.REDACTED C
OPY
as categorical data (≤2 per 28 days and >2 per 28 days) from the CRF and IRT at randomization.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Imputation for partial dates of first epilepsy diagnosis will be imputed as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Imputation for partial dates of first epilepsy diagnosis will be imputed as described in
Age at diagnosis of epilepsy will be calculated using the first epilepsy diagnosis date and the date
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Age at diagnosis of epilepsy will be calculated using the first epilepsy diagnosis date and the date of birth. Imputation for partial dates of first epilepsy diagnosis will be imputed as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of birth. Imputation for partial dates of first epilepsy diagnosis will be imputed as described in
Analysis of other Baseline characteristics
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis of other Baseline characteristics
week Historical Baseline PGTCS frequency, and 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Historical Baseline PGTCS frequency, and 4week Prospective Baseline PGTCS frequency derived as frequenc
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Prospective Baseline PGTCS frequency derived as frequencsummarized as continuous data. Combined Baseline PGTCS frequency will also be summarized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
summarized as continuous data. Combined Baseline PGTCS frequency will also be summarized as categorical data (≤2 per 28 days and >2 per 28 days) from the CRF and IRT at randomization.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as categorical data (≤2 per 28 days and >2 per 28 days) from the CRF and IRT at randomization.
The following Baseline characteristics will also
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following Baseline characteristics will also
Time since first diagnosis at date of consent
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Time since first diagnosis at date of consent
Age at diagnosis of epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Age at diagnosis of epilepsy
Number of lifetime AEDs and Benzodiazepines (0, 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of lifetime AEDs and Benzodiazepines (0, 1
Concomitant benzodiazepine use at study entry (yes, no)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Concomitant benzodiazepine use at study entry (yes, no)
ILAE (1989) Seizure classification history
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ILAE (1989) Seizure classification history
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
sification of epileptic syndrome
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
sification of epileptic syndrome
Etiology of epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Etiology of epilepsy
All Baseline characteristics will be presented in data listings. All reproductive potential and birth
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All Baseline characteristics will be presented in data listings. All reproductive potential and birth control information will be presented in data listings.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
control information will be presented in data listings.
6.3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6.3
![Page 29: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/29.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
6.4 Medical history and concomitant diseases
Previous and ongoing medical history conditions will be summarized by system organ class (SOC) and preferred term (PT) for the SS. A similar summary will be provided for concomitant diseases for the SS. Concomitant diseases are medical history events which are ongoing at the Screening Visit.
The data, including the SOC, PT and verbatim reported term, will also be presented in data listings. A glossary of medical history SOC and PTs will also be completed.
6.5 Procedure history
All procedure history will be presented in data listings.
6.6 Prior and concomitant medications
Medications with a start date before the first dose of study medication will be considered prior medications. Medications taken on or after the date of the first dose of study medication will be considered concomitant medications. Medications with a missing start date whose stop date is either unknown or after the date of the first dose of study medication will be considered concomitant. Medications with a missing start date whose stop date is prior to the date of the first dose of study medication will be considered as prior medications.
Details regarding imputation of incomplete dates are described in Section 4.2.3.
Medications will be summarized using the Anatomical Therapeutic Chemical (ATC) codes from the WHO-DD. All tabulations will be sorted by frequency of the higher-level ATC code and by frequency of the lower level ATC code within the higher-level ATC code.
Medications (excluding AEDs and benzodiazepines) will be summarized separately for prior and concomitant medications by ATC level 1 (anatomical main group) and ATC level 2 (therapeutic subgroup) for the SS.
Lifetime AEDs and benzodiazepines will be summarized separately by ATC level 4 (chemical subgroup) and PT for the SS. AEDs and benzodiazepines at study entry will also be summarized separately by ATC level 4 and PT for the SS.
Concomitant AEDs will be defined by a manual medical review of all unique ATC codes and indications reported in the database to identify medications taken to treat epilepsy. Concomitant AEDs and benzodiazepines taken for any epilepsy indication during the Treatment Period will be summarized separately by ATC level 4 and PT for the SS.
A glossary of ATC codes and associated investigator’s terms for all AEDs or benzodiazepines and all other medications (excluding AEDs and benzodiazepines) will be listed separately in data listings. The WHO-DD coding and other information for AEDs or benzodiazepines and all other medications (excluding AEDS and benzodiazepines) will be listed separately in subject data listings. AEDs flagged as rescue medications will also be listed in subject data listings.
7 MEASUREMENTS OF TREATMENT COMPLIANCE
Compliance data will be included in subject data listings.
REDACTED COPY Details regarding imputation of incomplete dates are described in
REDACTED COPY Details regarding imputation of incomplete dates are described in
Medications will be summarized using the Anatomical Therapeutic Chemical (ATC) codes from
REDACTED COPY
Medications will be summarized using the Anatomical Therapeutic Chemical (ATC) codes from rted by frequency of the higher
REDACTED COPY
rted by frequency of the higherevel ATC code within the higher
REDACTED COPY
evel ATC code within the higher
Medications (excluding AEDs and benzodiazepines) will be summarized separately for prior and
REDACTED COPY
Medications (excluding AEDs and benzodiazepines) will be summarized separately for prior and concomitant medications by ATC level 1 (anatomical main group) and ATC level 2 (therapeutic REDACTED C
OPY
concomitant medications by ATC level 1 (anatomical main group) and ATC level 2 (therapeutic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Medications with a start date before the first dose of study medication will be considered prior
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Medications with a start date before the first dose of study medication will be considered prior medications. Medications taken on or after the date of the first dose of study medication will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
medications. Medications taken on or after the date of the first dose of study medication will be concomitant medications. Medications with a missing start date whose stop date is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
concomitant medications. Medications with a missing start date whose stop date is either unknown or after the date of the first dose of study medication will be considered
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either unknown or after the date of the first dose of study medication will be considered concomitant. Medications with a missing start date whose stop date is prior to the d
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
concomitant. Medications with a missing start date whose stop date is prior to the ddose of study medication will be considered as prior medications.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dose of study medication will be considered as prior medications.
Details regarding imputation of incomplete dates are described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Details regarding imputation of incomplete dates are described in
Medications will be summarized using the Anatomical Therapeutic Chemical (ATC) codes from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Medications will be summarized using the Anatomical Therapeutic Chemical (ATC) codes from rted by frequency of the higher
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
rted by frequency of the higherevel ATC code within the higher
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
evel ATC code within the higher
Medications (excluding AEDs and benzodiazepines) will be summarized separately for prior and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Medications (excluding AEDs and benzodiazepines) will be summarized separately for prior and concomitant medications by ATC level 1 (anatomical main group) and ATC level 2 (therapeutic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
concomitant medications by ATC level 1 (anatomical main group) and ATC level 2 (therapeutic
Lifetime AEDs and benzodiazepines will be summarized separately by ATC level 4 (chemical
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Lifetime AEDs and benzodiazepines will be summarized separately by ATC level 4 (chemical subgroup) and PT for the SS. AEDs and benzodiazepines at study entry will also be summarized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subgroup) and PT for the SS. AEDs and benzodiazepines at study entry will also be summarized separately by ATC level 4 and PT for the SS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
separately by ATC level 4 and PT for the SS.
EDs will be defined by a manual medical review of all unique ATC codes and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
EDs will be defined by a manual medical review of all unique ATC codes and indications reported in the database to identify medications taken to treat epilepsy. Concomitant
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
indications reported in the database to identify medications taken to treat epilepsy. Concomitant AEDs and benzodiazepines taken for any epilepsy indication during the Treatment Per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
AEDs and benzodiazepines taken for any epilepsy indication during the Treatment Persummarized separately by ATC level 4 and PT for the SS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
summarized separately by ATC level 4 and PT for the SS.
A glossary of ATC codes and associated investigator’s terms for all AEDs or benzodiazepines
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A glossary of ATC codes and associated investigator’s terms for all AEDs or benzodiazepines and all other medications (excluding AEDs and benzodiazepines) will be listed separately in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and all other medications (excluding AEDs and benzodiazepines) will be listed separately inlistings. The WHO
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
listings. The WHOmedications (excluding AEDS and benzodiazepines) will be listed separately in subject data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
medications (excluding AEDS and benzodiazepines) will be listed separately in subject data listings.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
listings.
7
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
7
![Page 30: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/30.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
8 EFFICACY ANALYSES
Most efficacy analyses will be performed using the FAS population; in other cases, the population will be stated.
For primary efficacy endpoint analyses, only data up to and including the day of the event, the Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125th event, whichever is earlier, will be included. For the secondary efficacy endpoint analyses, only data up to and including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day 166 or the date of the 125th event, whichever is earlier, will be included. For all other exploratory efficacy variables, all appropriate seizure data during the Treatment Period, will be included. All seizure diary data will be listed including data not included in efficacy analyses.
Testing for the primary efficacy endpoint will be done at the 5% level (2-sided). Provided that the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to test the key secondary efficacy variable, seizure freedom. No additional adjustments for multiplicity are required as all additional inferences will be hypothesis-generating only.
8.1 Statistical analysis of the primary efficacy variable
8.1.1 Derivations of primary efficacy variable
For the primary efficacy variable, an event and how time to event is calculated is described in Section 3.2.3, keeping in mind Section 3.2.2. Censoring of subjects for this analysis will be as described in Section 3.2.4 . If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that day.
8.1.2 Primary analysis of the primary efficacy variable
The primary efficacy variable, time to event during the 166-day Treatment Period, will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section 4.9.
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
H0: β=0
Versus
H1: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented by
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
)
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The
REDACTED COPY and how time to event
REDACTED COPY and how time to event
oring of subjects for this analysis will be as
REDACTED COPY
oring of subjects for this analysis will be as . If a day is marked in the CRF as “not done”, it will be assumed that
REDACTED COPY
. If a day is marked in the CRF as “not done”, it will be assumed that
Primary analysis of the primary efficacy variable
REDACTED COPY
Primary analysis of the primary efficacy variable
e, time to event during the 166REDACTED C
OPY
e, time to event during the 166evaluated using a Cox proportional hazards regression modelREDACTED C
OPY
evaluated using a Cox proportional hazards regression model
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day For all other exploratory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For all other exploratory propriate seizure data during the Treatment Period, will be included. All
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
propriate seizure data during the Treatment Period, will be included. All
sided). Provided that
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
sided). Provided that e primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to . No additional adjustments for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. No additional adjustments for generating only.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
generating only.
Statistical analysis of the primary efficacy variable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Statistical analysis of the primary efficacy variable
and how time to event
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and how time to event is calculated is described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is calculated is described in oring of subjects for this analysis will be as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
oring of subjects for this analysis will be as . If a day is marked in the CRF as “not done”, it will be assumed that
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. If a day is marked in the CRF as “not done”, it will be assumed that
Primary analysis of the primary efficacy variable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Primary analysis of the primary efficacy variable
e, time to event during the 166
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e, time to event during the 166evaluated using a Cox proportional hazards regression model
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
evaluated using a Cox proportional hazards regression model
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 yea
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
rs of age). The analysis will use the stratification factors from IRT and pooled as described in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IRT and pooled as described in Section
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
here β is the coefficient of an independent variable representing the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
here β is the coefficient of an independent variable representing the model.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
model. The hazard function is represented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The hazard function is represented by
![Page 31: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/31.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
assumptions of proportional hazards will also be assessed graphically (e.g. log (log S) plot vs time, empirical score process) for any departure; non-proportionality is not expected when using a stratified Cox model. Depending on the departure from proportional hazards, a sensitivity analysis (e.g. piecewise proportional hazards, time-varying coefficient, restricted mean survival) may be performed.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. The 95% CI for the HR will also be reported.
Additionally, a Kaplan-Meier (KM) plot for time to event as well as the KM estimate for the median time to event and 95% CI will be provided. If the median time is not estimable, then the 25th percentile and 95% CI will be provided. The number of events will be reported by treatment group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects who were censored in the analysis.
8.1.3 Secondary analyses of the primary efficacy variable
The summary of time to the event during the 166-day Treatment Period will be presented by all subgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be provided.
8.1.4 Supportive and sensitivity analyses of the primary efficacy variable
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted in order to assess the effect of dropouts, important protocol deviations, and operational bias on the primary endpoint:
Repeat the primary efficacy analysis using the PPS.
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events after the date of the 125th event) through each subject’s first 166 days of treatment, on the FAS.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed as treatment failures (ie, events at the time of discontinuation).
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures.
Repeat the primary efficacy analysis using the FAS, comparing the event rates prior to vs after each interim analysis to examine possible operational bias due to unblinding.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue after their 1st PGTCS will be analyzed as treatment failures.
8.2 Statistical analysis of the secondary efficacy variables
Provided that the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to test the key secondary efficacy variable. Analyses of all other secondary efficacy variables will be descriptive in manner only. Any p-values or confidence limits provided other than those for the primary efficacy analysis of the primary efficacy variable (as described in Section 8.1.2) and the analysis of the key secondary efficacy variable will be exploratory only.
REDACTED COPY
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted
REDACTED COPY
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted in order to assess the effect of dropouts, importan
REDACTED COPY
in order to assess the effect of dropouts, important protocol deviations, and operational bias on
REDACTED COPY
t protocol deviations, and operational bias on
Repeat the primary efficacy analysis using the PPS.
REDACTED COPY
Repeat the primary efficacy analysis using the PPS.
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported eventsREDACTED C
OPY
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events) through each suREDACTED C
OPY
) through each su
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Meier (KM) plot for time to event as well as the KM estimate for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Meier (KM) plot for time to event as well as the KM estimate for the nt and 95% CI will be provided. If the median time is not estimable, then the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nt and 95% CI will be provided. If the median time is not estimable, then the percentile and 95% CI will be provided. The number of events will be reported by treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
percentile and 95% CI will be provided. The number of events will be reported by treatment e % of subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e % of subjects
Secondary analyses of the primary efficacy variable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Secondary analyses of the primary efficacy variable
Treatment Period will be presented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period will be presented by subgroups will also be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subgroups will also be
Supportive and sensitivity analyses of the primary efficacy variable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Supportive and sensitivity analyses of the primary efficacy variable
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted t protocol deviations, and operational bias on
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
t protocol deviations, and operational bias on
Repeat the primary efficacy analysis using the PPS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis using the PPS.
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
) through each su
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
) through each subject’s first 166 days of treatment, on the FAS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
bject’s first 166 days of treatment, on the FAS.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy, consent withdrawn, or lost to follow
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
discontinue due to lack of efficacy, consent withdrawn, or lost to follow, events at the time of discontinuation).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, events at the time of discontinuation).
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis u
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis uafter each interim analysis to examine possible operational bias due to unblinding.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
after each interim analysis to examine possible operational bias due to unblinding.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue after their 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
discontinue after their 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Provided that the primary efficacy endpoint is statistically significant, a gatekeeping strategy will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Provided that the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to test the key secondary efficacy variable. An
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be used to test the key secondary efficacy variable. Anvariables will be descriptive in manner only. Any p
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
variables will be descriptive in manner only. Any p
![Page 32: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/32.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
8.2.1 Derivations of secondary efficacy variables
8.2.1.1 Variable: Seizure freedom for PGTCS for the 166-day Treatment Period
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the seizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not done” on the CRF will be counted as seizure-free days from PGTCS.
A subject will have seizure freedom from PGTCS for the 166-day Treatment Period if the subject completed the Treatment Period and reported zero PGTCS or “not done” for all days during the 166-day Treatment Period. Ongoing subjects who are seizure-free from PGTCS on the date of the 125th event do not have seizure-freedom from PGTCS unless they are seizure-free from PGTCS for 166 days.
8.2.1.2 Variable: Time to first PGTCS during the 166-day Treatment Period
For PGTCS, how the time to first PGTCS is calculated is described in Section 3.2.3. Censoring of subjects for this analysis will be as described in Section 3.2.4 .
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that seizure diary day.
8.2.2 Analysis of secondary efficacy variables
Analyses of secondary efficacy variables will be performed for the FAS.
8.2.2.1 Analysis: Seizure freedom for PGTCS for the 166-day Treatment Period
Analysis of the key secondary efficacy variable, seizure freedom for PGTCS for the 166-day Treatment Period, will be evaluated using an extended Mantel-Haenszel testing procedure which takes into account that the subjects were initially stratified for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section 4.9.
The hypothesis for the assessment of the key secondary efficacy (PGTC seizure-freedom) is as follows:
H0: S(t=166)LCM = S(t=166)PBO
Versus
H1: S(t=166)LCM ≠ S(t=166)PBO
Where S(t=166) is the cumulative rate of subjects remaining seizure-free from PGTCS for 166 days.
Estimation of treatment difference:
KM methods will be used to estimate the proportion of subjects remaining seizure-free from PGTCS at Day 166. The estimate for the difference in Day 166 seizure-freedom from PGTCS will be adjusted for subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The estimate for the stratified difference in proportion of
REDACTED COPY secondary efficacy variables
REDACTED COPY secondary efficacy variables
Analyses of secondary efficacy variables will be performed for the FAS.
REDACTED COPY
Analyses of secondary efficacy variables will be performed for the FAS.
Analysis: Seizure freedom for PGTCS for the
REDACTED COPY
Analysis: Seizure freedom for PGTCS for the
Analysis of the key secondary efficacy variable, seizurREDACTED C
OPY
Analysis of the key secondary efficacy variable, seizurTreatment Period, will be evaluated using an extended MantelREDACTED C
OPY
Treatment Period, will be evaluated using an extended Mantel
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or “not done” for all days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or “not done” for all days from PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from PGTCS on the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
on the unless they are seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
unless they are seizure-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-free
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free
Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period
how the time to first PGTCS is calculated is described in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
how the time to first PGTCS is calculated is described in Section 3.2.3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3.2.3
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that
secondary efficacy variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
secondary efficacy variables
Analyses of secondary efficacy variables will be performed for the FAS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analyses of secondary efficacy variables will be performed for the FAS.
Analysis: Seizure freedom for PGTCS for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis: Seizure freedom for PGTCS for the
Analysis of the key secondary efficacy variable, seizur
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis of the key secondary efficacy variable, seizurTreatment Period, will be evaluated using an extended Mantel
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period, will be evaluated using an extended Manteltakes into account that the subjects were initially stratified for the subjects’ Baseline PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
takes into account that the subjects were initially stratified for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined B
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency (≤2 per 28 days vs >2 per 28 days in the Combined Binformed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
analysis will use the stratification factors from IRT and pooled as described in Section
The hypothesis for the assessment of the key secondary efficacy (PGTC seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The hypothesis for the assessment of the key secondary efficacy (PGTC seizure
Where
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Where S
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
S(
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(S(S
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
S(S t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
t=166) is the cumulative rate of subjects remaining seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
=166) is the cumulative rate of subjects remaining seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days.
Estimation of treatment difference
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Estimation of treatment difference
KM methods will be used to estimate the proportion of subjects remaining seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
KM methods will be used to estimate the proportion of subjects remaining seizure
![Page 33: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/33.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
subjects who are seizure-free from PGTCS on LCM vs PBO and a corresponding 95% two-sided confidence interval (CILCM-PBO) will be produced using mantel Haenszel methods (LaVange et al, 2005). The statistical methodology is expressed as follows:
d=∑ wh(Sh1-Sh2)6h=1
Where Shi=KM estimate of 166-day seizure freedom from PGTCS for treatment i (1=LCM and 2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, 2= ≤2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, 5= >2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age and 6= >2 per 28 days Baseline PGTCS frequency and ≥18 years of age and wh={(nh1*nh2)/(nh1+nh2)}/∑ {(nh1*nh2)
6h=1 /(nh1+nh2)}}
where nhi is the number of subjects in I treatment group and stratum h. The variance of d is calculated as Var(d)=∑ wh
26h=1 {Var(Sh1)+Var(Sh2)} where Var(Sh1) and Var(Sh2) are the
Greenwood estimates of variance for Sh1 and Sh2.
The stratified proportion of subjects remaining seizure free from PGTCS for at least 166 days in each treatment group and the associated variance are derived as follows using Mantel Haneszel methods:
The KM estimate for the LCM 166-day seizure-freedom from PGTCS rate is calculated as 𝑆1=∑ 𝑤ℎ
6ℎ=1 𝑆ℎ1
The KM estimate for the PBO 166-day seizure-freedom from PGTCS rate is calculated as 𝑆2=∑ 𝑤ℎ
6ℎ=1 𝑆ℎ2
The variance is S1 is calculated as Var (𝑆1) =∑ 𝑤ℎ66
ℎ=1 𝑉𝑎𝑟(𝑆ℎ1)
The variance of S2 is calculated as Var (𝑆2) =∑ 𝑤ℎ66
ℎ=1 𝑉𝑎𝑟(𝑆ℎ2)
In order to assess superiority, 2-sided testing with α=0.05 will be used. The superiority test statistic, Q=d2/Var(d) will be assessed by a chi-square distribution with 1 degree of freedom. This statistic is referred to as the “row mean score statistic” when using Proc Freq.
The number and percentage of subjects who experience a PGTCS or censoring and the KM seizure-free rate from PGTCS (and 2-sided 95% CI) by Day 166 will be presented by treatment group for each stratum and overall. The stratified seizure-freedom rate from PGTCS (and 2-sided 95% CI) at Day 166 for each treatment group and the difference between treatment groups will be presented. A Kaplan-Meier plot will be presented by treatment group for each stratum and overall.
For the gatekeeping strategy, if the primary endpoint is statistically significant at the 5% level, then the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint will be exploratory only.
8.2.2.2 Analysis: Time to first PGTCS during the 166-day Treatment Period
Time to the first PGTCS during the 24-week Treatment Period will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined
REDACTED COPY freedom
REDACTED COPY freedom from PGTCS
REDACTED COPY from PGTCS
day seizure
REDACTED COPY
day seizure-
REDACTED COPY
-freedom
REDACTED COPY
freedom
VarREDACTED C
OPY
Var (REDACTED C
OPY
(𝑆REDACTED C
OPY
𝑆1REDACTED C
OPY
1)
REDACTED COPY
)
VarREDACTED C
OPY
Var
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency cy and ≥12 to <18 years
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
cy and ≥12 to <18 years
is the number of subjects in I treatment group and stratum h. The variance of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is the number of subjects in I treatment group and stratum h. The variance of Var(S
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Var(Sh2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
h2Var(Sh2Var(S
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Var(Sh2Var(S )
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
)
from PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from PGTCS for at least 166 days in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for at least 166 days in each treatment group and the associated variance are derived as follows using Mantel Haneszel
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
each treatment group and the associated variance are derived as follows using Mantel Haneszel
from PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from PGTCS
freedom
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
freedom from PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from PGTCS
=
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
=∑
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
∑6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6ℎ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ℎ
(
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(𝑆
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
𝑆2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
) =
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
=
sided testi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
sided testiwill be assessed by a chi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be assessed by a chiThis statistic is referred to as the “row mean score statistic” when using Proc Freq.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This statistic is referred to as the “row mean score statistic” when using Proc Freq.
The number and percentage
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects who experience a PGTCS or censoring and the KM
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of subjects who experience a PGTCS or censoring and the KM from PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from PGTCSgroup for each stratum and overall. The stratified seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
group for each stratum and overall. The stratified seizureat Day 166 for each treatment group and the difference between treatment groups will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
at Day 166 for each treatment group and the difference between treatment groups will be presented. A Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be presented. A Kaplan
For the gatekeeping strategy, i
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the gatekeeping strategy, ithen the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
then the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint will be exploratory only.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be exploratory only.
![Page 34: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/34.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section 4.9.
The hypothesis for the assessment of the time to first PGTCS is as follows:
H0: β=0
Versus
H1: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented by
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
)
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For the null hypothesis, the testing will be 2-sided with an α=0.05. The assumptions of proportional hazards will also be checked using the same approach as for the primary efficacy endpoint.
The stratified HR will be calculated using the placebo arm as the reference group. The 95% CI for the HR will also be reported.
Additionally, a KM plot for time to 1st PGTCS as well as the KM estimate for the median time to 1st PGTCS and 95% CI will be provided. If the median time is not estimable, then the 25th percentile and 95% CI will be provided. The number of 1st PGTCS will be reported by treatment group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects who were censored.
8.3 Analysis of seizure related other efficacy variables
All seizure data recorded during the treatment period will be summarized and listed for the seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will be performed for the FAS. For absence seizure analyses, this analysis population will be further restricted to the subset of subjects who reported a history of absence seizures or reported absence seizures during baseline or the 24-week treatment period. For myoclonic seizure analyses, this analysis population will be further restricted to the subset of subjects who reported a history of myoclonic seizures or reported myoclonic seizures during baseline or the 24-week treatment period.
8.3.1 Derivations of seizure related other efficacy variables
8.3.1.1 Variable: PGTCS frequency per 28 days
In order to account for potential differences in the durations of the study periods for individuals, PGTCS data will be normalized to 28 days.
The 28-day PGTCS frequency (SF) will be calculated for the Combined Baseline and Treatment Periods as:
SF =
(# PGTCS in the relative period/# days in relative period with evaluable PGTCS data)*28
REDACTED COPY
as well as the KM estimate for the median time to
REDACTED COPY
as well as the KM estimate for the median time to ovided. If the median time is not estimable, then the 25
REDACTED COPY
ovided. If the median time is not estimable, then the 25e provided. The number of 1
REDACTED COPY
e provided. The number of 112 Weeks
REDACTED COPY
12 Weeks, and
REDACTED COPY
, and
Analysis of seizure related other efficacy variablesREDACTED C
OPY
Analysis of seizure related other efficacy variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where β is the coefficient of an independent variable representing the treatment effect in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where β is the coefficient of an independent variable representing the treatment effect in the
) is the baseline hazard at time
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
) is the baseline hazard at time =0.05. The assumptions of proportional
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
=0.05. The assumptions of proportional using the same approach as for the primary efficacy endpoint
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
using the same approach as for the primary efficacy endpoint
The stratified HR will be calculated using the placebo arm as the reference group. The 95% CI
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified HR will be calculated using the placebo arm as the reference group. The 95% CI
as well as the KM estimate for the median time to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as well as the KM estimate for the median time to ovided. If the median time is not estimable, then the 25
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ovided. If the median time is not estimable, then the 25e provided. The number of 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e provided. The number of 1, and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, and Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period
Analysis of seizure related other efficacy variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis of seizure related other efficacy variables
All seizure data recorded during the treatment period will be summarized and listed for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All seizure data recorded during the treatment period will be summarized and listed for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure related other efficacy variables. Analyses of seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure related other efficacy variables. Analyses of seizureFor absence seizure analyses, this analysis population will be further
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For absence seizure analyses, this analysis population will be further restricted to the subset of subjects who reported a history of absence seizures or reported absence
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
restricted to the subset of subjects who reported a history of absence seizures or reported absence seizures during baseline or the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures during baseline or the 24analysis population will be further restricted to the subset of subjects who reported a history of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
analysis population will be further restricted to the subset of subjects who reported a history of myoclonic seizures or reported myoclonic seizures during baseline or the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
myoclonic seizures or reported myoclonic seizures during baseline or the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Derivations of sei
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Derivations of sei
8.3.1.1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.3.1.1
In order to account for potential differences in the durations of the study periods for individuals,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
In order to account for potential differences in the durations of the study periods for individuals, PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS
The 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The 28
![Page 35: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/35.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The percent change (PCH) in PGTCS frequency per 28 days from the Combined Baseline (CB) to the appropriate analysis period (T) is defined as:
PCH = [(SFT – SFCB) / SFCB] x 100
where SFT corresponds to the 28-day PGTCS frequency during the relative period and SFCB corresponds to the 28-day Combined Baseline PGTCS frequency. PCH is calculated for 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
8.3.1.2 Variable: Days with seizures per 28 days
The number of days with absence seizures per 28 days will be calculated separately for the Prospective Baseline and the Treatment Period as:
D = ([# days with absence seizures in the relative period] / [# days in relative period with evaluable seizure data]) * 28.
Similarly, the number of days with myoclonic seizures per 28 days will be calculated.
The percent change (PCH) in days with absence seizures per 28 days from the Prospective Baseline (B) to the appropriate analysis period (T) is defined as:
PCH = [(DT – DB) / DB] x 100
where DT corresponds to the number of days with absence seizures per 28 days during the relative period and DB corresponds to the number of days with absence seizures per 28 days during the Prospective Baseline Period. If DB is zero, then PCH will be missing and any such subjects will be excluded from the percent change summary. PCH will be calculated for the 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from the Prospective Baseline Period will be calculated.
8.3.1.3 Variable: Seizure-free status
A subject will have seizure-free status for PGTCS=yes for the Treatment Period if the subject completed the Treatment Period (with a minimum 166 days) and reported zero PGTCS or “not done” for all days during the Treatment Period. If the subject is exited from the study due to the 125th event occurring reporting zero PGTCS or “not done” for all days and duration of the Treatment Period is < 166 days, then the subject has not achieved seizure-free status for PGTCS.
A subject will have seizure free status=yes for all generalized seizure types for the applicable Treatment Period if the subject completed the Treatment Period and reported zero generalized seizures for all days during the Treatment Period when the number of generalized seizures was available, and had <10% of days during the Treatment Period with seizure data reported as “not done”.
Seizure-free statuses will be calculated for 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
8.3.1.4 Variable: Responder status – reduction in PGTCS frequency
Response to treatment will be based on the percent change in PGTCS frequency, calculated as described in Section 8.3.1.1 . A 50% responder is defined as a subject experiencing ≥50%
REDACTED COPY
where DT corresponds to the number of days with absence seizures per 28
REDACTED COPY
where DT corresponds to the number of days with absence seizures per 28 relative period and DB corresponds to the number of days with absence seizures per 28 days
REDACTED COPY
relative period and DB corresponds to the number of days with absence seizures per 28 days Baseline Period. If DB is zero, then PCH will be missing and any such
REDACTED COPY
Baseline Period. If DB is zero, then PCH will be missing and any such subjects will be excluded from the percent change summar
REDACTED COPY
subjects will be excluded from the percent change summarweek Titration Period, first 12 weeks of the Treatment Period and the 24
REDACTED COPY
week Titration Period, first 12 weeks of the Treatment Period and the 24
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from REDACTED COPY
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number of days with absence seizures per 28 days will be calculated separately for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number of days with absence seizures per 28 days will be calculated separately for the
D = ([# days with absence seizures in the relative period] / [# days in relative period with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
D = ([# days with absence seizures in the relative period] / [# days in relative period with
Similarly, the number of days with myoclonic seizures per 28 days will be calculated.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, the number of days with myoclonic seizures per 28 days will be calculated.
The percent change (PCH) in days with absence seizures per 28 days from the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change (PCH) in days with absence seizures per 28 days from the Baseline (B) to the appropriate analysis period (T) is defined as:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline (B) to the appropriate analysis period (T) is defined as:
where DT corresponds to the number of days with absence seizures per 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where DT corresponds to the number of days with absence seizures per 28 relative period and DB corresponds to the number of days with absence seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
relative period and DB corresponds to the number of days with absence seizures per 28 days Baseline Period. If DB is zero, then PCH will be missing and any such
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period. If DB is zero, then PCH will be missing and any such subjects will be excluded from the percent change summar
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects will be excluded from the percent change summarweek Titration Period, first 12 weeks of the Treatment Period and the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of the Treatment Period and the 24
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from will be calculated.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be calculated.
Variable: Seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Variable: Seizure-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-free status
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status
free status
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free statuscompleted the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
completed the Treatment Perioddone” for all days during the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
done” for all days during the Treatment Period.event occurring
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event occurring reporting zero PGTCS or “not done” for all days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reporting zero PGTCS or “not done” for all daysTreatment Period is < 166 days, th
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period is < 166 days, th
A subject will have seizure free status=yes for all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A subject will have seizure free status=yes for all Treatment Period if the subject completed the Treatment Period and reported zero
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period if the subject completed the Treatment Period and reported zero izures for all days during the Treatment Period when the number of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
izures for all days during the Treatment Period when the number of available, and had <10% of days during the Treatment Period with seizure data reported as “not
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
available, and had <10% of days during the Treatment Period with seizure data reported as “not done”.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
done”.
Seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SeizureTreatment Period and the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period and the 24
![Page 36: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/36.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
reduction in PGTCS frequency per 28 days from the Combined Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in PGTCS frequency per 28 days from Combined Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
8.3.1.5 Variable: PGTCS frequency - worsening
Seizure worsening is defined as a subject experiencing ≥50% increase in PGTCS frequency per 28 days from Combined Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
8.3.1.6 Variable: Responder status – reduction in days with absence seizures
Response to treatment for absence seizures per 28 days will be based on the percent change in days with absence seizures, calculated as described in Section 8.3.1.2. A 50% responder is defined as a subject experiencing ≥50% reduction in days with absence seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in days with absence seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
8.3.1.7 Variable: Responder status – reduction in days with myoclonic seizures
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in days with myoclonic seizures, calculated as described in Section 8.3.1.2. A 50% responder is defined as a subject experiencing ≥50% reduction in days with myoclonic seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
8.3.1.8 Variable: Days with absence and myoclonic seizures – worsening
Safety of the LCM treatment will be based on the percent change in days with absence seizure per 28 days and days with myoclonic seizure per 28 days. The increase in days with absence seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period. The increase in days with myoclonic seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period.
8.3.1.9 Variable: Absence and myoclonic seizure frequencies per 28 days
In order to account for potential differences in the durations of the study periods for individuals, absence and myoclonic seizure data will be normalized to 28 days.
The 28-day absence SF will be calculated for the Prospective Baseline and Treatment Periods as:
SF =
REDACTED COPY on Period, first 12 weeks of the Treatment
REDACTED COPY on Period, first 12 weeks of the Treatment
–
REDACTED COPY
– reduction in days with myoclonic
REDACTED COPY
reduction in days with myoclonic
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in
REDACTED COPY
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in with myoclonic seizures, calculated as described in
REDACTED COPY
with myoclonic seizures, calculated as described indefined as a subject experiencing ≥50% reduction in days withREDACTED C
OPY
defined as a subject experiencing ≥50% reduction in days with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure worsening is defined as a subject experiencing ≥50% increase in PGTCS frequency per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure worsening is defined as a subject experiencing ≥50% increase in PGTCS frequency per
reduction in days with absence
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in days with absence
s will be based on the percent change in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
s will be based on the percent change in . A 50% responder is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. A 50% responder is defined as a subject experiencing ≥50% reduction in days with absence seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
defined as a subject experiencing ≥50% reduction in days with absence seizures per 28 days week Titration Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Periodweek Treatment Period). A 75% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in days with absence seizures per 28 days from the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experiencing ≥75% reduction in days with absence seizures per 28 days from the Prospective on Period, first 12 weeks of the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
on Period, first 12 weeks of the Treatment
reduction in days with myoclonic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in days with myoclonic
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in with myoclonic seizures, calculated as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with myoclonic seizures, calculated as described indefined as a subject experiencing ≥50% reduction in days with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
defined as a subject experiencing ≥50% reduction in days withfrom the Prospective Baseline to the period of interest (6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from the Prospective Baseline to the period of interest (6week Treatment Period). A 75% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period). A 75% responder is defined as a subject n days with myoclonic seizures per 28 days from the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
n days with myoclonic seizures per 28 days from the Prospective Baseline to the period of interest (6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline to the period of interest (6week Treatment Period).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period).
Variable: Days with absence and myoclonic seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Variable: Days with absence and myoclonic seizures
Safety of the LCM treatment will be based on the percent change in days with absence seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Safety of the LCM treatment will be based on the percent change in days with absence seizure per 28 days and days with myoclonic seizure per 28 days. The increase in days with absence
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days and days with myoclonic seizure per 28 days. The increase in days with absence
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days from Prospective Baseline will be categorized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days from Prospective Baseline will be categorized >50 to 75%, and >75% for the Treatment Period. The increase in days with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>50 to 75%, and >75% for the Treatment Period. The increase in days withper 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
75%, and >75% for the Treatment Period.
8.3.1.9
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.3.1.9
In order to account for potential differences in the durations of the study periods for individuals,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
In order to account for potential differences in the durations of the study periods for individuals,
![Page 37: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/37.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
(# absence seizures in the relative period/# days in relative period with evaluable absence seizure data)*28
The PCH in Absence seizure frequency per 28 days from the Prospective Baseline (PB) to the appropriate analysis period (T) is defined as:
PCH = [(SFT – SFPB) / SFPB] x 100
where SFT corresponds to the 28-day absence seizure frequency during the relative period and SFPB corresponds to the 28-day Prospective Baseline absence frequency; if subjects had no absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calculated for 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
SF and PCH are calculated for subjects with myoclonic seizures using the same algorithm described above.
8.3.1.10 Variable: Responder status – reduction in absence and myoclonic seizure frequencies
Response to treatment will be based on the percent change in absence and myoclonic seizure frequencies, calculated as described in Section 8.3.1.9. A 50% responder is defined as a subject experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
8.3.1.11 Variable: Absence and myoclonic seizure frequency - worsening
Safety of the LCM treatment will be based on the percent change in absence seizure frequency per 28 days and myoclonic seizure frequency per 28 days. The increase in absence seizure frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period. The increase in myoclonic seizure frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period.
8.3.2 Analysis of seizure related other efficacy variables
8.3.2.1 Analysis: Percent change in PGTCS frequency per 28 days from Combined Baseline
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.
All PGTCS frequency per 28 days data will be listed.
8.3.2.2 Analysis: Reduction in days with seizures per 28 days
The following data will be summarized with descriptive statistics only:
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
REDACTED COPY n absence (or myoclonic) seizure
REDACTED COPY n absence (or myoclonic) seizure
week Titr
REDACTED COPY
week Titrweek Treatment Period). A 75% responder is defined as a subject
REDACTED COPY
week Treatment Period). A 75% responder is defined as a subject riencing ≥75% reduction in absence (or myoclonic) seizure
REDACTED COPY
riencing ≥75% reduction in absence (or myoclonic) seizureterest (6
REDACTED COPY
terest (6-
REDACTED COPY
-week Titration Period, first 12 weeks of the
REDACTED COPY
week Titration Period, first 12 weeks of the week Treatment Period).
REDACTED COPY
week Treatment Period).
Variable: Absence and myoclonic seizure REDACTED COPY
Variable: Absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calculated for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calculated for week Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment
ith myoclonic seizures using the same algorithm
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ith myoclonic seizures using the same algorithm
reduction in absence and myoclonic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in absence and myoclonic
d on the percent change in absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
d on the percent change in absence and myoclonic seizure . A 50% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. A 50% responder is defined as a subject n absence (or myoclonic) seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
n absence (or myoclonic) seizure frequen
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequenation Period, first 12 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ation Period, first 12 weeks of the week Treatment Period). A 75% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period). A 75% responder is defined as a subject riencing ≥75% reduction in absence (or myoclonic) seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
riencing ≥75% reduction in absence (or myoclonic) seizureweek Titration Period, first 12 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of the week Treatment Period).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period).
Variable: Absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Variable: Absence and myoclonic seizure
LCM treatment will be based on the percent change in absence
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
LCM treatment will be based on the percent change in absence frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency er 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
er 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period. The increase in myocl
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>50 to 75%, and >75% for the Treatment Period. The increase in myocl28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
75%, and >75% for the Treatment
Analysis of seizure related other efficacy variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis of seizure related other efficacy variables
Analysis: Percent change in PGTCS frequency per 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis: Percent change in PGTCS frequency per 2Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Combined Baseline
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks of (entire
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(entire
All PGTCS frequency per 28 days data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All PGTCS frequency per 28 days data
8.3.2.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.3.2.2
![Page 38: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/38.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percent change in days with absence seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the first 12 weeks of the Treatment Period relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the first 12 weeks of the Treatment Period relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
All seizure days data for absence and myoclonic seizures will be listed.
8.3.2.3 Analysis: Seizure-free status
The following seizure-free status (yes/no) summaries will be provided:
Seizure-free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period (Titration Period)
Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the first 6 weeks of the Treatment Period (Titration Period)
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment Period
8.3.2.4 Analysis: Responder status – reduction in PGTCS frequency
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 6 weeks (Titration Period) compared to the Combined Baseline
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to the Combined Baseline
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Treatment Period compared to the Combined Baseline
REDACTED COPY
free status (yes/no) summaries will be provided:
REDACTED COPY
free status (yes/no) summaries will be provided:
free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period
REDACTED COPY
free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period
s, no) for PGTCS for the first 12 weeks of the Treatment Period REDACTED C
OPY
s, no) for PGTCS for the first 12 weeks of the Treatment Period
free status (yes, no) for PGTCS for the 24REDACTED COPY
free status (yes, no) for PGTCS for the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ive to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ive to
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the
uring the first 12 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
uring the first 12 weeks of the
Percent change in days with myoclonic seizures per 28 days during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 days during the Treatment Period
c seizures will be listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
c seizures will be listed.
free status (yes/no) summaries will be provided:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes/no) summaries will be provided:
free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period
s, no) for PGTCS for the first 12 weeks of the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
s, no) for PGTCS for the first 12 weeks of the Treatment Period
free status (yes, no) for PGTCS for the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for PGTCS for the 24
free status (yes, no) for all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for all generalized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
generalized (Titration Period)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(Titration Period)
free status (yes, no) for all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for all
free status (yes, no) for all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for all
Analysis: Responder st
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis: Responder st
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following data will be summarized with descriptive statistics only:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 6 weeks (Titration Period) compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6 weeks (Titration Period) compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 39: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/39.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 6 weeks (Titration Period) compared to the Combined Baseline
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to the Combined Baseline
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the Treatment Period compared to the Combined Baseline
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for PGTCS frequency during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
8.3.2.5 Analysis: Responder status – reduction in days with absence seizures
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in absence seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the Treatment Period compared to the Prospective Baseline
A histogram of ≥50% and ≥75% responder status for reduction in days with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
8.3.2.6 Analysis: Responder status – reduction in days with myoclonic seizures
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the Treatment Period compared to the Prospective Baseline
REDACTED COPY 12 weeks of the Treatment Period compared to the Prospective Baseline
REDACTED COPY 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days during the
REDACTED COPY
Percentage of subjects with at least a 50% reduction in absence seizure days during the Period compared to the Prospective Baseline
REDACTED COPY
Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6
REDACTED COPY
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6 (Titration Period)
REDACTED COPY
(Titration Period)
at least a 75% reduction in absence seizure days during the first REDACTED C
OPY
at least a 75% reduction in absence seizure days during the first 12 weeks of the Treatment Period compared to the Prospective BaselineREDACTED C
OPY
12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment
reduction in days with absence
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in days with absence
Percentage of subjects with at least a 50% reduction in absence seizure days during the first 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure days during the first 6 compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
compared to the Prospective Baseline
ntage of subjects with at least a 50% reduction in absence seizure days during the first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ntage of subjects with at least a 50% reduction in absence seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure days during the Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6 (Titration Period)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
compared to the Prospective Baseline
at least a 75% reduction in absence seizure days during the first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
at least a 75% reduction in absence seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in absence seizure days during the Treatment Period compared to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline
and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and ≥75% responder status for reduction in days with absence seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥75% responder status for reduction in days with absence seizures during the first 6 weeks
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the first 6 weeks (Titration Period)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(Titration Period)by treatment group will be provided.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
by treatment group will be provided.
Analysis: Res
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis: Resseizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures
The following data will be summarized with descriptive statistics only:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Perio
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first 6 weeks of the Treatment Perio
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the
![Page 40: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/40.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the Treatment Period compared to the Prospective Baseline
A histogram of ≥50% and ≥75% responder status for reduction in days with myoclonic seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
8.3.2.7 Analysis: Percent change in absence and myoclonic seizure frequency per 28 days from Prospective Baseline
Descriptive statistics will be provided on the percent change in absence and myoclonic seizure frequencies for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.
All absence and myoclonic seizure frequency per 28 days data will be listed.
8.3.2.8 Analysis: Responder status – reduction in absence and myoclonic seizure frequency
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
REDACTED COPY
The following data will be summarized with descriptive statistics only:
REDACTED COPY
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in absence seizure frequency during
REDACTED COPY
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospec
REDACTED COPY
the first 6 weeks (Titration Period) compared to the Prospec
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency REDACTED C
OPY
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective BaselineREDACTED C
OPY
during the first 6 weeks (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
absence and myoclonic seizure
absence and myoc
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lonic seizure for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire
frequency per 28 days data will be listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency per 28 days data will be listed.
reduction in absen
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in absen
The following data will be summarized with descriptive statistics only:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospec
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 6 weeks (Titration Period) compared to the Prospec
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure frequ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure frequthe first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Ba
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the first 12 weeks of the Treatment Period compared to the Prospective Ba
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the Treatme
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the Treatme
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduc
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reducthe first 6 weeks (Titration
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 6 weeks (Titration
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 41: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/41.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure frequency during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency during the Treatment Period compared to the Prospective Baseline
8.4 Analysis of health outcome other efficacy variables
8.4.1 Derivations of health outcome other efficacy variables
8.4.1.1 QOLIE-31-P variables
The Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Version 2 will be used to evaluate the health-related quality of life (HRQoL) of study subjects ≥18 years of age.
The QOLIE‑31‑P total score, subscale scores, and health status item score are calculated according to the scoring algorithm defined in Section 12.1 which accounts for the possibility of missing values. Scores range from 0 to 100 and higher scores indicating better functioning. QOLIE- 31-P data that are completely missing will not be replaced.
Subscale scores
As a first step to calculating the subscale scores, the individual responses for the 30 subscale items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the rescaled values for each item are defined in Section 12.1. Each subscale score is then calculated by summing the rescaled responses for that subscale and dividing by the number of items with a non-missing response. A subscale score will be calculated only if at least 50% of the items within the subscale are present.
Total score
Total score is calculated as a weighted sum of the subscale scores based on the weighting in Section 12.1. Total score will be missing if at least 1 subscale score is missing. Total score will range from 0 to 100 with a higher score reflecting better functioning.
Health status item
The response for the health status item is a multiple of 10 ranging from 0 to 100 with a higher score corresponding to a better health status. The health status item response is analyzed without rescaling.
Distress items
Each subscale includes 1 distress item. The response for each distress item is an integer ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale (ie, 0, 25, 50, 75, and 100) with a higher score corresponding to greater distress.
Prioritization item
The response for each subscale for the prioritization item is an integer ranging from 1 to 7. The prioritization ranking is analyzed without rescaling.
REDACTED COPY P data that are completely missing will not be replaced.
REDACTED COPY P data that are completely missing will not be replaced.
As a first step to calculating the subscale scores, the individual responses for the 30 subscale
REDACTED COPY
As a first step to calculating the subscale scores, the individual responses for the 30 subscale items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the rescaled
REDACTED COPY
items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the rescaled values for each item are defined in Section 12.
REDACTED COPY
values for each item are defined in Section 12.
REDACTED COPY
1. Each subscale score is then calculated by
REDACTED COPY
1. Each subscale score is then calculated by summing the rescaled responses for that subscale and dividing by the number of items with a
REDACTED COPY
summing the rescaled responses for that subscale and dividing by the number of items with a missing response. A subscale score will be calculated only if at least 50% of the items REDACTED C
OPY
missing response. A subscale score will be calculated only if at least 50% of the items
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
31
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
31-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-P) Version 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P) Version 2 of life (HRQoL) of study subjects ≥18 years of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of life (HRQoL) of study subjects ≥18 years of
P total score, subscale scores, and health status item score are calculated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P total score, subscale scores, and health status item score are calculated which accounts for the possibility of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
which accounts for the possibility of missing values. Scores range from 0 to 100 and higher scores indicating better functioning.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
missing values. Scores range from 0 to 100 and higher scores indicating better functioning. P data that are completely missing will not be replaced.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P data that are completely missing will not be replaced.
As a first step to calculating the subscale scores, the individual responses for the 30 subscale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
As a first step to calculating the subscale scores, the individual responses for the 30 subscale items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the rescaled
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the rescaled
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1. Each subscale score is then calculated by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1. Each subscale score is then calculated by summing the rescaled responses for that subscale and dividing by the number of items with a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
summing the rescaled responses for that subscale and dividing by the number of items with a missing response. A subscale score will be calculated only if at least 50% of the items
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
missing response. A subscale score will be calculated only if at least 50% of the items
Total score is calculated as a weighted sum of the subscale scores based on the weighting in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Total score is calculated as a weighted sum of the subscale scores based on the weighting in Section 12.1. Total score will be missing if at least 1 subscale score is missing. Total score will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 12.1. Total score will be missing if at least 1 subscale score is missing. Total score will range from 0 to 100 with a higher score refle
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
range from 0 to 100 with a higher score refle
Health status item
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Health status item
The response for the health status item is a multiple of 10 ranging from 0 to 100 with a higher
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The response for the health status item is a multiple of 10 ranging from 0 to 100 with a higher
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score corresponding to a better health status. The health status item response is analyzed without
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score corresponding to a better health status. The health status item response is analyzed without
ess items
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ess items
Each subscale includes 1 distress item. The response for each distress item is an integer ranging
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Each subscale includes 1 distress item. The response for each distress item is an integer ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale (ie, 0, 25,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale (ie, 0, 25, 50, 75, and 100) with a higher score correspondin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
50, 75, and 100) with a higher score correspondin
![Page 42: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/42.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
8.4.1.2 PedsQL variables
The PedsQL is a validated instrument that consists of generic core scales suitable for use with pediatric populations (<18 years), including those with acute or chronic health conditions.
PedsQL generic core scale scores will be calculated for each of the following 4 PedsQL scales: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. The PedsQL assessment is retrospective to the prior 4 weeks, and individual items are scored using a 5-point Likert scale (0 to 4 representing responses of: never, almost never, sometimes, often, or almost always). These scores of 0 to 4 will be transformed by the function: 100 – (response x 25) in order to generate scores of 0, 25, 50, 75, and 100, where a higher value represents a better HRQoL.
Each scale score is then calculated as the mean of the non-missing categorized items if 50% or more of the items are non-missing.
The above algorithm will also be used to calculate an overall total scale score (all scales) for each subject. To create the Total Scale Score, the mean is computed over the number of items answered on all the Scales
8.4.1.3 EQ-5D-3L quality of life variables
The 3-Level EuroQol-5 Dimensional Quality of Life Assessment (EQ-5D-3L) is a self-administered questionnaire designed to measure health status in subjects ≥12 years of age.
The EQ-5D-3L defines health in terms of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is divided into 3 levels:
No problem=1
Some or moderate problems=2
Extreme problems=3
The EQ-5D-3L also captures a self-rating of health status on a 20cm vertical visual analog scale, anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at the bottom.
At each time point, an EQ-5D-3L utility value will be mapped to each subject’s health state. Health state is derived from the subject’s numerical ratings of the 5 EQ-5D-3L Dimensions. The order of the ratings is Mobility, Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression. Health state is derived by concatenating the numerical ratings of the 5 dimensions. For example, a health state may be derived as 11111, indicating best possible health.
A utility value will then be mapped to the derived health states, using the UK EQ-5D-3L value set. This set is available to Global Statistical Programming in excel format.
The mapped utility values will make up the utility variable.
8.4.1.4 Hospital stays
An event logged on the Hospitalization/Emergency Room (ER) Visit form of the eCRF where “Emergency room” is marked as initial entry point will be defined as an ER visit. An ER visit with a subject transfer to an inpatient general ward will also be counted as a hospitalization.
REDACTED COPY 5 Dimensional Quality of Life Assessment (EQ
REDACTED COPY 5 Dimensional Quality of Life Assessment (EQ
administered questionnaire designed to measure health status in subjects ≥12 years
REDACTED COPY
administered questionnaire designed to measure health status in subjects ≥12 years
3L defines health in terms of 5 dimensions (mobility, self
REDACTED COPY
3L defines health in terms of 5 dimensions (mobility, selfpain/discomfort, and anxiety/depression). Each dimension is divided into 3 levels:
REDACTED COPY
pain/discomfort, and anxiety/depression). Each dimension is divided into 3 levels:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
imes, often, or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
imes, often, or (response x 25)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(response x 25) in order to generate scores of 0, 25, 50, 75, and 100, where a higher value represents a better
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in order to generate scores of 0, 25, 50, 75, and 100, where a higher value represents a better
missing categorized items if 50% or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
missing categorized items if 50% or
The above algorithm will also be used to calculate an overall total scale score (all scales) for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The above algorithm will also be used to calculate an overall total scale score (all scales) for uted over the number of items
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
uted over the number of items
5 Dimensional Quality of Life Assessment (EQ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5 Dimensional Quality of Life Assessment (EQadministered questionnaire designed to measure health status in subjects ≥12 years
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
administered questionnaire designed to measure health status in subjects ≥12 years
3L defines health in terms of 5 dimensions (mobility, self
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3L defines health in terms of 5 dimensions (mobility, selfpain/discomfort, and anxiety/depression). Each dimension is divided into 3 levels:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
pain/discomfort, and anxiety/depression). Each dimension is divided into 3 levels:
3L also captures a self
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3L also captures a self-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-3L also captures a self-3L also captures a self
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3L also captures a self-3L also captures a self rating of health status on a 20cm vertical visual analog scale,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
rating of health status on a 20cm vertical visual analog scale,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at
At each time point, an EQ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
At each time point, an EQ-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-5D
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5DHealth state is derived from the subject’s numerical ratings of the 5 EQ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Health state is derived from the subject’s numerical ratings of the 5 EQorder of the ratings is Mobility, Self
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
order of the ratings is Mobility, Self
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Anxiety/Depression. Health state is derived
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Anxiety/Depression. Health state is deriveddimensions. For example, a health state may be derived as 11111, indicating best possible health.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dimensions. For example, a health state may be derived as 11111, indicating best possible health.
A utility value will then be mapped to the derived health states, using the UK EQ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A utility value will then be mapped to the derived health states, using the UK EQset. This set i
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
set. This set i
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The mapped utility values will make up the utility variable.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The mapped utility values will make up the utility variable.
8.4.1.4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.4.1.4
![Page 43: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/43.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
However, all other instances of ER visits (where subject transfer is not to an inpatient general ward) will not be counted as hospitalizations.
For hospital stays with a discharge date, the duration of each hospital stay will be calculated as the discharge date minus the admission date (Hospitalization/ER Visit Date on the eCRF) plus 1 day. For hospitalizations with either a partial admission or discharge date, the duration of hospital stay will be set to missing. The non-missing durations of hospital stays will be summed within each of the study periods (Baseline, Titration, and Maintenance, respectively). Should distinct records for hospital stays overlap, then the days during the overlap will only be counted once. Subjects with no hospital stays within a study period will have duration of 0 days for that period. For subjects with hospital stays but no calculable hospital duration, the duration of hospitalization in the respective study period will be missing.
8.4.2 Analysis of health outcome other efficacy variables
8.4.2.1 QOLIE-31-P variables
QOLIE-31-P data, for a specific visit may have a status of Abandoned if the subject doesn’t complete the questionnaire. If the subject has duplicate QOLIE-31-P data for the same visit, where one record is deemed as Abandoned and one record is deemed as Completed, the Completed data will be used in the analysis and not the Abandoned record. All recorded QOLIE-31-P data will be listed.
The observed values and change from Baseline will be summarized descriptively for the total score, the subscale scores, health score and the distress items for each visit and Last Visit. The mean observed values for the prioritization items will laso be summarized for each visit and Last Visit. They will all be summarized for both Visit 10 and Visit 10/ET. The scores for individual subscales will only be analyzed when a total score can be calculated (ie, all subscales have a non-missing score). Individual questions will not be summarized. Individual questions, subscale scores, and total scores will be presented in subject data listings. The means of the QOLIE-31-P total score, subscale scores and health status item score will be plotted by visit.
8.4.2.2 PedsQL variables
The observed values and change from Baseline for the total scale score and each of the 4 scale scores will be summarized for each visit and Last Visit by treatment group. They will be summarized for both Visit 10 and Visit 10/ET. Subgroup summaries by age will be performed using the age groupings for which different questionnaires were entered: 4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years.
All PedsQL data will be listed. The means of the PedsQL subscale scores and total score will be plotted by visit.
8.4.2.3 EQ-5D-3L quality of life variables
The observed values for each dimension and the mapped utility values will be summarized for each visit and Last Visit. They will be summarized for both Visit 10 and Visit 10/ET.
Observed values and the change from Baseline for the VAS score for general health state will also be summarized.
REDACTED COPY
The observed values and change from Baseline will be summarized
REDACTED COPY
The observed values and change from Baseline will be summarized score, the subscale scores, health score and the distress items for each visit and Last Visit. The
REDACTED COPY
score, the subscale scores, health score and the distress items for each visit and Last Visit. The mean observed values for the prioritization items will laso be summarized for each visit and Last
REDACTED COPY
mean observed values for the prioritization items will laso be summarized for each visit and Last zed for both Visit 10 and Visit 10/ET. The scores for individual
REDACTED COPY
zed for both Visit 10 and Visit 10/ET. The scores for individual subscales will only be analyzed when a total score can be calculated (ie, all subscales have a non
REDACTED COPY
subscales will only be analyzed when a total score can be calculated (ie, all subscales have a nonmissing score). Individual questions will not be summarized. Individual questions, subscaleREDACTED C
OPY
missing score). Individual questions will not be summarized. Individual questions, subscale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
distinct records for hospital stays overlap, then the days during the overlap will only be counted
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
distinct records for hospital stays overlap, then the days during the overlap will only be counted hospital stays within a study period will have duration of 0 days for that
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
hospital stays within a study period will have duration of 0 days for that period. For subjects with hospital stays but no calculable hospital duration, the duration of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
period. For subjects with hospital stays but no calculable hospital duration, the duration of
P data, for a specific visit may have a status of Abandoned if the subject doesn’t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P data, for a specific visit may have a status of Abandoned if the subject doesn’t P data for the same visit,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P data for the same visit, deemed as Abandoned and one record is deemed as Completed, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
deemed as Abandoned and one record is deemed as Completed, the Completed data will be used in the analysis and not the Abandoned record. All recorded QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completed data will be used in the analysis and not the Abandoned record. All recorded QOLIE
The observed values and change from Baseline will be summarized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The observed values and change from Baseline will be summarized score, the subscale scores, health score and the distress items for each visit and Last Visit. The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score, the subscale scores, health score and the distress items for each visit and Last Visit. The mean observed values for the prioritization items will laso be summarized for each visit and Last
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mean observed values for the prioritization items will laso be summarized for each visit and Last zed for both Visit 10 and Visit 10/ET. The scores for individual
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
zed for both Visit 10 and Visit 10/ET. The scores for individual subscales will only be analyzed when a total score can be calculated (ie, all subscales have a non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subscales will only be analyzed when a total score can be calculated (ie, all subscales have a nonmissing score). Individual questions will not be summarized. Individual questions, subscale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
missing score). Individual questions will not be summarized. Individual questions, subscalescores, and total scores will be presented in subject data listings. The means of the QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores, and total scores will be presented in subject data listings. The means of the QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
total score, subscale scores and health status item score will be plotted by visit.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
total score, subscale scores and health status item score will be plotted by visit.
PedsQL variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PedsQL variables
The observed values and change from Baseline for the tota
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The observed values and change from Baseline for the totascores will be summarized for each visit and Last Visit by treatment group. They will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores will be summarized for each visit and Last Visit by treatment group. They will be summarized for both Visit 10 and Visit 10/ET. Subgroup summaries by age will be performed
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
summarized for both Visit 10 and Visit 10/ET. Subgroup summaries by age will be performed using the age groupings for which diff
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
using the age groupings for which diff
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥8 to ≤12 years, and ≥13 to ≤18 years.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥8 to ≤12 years, and ≥13 to ≤18 years.
All PedsQL data will be listed. The means of the PedsQL subscale scores and total score will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All PedsQL data will be listed. The means of the PedsQL subscale scores and total score will be plotted by visit.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
plotted by visit.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.4.2.3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.4.2.3
The obse
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The obseeach visit and Last Visit. They will be summarized for both Visit 10 and Visit 10/ET.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
each visit and Last Visit. They will be summarized for both Visit 10 and Visit 10/ET.
![Page 44: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/44.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
All EQ-5D-3L data will be presented in subject data listings. The mean of the EQ-5D-3L VAS will be plotted by visit. For the EQ-5D-3L, the percentage of subjects reporting a level within each dimension will be plotted in a histogram.
8.4.2.4 Concomitant medical procedures
Subjects who had any concomitant medical procedures during the course of the study based on the Concomitant Medical Procedures eCRF will be listed. Additionally, subjects who had any procedures or surgeries prior to study entry based on the Procedure History eCRF will also be listed.
8.4.2.5 Healthcare provider consultations
All healthcare provider consultations data will be listed.
8.4.2.6 Hospital stays
All hospitalization/ER data will be listed.
8.4.2.7 Number of working or school days lost due to epilepsy
All working or school days lost data will be listed.
8.4.2.8 Number of days with help from a paid caregiver due to epilepsy
All data regarding help from a paid caregiver will be listed.
8.4.2.9 Socio-professional data
The number and percentage of subjects by each response level for highest level of education, housing status, current professional status, regular assistance in usual activities, and driving status will be summarized for each visit and Last Visit for the FAS. Percentages will be relative to the number of subjects with a response to each item. No statistical comparisons will be carried out for socio-professional data.
All socio-professional data will be listed.
9 PHARMACOKINETICS
LCM plasma concentration will be summarized using the SS. Descriptive statistics of LCM plasma concentrations will be presented by visit and actual dose. The actual dose is defined as the most recent dose administrated prior to PK sampling.
The following parameters will be calculated for each of the sampling points: n, nLOQ (number of measurements above or equal to the lower limit of quantification [LOQ]), arithmetic mean, standard deviation (SD) and coefficient of variation (CV), median, minimum, and maximum value.
Values below LOQ will be replaced by 0 in calculations of mean, SD, CV(%) and median. Mean, SD and CV(%) will only be calculated if at least 2/3 of the data are above LOQ at the respective time point. In tables showing mean values, where values below LOQ are included in the calculation of mean values, these mean values will be marked.
A listing of LCM plasma concentration data by subject and visit will include actual doses, date and time of the most recent administration, date and time of sampling, time interval between
REDACTED COPY All data regarding help from a paid caregiver will be listed.
REDACTED COPY All data regarding help from a paid caregiver will be listed.
ts by each response level for highest level of education,
REDACTED COPY
ts by each response level for highest level of education, housing status, current professional status, regular assistance in usual activities, and driving
REDACTED COPY
housing status, current professional status, regular assistance in usual activities, and driving status will be summarized for each visit and Last Visit for the FAS. Percentages will be relative
REDACTED COPY
status will be summarized for each visit and Last Visit for the FAS. Percentages will be relative the number of subjects with a response to each item. No statistical comparisons will be carried REDACTED C
OPY
the number of subjects with a response to each item. No statistical comparisons will be carried
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
st due to epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
st due to epilepsy
Number of days with help from a paid caregiver due to epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of days with help from a paid caregiver due to epilepsy
All data regarding help from a paid caregiver will be listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All data regarding help from a paid caregiver will be listed.
ts by each response level for highest level of education,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ts by each response level for highest level of education, housing status, current professional status, regular assistance in usual activities, and driving
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
housing status, current professional status, regular assistance in usual activities, and driving status will be summarized for each visit and Last Visit for the FAS. Percentages will be relative
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
status will be summarized for each visit and Last Visit for the FAS. Percentages will be relative the number of subjects with a response to each item. No statistical comparisons will be carried
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the number of subjects with a response to each item. No statistical comparisons will be carried
professional data will be listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
professional data will be listed.
PHARMACOKINETICS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PHARMACOKINETICS
plasma concentration will be summarized using the SS. Descrip
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
plasma concentration will be summarized using the SS. Descripplasma concentrations will be presented by visit and actual dose. The actual dose is defined as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
plasma concentrations will be presented by visit and actual dose. The actual dose is defined as the most recent dose administrated prior to PK sampling.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the most recent dose administrated prior to PK sampling.
The following parameters will be calculated for each of the sampling points: n, nLOQ (number
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following parameters will be calculated for each of the sampling points: n, nLOQ (number of measurements above or equal to the lower limit of quantification [LOQ]), arithmetic mean,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of measurements above or equal to the lower limit of quantification [LOQ]), arithmetic mean,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
standard deviation (SD) and coefficient of variation (CV), median, min
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
standard deviation (SD) and coefficient of variation (CV), median, min
Values below LOQ will be replaced by 0 in calculations of mean, SD, CV(%) and median.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Values below LOQ will be replaced by 0 in calculations of mean, SD, CV(%) and median. Mean, SD and CV(%) will only be calculated if at least 2/3 of the data are above LOQ at the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Mean, SD and CV(%) will only be calculated if at least 2/3 of the data are above LOQ at the respective time point. In tables showing mean value
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
respective time point. In tables showing mean valuethe calculation of mean values, these mean values will be marked.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the calculation of mean values, these mean values will be marked.
![Page 45: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/45.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
plasma sample and the most recent administration (in hours), visit, relative day, and the kit number. Samples that were excluded from the descriptive statistics will be marked in the listing.
10 SAFETY ANALYSES
10.1 Extent of exposure
10.1.1 Derivation of exposure variables
Study medication treatment duration will be calculated as ([last study medication dose during the Treatment Period – first study medication dose] + 1 day). Subject-years of exposure is the total treatment duration in days divided by 365.25.
The mean exposure per day for an analysis period is calculated as the total exposure in milligrams during the analysis period (based on the randomized treatment group or protocol defined treatment regimen incorporating any scheduled dose changes) divided by the duration of exposure (days). Days during an analysis period with unknown dosing are to be excluded from both the numerator and the denominator for the calculation of mean exposure per day.
10.1.2 Analysis of exposure variables
Total duration of exposure (days) for each treatment group during the Titration Period, Maintenance Period, and Treatment Period will be summarized by region for the SS using descriptive statistics. The number of days of exposure in the Treatment Period will be calculated as the last dose date minus the first dose date +1. Study medication taken during the Taper and Transition Periods will not be included in these calculations.
Treatment duration will be summarized with the number and percentage of subjects with treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84 days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. Furthermore, the subject years exposed will be presented for the entire Treatment Period.
If actual dosing information is presented, the LCM dose categories for oral solution are as follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg day. The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to <200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.
The mean dose per day will be presented for the 3 different weight categories: <30kg (mg/kg/day), ≥30kg to <50kg (mg/kg/day) and ≥50kg (mg/day).
This analysis will be repeated for each subgroup as detailed in Section 4.8.
Detailed LCM exposure, LCM dosing, and drug accountability will be presented in subject data listings.
10.2 Adverse events
Adverse events will be coded using MedDRA, and tabulated by SOC and PT for each treatment group for the SS and will include the number and percentage of subjects experiencing each event at least once. All summaries will be sorted alphabetically by SOC and by frequency of events within each SOC, starting with the most frequent event for the LCM arm.
Adverse events will be considered treatment-emergent if the event had onset on or after the date of the first study medication dose and within 30 days following the last study medication dose or
REDACTED COPY Maintenance Period, and Treatment Period will be summarized by region for the SS using
REDACTED COPY Maintenance Period, and Treatment Period will be summarized by region for the SS using
descriptive statistics. The number of days of exposure in the Treatment Period
REDACTED COPY descriptive statistics. The number of days of exposure in the Treatment Period
as the last dose date minus the first dose date +1. Study medication taken during the Taper and
REDACTED COPY
as the last dose date minus the first dose date +1. Study medication taken during the Taper and Transition Periods will not be included in these calculations.
REDACTED COPY
Transition Periods will not be included in these calculations.
Treatment duration will be summarized with the number and percentage of subjec
REDACTED COPY
Treatment duration will be summarized with the number and percentage of subjectreatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84
REDACTED COPY
treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84 days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days.
REDACTED COPY
days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. Furthermore, the subject years exposed will be presented for the REDACTED C
OPY
Furthermore, the subject years exposed will be presented for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Study medication treatment duration will be calculated as ([last study medication dose during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Study medication treatment duration will be calculated as ([last study medication dose during the years of exposure is the total
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
years of exposure is the total
The mean exposure per day for an analysis period is calculated as the total exposure in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The mean exposure per day for an analysis period is calculated as the total exposure in milligrams during the analysis period (based on the randomized treatment group or protocol
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
milligrams during the analysis period (based on the randomized treatment group or protocol cheduled dose changes) divided by the duration of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
cheduled dose changes) divided by the duration of exposure (days). Days during an analysis period with unknown dosing are to be excluded from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
exposure (days). Days during an analysis period with unknown dosing are to be excluded from both the numerator and the denominator for the calculation of mean exposure per day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
both the numerator and the denominator for the calculation of mean exposure per day.
Total duration of exposure (days) for each treatment group during the Titration Period,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Total duration of exposure (days) for each treatment group during the Titration Period, Maintenance Period, and Treatment Period will be summarized by region for the SS using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Maintenance Period, and Treatment Period will be summarized by region for the SS using descriptive statistics. The number of days of exposure in the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
descriptive statistics. The number of days of exposure in the Treatment Period as the last dose date minus the first dose date +1. Study medication taken during the Taper and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as the last dose date minus the first dose date +1. Study medication taken during the Taper and Transition Periods will not be included in these calculations.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Transition Periods will not be included in these calculations.
Treatment duration will be summarized with the number and percentage of subjec
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment duration will be summarized with the number and percentage of subjectreatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84 days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. Furthermore, the subject years exposed will be presented for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Furthermore, the subject years exposed will be presented for the
If actual dosing information is presented, the LCM dose categories for oral solution are as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If actual dosing information is presented, the LCM dose categories for oral solution are as follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg day. The LCM dose categories for tablets are as fo
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day. The LCM dose categories for tablets are as fo<200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.
The mean dose per day will be presented for the 3 different weight categories: <30kg
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The mean dose per day will be presented for the 3 different weight categories: <30kg (mg/kg/day), ≥30kg to <50kg (mg/kg/day) and ≥50kg (mg/
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(mg/kg/day), ≥30kg to <50kg (mg/kg/day) and ≥50kg (mg/
This analysis will be repeated for each subgroup as detailed in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This analysis will be repeated for each subgroup as detailed in
Detailed LCM exposure, LCM dosing, and drug accountability will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Detailed LCM exposure, LCM dosing, and drug accountability will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10.2
Adverse events will be coded using MedDRA, and tabulated by SOC and PT for each treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Adverse events will be coded using MedDRA, and tabulated by SOC and PT for each treatment group for the SS and will include the number and percentage of subjects experiencing each event
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
group for the SS and will include the number and percentage of subjects experiencing each event at least once.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
at least once.
![Page 46: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/46.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
events whose intensity worsened on or after the date of first study medication dose and within 30 days following the date of last study medication administration.
If the last dose of study medication administration is unknown, any event occurring after the first study medication dose will be considered treatment-emergent. If the start date of an AE is completely missing and the stop date is either unknown or after the date of the first dose of study medication, the AE will be considered as treatment-emergent. Incomplete dates for AEs will be handled as described in Section 4.2.3.
Treatment emergent adverse events (TEAEs) during the Treatment Period, Maintenance Period and Taper/Safety Follow-Up Period, respectively, are TEAEs with an onset date during the respective period.
The following summaries will be presented by randomized treatment group:
Overview of TEAEs
Overview of TEAEs by subgroup as detailed in Section 4.8
Incidence of TEAEs
Incidence of TEAEs by subgroup as detailed in Section 4.8
Incidence of TEAEs in the Titration Period
Incidence of TEAEs in the Maintenance Period
Incidence of TEAEs in the Taper Period
Incidence of TEAEs in the Transition Period
Incidence of TEAEs by intensity
Incidence of common TEAEs for US labeling (above or equal to reporting threshold of 2% (prior to rounding) of subjects in the total LCM group)
Incidence of common drug-associated TEAEs (TEAEs occurring in ≥5% of subjects in the LCM group and occurring twice as often as in the placebo group)
Incidence of common TEAEs for EU labeling (above or equal to reporting threshold of 1% (prior to rounding) of subjects in the total LCM group) and occurring >1% than in the placebo group
Incidence of serious TEAEs
Incidence of serious TEAEs – Subject numbers
Incidence of TEAEs leading to discontinuation
Incidence in TEAEs leading to discontinuation in the Titration Period
Incidence in TEAEs leading to discontinuation in the Maintenance Period
Incidence in TEAEs leading to discontinuation – Subject numbers
Incidence of other significant TEAEs (See Section 12.2.1 for details)
REDACTED COPY
Incidence of TEAEs in the Maintenance Period
REDACTED COPY
Incidence of TEAEs in the Maintenance Period
Incidence of TEAEs in the Transition Period
REDACTED COPY
Incidence of TEAEs in the Transition Period
Incidence of common TEAEs for US labeling (above or equal to reporting threshold of 2% REDACTED COPY
Incidence of common TEAEs for US labeling (above or equal to reporting threshold of 2%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment emergent adverse events (TEAEs) during the Treatment Period, Maintenance Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment emergent adverse events (TEAEs) during the Treatment Period, Maintenance Period Up Period, respectively, are TEAEs with an onset date during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Up Period, respectively, are TEAEs with an onset date during the
Incidence of TEAEs in the Transition Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs in the Transition Period
Incidence of common TEAEs for US labeling (above or equal to reporting threshold of 2%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of common TEAEs for US labeling (above or equal to reporting threshold of 2% (prior to rounding) of subjects in the total LCM group)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(prior to rounding) of subjects in the total LCM group)
associated TEAEs (TEAEs occurring in ≥5% of subjects in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
associated TEAEs (TEAEs occurring in ≥5% of subjects in the LCM group and occurring twice as often as in the placebo group)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
LCM group and occurring twice as often as in the placebo group)
Incidence of common TEAEs for EU labeling (above or equal to reporting threshold of 1%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of common TEAEs for EU labeling (above or equal to reporting threshold of 1% (prior to rounding) of subjects in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(prior to rounding) of subjects in the
Incidence of serious TEAEs
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of serious TEAEs
Incidence of serious TEAEs
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of serious TEAEs
Incidence of TEAEs leading to discontinuation
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs leading to discontinuation
Incidence in TEAEs leading to discontinuation in the Titration Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence in TEAEs leading to discontinuation in the Titration Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 47: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/47.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Incidence of TEAEs for potential drug-induced liver injury (PDILI) (See Section 12.2.2 for details)
To assess TEAEs related to epilepsy, PTs will be identified by ongoing manual medical review. The following PTs (including those identified from continuing medical review) will be summarized: petit mal epilepsy, myoclonus, and myoclonic epilepsy.
Incidence of TEAEs related to epilepsy by 3-month exposure period of TEAE onset
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in Section 10.1.2. AEs of unknown dosing are those with no known dose or known dosing and partial AE start or stop dates.
Incidence of TEAEs by actual dose at onset
Subject data listings will be presented for the following:
Subjects experiencing adverse events on the ES
Subjects experiencing Serious TEAEs on the SS
Subjects experiencing TEAEs leading to discontinuation on the SS
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC and PTs.
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in Section 12.5.
10.3 Clinical laboratory evaluations
Measurement and change from Baseline in continuous laboratory parameters, including hematology, clinical chemistry, endocrinology, and urinalysis will be summarized using descriptive statistics for the scheduled visits. When analyzing categorical data, the number and percentage of subjects in each category will be presented. In addition, summary statistics for the actual value and change from Baseline will be presented for Last Visit, minimum, and maximum post-Baseline values obtained during the Treatment Period. Repeated or unscheduled laboratory assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last visit, minimum, and maximum post-Baseline values during the Treatment Period.
Shifts based on the normal range (ie, low, normal, high, and missing) for each hematology and clinical chemistry lab parameter will be presented by maximum value during the Treatment Period relative to Baseline by treatment group. Similar shift tables for Baseline versus minimum value during the Treatment Period will also be presented. Unscheduled visits will be considered when determining the maximum and minimum value during the defined treatment period.
Treatment-emergent markedly abnormal (TEMA) values indicate significant deviations from the expected range of age-appropriate values. TEMA laboratory abnormalities results are those that are observed post-Baseline during the Treatment Period but are not present at Baseline. TEMA values for serum chemistry and hematology laboratory parameters are provided in UCB conventional (traditional) and standard units. The definition of MA values for hematology and chemistry values can be found in Section 12.3. The number and percentage of subjects with at
REDACTED COPY A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC
REDACTED COPY A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC
of further AE tables required for EudraCT and clinicaltrials.gov is provided in
REDACTED COPY
of further AE tables required for EudraCT and clinicaltrials.gov is provided in
Clinical laboratory evaluations
REDACTED COPY
Clinical laboratory evaluations
from Baseline in continuous laboratory parameters, including REDACTED C
OPY
from Baseline in continuous laboratory parameters, including hematology, clinical chemistry, endocrinology, and urinalysis will be summarized using REDACTED C
OPY
hematology, clinical chemistry, endocrinology, and urinalysis will be summarized using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in . AEs of unknown dosing are those with no known dose or known dosing and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. AEs of unknown dosing are those with no known dose or known dosing and
Subjects experiencing TEAEs leading to discontinuation on the SS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects experiencing TEAEs leading to discontinuation on the SS
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC
of further AE tables required for EudraCT and clinicaltrials.gov is provided in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of further AE tables required for EudraCT and clinicaltrials.gov is provided in
Clinical laboratory evaluations
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Clinical laboratory evaluations
from Baseline in continuous laboratory parameters, including
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from Baseline in continuous laboratory parameters, including hematology, clinical chemistry, endocrinology, and urinalysis will be summarized using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
hematology, clinical chemistry, endocrinology, and urinalysis will be summarized using descriptive statistics for the scheduled visits. When analyzing categorical data, the number and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
descriptive statistics for the scheduled visits. When analyzing categorical data, the number and of subjects in each category will be presented. In addition, summary statistics for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of subjects in each category will be presented. In addition, summary statistics for the actual value and change from Baseline will be presented for Last Visit, minimum, and maximum
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
actual value and change from Baseline will be presented for Last Visit, minimum, and maximum Baseline values obtained during the Treatment Period. Repeated or uns
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values obtained during the Treatment Period. Repeated or unsassessments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
assessments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
when determining the last visit, minimum, and maximum post
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
when determining the last visit, minimum, and maximum post
Shifts based on the normal range (i
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Shifts based on the normal range (iclinical chemistry lab parameter will be presented by maximum value during the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
clinical chemistry lab parameter will be presented by maximum value during the Treatment Period relative to Baseline by treatment group. Similar shift tables for Baseline versus minimum
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period relative to Baseline by treatment group. Similar shift tables for Baseline versus minimum value durin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
value during the Treatment Period will also be presented. Unscheduled visits will be considered
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
g the Treatment Period will also be presented. Unscheduled visits will be considered
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
when determining the maximum and minimum value during the defined treatment period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
when determining the maximum and minimum value during the defined treatment period.
Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatmentexpected range of age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
expected range of ageare observed post
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
are observed post
![Page 48: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/48.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
least 1 TEMA value will be summarized by scheduled visit, Last Visit, minimum and maximum post-Baseline values obtained during the Treatment Period for each laboratory parameter (hematology and clinical chemistry) with markedly abnormal criteria specified. TEMA values are those that are observed during the defined treatment period at scheduled or unscheduled visits and were not observed at any visit during the Baseline period. A table summarizing the number of subjects meeting the potential drug induced liver injury criteria will also be presented.
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC) can be found in Section 12.4. The number and percentage of subjects with treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will be summarized by treatment group, laboratory parameter, and visit for the Treatment Period. Treatment emergent abnormalities of grade 2 or higher are those that were observed during the Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during the Baseline Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher will be presented in a subject number listing.
Subject data listings of all laboratory data will also be presented. Within the listings TEMA values will be identified. Separate tables will also be provided to show the subject numbers of those who meet any of the TEMA and NCI CTC grade 2 or higher criteria.
Any additional lab data will be listed, including positive pregnancy test results listed by subject.
10.4 Vital signs, physical findings, and other observations related to safety
10.4.1 Vital signs
Observed values and changes from Baseline in vital sign parameters will be summarized using descriptive statistics for the scheduled visits. In addition, summary statistics for the observed value and change from Baseline will be presented for Last Visit, minimum, and maximum post-Baseline values obtained during the Treatment Period. Repeated or unscheduled assessments during the study will not be presented in by-visit summaries, but will be considered when determining the minimum, and maximum post-Baseline values during the Treatment Period. The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high value, at each post-Baseline visit, for which systolic blood pressure, diastolic blood pressure, pulse rate, and body weight were scheduled to be assessed, and Last Visit, will be presented. Percentages will be relative to the number of subjects with a value at each time point. All TEMA results summarized will be presented in a subject number listing. The abnormal vital sign criteria are defined in Section 12.3.3.
A subject data listing of all vital signs data will be created, indicating any abnormal values.
10.4.2 Electrocardiograms
ECGs will be performed locally and no standardization techniques will be employed. The data will be analyzed as reported.
10.4.2.1 Derivation of corrected QT values
The Bazett corrected QT (QTcB) will be calculated as
REDACTED COPY those who meet any of the TEMA and NCI CTC grade 2 or higher criteria.
REDACTED COPY those who meet any of the TEMA and NCI CTC grade 2 or higher criteria.
Any additional lab data will be listed, including positive pregnancy test results listed by subject.
REDACTED COPY
Any additional lab data will be listed, including positive pregnancy test results listed by subject.
signs, physical findings, and other observations related to
REDACTED COPY
signs, physical findings, and other observations related to
Observed values and changes from Baseline in vital sign parameters will be summarized using REDACTED COPY
Observed values and changes from Baseline in vital sign parameters will be summarized using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
NCI CTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
NCI CTC)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
). The number and percentage of subjects with treatment emergent
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. The number and percentage of subjects with treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will t group, laboratory parameter, and visit for the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
t group, laboratory parameter, and visit for the Treatment Period. Treatment emergent abnormalities of grade 2 or higher are those that were observed during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment emergent abnormalities of grade 2 or higher are those that were observed during the Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during tBaseline Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher
Subject data listings of all laboratory data will also be presented. Within the listings TEMA
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subject data listings of all laboratory data will also be presented. Within the listings TEMA ntified. Separate tables will also be provided to show the subject numbers of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ntified. Separate tables will also be provided to show the subject numbers of those who meet any of the TEMA and NCI CTC grade 2 or higher criteria.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
those who meet any of the TEMA and NCI CTC grade 2 or higher criteria.
Any additional lab data will be listed, including positive pregnancy test results listed by subject.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Any additional lab data will be listed, including positive pregnancy test results listed by subject.
signs, physical findings, and other observations related to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
signs, physical findings, and other observations related to
Observed values and changes from Baseline in vital sign parameters will be summarized using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Observed values and changes from Baseline in vital sign parameters will be summarized using descriptive statistics for the scheduled visits. In addition, summary statistics for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
descriptive statistics for the scheduled visits. In addition, summary statistics for value and change from Baseline will be presented for Last Visit, minimum, and maximum post
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
value and change from Baseline will be presented for Last Visit, minimum, and maximum postBaseline values obtained during the Treatment Period. Repeated or unscheduled assessments
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values obtained during the Treatment Period. Repeated or unscheduled assessments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the study will not be presented in bydetermining the minimum, and maximum post
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
determining the minimum, and maximum postThe number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high Baseline visit, for which systolic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline visit, for which systolicpulse rate, and body weight were scheduled to be assessed, and Last Visit, will be presented.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
pulse rate, and body weight were scheduled to be assessed, and Last Visit, will be presented. Percentages will be relative to the number of subjects with a value at each time point. All TEMA
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentages will be relative to the number of subjects with a value at each time point. All TEMA results summarized wil
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
results summarized wilare defined in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
are defined in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A subject data listing of all vital sign
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A subject data listing of all vital sign
10.4.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10.4.2
ECGs will be performed locally and no standardization techniques will be employed. The data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ECGs will be performed locally and no standardization techniques will be employed. The data
![Page 49: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/49.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
QT/√𝑅𝑅, where RR = 60/heart rate.
The Fridericia corrected QT (QTcF) will be calculated as
QT/√𝑅𝑅3 , where RR = 60/heart rate.
10.4.2.2 Analysis of ECG parameters
For quantitative ECG measurements (heart rate, PR interval, QRS interval, QT interval, RR Interval and corrected QT intervals using Bazett and Fridiricia correction methods), summary statistics of the actual values and change from Baseline will be summarized using descriptive statistics for the scheduled visits, overall, Last Visit, minimum and maximum post-Baseline values obtained during the Treatment Period, and in each of the TEMA ECG criteria age categories. Last visit is the value from the last post baseline visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last visit, minimum, and maximum post-Baseline values during the Treatment Period. If repeat measurements are taken at a particular visit, then the average value is used in summaries and the original values are listed.
The number and percentage of subjects who met each of the TEMA criteria specified in Section 12.3.4 will be presented within the specified age groups. For each parameter, the number and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last visit values during the Treatment Period. Subject numbers for those with TEMA ECG values will be listed by abnormality criteria. TEMA results for a subject are those that are observed during the defined treatment period at scheduled or unscheduled visits and were not observed at any visit during the Baseline period.
Detailed information on the quantitative and qualitative ECG findings will be presented in subject data listings.
10.4.3 Physical examination
A listing of abnormal physical examination findings will be provided.
10.4.4 Safety Seizure Information
10.4.4.1 New Seizure Type
The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure type was present or absent in Combined Baseline will be tabulated. The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure type was present or absent in Seizure History (including Combined Baseline) will be tabulated.
The number and percentage of subjects with new absence or myoclonic seizure types experienced in the Treatment Period with absence or myoclonic seizure type, respectively, indicated by the Seizure History Classification but not experienced in the Combined Baseline as recorded in the diary will be summarized.
REDACTED COPY and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific
REDACTED COPY and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific
PR interval, QRS interval, QT interval and
REDACTED COPY PR interval, QRS interval, QT interval and
corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated
REDACTED COPY
corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by
REDACTED COPY
or unscheduled ECG assessments during the study will not be presented in byhen determining the last visit values during the Treatment Period.
REDACTED COPY
hen determining the last visit values during the Treatment Period. ECG values will be listed by abnormality criteria.
REDACTED COPY
ECG values will be listed by abnormality criteria.results for a subject are those that are observed during the defined treatment period at schedule
REDACTED COPY
results for a subject are those that are observed during the defined treatment period at scheduleor unscheduled visits and were not observed at any visit during the Baseline period.REDACTED C
OPY
or unscheduled visits and were not observed at any visit during the Baseline period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
statistics of the actual values and change from Baseline will be summarized using descriptive
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
statistics of the actual values and change from Baseline will be summarized using descriptive Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values obtained during the Treatment Period, and in each of the TEMA ECG criteria age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
values obtained during the Treatment Period, and in each of the TEMA ECG criteria age categories. Last visit is the value from the last post baseline visit during the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
categories. Last visit is the value from the last post baseline visit during the Treatment Period. essments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
essments during the study will not be presented in bysummaries, but will be considered when determining the last visit, minimum, and maximum
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
summaries, but will be considered when determining the last visit, minimum, and maximum Baseline values during the Treatment Period. If repeat measurements are taken at a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values during the Treatment Period. If repeat measurements are taken at a en the average value is used in summaries and the original values are listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
en the average value is used in summaries and the original values are listed.
The number and percentage of subjects who met each of the TEMA criteria specified in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects who met each of the TEMA criteria specified in will be presented within the specified age groups. For each parameter, the number
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be presented within the specified age groups. For each parameter, the number and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific PR interval, QRS interval, QT interval and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PR interval, QRS interval, QT interval and corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or unscheduled ECG assessments during the study will not be presented in byhen determining the last visit values during the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
hen determining the last visit values during the Treatment Period. ECG values will be listed by abnormality criteria.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ECG values will be listed by abnormality criteria.results for a subject are those that are observed during the defined treatment period at schedule
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
results for a subject are those that are observed during the defined treatment period at scheduleor unscheduled visits and were not observed at any visit during the Baseline period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or unscheduled visits and were not observed at any visit during the Baseline period.
Detailed information on the quantitative and qualitative ECG findings will be presented in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Detailed information on the quantitative and qualitative ECG findings will be presented in
Physical examination
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Physical examination
A listing of abnormal physical exa
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A listing of abnormal physical exa
Safety Seizure Information
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Safety Seizure Information
New Seizure Type
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
New Seizure Type
The number and percentage of subjects with seizure types present or absent in the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure type was present or absent in Combined Baseline will b
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period vs whether the seizure type was present or absent in Combined Baseline will b
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects with seizure types present or absent in the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure type was present or absent in Seizure History (including Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period vs whether the seizure type was present or absent in Seizure History (including Combined Baseline) will be tabulated.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline) will be tabulated.
The number and percentage
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage experienced in the Treatment Period with absence or myoclonic seizure type, respectively,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experienced in the Treatment Period with absence or myoclonic seizure type, respectively,
![Page 50: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/50.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The number and percentage of subjects with new absence or myoclonic seizure types experienced in the Treatment Period but not experienced in the Combined Baseline or indicated in Seizure History Classification will also be summarized.
The number and percentage of subjects with new absence or myoclonic seizure types in the Treatment Period, with absence or myoclonic, respectively, indicated by the Seizure History Classification but not experienced in the Combined Baseline Period or subjects with ≥50% worsening in days with absence or myoclonic seizures, respectively, will be summarized.
10.4.4.2 Increase in days with absence seizures
Response to treatment regarding absence seizures will be based on the percent change in the number of days with absence seizures per 28 days, calculated as described in Section 8.3.1.2. The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the number of days with absence seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
10.4.4.3 Increase in days with myoclonic seizures
Response to treatment regarding myoclonic seizures will be based on the percent change in the number of days with myoclonic seizures per 28 days, calculated as described in Section 8.3.1.2. The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the number of days with myoclonic seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
10.4.4.4 Increase in absence seizure frequency
Response to treatment regarding absence seizures will also be based on the percent change in the absence seizure frequency per 28 days, calculated as described in Section 8.3.1.9. The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in absence seizure frequency per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
10.4.4.5 Increase in myoclonic seizure frequency
Response to treatment regarding myoclonic seizures will also be based on the percent change in the myoclonic seizure frequency per 28 days, calculated as described in Section 8.3.1.9. The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in myoclonic seizure frequency per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
10.4.5 Tanner stage assessment
The investigator will evaluate the subject’s sexual development using the 3-item Tanner scale (ie, for females: breasts, pubic hair, and overall stage; and for males: genitals, pubic hair, and overall stage). The investigator should use clinical judgment in deciding which subjects are selected for evaluation of Tanner stage (ie, those subjects who are pubescent at Visit 2 or who will enter puberty during the course of the study).
A listing of Tanner stage assessments will be provided.
REDACTED COPY >50% to 75%, and >75% in the number of days with myoclonic seizures per 28 days during the
REDACTED COPY >50% to 75%, and >75% in the number of days with myoclonic seizures per 28 days during the
Period compared to the Prospective Baseline Period will be presented.
REDACTED COPY
Period compared to the Prospective Baseline Period will be presented.
Increase in absence seizure frequency
REDACTED COPY
Increase in absence seizure frequency
nce seizures will also be
REDACTED COPY
nce seizures will also be per 28 days, calculat
REDACTED COPY
per 28 days, calculatand percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, REDACTED C
OPY
and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, bsence seizure frequencyR
EDACTED COPY
bsence seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment regarding absence seizures will be based on the percent change in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment regarding absence seizures will be based on the percent change in the 8.3.1.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.3.1.2%, >25% to 50%,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
%, >25% to 50%, >50% to 75%, and >75% in the number of days with absence seizures per 28 days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>50% to 75%, and >75% in the number of days with absence seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to the Prospective Baseline Period will be presented.
ding myoclonic seizures will be based on the percent change in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ding myoclonic seizures will be based on the percent change in the number of days with myoclonic seizures per 28 days, calculated as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
number of days with myoclonic seizures per 28 days, calculated as described in The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the number of days with myoclonic seizures per 28 days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>50% to 75%, and >75% in the number of days with myoclonic seizures per 28 days during the Period compared to the Prospective Baseline Period will be presented.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period compared to the Prospective Baseline Period will be presented.
Increase in absence seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Increase in absence seizure frequency
nce seizures will also be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nce seizures will also be per 28 days, calculat
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days, calculated as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ed as described in and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, bsence seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
bsence seizure frequency per 28 days during the Treatment Period compared to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline Period will be presented.
Increase in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Increase in myoclonic seizure frequency
Response to treatment regarding myoclonic seizures will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment regarding myoclonic seizures will myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
myoclonic seizure frequencynumber and percentage of subjects experiencing an
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
number and percentage of subjects experiencing an to 75%, and >75% in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
to 75%, and >75% in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
myoclonic seizure frequencycompared to the Prospective Baseline Period will be presented.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
compared to the Prospective Baseline Period will be presented.
Tanner stage assessment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Tanner stage assessment
The investigator will evaluate the subj
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The investigator will evaluate the subj(ie, for females: breasts, pubic hair, and overall stage; and for males: genitals, pubic hair, and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(ie, for females: breasts, pubic hair, and overall stage; and for males: genitals, pubic hair, and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
overall stage). The investigator should use clinical judgment in deciding which subjects are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
overall stage). The investigator should use clinical judgment in deciding which subjects are selected
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
selected will enter puberty during the course of the study).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will enter puberty during the course of the study).
![Page 51: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/51.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
10.4.6 Neurological examination
Summaries of shift from Baseline to Last Visit will be provided by major neurological category and treatment group based on categories normal, abnormal, not clinically significant, and abnormal, clinically significant. The major neurological categories collected on the CRF are General, Cranial Nerves, Reflexes, Motor System (including General, Muscle Strength and Muscle Tone), Coordination/Cerebellar Function and Sensation (including Upper and Lower Extremities). A listing of abnormal neurological examination findings will also be provided.
10.4.7 Assessment of suicidality
Suicidality will be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS). This scale will be used for screening as well as to assess suicide ideation and behavior that may occur during the study. All subjects who are ≥6 years of age will complete the “Baseline/Screening” version of the C-SSRS at the first visit and will complete the “Since Last Visit” version at subsequent visits. If a subject becomes 6 years of age during the study, the “Already Enrolled” version of the C-SSRS should be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” version should be used at subsequent visits. The C-SSRS is not validated for subjects <6 years of age and will not be used for this population.
Subject data listings of the data for the C-SSRS will be provided. No summaries of the C-SSRS data are planned.
10.4.8 Achenbach Child Behavior Checklist
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and behavioral/emotional problems. Depending on the subject’s age, 1 of 2 versions of the Achenbach CBCL is used. The CBCL/1½-5 is intended for use in children 4 years to 5 years and 11 months of age. For subjects ≥6 years to <17 years, the CBCL/6-18 will be used. For each subject, the same version (CBCL/1½-5 or CBCL/6-18) that is used at Visit 2 (Baseline) should be used at all following visits, even if the subject passes the applicable age range during the study, and should be completed by the same parent/legal representative.
10.4.8.1 Derivation of Achenbach variables
The CBCL/1½-5 will be grouped according to syndrome scales in Table 2 and the CBCL/6-18 will be grouped according to empirically based syndrome scales in Table 3. The Achenbach CBCL has a 6 month recall. If a subject leaves the study early, and has been in the study for less than 6 months, this subject’s data will not be included in the analysis and will be listed only.
Table 2: CBCL/1½-5
Syndrome scale Questions
Aggressive behavior 8, 15, 16, 18, 20, 27, 29, 35, 40, 42, 44, 53, 58, 66, 69, 81, 85, 88, 96
Anxious/depressed 10, 33, 37, 43, 47, 68, 87, 90
Attention problems 5, 6, 56, 59, 95
Emotionally reactive 21, 46, 51, 79, 82, 83, 92, 97, 99
REDACTED COPY
Achenbach Child Behavior Checklist
REDACTED COPY
Achenbach Child Behavior Checklist
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and
REDACTED COPY
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and al problems. Depending on the subject’s age, 1 of 2 versions of the
REDACTED COPY
al problems. Depending on the subject’s age, 1 of 2 versions of the Achenbach CBCL is used. The CBCL/1½
REDACTED COPY
Achenbach CBCL is used. The CBCL/1½-
REDACTED COPY
-5 is intended for use in children 4 years to 5 years and
REDACTED COPY
5 is intended for use in children 4 years to 5 years and 11 months of age. For subjects ≥6 years to <17 years, the CBCL/6
REDACTED COPY
11 months of age. For subjects ≥6 years to <17 years, the CBCL/65 or CBCL/6REDACTED C
OPY
5 or CBCL/6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SSRS). This
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SSRS). This scale will be used for screening as well as to assess suicide ideation and behavior that may occur
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scale will be used for screening as well as to assess suicide ideation and behavior that may occur ≥6 years of age will complete the “Baseline/Screening”
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥6 years of age will complete the “Baseline/Screening” SSRS at the first visit and will complete the “Since Last Visit” version at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SSRS at the first visit and will complete the “Since Last Visit” version at subsequent visits. If a subject becomes 6 years of age during the study, the “Already Enrolled”
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subsequent visits. If a subject becomes 6 years of age during the study, the “Already Enrolled” SSRS should be used at the first visit at which the subject is 6 years of age and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SSRS should be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” version should be used at subsequent visits. The C
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the “Since Last Visit” version should be used at subsequent visits. The C-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-SSRS is not validated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SSRS is not validated for subjects <6 years of age and will not be used for this population.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for subjects <6 years of age and will not be used for this population.
SSRS will be provided. No summaries of the C
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SSRS will be provided. No summaries of the C
Achenbach Child Behavior Checklist
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Achenbach Child Behavior Checklist
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and al problems. Depending on the subject’s age, 1 of 2 versions of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
al problems. Depending on the subject’s age, 1 of 2 versions of the 5 is intended for use in children 4 years to 5 years and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5 is intended for use in children 4 years to 5 years and 11 months of age. For subjects ≥6 years to <17 years, the CBCL/6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
11 months of age. For subjects ≥6 years to <17 years, the CBCL/65 or CBCL/6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5 or CBCL/6be used at all following visits, even if the subject passes the applicable age range during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be used at all following visits, even if the subject passes the applicable age range during the study, and should be completed by the same parent/legal representative.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
study, and should be completed by the same parent/legal representative.
Derivation of Achenbach variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Derivation of Achenbach variables
5 will be grouped according to syndrome scales in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5 will be grouped according to syndrome scales in will be grouped according to empirically based syndrome scales in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be grouped according to empirically based syndrome scales inCBCL has a 6 month recall. If a subject leaves the study early, and has been in the study for less
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
CBCL has a 6 month recall. If a subject leaves the study early, and has been in the study for less than 6 months, this subject’s data will not be included in the analysis and will be listed only.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
than 6 months, this subject’s data will not be included in the analysis and will be listed only.
CBCL/1½
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
CBCL/1½
Syndrome scale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Syndrome scale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Aggressive behavior
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Aggressive behavior
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Anxious/depressed
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Anxious/depressed
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 52: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/52.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Table 2: CBCL/1½-5
Syndrome scale Questions
Sleep problems 22, 38, 48, 64, 74, 84, 94
Somatic complaints 1, 7, 12, 19, 24, 39, 45, 52, 78, 86, 93
Withdrawn 2, 4, 23, 62, 67, 70, 71, 98
Other problems 3, 9, 11, 13, 14, 17, 25, 26, 28, 30, 31, 32, 34, 36, 41, 49, 50, 54, 55, 57, 60, 61, 63, 65, 72, 73, 75, 76, 77, 80, 89, 91, 100
CBCL= Child Behavior Checklist
Table 3: CBCL/6-18
Syndrome scale Questions
Aggressive behavior 3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 94, 95, 97, 104
Anxious/depressed 14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112
Attention problems 1, 4, 8, 10, 13, 17, 41, 61, 78, 80
Rule-breaking behavior 2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 101, 105, 106
Social problems 11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79
Somatic complaints 47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g
Thought problems 9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 100
Withdrawn/depressed 5, 42, 65, 69, 75, 102, 103, 111 CBCL= Child Behavior Checklist
The Syndrome scale scores are calculated as the sum of the associated individual items scores. Each individual item score has the response options of:
0=not true (as far as known)
1=somewhat or sometimes true
2=very true or often true.
Missing data will not be replaced. Standardized T-scores are determined for each subject’s raw syndrome and overall scores based on the subject’s age and gender. Tables mapping each raw score to the appropriate T-score are provided in the CBCL Professional Manual and will be reproduced programmatically.
10.4.8.2 Analysis of Achenbach variables
Calculated T-score values and change from Baseline for each CBCL/1½-5 syndrome (aggressive behavior, anxious/depressed, attention problems, emotionally reactive, other problems, sleep
REDACTED COPY 1, 4, 8, 10, 13, 17, 41, 61, 78, 80
REDACTED COPY 1, 4, 8, 10, 13, 17, 41, 61, 78, 80
REDACTED COPY
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99,
REDACTED COPY
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 101, 105, 106
REDACTED COPY
101, 105, 106
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3, 9, 11, 13, 14, 17, 25, 26, 28, 30, 31, 32, 34, 36,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3, 9, 11, 13, 14, 17, 25, 26, 28, 30, 31, 32, 34, 36, 63, 65, 72, 73, 75, 76,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
63, 65, 72, 73, 75, 76,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1, 4, 8, 10, 13, 17, 41, 61, 78, 80
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1, 4, 8, 10, 13, 17, 41, 61, 78, 80
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 101, 105, 106
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
101, 105, 106
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
11, 12, 25, 27, 34,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
11, 12, 25, 27, 34,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The Syndrome scale scores are calculated as the sum of the associated individual items scores.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The Syndrome scale scores are calculated as the sum of the associated individual items scores.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Each individual item score has the response options of:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Each individual item score has the response options of:
0=not true (as far as known)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0=not true (as far as known)
1=somewhat or sometimes true
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1=somewhat or sometimes true
2=very true or often true.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2=very true or often true.
Missing data will not be replaced. Standardized T
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Missing data will not be replaced. Standardized Tsyndrome and overall scores based on the subject’s age and gender. Tables mapping each raw
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
syndrome and overall scores based on the subject’s age and gender. Tables mapping each raw score to the appropriate T
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score to the appropriate Treproduced programmatically.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reproduced programmatically.
![Page 53: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/53.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
problems, somatic complaints, and withdrawn) will be summarized for each visit, and Last Visit, by treatment group.
Calculated T-score values and change from Baseline for each CBCL/6-18 syndrome (aggressive behavior, anxious/depressed, attention problems, rule-breaking behavior, social problems, somatic complaints, thought problems, and withdrawn/depressed) will be summarized for each visit, and Last Visit, by treatment group.
Subject data listings of the data for the Achenbach CBCL will be provided. The means of the calculated T-score will be plotted by visit.
10.4.9 BRIEF-P and BRIEF assessment
The BRIEF-P and BRIEF are validated tools that will be used for the evaluation of subjects ≥4 to <5 years of age, and ≥5 years of age, respectively. The BRIEF-P and BRIEF will be used only in countries where a translated scale is available. For each subject, the same version (BRIEF-P or BRIEF) that is used at Visit 2 (Baseline) should be used at all following visits, even if the subject passes the applicable age range during the study. The BRIEF-P and BRIEF have a 6 month recall. If a subject leaves the study early, and has been in the study for less than 6 months, this subject’s data will not be included in the analysis and will be listed only.
10.4.9.1 BRIEF-P scores
The BRIEF-P form comprises of 63 questions which can be answered Never (scored as 1 point), Sometimes (scored as 2 points), and Often (scored as 3 points).
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges from 63 to 189, with higher scores reflecting poorer functioning.
The 3 subscale scores and 5 individual component scores that make up these subscale scores are outlined in Table 4 .
Table 4: BRIEF-P questionnaire scoring
Scale/Index Questions
Inhibit 3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Shift 5,10, 15, 20, 25, 30, 35, 40, 45, 50
Emotional Control 1, 6, 11, 16, 21, 26, 31, 36, 41, 46
Inhibitory self-control All from {Inhibit and Emotional Control}
Flexibility All from {Shift and Emotional Control}
Working Memory 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Plan/Organize 4, 9, 14, 19, 24, 29, 34, 39, 44, 49
Emergent metacognition All from {Working Memory and Plan/Organize}
REDACTED COPY
P form comprises of 63 questions which can be answered Never (scored as 1 point),
REDACTED COPY
P form comprises of 63 questions which can be answered Never (scored as 1 point), Sometimes (scored as 2 points), and Often (scored as 3 points).
REDACTED COPY
Sometimes (scored as 2 points), and Often (scored as 3 points).
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges
REDACTED COPY
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges , with higher scores reflecting poorer functioning.
REDACTED COPY
, with higher scores reflecting poorer functioning.
The 3 subscale scores and 5 individual component scores that make up these subscale scores are REDACTED C
OPY
The 3 subscale scores and 5 individual component scores that make up these subscale scores are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P and BRIEF are validated tools that will be used for the evaluation of subjects ≥4 to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P and BRIEF are validated tools that will be used for the evaluation of subjects ≥4 to and BRIEF will be used only in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and BRIEF will be used only in countries where a translated scale is available. For each subject, the same version (BRIEF
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
countries where a translated scale is available. For each subject, the same version (BRIEFBRIEF) that is used at Visit 2 (Baseline) should be used at all following visits, even if the subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRIEF) that is used at Visit 2 (Baseline) should be used at all following visits, even if the subject P and BRIEF have a 6 month
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P and BRIEF have a 6 month recall. If a subject leaves the study early, and has been in the study for less than 6 months, this
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
recall. If a subject leaves the study early, and has been in the study for less than 6 months, this subject’s data will not be included in the analysis and will be listed only.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subject’s data will not be included in the analysis and will be listed only.
P form comprises of 63 questions which can be answered Never (scored as 1 point),
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P form comprises of 63 questions which can be answered Never (scored as 1 point), Sometimes (scored as 2 points), and Often (scored as 3 points).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Sometimes (scored as 2 points), and Often (scored as 3 points).
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges , with higher scores reflecting poorer functioning.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, with higher scores reflecting poorer functioning.
The 3 subscale scores and 5 individual component scores that make up these subscale scores are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The 3 subscale scores and 5 individual component scores that make up these subscale scores are
P questionnaire scoring
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P questionnaire scoring
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Emotional Control
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Emotional Control
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Inhibitory self
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Inhibitory self
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Flexibility
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Flexibility
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Working Memory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Working Memory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 54: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/54.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Table 4: BRIEF-P questionnaire scoring
Scale/Index Questions
GEC Score 1-63 GEC=Global Executive Composite
Standardized T-scores are determined from each subject’s raw GEC, inhibitory self-control, flexibility, emergent metacognition, and component scores based on the subject’s age and gender. Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P Professional Manual and will be reproduced programmatically.
Two validity scales will also be derived: Negativity to assess the extent to which the respondent answers selected BRIEF-P items in an unusually negative manner and Inconsistency to assess the extent to which the respondent answers similar BRIEF-P items in an inconsistent manner. The Negativity scale is the number of items in 30, 44, 46, 47, 53, 55, 56, 57, 59 and 63 with a score of 3, and so has a range of 0 to10. A score of 2 or less is considered acceptable, 3 as elevated and 4 or more highly elevated.
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale is the sum of the absolute values of the difference in scores for the items in each item pair, and so ranges from 0 to 20. The item pairs are questions 1 and 11, 3 and 33, 5 and 45, 10 and 20, 11 and 26, 16 and 21, 18 and 52, 33 and 38, 43 and 52, and 48 and 54. A score of 7 or less is acceptable and 8 or more inconsistent.
Calculated T-score values and change from Baseline for the 2 indexed scores (BRI and MI), and GEC for the BRIEF-P questionnaire will be summarized at each visit, and Last Visit, by treatment group.
All BRIEF-P assessment data will be listed. The means of the BRIEF-P assessment data will be plotted by visit.
10.4.9.2 BRIEF scores
The BRIEF form comprises of 86 questions which can be answered as Never (scored as 1 point), Sometimes (scored as 2 points), and Often (scored as 3 points).
The first 72 items are included in the GEC score which ranges from 72 to 216, with higher scores reflecting poorer functioning.
The 2 subscale scores and 8 individual component scores that make up these subscale scores are outlined in Table 5 .
Table 5: BRIEF questionnaire scoring
Scale/Index Questions
Inhibit 38, 41, 43, 44, 49, 54, 55, 56, 59, 65
Shift 5, 6, 8, 12, 13, 23, 30, 39
Emotional Control 1, 7, 20, 25, 26, 45, 50, 62, 64, 70
REDACTED COPY For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale
REDACTED COPY For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale
is the sum of the absolute values of the difference in scores for the items in each item pair, and so
REDACTED COPY
is the sum of the absolute values of the difference in scores for the items in each item pair, and so stions 1 and 11, 3 and 33, 5 and 45, 10 and 20,
REDACTED COPY
stions 1 and 11, 3 and 33, 5 and 45, 10 and 20, 26, 16 and 21, 18 and 52, 33 and 38, 43 and 52, and 48 and 54. A score of 7 or less is
REDACTED COPY
26, 16 and 21, 18 and 52, 33 and 38, 43 and 52, and 48 and 54. A score of 7 or less is
score values and change from Baseline for the 2 indexed scoreREDACTED C
OPY
score values and change from Baseline for the 2 indexed scoreP questionnaire will be summarized at each visit, and Last Visit, by REDACTED C
OPY
P questionnaire will be summarized at each visit, and Last Visit, by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
control,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
control, and component scores based on the subject’s age and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and component scores based on the subject’s age and score are provided in the BRIEF
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score are provided in the BRIEF
Two validity scales will also be derived: Negativity to assess the extent to which the respondent
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Two validity scales will also be derived: Negativity to assess the extent to which the respondent P items in an unusually negative manner and Inconsistency to assess the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P items in an unusually negative manner and Inconsistency to assess the P items in an inconsistent manner. The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P items in an inconsistent manner. The Negativity scale is the number of items in 30, 44, 46, 47, 53, 55, 56, 57, 59 and 63 with a score
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Negativity scale is the number of items in 30, 44, 46, 47, 53, 55, 56, 57, 59 and 63 with a score of 3, and so has a range of 0 to10. A score of 2 or less is considered acceptable, 3 as elevated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of 3, and so has a range of 0 to10. A score of 2 or less is considered acceptable, 3 as elevated
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale is the sum of the absolute values of the difference in scores for the items in each item pair, and so
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is the sum of the absolute values of the difference in scores for the items in each item pair, and so stions 1 and 11, 3 and 33, 5 and 45, 10 and 20,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
stions 1 and 11, 3 and 33, 5 and 45, 10 and 20, 26, 16 and 21, 18 and 52, 33 and 38, 43 and 52, and 48 and 54. A score of 7 or less is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
26, 16 and 21, 18 and 52, 33 and 38, 43 and 52, and 48 and 54. A score of 7 or less is
score values and change from Baseline for the 2 indexed score
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score values and change from Baseline for the 2 indexed scoreP questionnaire will be summarized at each visit, and Last Visit, by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P questionnaire will be summarized at each visit, and Last Visit, by
P assessment data will be listed. The means of the BRIEF
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P assessment data will be listed. The means of the BRIEF
BRIEF scores
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRIEF scores
EF form comprises of 86 questions which can be answered as Never (scored as 1 point),
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
EF form comprises of 86 questions which can be answered as Never (scored as 1 point), Sometimes (scored as 2 points), and Often (scored as 3 points).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Sometimes (scored as 2 points), and Often (scored as 3 points).
The first 72 items are included in the GEC score which ranges from 72 to 216, with higher scores
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The first 72 items are included in the GEC score which ranges from 72 to 216, with higher scores ng poorer functioning.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ng poorer functioning.
The 2 subscale scores and 8 individual component scores that make up these subscale scores are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The 2 subscale scores and 8 individual component scores that make up these subscale scores are outlined in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
outlined in Table
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Table
Table
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Table
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Scale/Index
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Scale/Index
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 55: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/55.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Table 5: BRIEF questionnaire scoring
Scale/Index Questions
BRI All from {Inhibit, Shift, and Emotional Control}
Initiate 3, 10, 16, 47, 48, 61, 66, 71
Working Memory 2, 9, 17, 19, 24, 27, 32, 33, 37, 57
Plan/Organize 11, 15, 18, 22, 35, 36, 40, 46, 51, 53, 58
Organization of Materials 4, 29, 67, 68, 69, 72
Monitor 14, 21, 31, 34, 42, 52, 60, 63
MI All from {Initiate, Working Memory, Plan/Organize, Organization of Materials, and Monitor}
GEC Score 1-72 BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite
The BRI score is the total of 28 items and ranges from 28-84. The MI score is the total of 44 items and ranges from 44 to 132.
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component scores based on the subject’s age and gender. Tables that map each raw score to the appropriate T-score are provided in the BRIEF Professional Manual and will be reproduced programmatically.
Two validity scales will also be derived: Negativity to assess the extent to which the respondent answers selected BRIEF items in an unusually negative manner, and Inconsistency to assess the extent to which the respondent answers similar BRIEF items in an inconsistent manner. The Negativity scale is the number of items in 8, 13, 23, 30, 62, 71, 80, 83, and 85 with a score of 3, and so has a range of 0 to 9. A score of 4 or less is considered acceptable, 5 and 6 elevated, and 7 or more highly elevated.
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale is the sum of the absolute values of the difference in scores for the items in each item pair, and so ranges from 0 to 20. The item pairs are questions 7 and 25, 11 and 22, 27 and 17, 33 and 32, 38 and 59, 41 and 65, 42 and 63, 44 and 54, 43 and 60, and 55 and 44. A score of 6 or less is acceptable, 7 and 8 questionable, and 9 or more inconsistent.
Calculated T-score values and change from Baseline for the 2 indexed scores (BRI and MI), and GEC for the BRIEF questionnaire will be summarized at each visit, and Last Visit, by treatment group.
All BRIEF assessment data will be listed. The means of the BRIEF assessment data will be plotted by visit.
10.4.10 Vagus nerve stimulation
Vagus nerve stimulation (VNS) status is recorded only for subjects with an implanted VNS device.
REDACTED COPY
scores are determined from each subject’s raw GEC, BRI, MI, and component
REDACTED COPY
scores are determined from each subject’s raw GEC, BRI, MI, and component scores based on the subject’s age and gender. Tables that map each raw score to the appropriate
REDACTED COPY
scores based on the subject’s age and gender. Tables that map each raw score to the appropriatescore are provided in the BRIEF Professional Manual and will be reproduced
REDACTED COPY
score are provided in the BRIEF Professional Manual and will be reproduced
Two validity scales will also be derived: Negativity to assess the extent to which the respondent REDACTED C
OPY
Two validity scales will also be derived: Negativity to assess the extent to which the respondent answers selected BRIEF items in an unusually negative manner, REDACTED C
OPY
answers selected BRIEF items in an unusually negative manner,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Initiate, Working Memory,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Initiate, Working Memory, Plan/Organize, Organization of Materials, and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Plan/Organize, Organization of Materials, and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite
84. The MI score is the total of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
84. The MI score is the total of
scores are determined from each subject’s raw GEC, BRI, MI, and component
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores are determined from each subject’s raw GEC, BRI, MI, and component scores based on the subject’s age and gender. Tables that map each raw score to the appropriate
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores based on the subject’s age and gender. Tables that map each raw score to the appropriatescore are provided in the BRIEF Professional Manual and will be reproduced
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score are provided in the BRIEF Professional Manual and will be reproduced
Two validity scales will also be derived: Negativity to assess the extent to which the respondent
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Two validity scales will also be derived: Negativity to assess the extent to which the respondent answers selected BRIEF items in an unusually negative manner,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
answers selected BRIEF items in an unusually negative manner, extent to which the respondent answers similar BRIEF items in an inconsistent manner. The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
extent to which the respondent answers similar BRIEF items in an inconsistent manner. The Negativity scale is the number of items in 8, 13, 23, 30, 62, 71, 80, 83, and 85 with a score of 3,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Negativity scale is the number of items in 8, 13, 23, 30, 62, 71, 80, 83, and 85 with a score of 3,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and so has a range of 0 to 9. A sc
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and so has a range of 0 to 9. A sc
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ore of 4 or less is considered acceptable, 5 and 6 elevated, and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ore of 4 or less is considered acceptable, 5 and 6 elevated, and
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale is the sum of the absolute values of the difference in scores for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is the sum of the absolute values of the difference in scores forranges from 0 to 20. The item pairs are questions 7 and 25, 11 and 22, 27 and 17, 33 and 32, 38
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ranges from 0 to 20. The item pairs are questions 7 and 25, 11 and 22, 27 and 17, 33 and 32, 38 and 59, 41 and 65, 42 and 63, 44 and 54, 43 and 60, and 55 and 44. A score of 6 or less is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and 59, 41 and 65, 42 and 63, 44 and 54, 43 and 60, and 55 and 44. A score of 6 or less is acceptable, 7 and 8 questionable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
acceptable, 7 and 8 questionable
Calculated T
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Calculated T-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-score values and change from Baseline for the 2 indexed scores (BRI and MI), and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
score values and change from Baseline for the 2 indexed scores (BRI and MI), and GEC for the BRIEF questionnaire will be summarized at each visit, and Last Visit, by treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
GEC for the BRIEF questionnaire will be summarized at each visit, and Last Visit, by treatment group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All BRIEF assessment data wil
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All BRIEF assessment data wilplotted by visit.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
plotted by visit.
![Page 56: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/56.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
A listing of VNS status data will be provided only for those subjects with an implanted VNS device. No summaries of VNS data are planned.
10.4.11 Ketogenic diet
A listing of ketogenic diet findings will be provided.
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 57: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/57.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
11 REFERENCES
Allison, PD. Survival Analysis Using SAS®: A Practical Guide. 2nd ed. Cary: SAS Institute; 2010
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study. Epilepsy & Behavior. 2010; 19: 352-8.
Collett D. Modelling survival data in medical research. 3rd ed. London: CRC Press; 2015
Cox DR. Regression models and life-tables. J R Stat Soc Series B Methodol. 1972;34(2):187-220.
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of lamotrigine as adjunctive therapy in subjects with primary generalized tonic-clonic seizures. Epilepsia. 2007;48(S6):77-78.
LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods for the analysis of multicentre trials. Stat Methods Med Res. 2005;14:281-301.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered analysis of variance. Biometrika. 1976;63:655-60.
SAS®/Stat 9.4: User’s Guide. Cary: SAS Institute Inc; 2015
REDACTED COPY
/Stat 9.4: User’s Guide. Cary: SAS Institute Inc; 20
REDACTED COPY
/Stat 9.4: User’s Guide. Cary: SAS Institute Inc; 2015
REDACTED COPY
15
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of clonic seizures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
clonic seizures.
based nonparametric methods for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
based nonparametric methods for the 301.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
301.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered
15
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
15
![Page 58: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/58.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
12 APPENDICES
12.1 Appendix 1: QOLIE-31-P total and subscale score calculations
The following outlines the calculation of the subscale scores for the QOLIE‑31‑P. The rescaled responses are provided for each item. The subscale scores are calculated by summing the rescaled responses for that subscale and dividing by the number of items with a non-missing response. Note that the divisors shown assume that all items for each subscale have a response; the divisor will differ if there are missing responses. A subscale score will be calculated only if at least 50% of the items within the subscale are present.
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be calculated only if at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be calculated only if at
![Page 59: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/59.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Response Final Score
Response Final Score
Scale/Item Numbers 1 2 3 4 5 6 Subtotal 0-100 point scale
Seizure Worry
30. 0 20 40 60 80 100 _____
31. 0 33.3 66.7 100 –– –– _____
32. 0 50 100 –– –– _____
33. 0 33.3 66.7 100 –– –– _____
34. 100 75 50 25 0 –– _____
TOTAL : _____ ÷ 5 = _____
Overall Quality of Life
1. Multiply each response by 10 _____
36. 100 75 50 25 0 –– _____
TOTAL : _____ ÷ 2 = _____
Emotional Well-Being
7. 0 20 40 60 80 100 _____
8. 0 20 40 60 80 100 _____
9. 100 80 60 40 20 0 _____
10. 0 20 40 60 80 100 _____
11. 100 80 60 40 20 0 _____
TOTAL : _____ ÷ 5 = _____
REDACTED COPY
REDACTED COPY
response by 10
REDACTED COPY
response by 10
50REDACTED COPY
50
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
_____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
_____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
_____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
_____
TOTAL :
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
TOTAL :
response by 10
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
response by 10
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
25
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
25
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 60: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/60.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Energy/Fatigue
2. 100 80 60 40 20 0 _____
3. 100 80 60 40 20 0 _____
4. 0 20 40 60 80 100 _____
5. 0 20 40 60 80 100 _____
TOTAL : _____ ÷ 4 = _____
Cognitive Functioning
19. 0 20 40 60 80 100 _____
20. 0 33.3 66.7 100 –– –– _____
21. 0 20 40 60 80 100 _____
22. 0 20 40 60 80 100 _____
23. 0 20 40 60 80 100 _____
24. 100 75 50 25 0 –– _____
TOTAL : _____ ÷ 6 = _____
Medication Effects
28. 0 33.3 66.7 100 –– –– _____
26. 100 75 50 25 0 –– _____
27. 100 75 50 25 0 –– _____
TOTAL : _____ ÷ 3 = _____
REDACTED COPY 80
REDACTED COPY 80
REDACTED COPY
REDACTED COPY
REDACTED COPY
60
REDACTED COPY
60
50REDACTED C
OPY
50 REDACTED C
OPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
÷ 4 =
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
÷ 4 = _____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
_____
_____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
_____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
100
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
100
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
80
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
80
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
80
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
80
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
25
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
25
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 61: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/61.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Daily Activities/Social Functioning
13. 0 20 40 60 80 100 _____
14. 0 25 50 75 100 –– _____
15. 0 25 50 75 100 –– _____
16. 100 75 50 25 0 –– _____
17. 100 75 50 25 0 –– _____
TOTAL : _____ ÷ 5 = _____
Total score is calculated as a weighted sum of the subscale scores based on the weighting shown below. Total score will be missing if at least 1 subscale score is missing. Total score will range from 0 to 100 with a higher score reflecting better functioning.
QOLIE-31-P Scale
Final Scale Score
Weight
Subtotal
Seizure worry (a) ____ 0.08 = ____ Overall quality of life (b) ____ 0.14 = ____ Emotional well-being (c) ____ 0.15 = ____ Energy/fatigue (d) ____ 0.12 = ____ Cognitive functioning (e) ____ 0.27 = ____ Medication effects (f) ____ 0.03 = ____ Daily activities/Social functioning (g) ____ 0.21 = ____ TOTAL SCORE : Sum subtotals (a) through (g)
____
REDACTED COPY Final Scale
REDACTED COPY Final Scale
Score
REDACTED COPY
Score
REDACTED COPY
(b)
REDACTED COPY
(b)(c)
REDACTED COPY
(c)(d)REDACTED C
OPY
(d)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
÷ 5 = _____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
÷ 5 = _____
Total score is calculated as a weighted sum of the subscale scores based on the weighting shown
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Total score is calculated as a weighted sum of the subscale scores based on the weighting shown al score will be missing if at least 1 subscale score is missing. Total score will range
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
al score will be missing if at least 1 subscale score is missing. Total score will range
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
____
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
________
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
____
(d)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(d)(e)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(e)(f)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(f)activities/Social functioning
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
activities/Social functioning
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
TOTAL SCORE : Sum subtotals (a) through (g)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
TOTAL SCORE : Sum subtotals (a) through (g)
![Page 62: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/62.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
12.2 Appendix 2: Adverse Events
12.2.1 Other Significant AEs
Table 6: Other Significant AEs
MedDRA Preferred Term
CARDIAC AND ECG RELATED TERMS
Atrioventricular block third degree
Atrioventricular block second degree
Bradyarrhythmia*
Bradycardia*
Cardiac pacemaker insertion
Atrial fibrillation
Atrial flutter
Sinus bradycardia*
Ventricular tachycardia
Ventricular fibrillation
Heart Rate decreased*
Sick sinus syndrome
Atrial conduction time prolongation
Atrioventricular dissociation
Conduction disorder
Cardiac fibrillation
Cardiac flutter
Sinus arrest
Torsade de pointes
Ventricular asystole
REDACTED COPY
REDACTED COPY
REDACTED COPY
tachycardia
REDACTED COPY
tachycardia
REDACTED COPY
Ventricular fibrillationREDACTED COPY
Ventricular fibrillationREDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tachycardia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tachycardia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Ventricular fibrillation
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Ventricular fibrillation
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Heart Rate decreased*
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Heart Rate decreased*
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Sick sinus syndrome
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Sick sinus syndrome
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Atrial conduction time prolongation
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Atrial conduction time prolongation
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Atrioventricular dissociation
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Atrioventricular dissociation
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 63: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/63.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
MedDRA Preferred Term
Ventricular flutter
Ventricular tachyarrhythmia
Implantable defibrillator insertion
SUICIDALITY RELATED TERMS
Completed suicide
Depression suicidal
Suicidal behavior
Suicidal ideation
Suicide attempt
Intentional self-injury
Self injurious behavior
Self-injurious ideation
Intentional overdose
Multiple drug overdose intentional
Poisoning deliberate
ADDITIONAL TERMS
Loss of consciousness
Syncope
Appetite disorder
Decreased appetite
Diet refusal
Hypophagia
Food allergy
REDACTED COPY
REDACTED COPY
injurious ideation
REDACTED COPY
injurious ideation
REDACTED COPY
Intentional overdoseREDACTED COPY
Intentional overdoseREDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Intentional overdose
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Intentional overdose
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Multiple drug overdose intentional
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Multiple drug overdose intentional
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Poisoning deliberate
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Poisoning deliberate
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ADDITIONAL TERMS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ADDITIONAL TERMS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Loss of consciousness
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Loss of consciousness
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 64: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/64.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
MedDRA Preferred Term
Abnormal behavior
*All cases with reported reduced heart rate will be reviewed and only cases with marked bradycardia (marked reduction in heart rate) with heart rate <45 bpm will be listed as ‘Other Significant AEs’.
12.2.2 List of AEs for Potentially Drug Induced Liver Injury (PDILI)
Table 7: AEs for PDILI
MedDRA Preferred Term for PDILI
Cholestasis
Cholestatic liver injury
Cholestatic pruritus
Drug-induced liver injury
Hepatitis cholestatic
Hyperbilirubinaemia
Icterus index increased
Jaundice
Jaundice cholestatic
Jaundice hepatocellular
Mixed liver injury
Ocular icterus
Acute hepatic failure
Asterixis
Cholestatic liver injury
Coma hepatic
Cryptogenic cirrhosis
REDACTED COPY induced liver injury
REDACTED COPY induced liver injury
Hepatitis cholestatic
REDACTED COPY
Hepatitis cholestatic
REDACTED COPY
Hyperbilirubinaemia
REDACTED COPY
Hyperbilirubinaemia
REDACTED COPY
Icterus index REDACTED C
OPY
Icterus index REDACTED C
OPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
induced liver injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
induced liver injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatitis cholestatic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatitis cholestatic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hyperbilirubinaemia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hyperbilirubinaemia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Icterus index
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Icterus index
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 65: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/65.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Drug-induced liver injury
Hepatic cirrhosis
Hepatic encephalopathy
Hepatic failure
Hepatic infiltration eosinophilic
Hepatic necrosis
Hepatic steatosis
Hepatitis fulminant
Hepatobiliary disease
Hepatocellular foamy cell syndrome
Hepatocellular injury
Hepatotoxicity
Liver disorder
Liver injury
Mixed liver injury
Non-alcoholic steatohepatitis
Subacute hepatic failure
Allergic hepatitis
Chronic hepatitis
Hepatitis
Hepatitis acute
Hepatitis cholestatic
Hepatitis chronic active
Hepatitis chronic persistent
REDACTED COPY Hepatocellular injury
REDACTED COPY Hepatocellular injury
Hepatotoxicity
REDACTED COPY
Hepatotoxicity
REDACTED COPY
Liver disorder
REDACTED COPY
Liver disorder
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatocellular foamy cell syndrome
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatocellular foamy cell syndrome
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatocellular injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatocellular injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatotoxicity
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hepatotoxicity
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Liver disorder
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Liver disorder
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Liver injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Liver injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Mixed liver injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Mixed liver injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 66: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/66.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Hepatitis fulminant
Hepatitis toxic
Non-alcoholic steatohepatitis
Blood bilirubin abnormal
Blood bilirubin increased
Hyperbilirubinaemia
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 67: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/67.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
12.3 Appendix 3: Markedly abnormal values
12.3.1 Hematology
Table 8: Hematology - Markedly Abnormal Values
Parameter Age Range
UNIT (conventional)
Abnormality Criteria (conventional unit)
Unit
(standard)
Abnormality Criteria (standard unit)
Hematocrit 2y - <17y %
≤29 >47
% ≤29 >47
≥17y ≤85% of LLN ≥115% of ULN
≤85% of LLN ≥115% of ULN
Hemoglobin 2y - <17y g/dL
≤9.5 >16.0
g/L ≤95 >160
≥17y ≤85% of LLN ≥115% of ULN
≤85% of LLN ≥115% of ULN
WBC/ Leukocytes
All 109/L ≤3.0 ≥16.0
G/L ≤3.0 ≥16.0
Lymphocytes Absolute
2y - <6y 109/L <0.7 >6.9
G/L <0.7 >6.9
≥6y <0.6 >5.0
<0.6 >5.0
Basophils >1m % ≥5.0 % ≥5.0
Basophils Absolute
>1m 109/L ≥0.4 G/L ≥0.4
Eosinophils >1m % ≥10 % ≥10
Eosinophils Absolute
>1m 109/L ≥1.0 G/L ≥1.0
Monocytes >1m % ≥20.0 % ≥20.0
Monocytes Absolute
>1m 109/L ≥2.0 G/L ≥2.0
Neutrophils Absolute
>1m 109/L <1.5
G/L <1.5
Platelets >1m 109/L ≤100 ≥600
G/L ≤100 ≥600
RBC/ Erythrocytes
≥2y 1012/L <3.5 T/L <3.5
Abbreviations: ANC = absolute neutrophil count; LLN = lower limit of normal; m = month; ULN = upper limit of normal; y = year.
A month is defined as 30 days; a year is defined as 365.25 days.
REDACTED COPY
>5.0
REDACTED COPY
>5.0
REDACTED COPY
≥5.0
REDACTED COPY
≥5.0
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
85%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
85% of LLN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of LLN115%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
115% of ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≤95
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≤95>160
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>160
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
G/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
G/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
G/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
G/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥0.4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥0.4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>1m
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>1m
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>1m
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>1m
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Erythrocytes
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Erythrocytes
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abbreviations: ANC = absolute neutrophil count
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abbreviations: ANC = absolute neutrophil countupper limit of normal; y = year.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
upper limit of normal; y = year.
![Page 68: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/68.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
12.3.2 Chemistry
Table 9: Chemistry: Markedly Abnormal Values
PARAMETER
AGE RANG
E
UNIT (conventional
)
ABNORMALITY CRITERIA (conventional)
UNIT (standard
)
ABNORMALITY CRITERIA
(standard) AST (SGOT) All U/L ≥3.0 x ULN
≥5.0 x ULN ≥10.0 x ULN
U/L ≥3.0 x ULN ≥5.0 x ULN ≥10.0 x ULN
ALT (SGPT) All U/L ≥3.0 x ULN ≥5.0 x ULN ≥10.0 x ULN
U/L ≥3.0 x ULN ≥5.0 x ULN ≥10.0 x ULN
Alkaline Phosphatase
4y - <10y U/L ≥834 U/L ≥834
10y - <17y
≥1761 ≥1761
≥17y ≥3.0 x ULN ≥3.0 x ULN GGT 1y - <13y U/L ≥66 U/L ≥66
13y - <17y
≥126 ≥126
≥17y ≥3.0 x ULN ≥3.0 x ULN
Total Bilirubin >1m mg/dL ≥2.0 umol/L ≥34.208
Total Protein 1y - <17y g/dL <4.3 >12.0
g/L <43 >120
≥17y <4.3 >13.0
<43 >130
Albumin ≥1y - <17y
g/dL <2.4 >8.4
g/L <24 >84
≥17y <2.6 <26
BUN 1y - <17y mg/dL ≥36 mmol/L ≥12.852
≥17y ≥40 ≥14.28 Urea ≥1y mg/dL >60 mmol/L >10.02 Creatinine 1y - <10y mg/dL >1.2 umol/L >106.8
10y - <16y
>1.8 >159.12
≥16y ≥2.0 ≥176.8
Creatinine Clearance*
All mL/min <50 mL/s <0.835
REDACTED COPY
3.0
REDACTED COPY
3.0 x ULN
REDACTED COPY
x ULN
REDACTED COPY
≥2.0
REDACTED COPY
≥2.0
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥3.0 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥3.0 x ULN≥5.0 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥5.0 x ULN10.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
10.0 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥834
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
834
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
U/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
U/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥2.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥2.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<4.3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<4.3>12.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>12.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
g/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
g/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Creatinine
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Creatinine
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 69: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/69.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
PARAMETER
AGE RANG
E
UNIT (conventional
)
ABNORMALITY CRITERIA (conventional)
UNIT (standard
)
ABNORMALITY CRITERIA
(standard) Bicarbonate >1m -
<17y mEq/L <15
>38 mmol/L <15
>38 ≥17y <18
>38 <18 >38
Calcium 1y - <17y mg/dL <7.4 >11.7
mmol/L <1.85 >2.925
≥17y ≤7.6 ≥11.0
≤1.9 ≥2.75
Chloride >1m mEq/L ≤90 ≥112
mmol/L ≤90 ≥112
Phosphorous 1y - <17y mg/dL <1.8 >7.4
mmol/L <0.5814 >2.3902
≥17y ≤2.0 ≥6.0
≤0.646 ≥1.938
Potassium ≥1y mEq/L ≤3.0 ≥6.0
mmol/L ≤3.0 ≥6.0
Sodium >1m mEq/L <127 >151
mmol/L <127 >151
Glucose >1m - <17y
mg/dL <50 ≥180
mmol/L <2.775 ≥9.99
≥17y <50 ≥200
<2.775 ≥11.1
Total Cholesterol
≥1y mg/dL >250 mmol/L >6.475
LDL (calculated)
1y - <17y mg/dL >140 mmol/L >3.626
≥17y >200 >5.18 HDL >2y mg/dL <20 mmol/L <0.518
Triglycerides ≥1y mg/dL >300 mmol/L >3.39
Uric Acid 1y - <13y mg/dL >6.5 umol/L >386.62 13y - <17y
>8.6 >511.528
≥17y >9.5 >565.06
Thyroxine (T4) ≥1y ug/dL ≤3.8 ≥13.5
nmol/L ≤48.9098 ≥173.7585
Globulin ≥1y g/dL <1.2 >5.3
g/L <12 >53
REDACTED COPY
>151
REDACTED COPY
>151
REDACTED COPY
<50
REDACTED COPY
<50≥
REDACTED COPY
≥180
REDACTED COPY
180
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2.75
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2.75
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≤90
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≤90≥112
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥112
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<0.5814
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<0.5814
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mmol/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mmol/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
180
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
180
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<50
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<50≥
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥200
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
200
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mg/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mg/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mg/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
mg/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1y -
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
- <13y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<13y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
13y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
13y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Thyroxine (T4)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Thyroxine (T4)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Globulin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Globulin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 70: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/70.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; dL = deciliter; GGT: gamma-glutamyltransferase; L = liter; LLN = lower limit of normal; m = month; mg = milligram; mmol = millimoles; μg = microgram; U = unit; ULN = upper limit of normal; y = year.
*Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine Cockroft equation (subjects >12); Male: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine); Female: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine)] x 0.85.
12.3.3 Vital signs
Abnormality criteria to be applied in the assessment of vital signs parameter values are given below:
Table 10: Vital Signs - Abnormality Criteria
Parameter Age Range Abnormality Criteria Pulse Rate (beats/minute)
3y - <12y <60 >130
12y - <17y <50 >120
≥17y <50 and a decrease from Baseline of ≥15 >120 and an increase from Baseline of ≥15 <60a >100a
Systolic Blood Pressure (mmHg)
3y - <12y <80 >140
12y - <17y <90 >160
≥17y ≤ 90 and a decrease from Baseline of ≥20 ≥ 180 and an increase from Baseline of ≥20 <90a >140a >160a
Diastolic Blood Pressure (mmHg)
3y - <12y <50 >80
12y - <17y <50 >105
≥17y <50 and a decrease from Baseline of ≥15 >105 and an increase from Baseline of ≥ 15 <50a >90a >100a
Body Weight 1m - <17y <3% or 97% of the normal body weight growth curve ranges based on gender and the age of subject on date of weight assessmenta
≥17y ≥ 10% change from Baseline (an increase or a decrease)b
≥7% change from Baseline (an increase or a decrease)a
Abbreviations: y = year.
REDACTED COPY 50 and a decrease from Baseline of ≥15
REDACTED COPY 50 and a decrease from Baseline of ≥15
120 and an increase from Baseline of ≥15
REDACTED COPY
120 and an increase from Baseline of ≥15
>100
REDACTED COPY
>100a
REDACTED COPY
a
<80
REDACTED COPY
<80>140
REDACTED COPY
>140
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abnormality criteria to be applied in the assessment of vital signs parameter values are given
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abnormality criteria to be applied in the assessment of vital signs parameter values are given
Abnormality Criteria
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abnormality Criteria
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
50 and a decrease from Baseline of ≥15
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
50 and a decrease from Baseline of ≥15120 and an increase from Baseline of ≥15
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
120 and an increase from Baseline of ≥15
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>140
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>140
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<90
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<90>160
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>160
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≤ 90 and a decrease from Baseline of ≥20
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≤ 90 and a decrease from Baseline of ≥20
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3y -
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
- <12y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<12y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Body Weight
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Body Weight
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 71: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/71.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
A month is defined as 30 days; a year is defined as 365.25 days. a Type C Meeting Written Response Dated 4 Mar 2019 (Response to the Type C Meeting Request submitted on Dec 12, 2018 to IND 057939 Sequence No. 1268 cross-reference IND 068407 and IND 073809)
bsource: http://www.cdc.gov/growthcharts/
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 72: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/72.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
12.3.4 ECGs
Abnormality criteria to be applied in the assessment of ECG parameter values are given below:
Table 11: ECGs - Abnormality Criteria
Parameter Age Abnormality Criteria QT interval (ms) 1m-<12y >500
>12y <450, 450-<480, 480-<500, >500 or <30, 30-<60, ≥60 increase from Baseline
QTc(F) (ms) 3y-<12y
>440, or >15% increase from Baseline
>12y- <17y >440, or >15% increase from Baseline
≥17y
<450, 450-<480, 480-<500, >500 or <30, 30-<60, ≥60 increase from Baseline >450, >480a
QTc(B) (ms) 3y-<12y
>450, or >15% increase from Baseline
>12y- <17y >450, or >15% increase from Baseline
≥17y
<450, 450-<480, 480-<500, >500 or <30, 30-<60, ≥60 increase from Baseline >450, >480a
PR interval (ms) 3y-<12y
>180, or >25% increase from Baseline
>12y - <17y >200, or >25% increase from Baseline ≥17y Treatment-emergent value >200, >220, >250
QRS interval (ms)
3y-<12y
>100, or >25% increase from Baseline
>12y - <17y >110, or >25% increase from Baseline ≥17y Treatment-emergent value >100, >120, >140
Heart rate (bpm)
3y-<12y <60, >130 >12y <50, >120
a Type C Meeting Written Response dated 4 Mar 2019 (Response to the Type C Meeting Request submitted on Dec 12, 2018 to IND 057939 Sequence No. 1268 cross-reference IND 068407 and IND 073809)
Abbreviations: bpm = beats per minute; m = month; ms = milliseconds; QTc = corrected QT interval; y = years.
A month is defined as 30 days; a year is defined as 365.25 days.
Note: Treatment-emergent is defined as meeting the criteria at any post-Baseline visit during the Treatment Period (including unscheduled visits) and not meeting the same criteria during Baseline.
REDACTED COPY <480, 480
REDACTED COPY <480, 480
REDACTED COPY increase from Baseline
REDACTED COPY increase from Baseline
>450, >480
REDACTED COPY
>450, >480a
REDACTED COPY
a
>180, or
REDACTED COPY
>180, or
REDACTED COPY
REDACTED COPY
>200, or
REDACTED COPY
>200, or
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
500 or <30, 30
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
500 or <30, 30-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-<60, ≥60
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<60, ≥60
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>450, or >15% increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>450, or >15% increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>450, or >15% increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>450, or >15% increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<480, 480
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<480, 480-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-<500, >
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<500, >
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>180, or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>180, or >
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>25% increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
25% increase from Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>200, or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>200, or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥17y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3y
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
eeting Written Response dat
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
eeting Written Response datIND 057939 Sequence No. 1268 cross
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IND 057939 Sequence No. 1268 cross
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abbreviations: bpm = beats per minute; m = month; ms = milliseconds; QTc = corrected QT interval; y = years.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abbreviations: bpm = beats per minute; m = month; ms = milliseconds; QTc = corrected QT interval; y = years.
A month is defined as 30 days; a year is defined as 365.25 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A month is defined as 30 days; a year is defined as 365.25 days.
Note: Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Note: Treatment(including unscheduled visits) and not meeting the same criteria during Baseline.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(including unscheduled visits) and not meeting the same criteria during Baseline.
![Page 73: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/73.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
12.4 Appendix 4: NCI CTC
Table 12: NCI CTC
Medical Term Lab parameter
Grade 1 Grade 2 Grade 3 Grade 4
Blood/bone marrow
Anemia Hemoglobin <LLN - 10.0 g/dL (C) <LLN - 6.2 mmol/L <LLN -100 g/L (S)
<10.0 - 8.0 g/dL (C) <6.2 - 4.9mmol/L <100 - 80g/L (S)
<8.0 g/dL (C) <4.9 mmol/L <80 g/L (S)
*
Neutrophil count decreased
Neutrophil count
<LLN - 1500/mm3 <LLN - 1.5 x10e9 /L (C) <LLN – 1.5G/L (S)
<1500 - 1000/mm3 <1.5 - 1.0 x10e9/L (C) <1.5 - 1.0G/L (S)
<1000 - 500/mm3 <1.0 - 0.5 x10e9/L (C) <1.0 - 0.5G/L (S)
<500/mm3 <0.5 x 10e9/L (C) <0.5G/L (S)
White blood cell decreased
White blood cell (WBC)
<LLN - 3000/mm3 <LLN - 3.0x10e9/L (C) <LLN - 3.0G/L (S)
<3000 - 2000/mm3 <3.0 - 2.0x10e9/L (C) <3.0 - 2.0G/L (S)
<2000 -1000/mm3 <2.0 - 1.0x10e9/L (C) <2.0 - 1.0G/L (S)
<1000/mm3 <1.0 x 10e9/L (C) <1.0G/L (S)
Platelet count decreased
Platelet count <LLN - 75,000/mm3 <LLN -75.0 x 10e9/L(C) <LLN -75.0G/L (S)
<75,000 - 50,000/mm3 <75.0 -50.0 x 10e9/L(C) <75.0 -50.0G/L (S)
<50,000 -25,000/mm3 <50.0 -25.0 x 10e9/L(C) <50.0 -25.0G/L (S)
<25,000/mm3 <25.0 x 10e9/L(C) <25.0G/L (S)
Lymphocyte count decreased
Lymphocyte count
<LLN-800/mm3 <LLN-0.8x10e9/L (C) <LLN-0.8G/L (S)
<800 -500/mm3 <0.8 – 0.5x10e9/L (C) <0.8 – 0.5G /L (S)
<500 - 200/mm3 <0.5 – 0.2x10e9/L (C) <0.5 – 0.2G/L (S)
<200mm3 <0.2x10e9/L (C) <0.2G/L (S)
Metabolic/chemistry GGT increased Gamma
glutaryl transferase
>ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0 x ULN
>20.0 x ULN
Hypercalcemia Calcium, corrected serum
>ULN - 11.5 mg/dL (C) >ULN - 2.9mmol/L (S)
>11.5 - 12.5 mg/dL (C) >2.9 - 3.1mmol/L (S)
>12.5 - 13.5 mg/dL (C) >3.1 - 3.4mmol/L (S)
>13.5 mg/dL (C) >3.4 mmol/L (S)
Hypocalcemia Calcium, corrected serum
<LLN - 8.0 mg/dL (C) <LLN - 2.0mmol/L (S)
<8.0 - 7.0 mg/dL (C) <2.0 - 1.75 mmol/L (S)
<7.0 - 6.0 mg/dL (C) <1.75 - 1.5mmol/L (S)
<6.0 mg/dL (C) <1.5 mmol/L (S)
Hyperglycemia Glucose, fasting
>ULN -160 mg/dL (C) >ULN - 8.9 mmol/L (S)
>160 -250 mg/dL (C) >8.9 - 13.9 mmol/L (S)
>250 - 500 mg/dL (C) >13.9 - 27.8mmol/L (S)
>500 mg/dL (C) >27.8 mmol/L (S)
Hypoglycemia Glucose <LLN - 55 mg/dL (C) <LLN - 3.0mmol/L (S)
<55 - 40 mg/dL (C) <3.0 - 2.2mmol/L (S)
<40 - 30 mg/dL (C) <2.2 - 1.7mmol/L (S)
<30 mg/dL (C) <1.7 mmol/L (S)
Hyperkalemia Potassium >ULN - 5.5 mmol/L (S)
>5.5 - 6.0 mmol/L (S)
>6.0 - 7.0 mmol/L (S)
>7.0 mmol/L (S)
Hypokalemia Potassium <LLN - 3.0 mmol/L (S)
* <3.0 - 2.5 mmol/L (S)
<2.5 mmol/L (S)
Hypernatremia Sodium >ULN - 150 mmol/L (S)
>150 - 155 mmol/L (S)
>155 - 160 mmol/L (S)
>160 mmol/L (S)
REDACTED COPY 10e9/L(C)
REDACTED COPY 10e9/L(C)
<75.0
REDACTED COPY
<75.0
REDACTED COPY
800/mm3
REDACTED COPY
800/mm30.8x10e9/L
REDACTED COPY
0.8x10e9/L
0.8G/L (S)
REDACTED COPY
0.8G/L (S)
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
Metabolic/chemistryREDACTED COPY
Metabolic/chemistryREDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<500/mm3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<500/mm3<0.5 x 10e9/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<0.5 x 10e9/L (C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(C)<0.5G/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<0.5G/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1000/mm3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1000/mm31.0x10e9/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1.0x10e9/L
<2.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<2.0 -
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
- 1.0G/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1.0G/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
50.0G/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
50.0G/L (S)
<50,000
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<50,000 25,000/mm3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
25,000/mm3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0.8G/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0.8G/L (S)
<800
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<800 500/mm3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
500/mm3<0.8
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<0.8 (C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Metabolic/chemistry
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Metabolic/chemistry
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
- 2.5 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2.5 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>ULN (C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Calcium,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Calcium, corrected
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
corrected serum
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serum
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Glucose,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Glucose,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hypoglycemia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hypoglycemia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hyperkalemia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Hyperkalemia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 74: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/74.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Medical Term Lab parameter
Grade 1 Grade 2 Grade 3 Grade 4
Hyponatremia Sodium <LLN - 130 mmol/L (S)
Not defined <130 - 120 mmol/L (S)
<120 mmol/L (S)
Hyper-triglyceridemia
Triglycerides 150 - 300 mg/dL (C) 1.71 - 3.42 mmol/L (S)
>300 - 500 mg/dL (C) >3.42 - 5.7 mmol/L (S)
>500 - 1000 mg/dL (C) >5.7 - 11.4 mmol/L (S)
>1000 mg/dL (C) >11.4 mmol/L (S)
Hyperuricemia Uric acid
>ULN - 10 mg/dL (C) >ULN - 0.5948 mmol/La >ULN – 594.8 umol/L (S)
Not defined *
>10 mg/dL (C) >0.5948 mmol/La >594.8 umol/L (S)
Hypoalbuminemia Albumin <LLN - 3 g/dL (C) <LLN - 30 g/L (S)
<3 - 2 g/dL (C) <30 - 20 g/L (S)
<2 g/dL (C) <20 g/L (S)
*
Hypo-phosphatemia
Phosphorus <LLN - 2.5 mg/dL (C) <LLN - 0.8mmol/L (S)
<2.5 - 2.0 mg/dL (C) <0.8 - 0.6mmol/L (S)
<2.0 - 1.0 mg/dL (C) <0.6 - 0.3mmol/L (S)
<1.0 mg/dL (C) <0.3 mmol/L (S)
Alanine aminotransferase increased
Alanine amino-transferase (ALT)
>ULN - 3.0 x ULN >3.0 - 5.0 x ULN >5.0 - 20.0 x ULN
>20.0 x ULN
Alkaline phosphatase increased
Alkaline phosphatase
>ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0 x ULN
>20.0 x ULN
Aspartate aminotransferase increased
Aspartate amino-transferase (AST)
>ULN - 3.0 x ULN >3.0 - 5.0 x ULN >5.0 - 20.0 x ULN
>20.0 x ULN
Blood bilirubin increased
Bilirubin >ULN - 1.5 x ULN >1.5 - 3.0 x ULN >3.0 - 10.0 x ULN
>10.0 x ULN
Cholesterol high Cholesterol, total
>ULN - 300 mg/dL (C) >ULN - 7.75mmol/L (S)
>300 - 400 mg/dL (C) >7.75-10.34 mmol/L (S)
>400 - 500 mg/dL (C) >10.34-12.92 mmol/L (S)
>500 mg/dL (C) >12.92 mmol/L (S)
Creatinine increased
Creatinine >ULN - 1.5x ULN
>1.5 - 3.0x ULN
>3.0 - 6.0 x ULN >6.0 x ULN
Abbreviations: LLN = lower limit of normal; ULN = upper limit of normal. The cutoffs are according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) (C)=Conventional units, (S)=Standard units
REDACTED COPY
>2.5
REDACTED COPY
>2.5
REDACTED COPY
REDACTED COPY
3.0 x ULN
REDACTED COPY
3.0 x ULN
REDACTED COPY
REDACTED COPY
>ULN REDACTED COPY
>ULN -REDACTED COPY
- 1.5 x ULNREDACTED COPY
1.5 x ULNREDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>10 mg/dL (C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>10 mg/dL (C)
>594.8 umol/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>594.8 umol/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
*
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
*
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1.0 mg/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1.0 mg/dL (C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(C)<0.6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<0.6 -
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
- 0.3mmol/L
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
0.3mmol/L (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5.0 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5.0 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5.0 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5.0 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>3.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>3.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1.5 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1.5 x ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>ULN -
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
- 300 mg/dL
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
300 mg/dL (C)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(C)>ULN
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>ULN (S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(S)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Creatinine
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Creatinine
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abbreviations: LLN = lower limit
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abbreviations: LLN = lower limit The cutoffs are according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The cutoffs are according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Published: May 28, 2009 (v4.03: June 14, 2010)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(C)=Conventional units, (S)=Standard units
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(C)=Conventional units, (S)=Standard units
![Page 75: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/75.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
12.5 Appendix 5: Registry Required Tables
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or Article 46 (European Pediatric Regulation). These tables will be produced at the same time as the CSR required Tables.
Disposition and Discontinuation Reasons by Development
Discontinuation due to AEs
Demographics by Development
Baseline Characteristics by Development
ILAE Seizure Classification History by Development
Classification of Epileptic Syndrome by Development
AEDs and Benzodiazepines at Study Entry by Development
Summary of Time to Second PGTCS by Development
Proportion of Subjects with Seizure Freedom at Day 166 by Development
PGTCS Frequency Observed Results and Percent Changes from Combined Baseline by Development
Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline by Development
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline by Development
Responder Status for PGCTS by Development
Responder Status for Absence Seizure Frequency by Development
Responder Status for Myoclonic Seizure Frequency by Development
Seizure-free Status for PGTCS by Development
Days with Absence Seizures Observed Results and Percent Changes from Prospective Baseline by Development
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective Baseline by Development
Increase in Absence Seizure Frequency During the Treatment Period Compared to Prospective Baseline by Development
Responder Status and Seizure Worsening for Days with Absence Seizures by Development
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective Baseline by Development
Increase in Days with Myoclonic Seizures During the Treatment Period Compared to Prospective Baseline by Development
REDACTED COPY
ency Observed Results and Percent Changes from Prospective Baseline
REDACTED COPY
ency Observed Results and Percent Changes from Prospective Baseline
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
REDACTED COPY
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
Responder Status for PGCTS by DevelopmentREDACTED COPY
Responder Status for PGCTS by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Proportion of Subjects with Seizure Freedom at Day 166 by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Proportion of Subjects with Seizure Freedom at Day 166 by Development
PGTCS Frequency Observed Results and Percent Changes from Combined Baseline by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS Frequency Observed Results and Percent Changes from Combined Baseline by
ency Observed Results and Percent Changes from Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ency Observed Results and Percent Changes from Prospective Baseline
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
Responder Status for PGCTS by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Responder Status for PGCTS by Development
nce Seizure Frequency by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nce Seizure Frequency by Development
Responder Status for Myoclonic Seizure Frequency by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Responder Status for Myoclonic Seizure Frequency by Development
free Status for PGTCS by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free Status for PGTCS by Development
Days with Absence Seizures Observed Results and Percent Changes from Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Days with Absence Seizures Observed Results and Percent Changes from Prospective Baseline
ase in Days with Absence Seizures During the Treatment Period Compared to Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ase in Days with Absence Seizures During the Treatment Period Compared to Prospective Baseline by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline by Development
Increase in Absence Seizure Frequency During the Treatment Period Compared to Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Increase in Absence Seizure Frequency During the Treatment Period Compared to Prospective Baseline by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline by Development
Responder Status and Seizure Wor
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Responder Status and Seizure Wor
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective Baseline by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline by Development
![Page 76: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/76.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Increase in Myoclonic Seizure Frequency During the Treatment Period Compared to Prospective Baseline by Development
Responder Status and Seizure Worsening for Days with Myoclonic Seizures by Development
Incidence of Absence Seizure Emergence or Worsening by Development
Incidence of Myoclonic Seizure Emergence or Worsening by Development
Seizure-free Status for All Generalized Seizure Types by Development
Study Medication Duration by Development
Cumulative Study Medication Duration by Development
Study Medication Daily Dosing by Development
Incidence of TEAEs by Development – Overview
Incidence of TEAEs by Development
Incidence of Serious TEAEs by Development
Incidence of Non-serious TEAEs
Incidence of TEAEs by Relationship and Development
Incidence of TEAEs Leading to Discontinuation by Development
Incidence of Serious TEAEs by Relationship
Incidence of Non-serious TEAEs by Relationship
Incidence of Fatal TEAEs by Relationship
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
12-Lead ECG Summary by Development
Treatment-Emergent Abnormal 12-Lead ECG Findings for Subjects by Development
12.6 Additional Subgroups to be programmed in ADSL
The following subgroup variable will also be programmed:
Subjects enrolled at Japanese study sites (Japanese, non-Japanese)
Subjects enrolled at Asian study sites (Asian, non-Asian) – Asian sites are those in Taiwan, South Korea, China and Japan
REDACTED COPY
Incidence of TEAEs Leading to Discontinuation by Development
REDACTED COPY
Incidence of TEAEs Leading to Discontinuation by Development
serious TEAEs by Relationship
REDACTED COPY
serious TEAEs by Relationship
Incidence of Fatal TEAEs by Relationship
REDACTED COPY
Incidence of Fatal TEAEs by Relationship
serious TEAEs Above Reporting REDACTED COPY
serious TEAEs Above Reporting
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs Leading to Discontinuation by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs Leading to Discontinuation by Development
serious TEAEs by Relationship
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serious TEAEs by Relationship
serious TEAEs Above Reporting
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serious TEAEs Above Reporting
serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
Lead ECG Summary by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Lead ECG Summary by Development
Emergent Abnormal 12
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Emergent Abnormal 12
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Additional Subgroups to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Additional Subgroups to
The following subgroup
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following subgroup
enrolled at Japanese study sites
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
enrolled at Japanese study sites
Subjects enrolled at Asian study sites (Asian, non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects enrolled at Asian study sites (Asian, non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
South Korea, Chin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
South Korea, Chin
![Page 77: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/77.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP)
13.1 Amendment 1
13.1.1 Rationale for the amendment
The SAP was amended to reflect changes adopted in Protocol Amendment 5 v1.0 which affected the definition of the titration and maintenance periods and the rules for pooling strata with low numbers of events in the SAP. The compliance derivation was also updated to allow for subjects that take more than 2 tablets as they titrate to a higher dose.
13.1.2 Modification and changes
13.1.2.1 Specific changes
The information below was revised:
SAP/Amendment Number Date Final SAP 09 Aug 2016
Has been changed to:
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017
Section 3.2.1, the following text was changed from:
Treatment Period: 24-week period following the 4-week Prospective Baseline. The Treatment Period is composed of the Titration Period and the Maintenance Period.
Titration Period: 6-week period following the 4-week Prospective Baseline. The Titration Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before Visit 6 (or the date of the Early Termination (ET) visit in the situation where a subject discontinues prior to the last visit in the Titration Period).
Maintenance Period: 18-week period following the 6-week Titration Period. The Maintenance Period starts on the day of Visit 6 and continues until 1 of the following occurs (whichever occurs first):
◦ Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures and completion of the ET Visit
◦ Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of 2 PGTC seizures.
And revised as follows:
Treatment Period: 24-week period following the 4-week Prospective Baseline. The Treatment Period is composed of the Titration Period and the Maintenance Period.
Titration Period: 6-week period following the 4-week Prospective Baseline. The Titration Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before
REDACTED COPY
Section 3.2.1, the following text was changed from:
REDACTED COPY
Section 3.2.1, the following text was changed from:
following the 4
REDACTED COPY
following the 4Treatment Period is composed of the Titration Period and the Maintenance Period.
REDACTED COPY
Treatment Period is composed of the Titration Period and the Maintenance Period.
week period following the 4REDACTED COPY
week period following the 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
numbers of events in the SAP. The compliance derivation was also updated to allow for subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
numbers of events in the SAP. The compliance derivation was also updated to allow for subjects
Section 3.2.1, the following text was changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 3.2.1, the following text was changed from:
following the 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
following the 4Treatment Period is composed of the Titration Period and the Maintenance Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period is composed of the Titration Period and the Maintenance Period.
week period following the 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week period following the 4Period starts on the date of the Random
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period starts on the date of the RandomVisit 6 (or the date of the Early Termination (ET) visit in the situation where a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit 6 (or the date of the Early Termination (ET) visit in the situation where a subject discontinues prior to the last visit in the Titration Period).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
discontinues prior to the last visit in the Titration Period).
Maintenance Period: 18
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Maintenance Period: 18-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-week period following the 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week period following the 6Maintenance Period starts on the day of Visit 6 and continues until 1 of the following
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Maintenance Period starts on the day of Visit 6 and continues until 1 of the following occurs (whichever occurs first):
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
occurs (whichever occurs first):
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures and completion of the ET Visit
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and completion of the ET Visit
Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of 2 PGTC seizures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2 PGTC seizures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
And revised as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
And revised as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period: 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period: 24
![Page 78: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/78.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Visit 5 (or the date of the Early Termination (ET) visit in the situation where a subject discontinues prior to the last visit in the Titration Period).
Maintenance Period: 18-week period following the 6-week Titration Period. The Maintenance Period starts on the day of Visit 5 and continues until 1 of the following occurs (whichever occurs first):
◦ Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures and completion of the ET Visit
◦ Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of 2 PGTC seizures.
Section 7, the following bullet point was changed from:
Compliance (%) = (Number of tablets dispensed – Number of tablets returned) / (Number of tablets prescribed per day (2 tablets) x Number of days between x 100.
And revised as follows:
Compliance (%) = (Number of tablets dispensed – Number of tablets returned) / (Number of tablets prescribed per day x Number of days between x 100.
Section 8.1.2, the following text was changed from:
If no events (ie, no subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
And revised as follows:
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
REDACTED COPY
If no events (ie, no subjects who had a second PGTC seizure) occur in a
REDACTED COPY
If no events (ie, no subjects who had a second PGTC seizure) occur in a be pooled by Baseline PGTC seizure frequency for analysis as follows:
REDACTED COPY
be pooled by Baseline PGTC seizure frequency for analysis as follows:
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2
REDACTED COPY
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for ana
REDACTED COPY
Baseline PGTC seizures per 28 days, then this group will be combined for anaeither the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
REDACTED COPY
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC REDACTED C
OPY
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of
Number of tablets returned) / (Number of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of tablets returned) / (Number of
Number of tablets returned) / (Number of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of tablets returned) / (Number of
If no events (ie, no subjects who had a second PGTC seizure) occur in a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events (ie, no subjects who had a second PGTC seizure) occur in a be pooled by Baseline PGTC seizure frequency for analysis as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be pooled by Baseline PGTC seizure frequency for analysis as follows:
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for ana
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for anaeither the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, whichever has the smallest number of events.
no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizure
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days.
And revised as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
And revised as follows:
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
then dat
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
then dat
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 79: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/79.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
Section 8.2.2.1, the following text was changed from:
If no events (ie, no subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
And revised as follows:
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
REDACTED COPY seizures per 28 days, whichever has the smallest number of events.
REDACTED COPY seizures per 28 days, whichever has the smallest number of events.
no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline
REDACTED COPY
no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of
REDACTED COPY
PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per
REDACTED COPY
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
REDACTED COPY
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects
REDACTED COPY
seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizurREDACTED C
OPY
who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizur
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
stratum, then data will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
stratum, then data will
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for an
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for aneither the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, whichever has the smallest number of events.
no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizur
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizur
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If 5 events or less occur in the group of subjects who are ≥12 and <18 ye
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥12 and <18 yeBaseline PGTC seizures per 28 days, then this group will be combined for analysis with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days or the group of subjects who are ≥18 years of aseizures per 28 days, whichever has the smallest number of events.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, whichever has the smallest number of events.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for a
![Page 80: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/80.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
Section 8.2.2.3, the following text was changed from:
If no events (ie, no subjects who had a PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
And revised as follows:
If 5 events or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
13.2 Amendment 2
13.2.1 Rationale for the amendment
The SAP was amended to include flexibility as an index for BRIEF-P.
REDACTED COPY Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
REDACTED COPY Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
vents or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data
REDACTED COPY
vents or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
REDACTED COPY
will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age wiREDACTED COPY
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age wi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of age with ≤2 Baseline PGTC
If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline ysis with the group of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC r analysis with the group of subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
r analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
vents or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
vents or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be pooled by Baseline PGTC seizure frequency for analysis as follows:
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age wi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age wiBaseline PGTC seizures per 28 days, then this group will be combined for analysis with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Ba
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseizures per 28 days, whichever has the smallest number of events.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, whichever has the smallest number of events.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizures per 28 days, then this group will be combined for asubjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days.
13.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
13.2
![Page 81: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/81.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
13.2.2 Modification and changes
13.2.2.1 Specific changes
The information below was revised:
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017
Has been changed to:
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017
Section 10.4.9.1, the following text was changed from:
The BRIEF-P form comprises of 63 questions which can be answered Never (scored as 1 point), Sometimes (scored as 2 points), and Often (scored as 3 points).
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges from 63 to 189, with higher scores reflecting poorer functioning.
The 2 subscale scores and 5 individual component scores that make up these subscale scores are outlined in Table 4 .
Table 4: BRIEF-P questionnaire scoring
Scale/Index Questions
Inhibit 3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Shift 5,10, 15, 20, 25, 30, 35, 40, 45, 50
Emotional Control 1, 6, 11, 16, 21, 26, 31, 36, 41, 46
BRI All from {Inhibit, Shift, and Emotional Control}
Working Memory 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Plan/Organize 4, 9, 14, 19, 24, 29, 34, 39, 44, 49
MI All from {Working Memory and Plan/Organize}
GEC Score 1-63 BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component scores based on the subject’s age and gender. Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P Professional Manual and will be reproduced programmatically.
And revised as follows:
REDACTED COPY from 63 to 189, with higher scores reflecting poorer functioning.
REDACTED COPY from 63 to 189, with higher scores reflecting poorer functioning.
The 2 subscale scores and 5 individual component scores that make up these subscale scores are
REDACTED COPY
The 2 subscale scores and 5 individual component scores that make up these subscale scores are
scoring
REDACTED COPY
scoring
REDACTED COPY
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P form comprises of 63 questions which can be answered Never (scored as 1 point),
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P form comprises of 63 questions which can be answered Never (scored as 1 point),
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges from 63 to 189, with higher scores reflecting poorer functioning.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from 63 to 189, with higher scores reflecting poorer functioning.
The 2 subscale scores and 5 individual component scores that make up these subscale scores are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The 2 subscale scores and 5 individual component scores that make up these subscale scores are
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
GEC Score
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
GEC Score
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRI=Behavioral Regulation Index, MI=Metacognition Index, GE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRI=Behavioral Regulation Index, MI=Metacognition Index, GE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Standardized T
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Standardized Tscores based on the subject’s age and gender. Tables that map each raw score to the appropriate
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores based on the subject’s age and gender. Tables that map each raw score to the appropriate
![Page 82: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/82.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The BRIEF-P form comprises of 63 questions which can be answered Never (scored as 1 point), Sometimes (scored as 2 points), and Often (scored as 3 points).
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges from 63 to 189, with higher scores reflecting poorer functioning.
The 3 subscale scores and 5 individual component scores that make up these subscale scores are outlined in Table 4 .
Table 4: BRIEF-P questionnaire scoring
Scale/Index Questions
Inhibit 3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Shift 5,10, 15, 20, 25, 30, 35, 40, 45, 50
Emotional Control 1, 6, 11, 16, 21, 26, 31, 36, 41, 46
Inhibitory self-control All from {Inhibit and Emotional Control}
Flexibility All from {Shift and Emotional Control}
Working Memory 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Plan/Organize 4, 9, 14, 19, 24, 29, 34, 39, 44, 49
Emergent metacognition All from {Working Memory and Plan/Organize}
GEC Score 1-63 GEC=Global Executive Composite
Standardized T-scores are determined from each subject’s raw GEC, inhibitory self-control, flexibility, emergent metacognition, and component scores based on the subject’s age and gender. Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P Professional Manual and will be reproduced programmatically.
13.3 Amendment 3
13.3.1 Rationale for the amendment
The SAP was amended to reflect changes adopted in Protocol Amendment 5 v4.0. The primary purpose of Protocol Amendment 5 v4.0 was to stop the subjects’ study participation once 125 events are observed to avoid exposing subjects to placebo unnecessarily. This SAP amendment provides more detail in how PGTCS data will be analyzed for the primary and secondary efficacy endpoints. In general, all variables and all statistical analyses are more clarified.
13.3.2 Modification and changes
13.3.2.1 Specific changes
The information below was revised from:
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017
REDACTED COPY 59, 61, 63
REDACTED COPY 59, 61, 63
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
REDACTED COPY
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
REDACTED COPY
scores are determined from each subject’s raw GEC, REDACTED COPY
scores are determined from each subject’s raw GEC,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
30, 35, 40, 45, 50
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
30, 35, 40, 45, 50
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1, 6, 11, 16, 21, 26, 31, 36, 41, 46
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1, 6, 11, 16, 21, 26, 31, 36, 41, 46
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Inhibit and Emotional Control}
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Inhibit and Emotional Control}
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Shift and Emotional Control}
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Shift and Emotional Control}
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 59, 61, 63
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
59, 61, 63
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Working Memory and Plan/Organize}
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All from {Working Memory and Plan/Organize}
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
1-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-63
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
63
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores are determined from each subject’s raw GEC,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores are determined from each subject’s raw GEC, and component scores based on the subject’s age and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and component scores based on the subject’s age and gender. Tables that map each raw score to the appropriate T
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
gender. Tables that map each raw score to the appropriate TProfessional Manual and will be reproduced progr
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Professional Manual and will be reproduced progr
Amendment 3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Amendment 3
Rationale for the amendment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Rationale for the amendment
The SAP was amended to reflect changes adopted in Protocol Amendment 5 v4.0. The primary
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The SAP was amended to reflect changes adopted in Protocol Amendment 5 v4.0. The primary
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
purpose of Protocol Amendment 5 v4.0 was to stop the subjects’ study participation once 125
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
purpose of Protocol Amendment 5 v4.0 was to stop the subjects’ study participation once 125 events are observed to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
events are observed toprovides more detail in how PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
provides more detail in how PGTCefficacy endpoints. In general, all variables and all statistical analyses are more clarified.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
efficacy endpoints. In general, all variables and all statistical analyses are more clarified.
13.3.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
13.3.2
13.3.2.1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
13.3.2.1
The information below was revised from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The information below was revised from:
![Page 83: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/83.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Amendment #2 14 Mar 2017
has been revised to:
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019
The following abbreviations were revised from:
IGE idiopathic generalized epilepsy
ILAE International League Against Epilepsy
IRT Interactive response technology
LCM lacosamide
LLN lower limit of normal
MedDRA Medical Dictionary for Regulatory Activities
MI Metacognition Index
PCH percent change
PedsQL Pediatric Quality of Life Inventory
PGTC primary generalized tonic-clonic
Has been revised to:
IGE idiopathic generalized epilepsy
IIA Absence seizures
IIB Myoclonic seizures
IIC Clonic seizures
IID Tonic seizures
IIE (primary generalized) tonic-clonic seizures
IIF Atonic seizures
III Unclassified seizures
ILAE International League Against Epilepsy
IRT Interactive response technology
KM Kaplan-Meier
LCM Lacosamide
LLN lower limit of normal
MedDRA Medical Dictionary for Regulatory Activities
MI Metacognition Index
REDACTED COPY
Pediatric Quality of Life Inventory
REDACTED COPY
Pediatric Quality of Life Inventory
primary generalized tonic
REDACTED COPY
primary generalized tonic
idiopathic REDACTED COPY
idiopathic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Medical Dictionary for Regulatory Activities
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Medical Dictionary for Regulatory Activities
Pediatric Quality of Life Inventory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Pediatric Quality of Life Inventory
primary generalized tonic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
primary generalized tonic
idiopathic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
idiopathic generalized epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
generalized epilepsy
Absence seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Absence seizures
Myoclonic seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Myoclonic seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IRT
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IRT
KM
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
KM
LCM
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
LCM
![Page 84: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/84.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
NCI CTC National Cancer Institute Common Terminology Criteria for Adverse Events
PCH percent change
PedsQL Pediatric Quality of Life Inventory
PGTC primary generalized tonic-clonic
PGTCS Primary generalized tonic-clonic seizure
Section 2.2.1.2 Secondary efficacy variables were changed from:
The key secondary efficacy variable is:
Seizure freedom for during the 24-week Treatment Period, estimated using Kaplan-Meier analysis
The other secondary efficacy variables are:
The percent change in PGTC seizure frequency per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Combined Baseline (combined 12-week Historical and 4-week Prospective Baseline)
The percent change in PGTC seizure frequency per 28 days during the Treatment Period relative to the Combined Baseline
Time to the first PGTC seizure during the 24-week Treatment Period
And revised as follows:
The key secondary efficacy variable is:
Seizure freedom for PGTCS during the 24-week Treatment Period, estimated using Kaplan-Meier analysis
The other secondary efficacy variable is:
Time to first seizure during the 24-week Treatment Period
Section 2.2.1.3 Other efficacy variables were changed from:
Other efficacy variables are:
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days compared to Prospective Baseline
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
REDACTED COPY The percent change in PGTC seizure frequency per 28 days
REDACTED COPY The percent change in PGTC seizure frequency per 28 days
week Treatment Period
REDACTED COPY
week Treatment Period
Seizure freedom for PGTCS during the 24REDACTED COPY
Seizure freedom for PGTCS during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period, estimated using Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period, estimated using Kaplan-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-Meier
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Meier
during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the first 6 weeks of the the Combined Baseline (combined 12
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the Combined Baseline (combined 12
The percent change in PGTC seizure frequency per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change in PGTC seizure frequency per 28 days during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the Treatment Period
week Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period
Seizure freedom for PGTCS during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure freedom for PGTCS during the 24-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-week Treatment Period, estimated using Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period, estimated using Kaplan
The other secondary efficacy variable is:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The other secondary efficacy variable is:
Time to first seizure during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Time to first seizure during the 24
Section 2.2.1.3 Other efficacy variables were changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 2.2.1.3 Other efficacy variables were changed from:
Other efficacy variables are:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Other efficacy variables are:
Change in days with absence seizures per 28 days during the Treatment Period relative to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Ba
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seline
Percent change in days with absence seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with absence seizures per 28 days Treatment Period (Titration Period) relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with absence seizures per 28 days re
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 85: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/85.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to Prospective Baseline
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the first 12 weeks of the Treatment Period compared to Combined Baseline
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the Treatment Period compared to Combined Baseline
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment Period
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total scores in subjects <18 years of age
Change from Baseline to end of treatment or early termination (ET) in the 3-Level EuroQol-5 Dimension Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and change in utility as converted from the 5 dimensions (for subjects ≥12 years of age)
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
Number of working or school days lost by subject due to epilepsy
Number of days with help from a caregiver due to epilepsy
And revised as follows:
Other efficacy variables are:
The percent change in PGTCS frequency per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Combined Baseline Period (combined 12-week Historical and 4-week Prospective Baseline Periods)
The percent change in PGTCS frequency per 28 days during the first 12 weeks of the Treatment Period relative to the Combined Baseline Period
REDACTED COPY
Weighted Qualit
REDACTED COPY
Weighted Quality of Life in Epilepsy Inventory
REDACTED COPY y of Life in Epilepsy Inventory
P) subscale (Seizure Worry, Daily Activities/Social Functioning,
REDACTED COPY
P) subscale (Seizure Worry, Daily Activities/Social Functioning, being, Mental Activity/Cognitive Functioning, Overall
REDACTED COPY
being, Mental Activity/Cognitive Functioning, Overall Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or
REDACTED COPY
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical
REDACTED COPY
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical ng, Emotional Functioning, Social Functioning, and School Functioning) and total REDACTED C
OPY
ng, Emotional Functioning, Social Functioning, and School Functioning) and total
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the
bjects with at least a 50% reduction in PGTC seizure frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
bjects with at least a 50% reduction in PGTC seizure frequency during the
seizure types for the first 12 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure types for the first 12 weeks of the
seizure types for the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure types for the 24
y of Life in Epilepsy Inventory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
y of Life in Epilepsy InventoryP) subscale (Seizure Worry, Daily Activities/Social Functioning,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P) subscale (Seizure Worry, Daily Activities/Social Functioning, being, Mental Activity/Cognitive Functioning, Overall
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
being, Mental Activity/Cognitive Functioning, Overall Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical ng, Emotional Functioning, Social Functioning, and School Functioning) and total
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ng, Emotional Functioning, Social Functioning, and School Functioning) and total scores in subjects <18 years of age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
scores in subjects <18 years of age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change from Baseline to end of treatment or early termination (ET) in the 3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change from Baseline to end of treatment or early termination (ET) in the 3Dimension Quality of Life Assessment (EQ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Dimension Quality of Life Assessment (EQchange in utility as converted from the 5 dimensions (for subjects ≥12 years of age)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
change in utility as converted from the 5 dimensions (for subjects ≥12 years of age)
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
Number of working or school days lost
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of working or school days lost
Number of days with help from a caregiver
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of days with help from a caregiver
And revised as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
And revised as follows:
Other efficacy variables are:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Other efficacy variables are:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change in PGTCS frequency per 28 days during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change in PGTCS frequency per 28 days during the first 6 weeks of the Treatment Period (Titration Period)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period (Titration Period)
![Page 86: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/86.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The percent change in PGTCS frequency per 28 days during the Treatment Period relative to the Combined Baseline Period
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
Percent change in days with absence seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline Period
Percent change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
Percentage of subjects with at least a 50% reduction in absence seizure days compared to Prospective Baseline Period
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline Period
Percent change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline Period
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to Prospective Baseline Period
Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Titration Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to Combined Baseline Period
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Treatment Period compared to Combined Baseline Period
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment Period
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total scores in subjects <18 years of age
REDACTED COPY
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to
REDACTED COPY
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to
for the first 12 weeks of the Treatment Peri
REDACTED COPY
for the first 12 weeks of the Treatment Peri
free status (yes, no) for PGTCS for the 24
REDACTED COPY
free status (yes, no) for PGTCS for the 24
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the REDACTED COPY
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure days compared to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure days compared to
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period (Titration Period) relative to the Prospective Baseline Period
Percent change in days with myoclonic seizures per 28 days during the Treatmen
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 days during the Treatmen
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to
for the first 12 weeks of the Treatment Peri
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for the first 12 weeks of the Treatment Peri
free status (yes, no) for PGTCS for the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for PGTCS for the 24
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Titration Period compared to Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Titration Period compared to Combined Baseline Period
Percentage of subjects with at least a 50%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50%weeks of the Treatment Period compared to Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks of the Treatment Period compared to Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Treatment Period compared to Combined Baseline Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to Combined Baseline Period
free status (yes, no) for all generalized seizure types for the f
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for all generalized seizure types for the fTreatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period
free status (yes, no) for all generalized seizure types for the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for all generalized seizure types for the 24Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period
Change from Baseline in Patient
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change from Baseline in Patient(QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(QOLIEEnergy/Fatigue, Emotional Well
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Energy/Fatigue, Emotional Well
![Page 87: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/87.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Change from Baseline to end of treatment or early termination (ET) in the 3-Level EuroQol-5 Dimension Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and change in utility as converted from the 5 dimensions (for subjects ≥12 years of age)
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
Number of working or school days lost by subject due to epilepsy
Number of days with help from a caregiver due to epilepsy
Section 2.2.2 was revised from:
The safety variables are:
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed by the investigator
Subject withdrawal due to AEs
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
Changes in 12-lead electrocardiograms (ECGs)
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body weight and height) and physical and neurological examination findings
Incidence of new seizure types during the Treatment Period
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
And revised as follows:
The safety variable is:
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed by the investigator
Section 2.2.2.1 was revised from:
Other safety variables are:
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½-5 or CBCL/6-18)
Cognitive function assessment (Behavior Rating Inventory of Executive Function®-Preschool Version [BRIEF-P] or Behavior Rating Inventory of Executive Function® [BRIEF])
And revised as follows:
Other safety variables are:
Subject withdrawal due to AEs
Incidence of new seizure types during the Treatment Period
REDACTED COPY weight and height) and physical and neurological examination findings
REDACTED COPY weight and height) and physical and neurological examination findings
Incidence of new seizure types during the Treatment Period
REDACTED COPY
Incidence of new seizure types during the Treatment Period
with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days
REDACTED COPY
with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with absence seizures per 28 days during the Treatment Period relative to the Prospective
REDACTED COPY
with absence seizures per 28 days during the Treatment Period relative to the Prospective
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in tREDACTED COPY
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or observed
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body weight and height) and physical and neurological examination findings
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weight and height) and physical and neurological examination findings
Incidence of new seizure types during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of new seizure types during the Treatment Period
with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with absence seizures per 28 days during the Treatment Period relative to the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with absence seizures per 28 days during the Treatment Period relative to the Prospective
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in twith myoclonic seizures per 28 days during the Treatment Period relative to the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed nvestigator
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nvestigator
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 2.2.2.1 was revised from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 2.2.2.1 was revised from:
Other safety variables are:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Other safety variables are:
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½
Cognitive function assessment (Behavior Rating Inventory of Executive Function
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Cognitive function assessment (Behavior Rating Inventory of Executive FunctionVersion
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Version
And revised as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
And revised as follows:
![Page 88: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/88.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
Changes in 12-lead electrocardiograms (ECGs)
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body weight and height) and physical and neurological examination findings
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½-5 or CBCL/6-18)
Cognitive function assessment (Behavior Rating Inventory of Executive Function®-Preschool Version [BRIEF-P] or Behavior Rating Inventory of Executive Function® [BRIEF]) for pediatric subjects only
Section 2.3.1, 2nd paragraph was revised from:
Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a total of 125 events, where an event is defined as the occurrence of the second PGTC seizure.
Has been revised to:
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible extension to other countries and regions, are planned to be randomized in this study to see 125 events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of study medication administration is 28 weeks. The study will last a maximum of 36 weeks per subject.
Section 2.3.1, 5th paragraph, the following sentence was added:
Seizures reported on the Historical Seizure Count CRF with incomplete dates will be assumed to have occurred with the 12-week Historical Baseline Period when checking eligibility for the study and inclusion in baseline PGTCS frequency per 28 days.
Section 2.3.1, 2nd paragraph from end, newly states:
If the 125th event occurs while the subject is still participating in the study, the subject can:
Complete the Visit 10 (Week 24) or ET Visit (if the next scheduled visit is not Visit 10) and choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic Visit.
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next scheduled visit is not Visit 10) and an up to 4-week blinded taper followed by an End of Taper visit.
Section 2.4, 2nd paragraph was revised from:
This is an event-driven study. The study will be closed to enrollment once 125 events have been observed. If 125 events are observed prior to 200 randomized subjects, then enrollment will stop
REDACTED COPY Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a
REDACTED COPY Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a
events, where an event is defined as the occurrence of the second PGTC seizure.
REDACTED COPY
events, where an event is defined as the occurrence of the second PGTC seizure.
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible
REDACTED COPY
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible extension to other countries and regions, are
REDACTED COPY
extension to other countries and regions, are planned to be randomized in this study to see 125
REDACTED COPY
planned to be randomized in this study to see 125 events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of
REDACTED COPY
events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of study medication administration is 28 weeks. The study will last a maximum of 36 weeks per REDACTED C
OPY
study medication administration is 28 weeks. The study will last a maximum of 36 weeks per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
d pulse rate) (including body
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
d pulse rate) (including body
5 or CBCL/6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
5 or CBCL/6
Cognitive function assessment (Behavior Rating Inventory of Executive Fu
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Cognitive function assessment (Behavior Rating Inventory of Executive Function
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nctionP] or Behavior Rating Inventory of Executive Function
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P] or Behavior Rating Inventory of Executive Function®
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
®
Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a events, where an event is defined as the occurrence of the second PGTC seizure.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
events, where an event is defined as the occurrence of the second PGTC seizure.
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible planned to be randomized in this study to see 125
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
planned to be randomized in this study to see 125 events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of study medication administration is 28 weeks. The study will last a maximum of 36 weeks per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
study medication administration is 28 weeks. The study will last a maximum of 36 weeks per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
paragraph, the following sentence was added:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
paragraph, the following sentence was added:
Seizures reported on the Historical Seizure Count CRF with incomplete dates will be assumed to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizures reported on the Historical Seizure Count CRF with incomplete dates will be assumed to week Historical Baseline Period when checking eligibility for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Historical Baseline Period when checking eligibility for the inclusion in baseline PGTCS frequency per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
inclusion in baseline PGTCS frequency per 28 days.
paragraph from end, newly states:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
paragraph from end, newly states:
event occurs while the subject is still participating in the study, the subject can:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event occurs while the subject is still participating in the study, the subject can:
Complete the Visit 10 (Week 24) or ET Visit (if the ne
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Complete the Visit 10 (Week 24) or ET Visit (if the ne
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic Visit.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next
![Page 89: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/89.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
and fewer than 200 subjects will be randomized. However, if 125 events are not observed after 200 subjects are randomized, then the study will continue to enroll up to a maximum of 250 subjects randomized or 125 events, whichever occurs first.
Has been revised to:
This is an event-driven study. Enrollment in the study will continue up to 125 events occurring or a maximum of 250 subjects randomized, whichever comes first.
Section 3.1 was revised from:
Statistical analysis and generation of tables, figures, subject data listings, and statistical output will be performed using SAS® Version 9.4 or higher.
Descriptive statistics will be used to provide an overview of the primary, secondary, and other variable results. For categorical parameters, the number and percentage of subjects in each category will be presented. The denominator for percentages will be based on the number of subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place except 100% which will be displayed to 0 decimal places. For continuous parameters, descriptive statistics will include number of subjects, mean, standard deviation, median, minimum, and maximum.
By-visit summaries will not include data from unscheduled clinic visits unless otherwise stated. Data provided at these visits will be included in subject data listings. Subject data listings will be provided and will present source data and key derived variables for statistical analyses.
Was revised to:
Statistical analysis and generation of tables, figures, subject data listings, and statistical output will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier New font size 9.
Descriptive statistics will be used to provide an overview of the primary, secondary, and other variable results. For categorical parameters, the number and percentage of subjects in each category will be presented. The denominator for percentages will be based on the number of subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will be displayed for zero counts, and no decimal will be presented when the percentage is 100%. For continuous parameters, descriptive statistics will include number of subjects, mean, standard deviation, median, minimum, and maximum.
Decimal places for descriptive statistics will always apply the following rules:
“n” will be an integer
Mean, SD and median will use 1 additional decimal place compared to the original data.
Minimum and maximum will have the same number of decimal places as the original value.
By-visit summaries will not include data from unscheduled clinic visits unless otherwise stated. Data provided at these visits will be included in subject data listings. A complete set of data listings containing all documented data and all calculated data (eg, change from Baseline) will be generated.
Section 3.2.1, Analysis Time Points, the following sentence was inserted:
REDACTED COPY t summaries will not include data from unscheduled clinic visits unless otherwise stated.
REDACTED COPY t summaries will not include data from unscheduled clinic visits unless otherwise stated.
Data provided at these visits will be included in subject data listings. Subject data listings will be
REDACTED COPY
Data provided at these visits will be included in subject data listings. Subject data listings will be provided and will present source data and key derived variables
REDACTED COPY
provided and will present source data and key derived variables
Statistical analysis and generation of tables, figures, subject data listings, and statistical output
REDACTED COPY
Statistical analysis and generation of tables, figures, subject data listings, and statistical output will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier
REDACTED COPY
will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tatistical analysis and generation of tables, figures, subject data listings, and statistical output
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tatistical analysis and generation of tables, figures, subject data listings, and statistical output
Descriptive statistics will be used to provide an overview of the primary, secondary, and other
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics will be used to provide an overview of the primary, secondary, and other le results. For categorical parameters, the number and percentage of subjects in each
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
le results. For categorical parameters, the number and percentage of subjects in each category will be presented. The denominator for percentages will be based on the number of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
category will be presented. The denominator for percentages will be based on the number of subjects appropriate for the purpose of the analysis. Unless otherwise noted, a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ll percentages will be displayed to 1 decimal place except 100% which will be displayed to 0 decimal places. For
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be displayed to 1 decimal place except 100% which will be displayed to 0 decimal places. For continuous parameters, descriptive statistics will include number of subjects, mean, standard
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
continuous parameters, descriptive statistics will include number of subjects, mean, standard
t summaries will not include data from unscheduled clinic visits unless otherwise stated.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
t summaries will not include data from unscheduled clinic visits unless otherwise stated. Data provided at these visits will be included in subject data listings. Subject data listings will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Data provided at these visits will be included in subject data listings. Subject data listings will be provided and will present source data and key derived variables
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
provided and will present source data and key derived variables
Statistical analysis and generation of tables, figures, subject data listings, and statistical output
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Statistical analysis and generation of tables, figures, subject data listings, and statistical output will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier
escriptive statistics will be used to provide an overview of the primary, secondary, and other
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
escriptive statistics will be used to provide an overview of the primary, secondary, and other variable results. For categorical parameters, the number and percentage of subjects in each
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
variable results. For categorical parameters, the number and percentage of subjects in each category will be presented. The denominator for percentages will be b
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
category will be presented. The denominator for percentages will be bsubjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will be displayed for zero counts, and no decimal
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be displayed to 1 decimal place. No percentage will be displayed for zero counts, and no decimal will be presented when the percentage
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be presented when the percentage will include number of subjects, mean, standard deviation, median, minimum, and maximum.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will include number of subjects, mean, standard deviation, median, minimum, and maximum.
Decimal places for descriptive statistics will always apply the following rules:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Decimal places for descriptive statistics will always apply the following rules:
“n” will be an integer
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
“n” will be an integer
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Mea
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Mea
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
n, SD and median will use 1 additional decimal place compared to the original data.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
n, SD and median will use 1 additional decimal place compared to the original data.
Minimum and maximum will have the same number of decimal places as the original value.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Minimum and maximum will have the same number of decimal places as the original value.
By
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
By visit summaries will not include data from unscheduled clinic visits unless otherw
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
visit summaries will not include data from unscheduled clinic visits unless otherwData provided at these visits will be included in subject data listings. A complete set of data
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Data provided at these visits will be included in subject data listings. A complete set of data
![Page 90: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/90.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
First 12 weeks: this is defined as the Titration Period + the first 6 weeks of the Maintenance Period
Section 3.2.2, Seizure cluster, this section was moved to occur earlier in Section 3 and the text was revised from:
For PGTC seizures, if a seizure cluster is reported, it will be assigned to the most dominant ILAE seizure type and the frequency will be set to 2 times the number of clusters reported.
Was revised to:
If a seizure cluster is reported, it will be assigned to the International League Against Epilepsy (ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters reported.
Section 3.2.3, Event, was added:
In the primary efficacy analysis, an event for analysis purposes is:
The 2nd PGTCS
While keeping in mind the definition of seizure clusters in Section 3.2.2.
For the primary and secondary efficacy analyses, these endpoints will be assessed using the at most the first 166 days, which is the 24-week Treatment Period minus a protocol-allowed 2 day window. For all other efficacy parameters, all data reported during the Treatment Period will be used in the analysis.
The primary efficacy endpoint, time to event, is defined as the “stop date” - the date of first dose of study drug + 1 day where the “stop date” is the first of the following to occur:
date of the event,
date of the premature discontinuation,
date of last dose of study medication in the Treatment Period,
date of the completion of the Treatment Period,
date of the 125th event,
Day 166
The same algorithm applies for the other secondary endpoint, where time to event, is replaced by time to 1st PGTCS.
Section 3.2.4, Censoring, was revised from:
Subjects who complete the Treatment Period without having a second PGTC seizure during the Treatment Period will be censored. If the subject’s Treatment Period participation is less than 24 weeks minus the visit window for Visit 10, they will be censored on the date of the last dose of study drug. If the subject’s Treatment Period participation is greater than 24 weeks minus the visit window for Visit 10, they will be censored as of 24 weeks minus the visit window for Visit 10.
Subjects who have important protocol deviations for inappropriate use of AEDs and benzodiazepines will be censored. The important protocol deviations and rules for censoring due
REDACTED COPY week Treatment Period minus a protocol
REDACTED COPY week Treatment Period minus a protocol
window. For all other efficacy parameters, all data reported during the Treatment Period will be
REDACTED COPY
window. For all other efficacy parameters, all data reported during the Treatment Period will be
fficacy endpoint, time to event, is defined as the “stop date”
REDACTED COPY
fficacy endpoint, time to event, is defined as the “stop date” of study drug + 1 day where the “stop date” is the first of the following to occur:
REDACTED COPY
of study drug + 1 day where the “stop date” is the first of the following to occur:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
o the International League Against Epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
o the International League Against Epilepsy (ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters
3.2.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3.2.2
For the primary and secondary efficacy analyses, these endpoints w
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the primary and secondary efficacy analyses, these endpoints will be assessed using the at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ill be assessed using the at week Treatment Period minus a protocol
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period minus a protocolwindow. For all other efficacy parameters, all data reported during the Treatment Period will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
window. For all other efficacy parameters, all data reported during the Treatment Period will be
fficacy endpoint, time to event, is defined as the “stop date”
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
fficacy endpoint, time to event, is defined as the “stop date” of study drug + 1 day where the “stop date” is the first of the following to occur:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of study drug + 1 day where the “stop date” is the first of the following to occur:
date of the premature discontinuation,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of the premature discontinuation,
dy medication in the Treatment Period,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dy medication in the Treatment Period,
date of the completion of the Treatment Period,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of the completion of the Treatment Period,
event,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The same algorithm applies for the other secondary endpoint, where time to event, is replaced by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The same algorithm applies for the other secondary endpoint, where time to event, is replaced by PGTCS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS.
Section 3.2.4, Cen
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 3.2.4, Cen
Subjects who complete the Treatment Period without having a second PGTC seizure during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects who complete the Treatment Period without having a second PGTC seizure during the Treatment Period will be censored. If the subject’s Treatment Period participation is less than
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period will be censored. If the subject’s Treatment Period participation is less than 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
24 weeks minus the visit window for Visit 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks minus the visit window for Visit 1of study drug. If the subject’s Treatment Period participation is greater than 24 weeks minus the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of study drug. If the subject’s Treatment Period participation is greater than 24 weeks minus the visit window for Visit 10, they will be censored as of 24 weeks minus the visit window for Visit
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
visit window for Visit 10, they will be censored as of 24 weeks minus the visit window for Visit
![Page 91: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/91.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
to important protocol deviations will be determined and documented prior to the database lock and unblinding.
Has been changed to:
For the primary and secondary efficacy analyses, a Treatment Period of 166 days will be utilized. The censoring for the primary efficacy analysis will be as follows:
Subjects who complete the Treatment Period without having an event during the Treatment Period will be censored as of Day 167.
If the subject’s Treatment Period participation is less than or equal to 166 days (premature discontinuation), their PGTCS information will be censored on the date after the last dose of study drug.
If the subject’s Treatment Period participation is greater than 166 days, their PGTCS information will be censored as of Day 167.
For the subjects who are ongoing in the study when the 125th event occurs, their PGTCS information for the primary efficacy endpoint analysis will be censored as of the day after the 125th event, even if the subjects experience an event after the date of the 125th event but before 166 days of treatment is completed.
Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on the same date in reporting the 125th event, the first event reported to IRT will be deemed the 125th event. Data after the 125th event will be censored.
Censoring for time to 1st PGTCS will be calculated in a similar manner, except using the date of the 1st PGTCS instead of the date of the event. For subjects who are ongoing in the study when the 125th event occurs, the time to 1st PGTCS information will be censored in the same manner as the time to event information (ie., censor all PGTCS information beyond the date of the 125th event).
Section 3.2.5, AEDs and Benzodiazepines, the 1st paragraph has been revised from:
Antiepileptic drugs and benzodiazepines (medications used for rescue) will be collected on the concomitant and prior medication case report form (CRF) for AEDs. At study entry, a subject should be taking 1 to 2 non-benzodiazepines or 1 to 3 AEDs where only 1 of the AEDs is identified as a benzodiazepine. This dosing regimen must be stable for at least 28 days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline and the Treatment Period.
Has been changed to:
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant and prior medication case report form (CRF) for AEDs. At study entry, a subject should be taking a stable dose of 1 to 2 non-benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1 of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for at least 28 days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline and the Treatment Period with or without additional concurrent stable VNS. Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with
REDACTED COPY Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on
REDACTED COPY Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on
event, the first event reported to IRT will be deemed the
REDACTED COPY
event, the first event reported to IRT will be deemed the event will be censored.
REDACTED COPY
event will be censored.
will be calculated in a similar manner, except using the date of
REDACTED COPY
will be calculated in a similar manner, except using the date of PGTCS instead of the date of the event. For subjects who are ongoing in the study when
REDACTED COPY
PGTCS instead of the date of the event. For subjects who are ongoing in the study when PGTCS information will be cenREDACTED C
OPY
PGTCS information will be cenas the time to event information (ie., censor all PGTCS information beyond the date of the 125REDACTED C
OPY
as the time to event information (ie., censor all PGTCS information beyond the date of the 125
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the subject’s Treatment Period participation is less than or equal to 166 days (premature
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the subject’s Treatment Period participation is less than or equal to 166 days (premature discontinuation), their PGTCS information will be censored on the date after the last dose of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
discontinuation), their PGTCS information will be censored on the date after the last dose of
er than 166 days, their PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
er than 166 days, their PGTCS
event occurs, their PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event occurs, their PGTCS information for the primary efficacy endpoint analysis will be censored as of the day after the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
information for the primary efficacy endpoint analysis will be censored as of the day after the event, even if the subjects experience an event after the date of the 125
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event, even if the subjects experience an event after the date of the 125
Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on event, the first event reported to IRT will be deemed the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event, the first event reported to IRT will be deemed the event will be censored.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event will be censored.
will be calculated in a similar manner, except using the date of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be calculated in a similar manner, except using the date of PGTCS instead of the date of the event. For subjects who are ongoing in the study when
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS instead of the date of the event. For subjects who are ongoing in the study when PGTCS information will be cen
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS information will be cenas the time to event information (ie., censor all PGTCS information beyond the date of the 125
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as the time to event information (ie., censor all PGTCS information beyond the date of the 125
Section 3.2.5, AEDs and Benzodiazepines, the 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 3.2.5, AEDs and Benzodiazepines, the 1
Antiepileptic drugs and benzodiazepines (med
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Antiepileptic drugs and benzodiazepines (medconcomitant and prior medication case report form (CRF) for AEDs. At study entry, a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
concomitant and prior medication case report form (CRF) for AEDs. At study entry, a subject should be taking 1 to 2 non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
should be taking 1 to 2 non-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-benzodiazepines or 1 to 3 AEDs where only 1 of the AEDs is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
benzodiazepines or 1 to 3 AEDs where only 1 of the AEDs is identified as a benzodiaze
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
identified as a benzodiazepine. This dosing regimen must be stable for at least 28 days prior to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
pine. This dosing regimen must be stable for at least 28 days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline and the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and the Treatment Period.
Has been changed to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been changed to:
AEDs and benzodiazepines (medications used
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
AEDs and benzodiazepines (medications used and prior medication case report form (CRF) for AEDs. At study entry, a subject should be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and prior medication case report form (CRF) for AEDs. At study entry, a subject should be taking a stable dose of 1 to 2 non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
taking a stable dose of 1 to 2 nonof the AEDs is identifie
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the AEDs is identifiedays prior to Visit 1. The subject must maintain this AED dosing regimen throughout the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the
![Page 92: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/92.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the Treatment Period.
Section 3.2.5.1, Prohibited concomitant treatments, has been added:
The following medications/therapies are prohibited during the Treatment Period:
Clozapine
Any MAO inhibitors
Barbiturates (except as antiepileptic medications)
Unstable dosing of non-benzodiazepine anxiolytics or once-daily hypnotics
Herbal medicines for epilepsy
The study physician will review the concomitant medications and flag prohibited medications.
Section 3.2.8, Month, has been added:
A month is defined as 28 days.
Section 3.3, Definition of baseline values, the 2nd paragraph had been revised from:
Baseline values for seizure data will be based on data collected during the Combined Baseline Period, excluding data collected on the day of Visit 2.
Has been revised to:
For PGTCS efficacy analyses, the data used for Baseline calculations come from the Combined Baseline Period. For absence and myoclonic seizure analyses, the data used for Baseline calculations come from the Prospective Baseline Period only.
Section 3.9, Changes to protocol-defined analyses, has been revised from:
There are no changes to analyses specified in the protocol.
Has been revised to:
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis. The analysis of the key secondary endpoint has been clarified to assess the seizure-free rate using an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates within each stratum. The extended Mantel-Haenszel technique is a randomization-based nonparametric method that provides a more robust method to assess seizure freedom.
Section 4.2.1, Missing seizure diary days, 2nd paragraph has been revised from:
For the purpose of the derivation of the primary endpoint of time to second PGTC seizure and for PGTC seizure-free status, if there are seizure counts reported as “not done” on a specific day, then the seizure count will be assumed to be zero on that date.
Has been changed to:
For the purpose of the derivation of the primary efficacy endpoint, secondary efficacy endpoints and for PGTC seizure-free status, if there are PGTCS counts reported as “not done” on a specific day, then the PGTCS count will be assumed to be zero on that date.
REDACTED COPY Baseline values for seizure data will be based on data collected during the Combined Baseline
REDACTED COPY Baseline values for seizure data will be based on data collected during the Combined Baseline
Period, excluding data collected on the day of Visit 2.
REDACTED COPY Period, excluding data collected on the day of Visit 2.
For PGTCS efficacy analyses, the data used for Baseline calculations
REDACTED COPY
For PGTCS efficacy analyses, the data used for Baseline calculationsBaseline Period. For absence and myoclonic seizure analyses, the data used for Baseline
REDACTED COPY
Baseline Period. For absence and myoclonic seizure analyses, the data used for Baseline calculations come from the Prospective Baseline Period only.
REDACTED COPY
calculations come from the Prospective Baseline Period only.
defined analyses, has been revised from:REDACTED COPY
defined analyses, has been revised from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The study physician will review the concomitant medications and flag prohibited medications.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The study physician will review the concomitant medications and flag prohibited medications.
paragraph had be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
paragraph had been revised from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
en revised from:
Baseline values for seizure data will be based on data collected during the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values for seizure data will be based on data collected during the Combined Baseline
For PGTCS efficacy analyses, the data used for Baseline calculations
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For PGTCS efficacy analyses, the data used for Baseline calculationsBaseline Period. For absence and myoclonic seizure analyses, the data used for Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period. For absence and myoclonic seizure analyses, the data used for Baseline calculations come from the Prospective Baseline Period only.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
calculations come from the Prospective Baseline Period only.
defined analyses, has been revised from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
defined analyses, has been revised from:
are no changes to analyses specified in the protocol.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
are no changes to analyses specified in the protocol.
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for week Treatment Period, will be estimated using Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period, will be estimated using KaplanThe analysis of the key secondary endpoint has been clarified to assess the seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The analysis of the key secondary endpoint has been clarified to assess the seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
an extended Mantel
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
an extended Mantel
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-Haenszel technique which combines Kaplan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Haenszel technique which combines Kaplanstratum. The extended Mantel
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
stratum. The extended Mantelmethod that provides a more robust method to assess seizure freedom.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
method that provides a more robust method to assess seizure freedom.
Section 4.2.1, Missing seizure diary days, 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 4.2.1, Missing seizure diary days, 2
For the purpose of the derivation of the primary endpoint of time to second PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the purpose of the derivation of the primary endpoint of time to second PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for PGTC seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for PGTC seizurethen the seizure count will be assumed to be zero on that date.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
then the seizure count will be assumed to be zero on that date.
Has been changed to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been changed to:
![Page 93: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/93.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Section 4.2.2, Incomplete dates for first epilepsy diagnosis, the following final imputation note was added:
Missing the day, month and year:
No imputation will be done.
Section 4.4, Multicenter studies, was revised from:
Due to the small number of subjects per site, pooling the sites for statistical analysis will be necessary. All sites will be pooled together for analysis.
has been changed to:
Due to the small number of subjects per site, all sites will be pooled together for analysis. There will be no planned analyses for multi-center effects.
Section 4.8, Examination of subgroups, was revised from:
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the FAS. Disposition will be presented by age subgroup for the SS and FAS. Exposure will be presented by age and region subgroups for the SS. Overall TEAE incidence will be presented by age subgroup for the SS. Selected disposition and safety analyses will be presented by age at enrollment for the purpose of addressing requirements set in Article 46 of the European Pediatric Regulation (see Section 12.5 for further details).
The subgroups to be examined include:
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
Racial group (white, non-white)
Gender (male, female)
Region
North America: United States
Latin America: Brazil, Mexico
Western Europe: Belgium, France, Germany, Italy, Portugal, Spain
Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, Turkey
Asia/Pacific/Other: Australia, Israel, Japan, South Korea, Taiwan
Baseline PGTC seizure frequency (≤2 per 28 days and >2 per 28 days in the Combined Baseline Period)
Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the subject is taking when enrolled into the study (1, 2, 3).
Separate age sub-groupings are used for the purpose of summarizing the following scales:
PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years)
Achenbach CBCL (4 to 5 years, 6 to 18 years)
REDACTED COPY enrollment for the purpose of addressing requirements set in Article 46 of the E
REDACTED COPY enrollment for the purpose of addressing requirements set in Article 46 of the E
Age at enrollment (≥ 4 to <12 years of ag
REDACTED COPY
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
REDACTED COPY
e, ≥12 to <18 years of age, 18 to <65, ≥65)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Due to the small number of subjects per site, all sites will be pooled together for analysis. There
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Due to the small number of subjects per site, all sites will be pooled together for analysis. There
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the FAS. Disposition will be presented by age subgroup for the SS and FAS. Exposure will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
FAS. Disposition will be presented by age subgroup for the SS and FAS. Exposure will be ge and region subgroups for the SS. Overall TEAE incidence will be presented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ge and region subgroups for the SS. Overall TEAE incidence will be presented by age subgroup for the SS. Selected disposition and safety analyses will be presented by age at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
age subgroup for the SS. Selected disposition and safety analyses will be presented by age at enrollment for the purpose of addressing requirements set in Article 46 of the E
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
enrollment for the purpose of addressing requirements set in Article 46 of the E
e, ≥12 to <18 years of age, 18 to <65, ≥65)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e, ≥12 to <18 years of age, 18 to <65, ≥65)
North America: United States
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
North America: United States
Latin America: Brazil, Mexico
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Latin America: Brazil, Mexico
Western Europe: Belgium, France, Germany, Italy, Portugal, Spain
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Western Europe: Belgium, France, Germany, Italy, Portugal, Spain
Eastern Europe: Bulgaria,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Eastern Europe: Bulgaria,
Asia/Pacific/Other: Australia, Israel, Japan, South Korea, Taiwan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Asia/Pacific/Other: Australia, Israel, Japan, South Korea, Taiwan
Baseline PGTC seizure frequency (≤2 per 28 days and >2 per 28 days in the Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizure frequency (≤2 per 28 days and >2 per 28 days in the Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period)
Concomitant AEDs at stu
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Concomitant AEDs at stusubject is taking when enrolled into the study (1, 2, 3).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subject is taking when enrolled into the study (1, 2, 3).
![Page 94: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/94.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
BRIEF-P/BRIEF (4 to <5 years, ≥5 years).
Has been changed to:
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the FAS. Disposition will be presented by age subgroup for the SS and FAS. Exposure will be presented by age and region subgroups for the SS. Overall TEAE incidence will be presented by age subgroup for the SS. Selected disposition and safety analyses will be presented by Development for the purpose of addressing requirements set in Article 46 of the European Pediatric Regulation (see Section 12.5 for further details).
The subgroups to be examined include:
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
Development (Pediatric [≥4 to < 18 years old], Adult [≥18 years old])
Racial group (white, non-white)
Gender (male, female)
Region
North America: United States, Puerto Rico
Latin America: Brazil, Mexico
Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland, Portugal, Slovakia, Spain
Eastern Europe: Bulgaria, Romania, Russia, Turkey
Asia/Pacific/Other: Australia, China, Israel, Japan, South Korea, Taiwan
Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baseline Period)
Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the subject is taking when enrolled into the study (1, 2, 3).
Separate age sub-groupings are used for the purpose of summarizing the following scales:
PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years)
Achenbach CBCL (4 to 5 years, 6 to 18 years)
BRIEF-P/BRIEF (4 to <5 years, ≥5 years).
Section 4.9, Stratum Pooling has been moved from a later section and the algorithm modified from saying:
The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
1. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
REDACTED COPY
Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy,
REDACTED COPY
Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy,
Eastern Europe: Bulgaria, Romania, Russia, Turkey
REDACTED COPY
Eastern Europe: Bulgaria, Romania, Russia, Turkey
stralia, China, Israel, Japan, South Korea, TaiwanREDACTED COPY
stralia, China, Israel, Japan, South Korea, Taiwan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65)
Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy,
Eastern Europe: Bulgaria, Romania, Russia, Turkey
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Eastern Europe: Bulgaria, Romania, Russia, Turkey
stralia, China, Israel, Japan, South Korea, Taiwan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
stralia, China, Israel, Japan, South Korea, Taiwan
Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baseline
Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the subject is taking when enro
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subject is taking when enrolled into the study (1, 2, 3).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lled into the study (1, 2, 3).
groupings are used for the purpose of summarizing the following scales:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
groupings are used for the purpose of summarizing the following scales:
PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years)
Achenbach CBCL (4 to 5 years, 6 to 18 years)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Achenbach CBCL (4 to 5 years, 6 to 18 years)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRIEF
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
BRIEF-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P/BRIEF (4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P/BRIEF (4
Section 4.9, Stratum Pooling has been moved from a later section and the algorithm modified
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 4.9, Stratum Pooling has been moved from a later section and the algorithm modified from saying:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
from saying:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects who had a second PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who had a second PGTC
![Page 95: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/95.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
2. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
3. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
4. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
Has been revised to:
The stratification factors for this study are Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analyses will use the stratification factors from IRT.
To determine if strata pooling should occur for time to event (2nd PGTCS) analysis:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age at informed consent categories will be summed.
If 2 of the age at informed consent categories combined have < 3 total events, then all age categories are combined for the analysis.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
If ≥18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the strata with the 2nd smallest number of events.
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to determine stratum pooling.
Time to 1st PGTCS analyses:
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that “events” will now be in reference to subjects having only 1 PGTCS.
Seizure freedom analyses:
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that “events” will now be in reference to subjects having 0 PGTCS.
Section 5.1, Subject disposition, the 3rd paragraph was modified from:
The overall number and percentage of subjects who completed and discontinued from the study will be presented for the SS, FAS and PPS including number and percentages for each reason for
REDACTED COPY ling should occur for time to event (2
REDACTED COPY ling should occur for time to event (2
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
REDACTED COPY
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age at informed consent categories will be summed.
REDACTED COPY
at informed consent categories will be summed.
If 2 of the age at informed consent categories combin
REDACTED COPY
If 2 of the age at informed consent categories combincategories are combined for the analysis.
REDACTED COPY
categories are combined for the analysis.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events REDACTED COPY
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.REDACTED C
OPY
or less, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizures per 28 days, then this group will be combined for analysis with the group of ears of age with ≤2 Baseline PGTC seizures per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ears of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
ncy (≤2 per 28 days vs >2 per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ncy (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥4 to <12 years of age,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
28 days in the Combined Baseline Period) and age at informed consent (≥4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analyses will use the stratification factors from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥12 to <18 years of age vs ≥18 years of age). The analyses will use the stratification factors from
ling should occur for time to event (2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ling should occur for time to event (2nd
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nd PGTCS) analysis:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS) analysis:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
If 2 of the age at informed consent categories combin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 2 of the age at informed consent categories combin
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or less, it should be combined with the ≥12 and <18 years of age category.
18 years of age is the category with the smallest number of events that are 2 events or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
less, it should be combined with the ≥12 and <18 years of age category.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2 or less, it should be combined with the strata with the 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or less, it should be combined with the strata with the 2
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to determine stratum pooling.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
determine stratum pooling.
PGTCS analyses:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS analyses:
The prior algorithm f
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The prior algorithm f“events” will now be in reference to subjects having only 1 PGTCS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
“events” will now be in reference to subjects having only 1 PGTCS.
Seizure freedom analyses:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure freedom analyses:
The prior algorithm for stratum pooling will be used to determine stratum pooling, except
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The prior algorithm for stratum pooling will be used to determine stratum pooling, except“events” will now be in reference to subjects having 0 PGTCS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
“events” will now be in reference to subjects having 0 PGTCS.
![Page 96: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/96.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
discontinuation. The completion of the study is defined as meeting any of the predetermined exit criteria or experiencing <2 PGTC seizures within the 24-week treatment period. Discontinuation is defined as the completion of the ET Visit. This summary will be repeated for specific subgroups as detailed in Section 4.8 for the SS and FAS. The study termination information will be presented in the subject data listings.
Has been changed to:
The overall number and percentage of subjects who completed and discontinued from the study will be presented for the SS, FAS, and PPS including number and percentages for each reason for discontinuation. The completion of the study is defined as meeting any of the predetermined exit criteria (including when the 125th event has occurred) or experiencing <2 PGTCS within the 24-week treatment period. Discontinuation is defined as the completion of the ET Visit in all other cases. This summary will be repeated for specific subgroups as detailed in Section 4.8 for the SS and FAS. The study termination information will be presented in the subject data listings.
Section 6.2.2, Analysis of baseline characteristics, the 2nd paragraph has been changed from:
The following Baseline characteristics will also be presented:
Time since first diagnosis at date of consent
Age at diagnosis of the disease
International League Against Epilepsy (ILAE) Seizure classification history
Classification of epileptic syndrome
Etiology of epilepsy
Has been changed to:
The following Baseline characteristics will also be presented:
Time since first diagnosis at date of consent
Age at diagnosis of epilepsy
Number of lifetime AEDs and Benzodiazepines (0, 1-3, 4-6, ≥7)
Concomitant benzodiazepine use at study entry (yes, no)
ILAE (1989) Seizure classification history
Classification of epileptic syndrome
Etiology of epilepsy
Section 7, Measurements of Treatment Compliance, the following text was removed:
For oral solution, compliance will be calculated using the following formula:
Compliance (%) = Actual weight of used oral solution (g) / Expected weight of used oral solution (g) x 100.
For tablets, compliance will be calculated using the following formula:
REDACTED COPY
International League Against Epilepsy (ILAE) Seizure classification history
REDACTED COPY
International League Against Epilepsy (ILAE) Seizure classification history
following Baseline characteristics will also be presented:REDACTED COPY
following Baseline characteristics will also be presented:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The overall number and percentage of subjects who completed and discontinued from the study
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The overall number and percentage of subjects who completed and discontinued from the study number and percentages for each reason
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
number and percentages for each reason for discontinuation. The completion of the study is defined as meeting any of the predetermined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for discontinuation. The completion of the study is defined as meeting any of the predetermined event has occurred) or experiencing <2 PGTCS within the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event has occurred) or experiencing <2 PGTCS within the Discontinuation is defined as the completion of the ET Visit in all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Discontinuation is defined as the completion of the ET Visit in all other cases. This summary will be repeated for specific subgroups as detailed in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
other cases. This summary will be repeated for specific subgroups as detailed in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the SS and FAS. The study termination information will be presented in the subject data listings.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the SS and FAS. The study termination information will be presented in the subject data listings.
paragraph has been changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
paragraph has been changed from:
International League Against Epilepsy (ILAE) Seizure classification history
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
International League Against Epilepsy (ILAE) Seizure classification history
following Baseline characteristics will also be presented:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
following Baseline characteristics will also be presented:
Time since first diagnosis at date of consent
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Time since first diagnosis at date of consent
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Age at diagnosis of epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Age at diagnosis of epilepsy
Number of lifetime AEDs and Benzodiazepines (0, 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Number of lifetime AEDs and Benzodiazepines (0, 1
Concomitant benzodiazepine use at study entry (yes, no)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Concomitant benzodiazepine use at study entry (yes, no)
E (1989) Seizure classification history
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
E (1989) Seizure classification history
Classification of epileptic syndrome
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Classification of epileptic syndrome
Etiology of epilepsy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Etiology of epilepsy
Section 7, Measurements of Treatment Compliance, the following text was removed:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 7, Measurements of Treatment Compliance, the following text was removed:
For oral solution, compliance will be calculated using the following formula:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For oral solution, compliance will be calculated using the following formula:
Compliance (%) = Actual weight of used oral solution (g) / Expected weight of used oral
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Compliance (%) = Actual weight of used oral solution (g) / Expected weight of used oral
![Page 97: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/97.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Compliance (%) = (Number of tablets dispensed – Number of tablets returned) / (Number of tablets prescribed per day x Number of days between x 100.
Rates of compliance will be calculated and summarized by category: <75%, 75-125%, >125%.
Section 8, Efficacy Analyses, were revised from:
All efficacy analyses will be performed using the FAS population.
For all efficacy analyses, only data up to and including the day of the second PGTC seizure, the Visit 10 date or the last maintenance dose date, whichever is earlier, will be included. All seizure diary data will be listed including data not included in the efficacy analyses.
Testing for the primary endpoint will be done at the 5% level (2-sided). Provided that the primary endpoint is statistically significant, a gatekeeping strategy will be used to test the key secondary efficacy variable. No additional adjustments for multiplicity are required as all additional inferences will be hypothesis-generating only.
Has been revised to:
Most efficacy analyses will be performed using the FAS population; in other cases, the population will be stated.
For primary efficacy endpoint analyses, only data up to and including the day of the event, the Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125th event, whichever is earlier, will be included. For the secondary efficacy endpoint analyses, only data up to and including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day 166 or the date of the 125th event, whichever is earlier, will be included. For all other exploratory efficacy variables, all appropriate seizure data during the Treatment Period, will be included. All seizure diary data will be listed including data not included in efficacy analyses.
Testing for the primary efficacy endpoint will be done at the 5% level (2-sided). Provided that the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to test the key secondary efficacy variable, seizure freedom. No additional adjustments for multiplicity are required as all additional inferences will be hypothesis-generating only.
Section 8.1.1, Derivations of primary efficacy variable, has been revised from:
For PGTC seizures, the number of days until the second seizure will be derived using the date of the second PGTC seizure – date of first dose of study medication +1. For subjects who prematurely discontinue or complete the 24-week Treatment Period prior to having a second PGTC seizure, time to censor will be calculated as the date of censoring - date of first dose of study medication + 1. Only data up to Week 24 will be included. Censoring of subjects for this analysis will be as described in Section 3.2.2.If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that day.
Has been changed to:
For the primary efficacy variable, an event and how time to event is calculated is described in Section 3.2.3, keeping in mind Section 3.2.2. Censoring of subjects for this analysis will be as described in Section 3.2.4 . If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that day.
Section 8.1.2, Primary analysis of the primary efficacy variable, has been modified from:
REDACTED COPY For primary efficacy endpoint analyses, only data up to and including the day of the event, the
REDACTED COPY For primary efficacy endpoint analyses, only data up to and including the day of the event, the
Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125
REDACTED COPY Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125
is earlier, will be included. For the secondary effica
REDACTED COPY
is earlier, will be included. For the secondary efficacy endpoint analyses, only data up to and
REDACTED COPY
cy endpoint analyses, only data up to and including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day
REDACTED COPY
including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day event, whichever is earlier, will be included. For all other exploratory
REDACTED COPY
event, whichever is earlier, will be included. For all other exploratory bles, all appropriate seizure data during the Treatment Period, will be included. All
REDACTED COPY
bles, all appropriate seizure data during the Treatment Period, will be included. All seizure diary data will be listed including data not included in efficacy analyses.
REDACTED COPY
seizure diary data will be listed including data not included in efficacy analyses.
Testing for the primary efficacy endpoint will be done at the 5% level (2REDACTED COPY
Testing for the primary efficacy endpoint will be done at the 5% level (2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For all efficacy analyses, only data up to and including the day of the second PGTC seizure, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For all efficacy analyses, only data up to and including the day of the second PGTC seizure, the Visit 10 date or the last maintenance dose date, whichever is earlier, will be included. All seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit 10 date or the last maintenance dose date, whichever is earlier, will be included. All seizure
sided). Provided that the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
sided). Provided that the primary endpoint is statistically significant, a gatekeeping strategy will be used to test the key
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
primary endpoint is statistically significant, a gatekeeping strategy will be used to test the key riable. No additional adjustments for multiplicity are required as all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
riable. No additional adjustments for multiplicity are required as all
; in other cases, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
; in other cases, the
For primary efficacy endpoint analyses, only data up to and including the day of the event, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For primary efficacy endpoint analyses, only data up to and including the day of the event, the Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125cy endpoint analyses, only data up to and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
cy endpoint analyses, only data up to and including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day event, whichever is earlier, will be included. For all other exploratory
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event, whichever is earlier, will be included. For all other exploratory bles, all appropriate seizure data during the Treatment Period, will be included. All
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
bles, all appropriate seizure data during the Treatment Period, will be included. All seizure diary data will be listed including data not included in efficacy analyses.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure diary data will be listed including data not included in efficacy analyses.
Testing for the primary efficacy endpoint will be done at the 5% level (2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Testing for the primary efficacy endpoint will be done at the 5% level (2the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to test the key secondary efficacy variable, seizure freedom. No additional adjustments for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
test the key secondary efficacy variable, seizure freedom. No additional adjustments for multiplicity are required as all additional inferences wil
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
multiplicity are required as all additional inferences wil
Section 8.1.1, Derivations of primary efficacy variable, has been revised from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.1.1, Derivations of primary efficacy variable, has been revised from:
For PGTC seizures, the number of days until the second seizure will be derived using the date of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For PGTC seizures, the number of days until the second seizure will be derived using the date of the second PGTC seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the second PGTC seizure prematurely discontinue or complete the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
prematurely discontinue or complete the 24PGTC seizure, time to censor will be calculated as the date of censoring
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizure, time to censor will be calculated as the date of censoring
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
study medication + 1. Only da
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
study medication + 1. Only daanalysis will be as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
analysis will be as described in be assumed that no seizures occurred on that day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be assumed that no seizures occurred on that day.
Has been changed to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been changed to:
For the primary efficacy variable, an event and how time to event is calculated is described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the primary efficacy variable, an event and how time to event is calculated is described in
![Page 98: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/98.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The primary efficacy variable, time to second PGTC seizure during the 24-week Treatment Period, will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
5. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
6. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
7. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
8. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
The stratified HR will be calculated using the placebo arm as the reference group.
Additionally, a KM plot for time to second PGTC seizure as well as the KM estimate for the median time to second PGTC seizure will be provided. If the median time is not estimable, then the 25th percentile will be provided.
Has been changed to:
The primary efficacy variable, time to event during the 166-day Treatment Period, will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section 4.9.
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
H0: β=0
Versus
H1: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented by
REDACTED COPY If 5 events or less occur in the group of subjects who are ≥18
REDACTED COPY If 5 events or less occur in the group of subjects who are ≥18
PGTC seizures per 28 days, then this group will be combined for analysis with the group of
REDACTED COPY PGTC seizures per 28 days, then this group will be combined for analysis with the group of
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
REDACTED COPY
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
Similarly, rules 1 to 3 apply to those age group
REDACTED COPY
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
REDACTED COPY
s within subjects with > 2 Baseline PGTC
The stratified HR will be calculated using the placebo arm as the reference group.REDACTED C
OPY
The stratified HR will be calculated using the placebo arm as the reference group.
Additionally, a KM plot for time to second PGTC seizure as well as the KM estimate for the REDACTED COPY
Additionally, a KM plot for time to second PGTC seizure as well as the KM estimate for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of ageBaseline PGTC seizures per 28 days, then this group will be combined for analysis with the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
If 5 events or less occur in the group of subjects who are ≥18
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
s within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
s within subjects with > 2 Baseline PGTC
The stratified HR will be calculated using the placebo arm as the reference group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified HR will be calculated using the placebo arm as the reference group.
Additionally, a KM plot for time to second PGTC seizure as well as the KM estimate for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Additionally, a KM plot for time to second PGTC seizure as well as the KM estimate for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ond PGTC seizure will be provided. If the median time is not estimable, then
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ond PGTC seizure will be provided. If the median time is not estimable, then percentile will be provided.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
percentile will be provided.
The primary efficacy variable, time to event during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The primary efficacy variable, time to event during the evaluated using a Cox proport
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
evaluated using a Cox proporttreatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days in the Combined Baseline Period) and age at informed consent (≥ 4≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
IRT and pooled as described in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
Versus
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Versus
![Page 99: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/99.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The assumptions of proportional hazards will also be checked.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. The SE and 95% CI for the HR will also be reported.
Additionally, a Kaplan-Meier (KM) plot for time to event as well as the KM estimate for the median time to event and 95% CI will be provided. If the median time is not estimable, then the 25th percentile and 95% CI will be provided. The number of events will be reported by treatment group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects who were censored in the analysis.
Section 8.1.3, Secondary analyses of the primary efficacy variable, has been changed from:
The summary of time to the second PGTC seizure during the 24-week Treatment Period will be presented by subgroup for the FAS. A KM plot for time to second PGTC seizure by selected subgroups will also be provided.
Has been changed to:
The summary of time to the event during the 166-day Treatment Period will be presented by all subgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be provided.
Section 8.1.4, Supportive and sensitivity analyses of the primary efficacy variable, has been changed from:
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted in order to assess the effect of dropouts, important protocol deviations, and operational bias on the primary endpoint:
Repeat the primary analysis using the PPS.
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed as treatment failures (ie, events at the time of discontinuation).
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures.
Repeat the primary analysis using the FAS, comparing the event rates prior to vs after each interim analysis to examine possible operational bias due to unblinding.
Has been changed to:
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted in order to assess the effect of dropouts, important protocol deviations, and operational bias on the primary endpoint:
Repeat the primary efficacy analysis using the PPS.
REDACTED COPY
166
REDACTED COPY
166-
REDACTED COPY
-day
REDACTED COPY
daysubgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be
REDACTED COPY
subgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be
REDACTED COPY
Section 8.1.4, Supportive and sensitivity analyses of the primary efficacy variable,REDACTED C
OPY
Section 8.1.4, Supportive and sensitivity analyses of the primary efficacy variable,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group.
ime to event as well as the KM estimate for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ime to event as well as the KM estimate for the median time to event and 95% CI will be provided. If the median time is not estimable, then the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
median time to event and 95% CI will be provided. If the median time is not estimable, then the percentile and 95% CI will be provided. The number of events will be reported by treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
percentile and 95% CI will be provided. The number of events will be reported by treatment as well as the % of subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as well as the % of subjects
Section 8.1.3, Secondary analyses of the primary efficacy variable, has been changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.1.3, Secondary analyses of the primary efficacy variable, has been changed from:
week Treatment Period will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period will be presented by subgroup for the FAS. A KM plot for time to second PGTC seizure by selected
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
presented by subgroup for the FAS. A KM plot for time to second PGTC seizure by selected
day
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day Treatment Period will be presented by all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period will be presented by all subgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.1.4, Supportive and sensitivity analyses of the primary efficacy variable,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.1.4, Supportive and sensitivity analyses of the primary efficacy variable,
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted in order to assess the effect of dropouts, important protocol deviations, and operational bias on
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in order to assess the effect of dropouts, important protocol deviations, and operational bias on
imary analysis using the PPS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
imary analysis using the PPS.
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy, consent withdrawn, or lost to follow
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
due to lack of efficacy, consent withdrawn, or lost to follow
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
failures (ie, events at the time of disc
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
failures (ie, events at the time of disc
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
due to lack of efficacy or AEs only will be analyzed as treatment failures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary analysis using the FAS, comparing the event rates prior
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary analysis using the FAS, comparing the event rates prior interim analysis to examine possible operational bias due to unblinding.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
interim analysis to examine possible operational bias due to unblinding.
Has been changed to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been changed to:
![Page 100: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/100.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events) through each subject’s first 166 days of treatment, on the FAS.
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed as treatment failures (ie, events at the time of discontinuation).
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures.
Repeat the primary efficacy analysis using the FAS, comparing the event rates prior to vs after each interim analysis to examine possible operational bias due to unblinding.
Section 8.2.1.1, Seizure freedom for PGTCS for the 166-day Treatment Period, has been modified from:
A seizure-free day will be defined as a day where no PGTC seizures were reported in the seizure diary and seizures were assessed. Days in the seizure diary which are marked as “not done” on the CRF will be counted as a seizure free day.
A subject will have seizure freedom (seizure free status=yes) for the 24-week Treatment Period if the subject completed the Treatment Period and reported zero seizures or “not done” for all days during the Treatment Period.
Has been changed to:
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the seizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not done” on the CRF will be counted as seizure-free days from PGTCS.
A subject will have seizure freedom from PGTCS for the 166-day Treatment Period if the subject completed the Treatment Period and reported zero PGTCS or “not done” for all days during the 166-day Treatment Period. Ongoing subjects who are seizure-free from PGTCS on the date of the 125th event do not have seizure-freedom from PGTCS unless they are seizure-free from PGTCS for 166 days.
Section 8.2.1.2, Time to 1st PGTCS during the 166-day Treatment Period, has been changed from:
For PGTC seizures, the number of days until the first seizure will be derived using the date of the first PGTC seizure – date of first dose of study medication +1. For subjects who prematurely discontinue or complete the 24-week Treatment Period prior to having a PGTC seizure, time to censor will be calculated as the date of censoring - date of first dose of study medication + 1. Only data up to Week 24 will be included. Censoring of subjects for this analysis will be as described in Section 3.2.2.
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that seizure diary day.
Has been changed to:
For PGTCS, how the time to first PGTCS is calculated is described in Section 3.2.3. Censoring of subjects for this analysis will be as described in Section 3.2.4 .
REDACTED COPY
free day from PGTCS will be defined as a day where no PGTCS were repor
REDACTED COPY
free day from PGTCS will be defined as a day where no PGTCS were reporseizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not
REDACTED COPY
seizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not done” on the CRF will be counted as seizure
REDACTED COPY
done” on the CRF will be counted as seizure-
REDACTED COPY
-free days from PGTCS.
REDACTED COPY
free days from PGTCS.
A subject will have seizure freedom from PGTCS for the REDACTED COPY
A subject will have seizure freedom from PGTCS for the subject completed the Treatment Period and reported zero PGTCS or “not done” for all days REDACTED C
OPY
subject completed the Treatment Period and reported zero PGTCS or “not done” for all days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nt rates prior to vs
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nt rates prior to vs
Treatment Period, has been
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period, has been
no PGTC seizures were reported in the seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
no PGTC seizures were reported in the seizure diary and seizures were assessed. Days in the seizure diary which are marked as “not done” on
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
diary and seizures were assessed. Days in the seizure diary which are marked as “not done” on
A subject will have seizure freedom (seizure free status=yes) for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A subject will have seizure freedom (seizure free status=yes) for the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
24 week Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period if the subject completed the Treatment Period and reported zero seizures or “not done” for all
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
if the subject completed the Treatment Period and reported zero seizures or “not done” for all
free day from PGTCS will be defined as a day where no PGTCS were repor
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free day from PGTCS will be defined as a day where no PGTCS were reporseizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not free days from PGTCS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free days from PGTCS.
A subject will have seizure freedom from PGTCS for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A subject will have seizure freedom from PGTCS for the subject completed the Treatment Period and reported zero PGTCS or “not done” for all days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subject completed the Treatment Period and reported zero PGTCS or “not done” for all days Treatment Period. Ongoing subjects who are seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period. Ongoing subjects who are seizuredate of the 125th event do not have seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of the 125th event do not have seizure
PGTCS during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For PGTC seizures, the number of days until the first seizure will be derived using the date
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For PGTC seizures, the number of days until the first seizure will be derived using the datefirst PGTC seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first PGTC seizure –
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
– date of first dose of study medication +1. For subjects who prematurely
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
date of first dose of study medication +1. For subjects who prematurely discontinue or complete the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
discontinue or complete the 24censor will be calculated as the date of censoring
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
censor will be calculated as the date of censoring Only data up to Week 24 will be included. Censoring of subjects for this analysis will be as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Only data up to Week 24 will be included. Censoring of subjects for this analysis will be as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
described in
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that seizure diary day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure diary day.
![Page 101: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/101.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that seizure diary day.
Section 8.2.2 has been updated to:
Analyses of secondary efficacy variables will be performed for the FAS.
Section 8.2.2.1: Seizure freedom for the 166-day Treatment Period, has been modified from:
Analysis of the key secondary efficacy variable, seizure freedom for PGTC seizures for the 24-week Treatment Period, will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
9. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
10. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
11. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
12. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
The percentage of seizure-free subjects at 24 weeks will be estimated from the KM estimates of time to first seizure using 2-sided 95% confidence intervals. A stratified estimate of the seizure freedom rate in each treatment arm will be derived using KM methods to estimate the seizure freedom rate for each stratum and then combining the rates using a Cochran-Mantel-Haenszel-like approach. The stratified HR will be calculated using the placebo arm as the reference group.
If the primary endpoint is statistically significant at the 5% level, then the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint will be exploratory only.
Has been modified to:
Analysis of the key secondary efficacy variable, seizure freedom for PGTCS for the 166-day Treatment Period, will be evaluated using an extended Mantel-Haenszel testing procedure which takes into account that the subjects were initially stratified for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at
REDACTED COPY per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
REDACTED COPY per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
seizures per 28 days, whichever has the smallest number of events.
REDACTED COPY seizures per 28 days, whichever has the smallest number of events.
in the group of subjects who are ≥4 to <12 years of age with ≤2
REDACTED COPY
in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the
REDACTED COPY
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
REDACTED COPY
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
ents or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline REDACTED COPY
ents or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of REDACTED C
OPY
PGTC seizures per 28 days, then this group will be combined for analysis with the group of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
portional hazards regression model
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
portional hazards regression model, with an effect for treatment, stratifying for the subjects’ Baseline PGTC seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, with an effect for treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at onsent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
onsent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects led by Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
led by Baseline PGTC
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with roup of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
roup of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, whichever has the smallest number of events.
in the group of subjects who are ≥4 to <12 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
ents or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ents or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC
The percentage of seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percentage of seizure-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-free subjects at 24 weeks will be estimated from the KM estimates of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free subjects at 24 weeks will be estimated from the KM estimates of time to first seizure using 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
time to first seizure using 2freedom rate in each treatment arm will be derived using KM methods to estimate the seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
freedom rate in each treatment arm will be derived using KM methods to estimate the seizure freedom rate for each stratum and then combining the rates using a Cochran
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
freedom rate for each stratum and then combining the rates using a Cochran
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
like approach. Th
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
like approach. The stratified HR will be calculated using the placebo arm as the reference group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e stratified HR will be calculated using the placebo arm as the reference group.
If the primary endpoint is statistically significant at the 5% level, then the key secondary efficacy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If the primary endpoint is statistically significant at the 5% level, then the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the prima
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
endpoint will also be assessed at the 5% significance level. If the prima
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
statistical significance, then the key secondary efficacy endpoint will be exploratory only.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
statistical significance, then the key secondary efficacy endpoint will be exploratory only.
Has been modified to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been modified to:
Analysis of the key secondary efficacy variable, seizure freedom for PGTCS for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Analysis of the key secondary efficacy variable, seizure freedom for PGTCS for the
![Page 102: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/102.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section 4.9.
The hypothesis for the assessment of the key secondary efficacy (PGTC seizure-freedom) is as follows:
H0: S(t=166)LCM = S(t=166)PBO
Versus
H1: S(t=166)LCM ≠ S(t=166)PBO
Where S(t=166) is the cumulative rate of subjects remaining seizure-free from PGTCS for 166 days.
Estimation of treatment difference:
KM methods will be used to estimate the proportion of subjects remaining seizure-free from PGTCS at Day 166. The estimate for the difference in Day 166 seizure-freedom from PGTCS will be adjusted for subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The estimate for the stratified difference in proportion of subjects who are seizure-free from PGTCS on LCM vs PBO and a corresponding 95% two-sided confidence interval (CILCM-PBO) will be produced using mantel Haenszel methods (LaVange et al, 2005). The statistical methodology is expressed as follows:
d=∑ wh(Sh1-Sh2)6h=1
Where Shi=KM estimate of 166-day seizure freedom from PGTCS for treatment i (1=LCM and 2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, 2= ≤2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, 5= >2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age and 6= >2 per 28 days Baseline PGTCS frequency and ≥18 years of age and wh={(nh1*nh2)/(nh1+nh2)}/∑ {(nh1*nh2)
6h=1 /(nh1+nh2)}}
where nhi is the number of subjects in I treatment group and stratum h. The variance of d is calculated as Var(d)=∑ wh
26h=1 {Var(Sh1)+Var(Sh2)} where Var(Sh1) and Var(Sh2) are the
Greenwood estimates of variance for Sh1 and Sh2.
The stratified proportion of subjects remaining seizure free from PGTCS for at least 166 days in each treatment group and the associated variance are derived as follows using Mantel Haneszel methods:
The KM estimate for the LCM 166-day seizure-freedom from PGTCS rate is calculated as 𝑆1=∑ 𝑤ℎ
6ℎ=1 𝑆ℎ1
The KM estimate for the PBO 166-day seizure-freedom from PGTCS rate is calculated as 𝑆2=∑ 𝑤ℎ
6ℎ=1 𝑆ℎ2
The variance is S1 is calculated as Var (𝑆1) =∑ 𝑤ℎ66
ℎ=1 𝑉𝑎𝑟(𝑆ℎ1)
The variance of S2 is calculated as Var (𝑆2) =∑ 𝑤ℎ66
ℎ=1 𝑉𝑎𝑟(𝑆ℎ2)
REDACTED COPY ) will be produced using mantel Haenszel methods (LaVange et al,
REDACTED COPY ) will be produced using mantel Haenszel methods (LaVange et al,
he statistical methodology is expressed as follows:
REDACTED COPY
he statistical methodology is expressed as follows:
seizure freedom from PGTCS for treatment i (1=LCM and
REDACTED COPY
seizure freedom from PGTCS for treatment i (1=LCM and 2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age,
REDACTED COPY
2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days REDACTED C
OPY
per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency REDACTED C
OPY
Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free from PGTCS for 166
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free from PGTCS for 166
KM methods will be used to estimate the proportion of subjects remaining seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
KM methods will be used to estimate the proportion of subjects remaining seizure free from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free from freedom from PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
freedom from PGTCS will be adjusted for subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be adjusted for subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 e). The estimate for the stratified difference in proportion of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e). The estimate for the stratified difference in proportion of free from PGTCS on LCM vs PBO and a corresponding 95% two
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free from PGTCS on LCM vs PBO and a corresponding 95% two) will be produced using mantel Haenszel methods (LaVange et al,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
) will be produced using mantel Haenszel methods (LaVange et al, he statistical methodology is expressed as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
he statistical methodology is expressed as follows:
seizure freedom from PGTCS for treatment i (1=LCM and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure freedom from PGTCS for treatment i (1=LCM and 2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, 5= >2 per 28 days Baseline PGTCS frequency and ≥12
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and ≥ 4 to <12 years of age, 5= >2 per 28 days Baseline PGTCS frequency and ≥12 of age and 6= >2 per 28 days Baseline PGTCS frequency and ≥18 years of age and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of age and 6= >2 per 28 days Baseline PGTCS frequency and ≥18 years of age and }/
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
}/∑
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
∑ {
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
{6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6h=1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
h=1
is the number of subjects in I treatment group and stratum h. The variance of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is the number of subjects in I treatment group and stratum h. The variance of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
∑
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
∑
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
w
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
w2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
26
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6h=1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
h=1
Greenwood estimates of variance for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Greenwood estimates of variance for
The stratified proportion of subjects remaining seizure free from PGTCS for at least 166 days in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified proportion of subjects remaining seizure free from PGTCS for at least 166 days in each treatment group and the associate
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
each treatment group and the associate
The KM estimate for the LCM 166
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The KM estimate for the LCM 166∑
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
∑6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6ℎ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ℎ=
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
=
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The KM estimate for the PBO 166
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The KM estimate for the PBO 166𝑆
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
𝑆
![Page 103: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/103.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
In order to assess superiority, 2-sided testing with α=0.05 will be used. The superiority test statistic, Q=d2/Var(d) will be assessed by a chi-square distribution with 1 degree of freedom. This statistic is referred to as the “row mean score statistic” when using Proc Freq.
The number and percentage of subjects who experience a PGTCS or censoring and the KM seizure-free rate from PGTCS (and 2-sided 95% CI) by Day 166 will be presented by treatment group for each stratum and overall. The stratified seizure-freedom rate from PGTCS (and 2-sided 95% CI) at Day 166 for each treatment group and the difference between treatment groups will be presented. A Kaplan-Meier plot will be presented by treatment group for each stratum and overall.
For the gatekeeping strategy, if the primary endpoint is statistically significant at the 5% level, then the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint will be exploratory only.
Section 9.2.2.2, Analysis of Percent Change in PGTC seizure frequency from Combined Baseline has been removed from the SAP.
The percent change in log-transformed PGTC seizure frequency during the first 6 weeks of the Treatment Period will be analyzed using analysis of covariance, controlling for Baseline seizure frequency.
The percent change in log-transformed PGTC seizure frequency during the Treatment Period will be analyzed analysis of covariance, controlling for Baseline seizure frequency.
All PGTC seizure frequency per 28 days data will be listed.
Section 8.2.2.2, Time to first PGTCS during the 166-day Treatment Period, has been changed from:
Time to the first PGTC seizure during the 24-week Treatment Period will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
13. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
14. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
REDACTED COPY
transformed PGTC seizure frequency during the Treatment Period
REDACTED COPY
transformed PGTC seizure frequency during the Treatment Period will be analyzed analysis of covariance, controlling for Baseline seizure frequency.
REDACTED COPY
will be analyzed analysis of covariance, controlling for Baseline seizure frequency.
All PGTC seizure frequency per 28 days data will be listed.
REDACTED COPY
All PGTC seizure frequency per 28 days data will be listed.
, Time to first PGTCS during the
REDACTED COPY
, Time to first PGTCS during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Meier plot will be presented by treatment group for each stratum and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Meier plot will be presented by treatment group for each stratum and
For the gatekeeping strategy, if the primary endpoint is statistically significant at the 5% level,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the gatekeeping strategy, if the primary endpoint is statistically significant at the 5% level, ndpoint will also be assessed at the 5% significance level. If the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ndpoint will also be assessed at the 5% significance level. If the primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint
uency from Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
uency from Combined Baseline
transformed PGTC seizure frequency during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
transformed PGTC seizure frequency during the first 6 weeks of the Treatment Period will be analyzed using analysis of covariance, controlling for Baseline seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period will be analyzed using analysis of covariance, controlling for Baseline seizure
transformed PGTC seizure frequency during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
transformed PGTC seizure frequency during the Treatment Period will be analyzed analysis of covariance, controlling for Baseline seizure frequency.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be analyzed analysis of covariance, controlling for Baseline seizure frequency.
All PGTC seizure frequency per 28 days data will be listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All PGTC seizure frequency per 28 days data will be listed.
, Time to first PGTCS during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, Time to first PGTCS during the 166
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
166
Time to the first PGTC seizure during the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Time to the first PGTC seizure during the 24Cox proportional hazards regression model
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Cox proportional hazards regression modelfor the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT. If 5
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ge). The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
events or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be pooled by Baseline PGTC seizure frequency for analysis as follows:
If 5 events or l
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ess occur in the group of subjects who are ≥12 and <18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures r 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
r 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, whichever has the smallest number of events.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days, whichever has the smallest number of events.
14.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
14. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2
![Page 104: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/104.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
15. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.
16. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC seizures per 28 days.
The stratified HR will be calculated using the placebo arm as the reference group.
Additionally, a KM plot for time to first PGTC seizure as well as the KM estimate for the median time to first PGTC seizure will be provided. If the median time is not estimable, then the 25th percentile will be provided.
Has been changed to:
Time to the first PGTCS during the 24-week Treatment Period will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as described in Section 4.9.
The hypothesis for the assessment of the time to first PGTCS is as follows:
H0: β=0
Versus
H1: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented by
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For the null hypothesis, the testing will be 2-sided with an α=0.05. The assumptions of proportional hazards will also be checked.
The stratified HR will be calculated using the placebo arm as the reference group. The SE and 95% CI for the HR will also be reported.
Additionally, a KM plot for time to 1st PGTCS as well as the KM estimate for the median time to 1st PGTCS and 95% CI will be provided. If the median time is not estimable, then the 25th percentile and 95% CI will be provided. The number of 1st PGTCS will be reported by treatment group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects who were censored.
Section 8.3, the following sentence has been added:
All seizure data recorded during the treatment period will be summarized and listed for the seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will be performed for the FAS.
REDACTED COPY of the time to first PGTCS is as follows:
REDACTED COPY of the time to first PGTCS is as follows:
: β=0
REDACTED COPY
: β=0
H
REDACTED COPY
H1
REDACTED COPY
1: β≠0
REDACTED COPY
: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the REDACTED C
OPY
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented byREDACTED C
OPY
model. The hazard function is represented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ided. If the median time is not estimable, then the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ided. If the median time is not estimable, then the
week Treatment Period will be evaluated using a Cox
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period will be evaluated using a Cox , with an effect for treatment, stratifying for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, with an effect for treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age 8 years of age). The analysis will use the stratification factors from IRT and pooled as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8 years of age). The analysis will use the stratification factors from IRT and pooled as
of the time to first PGTCS is as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the time to first PGTCS is as follows:
: β≠0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
model. The hazard function is represented by
ℎ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ℎ(
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(𝑡
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
𝑡,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, 𝑋
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
𝑋)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
)
is the collection of independent variables and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is the collection of independent variables and the null hypothesis, the testing will be 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the null hypothesis, the testing will be 2hazards will also be checked.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
hazards will also be checked.
The stratified HR will be calculated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified HR will be calculated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
95% CI for the HR will also be reported.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
95% CI for the HR will also be reported.
Additionally, a KM plot for time to 1st
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Additionally, a KM plot for time to 1st PGTCS and 95% CI will be provided. If the median time is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS and 95% CI will be provided. If the median time ispercentile and 95% CI will be provided.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
percentile and 95% CI will be provided. group
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
group for the Titration Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for the Titration Periodwho were censored.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
who were censored.
Section 8.3,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.3,
![Page 105: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/105.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Section 8.3.1.2 Days with seizures per 28 days, the following sentence was added to the 2nd to last paragraph:
PCH will be calculated for the 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
Section 8.3.1.3, Seizure-free status, was modified from:
Refer to Section 8.2.1.1 for PGTC seizure-free status.
A subject will have seizure freedom (seizure free status=yes) for all generalized seizure types for the applicable Treatment Period if the subject completed the Treatment Period and reported zero generalized seizures for all days during the Treatment Period when the number of seizures was available, and had <10% of days during the Treatment Period with seizure data reported as “not done”.
Has been changed to:
A subject will have seizure-free status for PGTCS=yes for the Treatment Period if the subject completed the Treatment Period (with a minimum 166 days) and reported zero PGTCS or “not done” for all days during the Treatment Period. If the subject is exited from the study due to the 125th event occurring reporting zero PGTCS or “not done” for all days and duration of the Treatment Period is < 166 days, then the subject has not achieved seizure-free status for PGTCS.
A subject will have seizure free status=yes for all generalized seizure types for the applicable Treatment Period if the subject completed the Treatment Period and reported zero generalized seizures for all days during the Treatment Period when the number of generalized seizures was available, and had <10% of days during the Treatment Period with seizure data reported as “not done”.
Seizure-free statuses will be calculated for 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
Section 8.3.1.4, Responder status – reduction in PGTCS frequency, has been changed from:
Response to treatment regarding PGTC seizure frequency will be based on the percent change in seizure frequency, calculated as described in Section 8.3.1.1. A responder is defined as a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the Combined Baseline to the period of interest (first 12 weeks of the Treatment Period or the 24-week Treatment Period).
Has been changed to:
Response to treatment will be based on the percent change in PGTCS frequency, calculated as described in Section 8.3.1.1 . A 50% responder is defined as a subject experiencing ≥50% reduction in PGTCS frequency per 28 days from the Combined Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in PGTCS frequency per 28 days from Combined Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
Section 8.3.1.5 PGTCS worsening, is new:
REDACTED COPY en the subject has not achieved seizure
REDACTED COPY en the subject has not achieved seizure
A subject will have seizure free status=yes for all generalized seizure types for the applicable
REDACTED COPY
A subject will have seizure free status=yes for all generalized seizure types for the applicable Treatment Period if the subject completed the Treatment Period and reported zero generalized
REDACTED COPY
Treatment Period if the subject completed the Treatment Period and reported zero generalized izures for all days during the Treatment Period when the number of generalized seizures was
REDACTED COPY
izures for all days during the Treatment Period when the number of generalized seizures was available, and had <10% of days during the Treatment Period with seizure data reported as “not
REDACTED COPY
available, and had <10% of days during the Treatment Period with seizure data reported as “not
free statuses will be calculated for 6REDACTED COPY
free statuses will be calculated for 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tatus=yes) for all generalized seizure types for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tatus=yes) for all generalized seizure types for the applicable Treatment Period if the subject completed the Treatment Period and reported zero
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the applicable Treatment Period if the subject completed the Treatment Period and reported zero generalized seizures for all days during the Treatment Period when the number of seizures was
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
generalized seizures for all days during the Treatment Period when the number of seizures was d <10% of days during the Treatment Period with seizure data reported as “not
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
d <10% of days during the Treatment Period with seizure data reported as “not
free status for PGTCS=yes for the Treatment Period if the subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status for PGTCS=yes for the Treatment Period if the subject and reported zero PGTCS or “not
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and reported zero PGTCS or “not done” for all days during the Treatment Period. If the subject is exited from the study due to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
done” for all days during the Treatment Period. If the subject is exited from the study due to the event occurring reporting zero PGTCS or “not done” for all days and duration of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event occurring reporting zero PGTCS or “not done” for all days and duration of the en the subject has not achieved seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
en the subject has not achieved seizure
A subject will have seizure free status=yes for all generalized seizure types for the applicable
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A subject will have seizure free status=yes for all generalized seizure types for the applicable Treatment Period if the subject completed the Treatment Period and reported zero generalized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period if the subject completed the Treatment Period and reported zero generalized izures for all days during the Treatment Period when the number of generalized seizures was
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
izures for all days during the Treatment Period when the number of generalized seizures was available, and had <10% of days during the Treatment Period with seizure data reported as “not
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
available, and had <10% of days during the Treatment Period with seizure data reported as “not
free statuses will be calculated for 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free statuses will be calculated for 6-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-week Titration
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration week Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period.
–
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
– reduction in PGTCS frequency, has been changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in PGTCS frequency, has been changed from:
Response to treatment regarding PGTC seizure frequency will be based on the percent ch
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment regarding PGTC seizure frequency will be based on the percent chseizure frequency, calculated as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure frequency, calculated as described inexperiencing ≥50% reduction in PGTC seizure frequency per 28 days from the Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the Combined Baseline to the period of interest (first 12 weeks of the Treatme
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline to the period of interest (first 12 weeks of the TreatmeTreatment Period).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period).
Has been changed to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been changed to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment will be based on the percent change in PGTCS frequency, calculated as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment will be based on the percent change in PGTCS frequency, calculated as described in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
described inreduction in PGTCS frequency per 28 days from the Combined Baseline to the period of interest
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in PGTCS frequency per 28 days from the Combined Baseline to the period of interest (6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(6-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-week Titration Period, first 12 weeks of the Treatment Period or the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of the Treatment Period or the 24Period). A
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period). A frequency per 28 days from Combined Baseline to the period of interest (6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency per 28 days from Combined Baseline to the period of interest (6
![Page 106: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/106.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Seizure worsening is defined as a subject experiencing ≥50% increase in PGTCS frequency per 28 days from Combined Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
Section 8.3.1.6 Responder status – reduction in days with absence seizures, is new:
Response to treatment for absence seizures per 28 days will be based on the percent change in days with absence seizures, calculated as described in Section 8.3.1.2. A 50% responder is defined as a subject experiencing ≥50% reduction in days with absence seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in days with absence seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
Section 8.3.1.7 Responder status – reduction in days with myoclonic seizures, is new:
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in days with myoclonic seizures, calculated as described in Section 8.3.1.2. A 50% responder is defined as a subject experiencing ≥50% reduction in days with myoclonic seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
Section 8.3.2.1, Percent Change in PGTCS frequency per 28 days from Combined Baseline, is new:
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.
All PGTCS frequency per 28 days data will be listed.
Section 8.3.2.2 Reduction in days with seizures per 28 days was changed from:
The following data will be summarized with descriptive statistics only:
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days compared to the Prospective Baseline
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
REDACTED COPY od). A 75% responder is defined as a subject
REDACTED COPY od). A 75% responder is defined as a subject
experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective
REDACTED COPY
experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective week Titration Period, first 12 weeks of the Treatment
REDACTED COPY
week Titration Period, first 12 weeks of the Treatment
Section 8.3.2.1, Percent Change in PGTCS frequency per 28 days from Combined Baseline, is
REDACTED COPY
Section 8.3.2.1, Percent Change in PGTCS frequency per 28 days from Combined Baseline, is
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6 REDACTED COPY
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of week Treatment Period). A 75% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in days with absence seizures per 28 days from the Pros
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experiencing ≥75% reduction in days with absence seizures per 28 days from the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
pective week Titration Period, first 12 weeks of the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of the Treatment
reduction in days with myoclonic seizures, is new:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in days with myoclonic seizures, is new:
oclonic seizures per 28 days will be based on the percent change in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
oclonic seizures per 28 days will be based on the percent change in 8.3.1.2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
8.3.1.2. A 50%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. A 50% defined as a subject experiencing ≥50% reduction in days with myoclonic seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
defined as a subject experiencing ≥50% reduction in days with myoclonic seizures per 28 days week Titration Period, first 12 weeks of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of od). A 75% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
od). A 75% responder is defined as a subject experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective week Titration Period, first 12 weeks of the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of the Treatment
Section 8.3.2.1, Percent Change in PGTCS frequency per 28 days from Combined Baseline, is
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.3.2.1, Percent Change in PGTCS frequency per 28 days from Combined Baseline, is
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.
All PGTCS frequency per 28 days data will be listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All PGTCS frequency per 28 days data will be listed.
Reduction in days with seizures per 28 days was changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Reduction in days with seizures per 28 days was changed from:
The following data will be summarized with descriptive statistics only:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following data will be summarized with descriptive statistics only:
Change in days with absence seizures per 28 days during the Treatment Period relative to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline
change in days with absence seizures per 28 days during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
change in days with absence seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with absence seizures per 28 days during the Treatment Period relative to the P
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
relative to the P
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure days compared to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure days compared to the
![Page 107: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/107.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to the Prospective Baseline
All seizure days data for absence and myoclonic seizures will be listed.
Has been changed to:
The following data will be summarized with descriptive statistics only:
Change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the first 12 weeks of the Treatment Period relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the first 12 weeks of the Treatment Period relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
All seizure days data for absence and myoclonic seizures will be listed.
Section 8.3.2.3, Seizure-free status, was modified from:
The following seizure-free status (yes/no) summaries will be provided:
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment Period
Has been changed to:
The following seizure-free status (yes/no) summaries will be provided:
REDACTED COPY ures per 28 days during the Treatment Period
REDACTED COPY ures per 28 days during the Treatment Period
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
REDACTED COPY
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
Percent change in days with myoclonic seizures per 28 daysREDACTED C
OPY
Percent change in days with myoclonic seizures per 28 daysTreatment Period (Titration Period) relative to the Prospective BaselineREDACTED C
OPY
Treatment Period (Titration Period) relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with absence seizures per 28 days during the Treatment Period relative to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with absence seizures per 28 days during the Treatment Period relative to the
Percent change in days with absence seizures per 28 days during the first 6 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with absence seizures per 28 days during the first 6 weeks of the reatment Period (Titration Period) relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with absence seizures per 28 days during the first 12 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with absence seizures per 28 days during the first 12 weeks of the
ures per 28 days during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ures per 28 days during the Treatment Period
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to
Percent change in days with myoclonic seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 daysTreatment Period (Titration Period) relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period (Titration Period) relative to the Prospective Baseline
Percent change in days with myoclonic seizures per 28 days during the first 12 weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percent change in days with myoclonic seizures per 28 days during the first 12 weeks of the Treatment Period relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period relative to the Prospective Baseline
ent change in days with myoclonic seizures per 28 days during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ent change in days with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
relative to the Prospective Baseline
All seizure days data for absence and myoclonic seizures will be listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All seizure days data for absence and myoclonic seizures will be listed.
Section 8.3.2.3, Seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.3.2.3, Seizure-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-free status, was modified from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status, was modified from:-free status, was modified from:-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-free status, was modified from:-
following seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
following seizure
Seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period
Seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Seizure free status (yes, no) for PGTC seizures for the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free status (yes, no) for PGTC seizures for the 24
Seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SeizureTreatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period
![Page 108: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/108.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Seizure-free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period (Titration Period)
Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the first 6 weeks of the Treatment Period (Titration Period)
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the Treatment Period
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment Period
Section 8.3.2.4, Responder status – reduction in PGTCS frequency
The number and percentage of responders will be summarized with descriptive statistics only for the following periods of interest:
PGTC seizures during the first 12 weeks of the Treatment Period
PGTC seizures during the 24-week Treatment Period
A histogram of ≥50%, ≥75% and 100% responder status for PGTC seizure frequency during the first 12 weeks and the 24-week Treatment Period by treatment group will be provided.
Has been changed to:
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 6 weeks (Titration Period) compared to the Combined Baseline
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to the Combined Baseline
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the Treatment Period compared to the Combined Baseline
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 6 weeks (Titration Period) compared to the Combined Baseline
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to the Combined Baseline
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the Treatment Period compared to the Combined Baseline
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for PGTCS frequency during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
Section 8.3.2.5, Responder status – reduction in days with absence seizures, is new:
The following data will be summarized with descriptive statistics only:
REDACTED COPY
A histogram of ≥50%, ≥75% and 100% responder status for PGTC seizure f
REDACTED COPY
A histogram of ≥50%, ≥75% and 100% responder status for PGTC seizure fweek Treatment Period by treatment group will be provided.
REDACTED COPY
week Treatment Period by treatment group will be provided.
The following data will be summarized with descriptive statistics only:
REDACTED COPY
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in REDACTED COPY
Percentage of subjects with at least a 50% reduction in 6 weeks (Titration Period) compared to the Combined BaselineREDACTED C
OPY
6 weeks (Titration Period) compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks of the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
weeks of the
week Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment
with descriptive statistics only for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with descriptive statistics only for
PGTC seizures during the first 12 weeks of the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTC seizures during the first 12 weeks of the Treatment Period
A histogram of ≥50%, ≥75% and 100% responder status for PGTC seizure f
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A histogram of ≥50%, ≥75% and 100% responder status for PGTC seizure fweek Treatment Period by treatment group will be provided.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period by treatment group will be provided.
The following data will be summarized with descriptive statistics only:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in 6 weeks (Titration Period) compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6 weeks (Titration Period) compared to the Combined Baseline
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
12 weeks of the Treatment Period compared to the Combined Baseline
tage of subjects with at least a 50% reduction in PGTCS frequency during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tage of subjects with at least a 50% reduction in PGTCS frequency during the Treatment Period compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 6 weeks (Titration Period) compared to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
6 weeks (Titration Period) compared to
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 12 weeks of the Treatment Period compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
12 weeks of the Treatment Period compared to the Combined Baseline
Percentage of subjects with at least a 75% reduction in PGTCS frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in PGTCS frequency duringTreatment Period compared to the Combined Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to the Combined Baseline
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for PGTCS frequency during the first 6 weeks (Titration Period), first 12 weeks, and the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency during the first 6 weeks (Titration Period), first 12 weeks, and the 24
![Page 109: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/109.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Percentage of subjects with at least a 50% reduction in absence seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure days during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the Treatment Period compared to the Prospective Baseline
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for reduction in days with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
Section 8.3.2.6, Responder status – reduction in days with myoclonic seizures
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the Treatment Period compared to the Prospective Baseline
Section 8.4.2.1, QOLIE-31-P variables, the following paragraph was added:
QOLIE-31-P data, for a specific visit may have a status of Abandoned if the subject doesn’t complete the questionnaire. If the subject has duplicate QOLIE-31-P data for the same visit, where one record is deemed as Abandoned and one record is deemed as Completed, the Completed data will be used in the analysis and not the Abandoned record. All recorded QOLIE-31-P data will be listed.
Section 8.4.2.1, QOLIE-31-P variables, the following sentence was added to the 2nd paragraph:
REDACTED COPY reduction in days with myoclonic seizures
REDACTED COPY reduction in days with myoclonic seizures
The following data will be summarized with descriptive st
REDACTED COPY
The following data will be summarized with descriptive st
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the
REDACTED COPY
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
REDACTED COPY
first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in
REDACTED COPY
Percentage of subjects with at least a 50% reduction in first 12 weeks of the Treatment Period compared to the Prospective Baseline
REDACTED COPY
first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6 of the Treatment Period (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure days during the first
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in absence seizure days during the first
of subjects with at least a 75% reduction in absence seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of subjects with at least a 75% reduction in absence seizure days during the
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for reduction in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for reduction in first 6 weeks (Titration Period), first 12 weeks, and the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first 6 weeks (Titration Period), first 12 weeks, and the week Treatment Period by treatment group will be provided.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period by treatment group will be provided.
reduction in days with myoclonic seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in days with myoclonic seizures
The following data will be summarized with descriptive st
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following data will be summarized with descriptive statistics only:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
atistics only:
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizur
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in myoclonic seizurfirst 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.4.2.1, Q
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.4.2.1, Q
QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
QOLIE-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-31
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
31
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P data, for a specific visit may have a status of Abandoned if the subject doesn’t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
P data, for a specific visit may have a status of Abandoned if the subject doesn’t complete the questionnaire. If the subject has duplicate QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
complete the questionnaire. If the subject has duplicate QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where one recor
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where one recorCompleted data will be used in the analysis and not the Abandoned record. All recorded QOLIE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Completed data will be used in the analysis and not the Abandoned record. All recorded QOLIE
![Page 110: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/110.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The means of the QOLIE-31-P total score, subscale scores and health status item score will be plotted by visit.
Section 8.4.2.2, PedsQL variables, the following sentence was added:
The means of the PedsQL subscale scores and total score will be plotted by visit.
Section 8.4.2.3, EQ-5D-3L quality of life variables, the following sentence was added:
The mean of the EQ-5D-3L VAS will be plotted by visit. For the EQ-5D-3L, the percentage of subjects reporting a level within each dimension will be plotted in a histogram.
Section 10.1.2, Analysis of exposure variables, the 2nd paragraph was changed from:
Treatment duration will be summarized with the number and percentage of subjects with treatment duration by 3 Week categories: 1-21 days, 22–42 days, 43–63 days, 64–84 days, 85-105 days, 106–126 days, 127-147 days, 148-168 days, and > 168 days. Furthermore, the subject years exposed will be presented for the entire Treatment Period.
Has been changed to:
Treatment duration will be summarized with the number and percentage of subjects with treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84 days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. Furthermore, the subject years exposed will be presented for the entire Treatment Period.
If actual dosing information is presented, the LCM dose categories for oral solution are as follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg day. The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to <200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.
Section 10.2, Adverse events, the following paragraphs were modified from:
Incidence of other significant TEAEs (See Section 12.2 for details).
The following summary will be presented by actual dose at onset (Placebo oral solution, 0mg/kg/day, >0 to <4mg/kg/day, ≥4 to <8mg/kg/day, ≥8 to <12mg/kg/day, >12mg/kg/day, Placebo tablets, 0mg/day, >0 to <200mg/day, ≥200 to <300mg/day, ≥300 to <400mg/day and ≥400mg/day). AEs of pediatric subjects weighing <50kg randomized to LCM but where no LCM was taken will be summarized in the 0mg/kg/day column; AEs of adult subjects and pediatric subjects weighing ≥50kg randomized to LCM but where no LCM was taken will be summarized in the 0mg/day column. AEs of unknown dosing are not summarized but those taken where LCM dose is 0mg/kg/day or 0mg/day are in the applicable column. AEs of unknown dosing are those with UNK as the dose or known dosing and partial AE start or stop dates.
Incidence of TEAEs by actual dose at onset
Subject data listings will be presented for the following:
Subjects experiencing TEAEs
Subjects experiencing Serious TEAEs
Subjects experiencing TEAEs leading to discontinuation
REDACTED COPY treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84
REDACTED COPY treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84
days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days.
REDACTED COPY
days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. he subject years exposed will be presented for the entire Treatment Period.
REDACTED COPY
he subject years exposed will be presented for the entire Treatment Period.
If actual dosing information is presented, the LCM dose categories for oral solution are as
REDACTED COPY
If actual dosing information is presented, the LCM dose categories for oral solution are as follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg
REDACTED COPY
follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg day. The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to
REDACTED COPY
day. The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to <200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.REDACTED C
OPY
<200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3L, the percentage of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
3L, the percentage of
Treatment duration will be summarized with the number and percentage of subjects with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment duration will be summarized with the number and percentage of subjects with –
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
–84 days,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
84 days, 168 days, and > 168 days. Furthermore, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
168 days, and > 168 days. Furthermore, the
summarized with the number and percentage of subjects with
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
summarized with the number and percentage of subjects with treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84 days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. he subject years exposed will be presented for the entire Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
he subject years exposed will be presented for the entire Treatment Period.
If actual dosing information is presented, the LCM dose categories for oral solution are as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If actual dosing information is presented, the LCM dose categories for oral solution are as follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg day. The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day. The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to <200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day.
Section 10.2, Adverse events, the following paragraphs were modified from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 10.2, Adverse events, the following paragraphs were modified from:
other significant TEAEs (See Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
other significant TEAEs (See Section
The following summary will be presented by actual dose at onset (Placebo oral solution,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following summary will be presented by actual dose at onset (Placebo oral solution, <4mg/kg/day, ≥4 to <8mg/kg/day, ≥8 to <12mg/kg/day, >12mg/kg/day,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
<4mg/kg/day, ≥4 to <8mg/kg/day, ≥8 to <12mg/kg/day, >12mg/kg/day, Placebo tablets, 0mg/day, >0 to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Placebo tablets, 0mg/day, >0 to≥400mg/day). AEs of pediatric subjects weighing <50kg randomized to LCM but where no LCM
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
≥400mg/day). AEs of pediatric subjects weighing <50kg randomized to LCM but where no LCM as taken will be summarized in the 0mg/kg/day column; AEs of adult subjects and pediatric
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
as taken will be summarized in the 0mg/kg/day column; AEs of adult subjects and pediatric subjects weighing ≥50kg randomized to LCM but where no LCM was taken will be summarized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects weighing ≥50kg randomized to LCM but where no LCM was taken will be summarized
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in the 0mg/day column. AEs of unknown dosing are not summarized but those take
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in the 0mg/day column. AEs of unknown dosing are not summarized but those takedose is 0mg/kg/day or 0mg/day are in the applicable column. AEs of unknown dosing are those
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
dose is 0mg/kg/day or 0mg/day are in the applicable column. AEs of unknown dosing are those with UNK as the dose or known dosing and partial AE start or stop dates.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with UNK as the dose or known dosing and partial AE start or stop dates.
Incidence of TEAEs by actual dose at onset
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs by actual dose at onset
Subject data listings will be pres
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subject data listings will be pres
![Page 111: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/111.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC and PTs.
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in Section 12.5.
Has been changed to:
Incidence of other significant TEAEs (See Section 12.2.1 for details)
Incidence of TEAEs for potential drug-induced liver injury (PDILI) (See Section 12.2.2 for details)
To assess TEAEs related to epilepsy, PTs will be identified by ongoing manual medical review. The following PTs (including those identified from continuing medical review) will be summarized: petit mal epilepsy, myoclonus, and myoclonic epilepsy.
Incidence of TEAEs of interest related to epilepsy by 3-month exposure period of TEAE onset
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in Section 10.1.2. AEs of unknown dosing are those with no known dose or known dosing and partial AE start or stop dates.
Incidence of TEAEs by actual dose at onset
Subject data listings will be presented for the following:
Subjects experiencing adverse events on the ES
Subjects experiencing Serious TEAEs on the SS
Subjects experiencing TEAEs leading to discontinuation on the SS
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC and PTs.
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in Section 12.5.
Section 10.3, clinical laboratory evaluations, the following paragraphs were modified from:
Markedly abnormal (MA) values indicate significant deviations from the expected range of age-appropriate values. Marked laboratory abnormalities observed post-Baseline during the Treatment Period but not present at Baseline are considered treatment emergent. MA values for serum chemistry and hematology laboratory parameters are provided in UCB conventional (traditional) and standard units. The definition of MA values for hematology and chemistry values can be found in Section 12.3.
The number and percentage of subjects with at least 1 treatment-emergent markedly abnormal (TEMA) value will be summarized by visit for each laboratory parameter (hematology and clinical chemistry) with markedly abnormal criteria specified. TEMA values are those that are observed during the defined treatment period at scheduled or unscheduled visits and were not observed at any visit during the Baseline period. A table summarizing the number of subjects meeting the potential drug induced liver injury criteria will also be presented.
REDACTED COPY
Subject data listings will be presented for the following:
REDACTED COPY
Subject data listings will be presented for the following:
Subjects experiencing adverse events on the ES
REDACTED COPY
Subjects experiencing adverse events on the ES
Subjects experiencing Serious TEAEs on the SS
REDACTED COPY
Subjects experiencing Serious TEAEs on the SS
Subjects experiencing TEAEs leading to discontinuation on the SSREDACTED COPY
Subjects experiencing TEAEs leading to discontinuation on the SS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
for
To assess TEAEs related to epilepsy, PTs will be identified by ongoing manual medical review.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
To assess TEAEs related to epilepsy, PTs will be identified by ongoing manual medical review. ng medical review) will be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ng medical review) will be
month exposure period of TEAE
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
month exposure period of TEAE
The dose at onset TEAE summaries will be presented by the LCM dosing c
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The dose at onset TEAE summaries will be presented by the LCM dosing c. AEs of unknown dosing are those with no known dose or known dosing and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. AEs of unknown dosing are those with no known dose or known dosing and
Subject data listings will be presented for the following:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subject data listings will be presented for the following:
Subjects experiencing adverse events on the ES
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects experiencing adverse events on the ES
Subjects experiencing Serious TEAEs on the SS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects experiencing Serious TEAEs on the SS
Subjects experiencing TEAEs leading to discontinuation on the SS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects experiencing TEAEs leading to discontinuation on the SS
glossary of AEs will be presented showing the mapping of investigator terms to coded SOC
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
glossary of AEs will be presented showing the mapping of investigator terms to coded SOC
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in
Section 10.3, clinical laboratory evaluations, the following paragraphs were modified from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 10.3, clinical laboratory evaluations, the following paragraphs were modified from:
Markedly abnormal (MA) values indicate significant deviations from the expected range of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Markedly abnormal (MA) values indicate significant deviations from the expected range of appropriate values. M
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
appropriate values. M
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period but not present at Baseline are considered treatment emergent. MA values for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period but not present at Baseline are considered treatment emergent. MA values for serum chemistry and hematology laboratory parameters are provided in UCB conventional
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serum chemistry and hematology laboratory parameters are provided in UCB conventional (traditiona
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(traditional) and standard units. The definition of MA values for hematology and chemistry
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
l) and standard units. The definition of MA values for hematology and chemistry values can be found in Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
values can be found in Section
The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects with at least 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
number and percentage of subjects with at least 1 (TEMA) value
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
(TEMA) value
![Page 112: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/112.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The NCI CTC criteria can be found in Section 12.4 . The number and percentage of subjects with treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will be summarized by treatment group, laboratory parameter, and visit for the Treatment Period. Treatment emergent abnormalities of grade 2 or higher are those that were observed during the Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during the Baseline Period.
Has been changed to:
Treatment-emergent markedly abnormal (TEMA) values indicate significant deviations from the expected range of age-appropriate values. TEMA laboratory abnormalities results are those that are observed post-Baseline during the Treatment Period but are not present at Baseline. TEMA values for serum chemistry and hematology laboratory parameters are provided in UCB conventional (traditional) and standard units. The definition of MA values for hematology and chemistry values can be found in Section 12.3. The number and percentage of subjects with at least 1 TEMA value will be summarized by scheduled visit, Last Visit, minimum and maximum post-Baseline values obtained during the Treatment Period for each laboratory parameter (hematology and clinical chemistry) with markedly abnormal criteria specified. TEMA values are those that are observed during the defined treatment period at scheduled or unscheduled visits and were not observed at any visit during the Baseline period. A table summarizing the number of subjects meeting the potential drug induced liver injury criteria will also be presented.
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC) can be found in Section 12.4. The number and percentage of subjects with treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will be summarized by treatment group, laboratory parameter, and visit for the Treatment Period. Treatment emergent abnormalities of grade 2 or higher are those that were observed during the Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during the Baseline Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher will be presented in a subject number listing.
Section 10.4.1, Vital Signs, the following sentence was inserted:
All TEMA results summarized will be presented in a subject number listing.
Section 10.4.2.2, Analysis of ECG parameters, was modified from:
Absolute values and change from Baseline of ECG parameters will be summarized using descriptive statistics for the scheduled visits, overall, Last Visit, minimum and maximum post-Baseline values obtained during the Treatment Period, and in each of the age groups. Unscheduled ECG assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last visit, minimum, and maximum post-Baseline values during the Treatment Period. If repeat measurements are taken at a particular visit, then the average value is used in summaries and the original values are listed.
The number and percentage of subjects who met each of the treatment-emergent abnormality criteria specified in Section 12.3.4 will be presented within the specified age groups. For each parameter, the number and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific to their age) will be summarized for heart rate, PR interval and QRS
REDACTED COPY ects meeting the potential drug induced liver injury
REDACTED COPY ects meeting the potential drug induced liver injury
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC)
REDACTED COPY
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC) . The number and percentage of subjects with treatment emergent
REDACTED COPY
. The number and percentage of subjects with treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will
REDACTED COPY
laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will laboratory parameter, and visit for the Treatment Period.
REDACTED COPY
laboratory parameter, and visit for the Treatment Period. Treatment emergent abnormalities of grade 2 or higher are those that were observed during the REDACTED C
OPY
Treatment emergent abnormalities of grade 2 or higher are those that were observed during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
emergent markedly abnormal (TEMA) values indicate significant deviations from the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
emergent markedly abnormal (TEMA) values indicate significant deviations from the appropriate values. TEMA laboratory abnormalities results are those that
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
appropriate values. TEMA laboratory abnormalities results are those that Baseline during the Treatment Period but are not present at Baseline. TEMA
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline during the Treatment Period but are not present at Baseline. TEMA UCB
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
UCB conventional (traditional) and standard units. The definition of MA values for hematology and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
conventional (traditional) and standard units. The definition of MA values for hematology and number and percentage of subjects with at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
number and percentage of subjects with at will be summarized by scheduled visit, Last Visit, minimum and maximum
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be summarized by scheduled visit, Last Visit, minimum and maximum Baseline values obtained during the Treatment Period for each laboratory parameter
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values obtained during the Treatment Period for each laboratory parameter criteria specified. TEMA values
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
criteria specified. TEMA values are those that are observed during the defined treatment period at scheduled or unscheduled visits
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
are those that are observed during the defined treatment period at scheduled or unscheduled visits
ects meeting the potential drug induced liver injury
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ects meeting the potential drug induced liver injury
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC) . The number and percentage of subjects with treatment emergent
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. The number and percentage of subjects with treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will laboratory parameter, and visit for the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
laboratory parameter, and visit for the Treatment Period. Treatment emergent abnormalities of grade 2 or higher are those that were observed during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment emergent abnormalities of grade 2 or higher are those that were observed during the Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during the ine Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ine Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher will be presented in a subject number listing.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be presented in a subject number listing.
Section 10.4.1, Vital Signs, the following sentence was inserted:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 10.4.1, Vital Signs, the following sentence was inserted:
All TEMA results summarized will be presented in a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All TEMA results summarized will be presented in a
Section 10.4.2.2, Analysis of ECG parameters, was modified from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 10.4.2.2, Analysis of ECG parameters, was modified from:
Absolute values and change from Baseline of ECG parameters will be summarized using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Absolute values and change from Baseline of ECG parameters will be summarized using descriptive statistics for the scheduled visits, overall, Last Visit, minimum and m
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
descriptive statistics for the scheduled visits, overall, Last Visit, minimum and mBaseline values obtained during the Treatment Period, and in each of the age groups.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values obtained during the Treatment Period, and in each of the age groups. Unscheduled ECG assessments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Unscheduled ECG assessments during the study will not be presented in bywill be considered when determining the last visit, minimum, and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
will be considered when determining the last visit, minimum, and values during the Treatment Period. If repeat measurements are taken at a particular visit, then
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
values during the Treatment Period. If repeat measurements are taken at a particular visit, then the average value is used in summaries and the original values are listed.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the average value is used in summaries and the original values are listed.
![Page 113: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/113.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
interval. Subject numbers for those with treatment-emergent abnormal ECG values will be listed by abnormality criteria. Treatment-emergent abnormal results for a subject are those that are observed during the defined treatment period at scheduled or unscheduled visits and were not observed at any visit during the Baseline period.
Detailed information on the quantitative and qualitative ECG findings will be presented in subject data listings.
Has been changed to
For quantitative ECG measurements (heart rate, PR interval, QRS interval, QT interval, RR Interval and corrected QT intervals using Bazett and Fridiricia correction methods), summary statistics of the actual values and change from Baseline will be summarized using descriptive statistics for the scheduled visits, overall, Last Visit, minimum and maximum post-Baseline values obtained during the Treatment Period, and in each of the TEMA ECG criteria age categories. Last visit is the value from the last post baseline visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last visit, minimum, and maximum post-Baseline values during the Treatment Period. If repeat measurements are taken at a particular visit, then the average value is used in summaries and the original values are listed.
The number and percentage of subjects who met each of the TEMA criteria specified in Section 12.3.4 will be presented within the specified age groups. For each parameter, the number and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by-visit summaries, but will be considered when determining the last visit values during the Treatment Period. Subject numbers for those with TEMA ECG values will be listed by abnormality criteria. TEMA results for a subject are those that are observed during the defined treatment period at scheduled or unscheduled visits and were not observed at any visit during the Baseline period.
Detailed information on the quantitative and qualitative ECG findings will be presented in subject data listings.
Section 10.4.4.1, New Seizure Type, was modified from:
The incidence of new seizure types i.e. those not experienced in the Prospective Baseline but experienced during the Treatment Period as recorded in the diary will be summarized.
Has been changed to:
The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure type was present or absent in Combined Baseline will be tabulated. The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure type was present or absent in Seizure History (including Combined Baseline) will be tabulated.
The number and percentage of subjects with new absence or myoclonic seizure types experienced in the Treatment Period with absence or myoclonic seizure type, respectively, indicated by the Seizure History Classification but not experienced in the Combined Baseline as recorded in the diary will be summarized.
REDACTED COPY The number and percentage of subjects who met each of the TEMA criteria specified in
REDACTED COPY The number and percentage of subjects who met each of the TEMA criteria specified in
d age groups. For each parameter, the number
REDACTED COPY
d age groups. For each parameter, the number and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific
REDACTED COPY
and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and
REDACTED COPY
to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and by scheduled visit and Last Visit during the Treatment Period. Repeated
REDACTED COPY
by scheduled visit and Last Visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by
REDACTED COPY
or unscheduled ECG assessments during the study will not be presented in bybut will be considered when determining the last visit values during the Treatment Period.
REDACTED COPY
but will be considered when determining the last visit values during the Treatment Period.TEMAREDACTED C
OPY
TEMA ECG values will be listed by abnormality criteria.REDACTED COPY
ECG values will be listed by abnormality criteria.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For quantitative ECG measurements (heart rate, PR interval, QRS interval, QT interval, RR
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For quantitative ECG measurements (heart rate, PR interval, QRS interval, QT interval, RR and Fridiricia correction methods), summary
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and Fridiricia correction methods), summary statistics of the actual values and change from Baseline will be summarized using descriptive
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
statistics of the actual values and change from Baseline will be summarized using descriptive statistics for the scheduled visits, overall, Last Visit, minimum and maximum post
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
statistics for the scheduled visits, overall, Last Visit, minimum and maximum post-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline Treatment Period, and in each of the TEMA ECG criteria age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period, and in each of the TEMA ECG criteria age categories. Last visit is the value from the last post baseline visit during the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
categories. Last visit is the value from the last post baseline visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeated or unscheduled ECG assessments during the study will not be presented in byies, but will be considered when determining the last visit, minimum, and maximum
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ies, but will be considered when determining the last visit, minimum, and maximum Baseline values during the Treatment Period. If repeat measurements are taken at a
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline values during the Treatment Period. If repeat measurements are taken at a particular visit, then the average value is used in summaries and the original values
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
particular visit, then the average value is used in summaries and the original values
The number and percentage of subjects who met each of the TEMA criteria specified in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects who met each of the TEMA criteria specified in d age groups. For each parameter, the number
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
d age groups. For each parameter, the number and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and by scheduled visit and Last Visit during the Treatment Period. Repeated
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
by scheduled visit and Last Visit during the Treatment Period. Repeated or unscheduled ECG assessments during the study will not be presented in by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or unscheduled ECG assessments during the study will not be presented in bybut will be considered when determining the last visit values during the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
but will be considered when determining the last visit values during the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ECG values will be listed by abnormality criteria.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ECG values will be listed by abnormality criteria.results for a subject are those that are observed during the defined treatment period at scheduled
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
results for a subject are those that are observed during the defined treatment period at scheduled or unscheduled visits and were not observed at any visit during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or unscheduled visits and were not observed at any visit during
Detailed information on the quantitative and qualitative ECG findings will be presented in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Detailed information on the quantitative and qualitative ECG findings will be presented in
Section 10.4.4.1, New Seizure Type, was modified from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 10.4.4.1, New Seizure Type, was modified from:
The incidence of new seizure types i.e. those not experienced in t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The incidence of new seizure types i.e. those not experienced in texperienced during the Treatment Period as recorded in the diary will be summarized.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experienced during the Treatment Period as recorded in the diary will be summarized.
Has been changed to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been changed to:
The number and percentage of subjects with seizure types present or absent in the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period vs whether the seizure The number and percentage of subjects with seizure types present or absent in the Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The number and percentage of subjects with seizure types present or absent in the Treatment Period vs whether the seizure type was present or absent in Seizure History (including Combined
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period vs whether the seizure type was present or absent in Seizure History (including Combined B
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline) will be tabulated.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
aseline) will be tabulated.
![Page 114: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/114.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The number and percentage of subjects with new absence or myoclonic seizure types experienced in the Treatment Period but not experienced in the Combined Baseline or indicated in Seizure History Classification will also be summarized.
The number and percentage of subjects with new absence or myoclonic seizure types in the Treatment Period, with absence or myoclonic, respectively, indicated by the Seizure History Classification but not experienced in the Combined Baseline Period or subjects with ≥50% worsening in days with absence or myoclonic seizures, respectively, will be summarized.
Section 10.4.8.2, Analysis of Achenbach variables, the following sentence was added:
The means of the calculated T-score will be plotted by visit.
Section 10.4.9.1, BRIEF-P scores, the following sentence was added:
The means of the BRIEF-P assessment data will be plotted by visit.
Section 10.4.9.2, BRIEF scores, the following sentence was added:
The means of the BRIEF assessment data will be plotted by visit.
Section 12.2.1, Other Significant AEs, the table has been update with the latest criteria. Liver injury related criteria has been moved to the table in Section 12.2.2.
Section 12.2.2, AEs for Potentially Drug Induced Liver Injury, this table is newly added.
Section 12.3.4, Table 11, ECGs – Abnormality Criteria, categories for QT, QTc(F), and QTc(B) have been updated.
Section 12.5, Registry Required Tables, the list of tables required has been updated.
Section 12.6, Additional Subgroups to be programmed in ADSL, is newly added.
13.4 Amendment 4
13.4.1 Rationale for the amendment
A Type C Meeting request was submitted to FDA on Dec 12, 2018 to IND 057939 Sequence No. 1268 cross-reference IND 068407 and IND 073809. Included in the package was the SP0982 SAP Amendment 3. A Type C Written Response dated 4Mar2019 was received which prompted this amendment. Other items were clarified or added.
13.4.2 Modification and changes
At the request of FDA, the following items were added or clarified:
New sensitivity analysis of the primary endpoint was added involving dropouts after 1st PGTCS
Clarification regarding the checking of the proportional hazards assumption was added
Variables and analyses involving reduction and increase in seizure frequency, responder status and worsening for absence and myoclonic seizures were added
Analyses involving post-treatment vital sign and QTc measurements were added
The following items were clarified:
Stratum pooling algorithm
REDACTED COPY iver Injury, this table is newly added.
REDACTED COPY iver Injury, this table is newly added.
Abnormality Criteria, categories for QT, QTc(F), and QTc(B)
REDACTED COPY
Abnormality Criteria, categories for QT, QTc(F), and QTc(B)
Section 12.5, Registry Required Tables, the list of tables required has been updated.
REDACTED COPY
Section 12.5, Registry Required Tables, the list of tables required has been updated.
Additional Subgroups to be programmed in ADSL, is newly added.REDACTED C
OPY
Additional Subgroups to be programmed in ADSL, is newly added.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
AEs, the table has been update with the latest criteria
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
AEs, the table has been update with the latest criteriainjury related criteria has been moved to the table in Section 12.2.2.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
injury related criteria has been moved to the table in Section 12.2.2.
iver Injury, this table is newly added.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
iver Injury, this table is newly added.
Abnormality Criteria, categories for QT, QTc(F), and QTc(B)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Abnormality Criteria, categories for QT, QTc(F), and QTc(B)
Section 12.5, Registry Required Tables, the list of tables required has been updated.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 12.5, Registry Required Tables, the list of tables required has been updated.
Additional Subgroups to be programmed in ADSL, is newly added.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Additional Subgroups to be programmed in ADSL, is newly added.
Rationale for the amendment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Rationale for the amendment
A Type C Meeting request was submitted to FDA on Dec 12, 2018 to IND 057939 Sequence No.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A Type C Meeting request was submitted to FDA on Dec 12, 2018 to IND 057939 Sequence No. reference IND 068407 and IND 073809. Included in th
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reference IND 068407 and IND 073809. Included in thSAP Amendment 3. A Type
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SAP Amendment 3. A Type C
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
C Written Response dated 4Mar2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Written Response dated 4Mar2this amendment. Other items were clarified
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
this amendment. Other items were clarified
Modification and changes
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Modification and changes
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
At the request of FDA, the following items were added or clarifie
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
At the request of FDA, the following items were added or clarifie
New sensitivity analysis of the primary endpoint was added involving dropouts after 1
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
New sensitivity analysis of the primary endpoint was added involving dropouts after 1PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Clarification regarding the checking of the proportional hazards assumption was added
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Clarification regarding the checking of the proportional hazards assumption was added
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 115: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/115.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Algorithm for identifying rescue medications
The following items were added:
A new listing of rescue medications
References specific to the Cox proportional hazards analysis
Additional analyses using the Development subgroup
New variable identifying Asian sites
13.4.2.1 Specific changes
The information below was revised from:
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019
Has been revised to:
SAP/Amendment Number Date Final SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 26 Mar 2019
Section 3.2.5, the 3rd paragraph was changed from:
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the CRF, although rescue benzodiazepines will also be identified programmatically as any benzodiazepines taken intermittently for 1 day at any frequency. Rescue medication is defined as the intermittent use of benzodiazepines (limited to 2 doses per 28 days) for epilepsy indications if established at least 28 days prior to Visit 1. Lifetime benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at least 28 days prior to Visit 1.
Has been revised to:
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the CRF, although rescue AEDs will also be identified programmatically as any AED taken intermittently for 1 or 2 days, at any frequency, with an epilepsy or seizure related indication. Rescue medication is defined as the intermittent use of benzodiazepines (limited to 2 doses per 28 days) for epilepsy indications if established at least 28 days prior to Visit 1. Lifetime benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at least 28 days prior to Visit 1.
Section 3.9, the changes to protocol-defined analyses has been changed from:
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis.
REDACTED COPY
26 Mar 2019
REDACTED COPY
26 Mar 2019
paragraph was changed from:REDACTED COPY
paragraph was changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
paragraph was changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
paragraph was changed from:
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the CRF, although rescue benzodiazepin
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
CRF, although rescue benzodiazepines will also be identified programmatically as any
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
es will also be identified programmatically as any benzodiazepines taken intermittently for 1 day at any frequency. Rescue medication is defined as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
benzodiazepines taken intermittently for 1 day at any frequency. Rescue medication is defined as the intermittent use of benzodiazepines (limited to 2 doses per 28 days) for epilepsy indications
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the intermittent use of benzodiazepines (limited to 2 doses per 28 days) for epilepsy indications shed at least 28 days prior to Visit 1. Lifetime benzodiazepines are defined as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
shed at least 28 days prior to Visit 1. Lifetime benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at least 28 days prior to Visit 1.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
benzodiazepines taken in the subject’s history and stopped at least 28 days prior to Visit 1.
Has been revised to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been revised to:
Benzodiazepines taken for rescue will be flagged with “RESCU
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Benzodiazepines taken for rescue will be flagged with “RESCU
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
CRF, although rescue AEDs will also be identified programmatically as any AED taken
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
CRF, although rescue AEDs will also be identified programmatically as any AED taken intermittently for 1 or 2 days, at any frequency, with an epilepsy or seizure related indication.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
intermittently for 1 or 2 days, at any frequency, with an epilepsy or seizure related indication. Rescue medication is defined as the inte
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Rescue medication is defined as the inte28 days) for epilepsy indications if established at least 28 days prior to Visit 1. Lifetime
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
28 days) for epilepsy indications if established at least 28 days prior to Visit 1. Lifetime benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at least 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
least 28 days
![Page 116: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/116.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The analysis of the key secondary endpoint has been clarified to assess the seizure-free rate using an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates within each stratum. The extended Mantel-Haenszel technique is a randomization-based nonparametric method that provides a more robust method to assess seizure freedom.
Has been revised to:
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis. Also, Protocol Section 13.3.2.1 states that the key secondary efficacy variable will be analyzed in the same manner as the primary endpoint using the FAS and that the percentage of seizure-free subjects at 24 weeks will be estimated from the KM estimates of time to first seizure. The analysis of the key secondary endpoint has been clarified to assess the seizure-free rate at 24 weeks using an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates within each stratum. The extended Mantel-Haenszel technique is a randomization-based nonparametric method that provides a more robust method to assess seizure freedom. Thus, the key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy endpoint; the other secondary efficacy variable, time to first PGTCS, will be analyzed in the same manner as the primary efficacy endpoint.
Section 4.9, the stratum pooling algorithm has been updated from:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age at informed consent categories will be summed.
If 2 of the age at informed consent categories combined have < 3 total events, then all age categories are combined for the analysis.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
If ≥18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the strata with the 2nd smallest number of events.
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to determine stratum pooling.
Has been revised to:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age at informed consent categories will be summed. For categories with < 3 total events, the combining should occur as follows:
If 2 of the age at informed consent categories combined have < 3 total events, then all age categories are combined for the analysis.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
REDACTED COPY Section 4.9, the stratum pooling algorithm has been updated from:
REDACTED COPY Section 4.9, the stratum pooling algorithm has been updated from:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
REDACTED COPY
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
If 2 of the age at informed consent categories combined have < 3 total events, then all age
REDACTED COPY
If 2 of the age at informed consent categories combined have < 3 total events, then all age ined for the analysis.
REDACTED COPY
ined for the analysis.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events REDACTED C
OPY
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.REDACTED C
OPY
or less, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
that the key secondary efficacy variable will be analyzed in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
that the key secondary efficacy variable will be analyzed in the same manner as the primary endpoint using the FAS and that the percentage of seizur
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the same manner as the primary endpoint using the FAS and that the percentage of seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-free
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free om the KM estimates of time to first seizure. The
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
om the KM estimates of time to first seizure. The free rate at 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free rate at 24 Meier estimates
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Meier estimates Haenszel technique is a randomization
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Haenszel technique is a randomization-
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
-based
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
based nonparametric method that provides a more robust method to assess seizure freedom. Thus, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nonparametric method that provides a more robust method to assess seizure freedom. Thus, the in the same manner as the primary efficacy
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in the same manner as the primary efficacy endpoint; the other secondary efficacy variable, time to first PGTCS, will be analyzed in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
endpoint; the other secondary efficacy variable, time to first PGTCS, will be analyzed in the
Section 4.9, the stratum pooling algorithm has been updated from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 4.9, the stratum pooling algorithm has been updated from:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age
If 2 of the age at informed consent categories combined have < 3 total events, then all age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 2 of the age at informed consent categories combined have < 3 total events, then all age
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
or less, it should be combined with the ≥12 and <18 years of age category.
If ≥18 years of age is the category with the smallest number o
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥18 years of age is the category with the smallest number oless, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
less, it should be combined with the ≥12 and <18 years of age category.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the strata with the 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
events or less, it should be combined with the strata with the 2
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to determine stratum pooling.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
determine stratum pooling.
Has been revised to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been revised to:
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of t
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of tat informed consent categories will be summed. For categories with < 3 total events, the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
at informed consent categories will be summed. For categories with < 3 total events, the combining should occur as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
combining should occur as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 2 of the age at informed consent categories combined have < 3 total events, then all age
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
If 2 of the age at informed consent categories combined have < 3 total events, then all age
![Page 117: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/117.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
If ≥18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the ≥12 and <18 years of age category.
If ≥12 and <18 years of age is the category with the smallest number of events that are 2 events or less, it should be combined with the strata with the 2nd smallest number of events.
Repeat the algorithm for combining strata for the subjects who did not have events if there are categories with < 3 total non-events.
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to determine stratum pooling for both events and non-events.
For each primary efficacy endpoint sensitivity analysis which uses stratum pooling, the pooling of the strata should be reassessed since the event distribution for the specific sensitivity may be different than the distribution in the primary efficacy endpoint analysis.
Section 6.6, the following sentence was added at the end of this section:
AEDs flagged as rescue medications will also be listed in subject data listings.
Section 8.1.2, the 2nd paragraph was revised from:
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
H0: β=0
Versus
H1: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented by
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
)
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The assumptions of proportional hazards will also be checked.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. The SE and 95% CI for the HR will also be reported.
Has been revised to:
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
H0: β=0
Versus
H1: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the model. The hazard function is represented by
REDACTED COPY
H
REDACTED COPY
H1
REDACTED COPY
1: β≠0
REDACTED COPY
: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the
REDACTED COPY
where β is the coefficient of an independent variable representing the treatment effect in the represented by
REDACTED COPY
represented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For each primary efficacy endpoint sensitivity analysis which uses stratum pooling, the pooling
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
For each primary efficacy endpoint sensitivity analysis which uses stratum pooling, the pooling of the strata should be reassessed since the event distribution for the specific sensitivity may be
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
of the strata should be reassessed since the event distribution for the specific sensitivity may be
in subject data listings.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
in subject data listings.
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows:
: β≠0
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
: β≠0
where β is the coefficient of an independent variable representing the treatment effect in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where β is the coefficient of an independent variable representing the treatment effect in the represented by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
represented by
𝑋
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
𝑋)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
=
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
= ℎ
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ℎ
is the collection of independent variables and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
is the collection of independent variables and the null hypothesis, the testing will be 2
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the null hypothesis, the testing will be 2ns of proportional hazards will also be checked.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ns of proportional hazards will also be checked.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The SE and 95% CI for the HR will also be reported.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The SE and 95% CI for the HR will also be reported.
Has been revised to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Has been revised to:
The hypothesis for the assessment of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The hypothesis for the assessment of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Versus
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Versus
![Page 118: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/118.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
)
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The assumptions of proportional hazards will also be assessed graphically (e.g. log (log S) plot vs time, empirical score process) for any departure; non-proportionality is not expected when using a stratified Cox model. Depending on the departure from proportional hazards, a sensitivity analysis (e.g. piecewise proportional hazards, time-varying coefficient, restricted mean survival) may be performed.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. The 95% CI for the HR will also be reported.
Section 8.1.4, the following sensitivity analysis was clarified from:
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events) through each subject’s first 166 days of treatment, on the FAS.
Was revised to:
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events after the date of the 125th event) through each subject’s first 166 days of treatment, on the FAS.
Section 8.1.4, the following sensitivity analysis was added:
Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely discontinue after their 1st PGTCS will be analyzed as treatment failures.
Section 8.2.2.2, the following sentence was clarified from:
The assumptions of proportional hazards will also be checked.
Was revised to:
The assumptions of proportional hazards will also be checked using the same approach as for the primary efficacy endpoint.
Section 8.3, was revised from:
All seizure data recorded during the treatment period will be summarized and listed for the seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will be performed for the FAS.
Was revised to:
All seizure data recorded during the treatment period will be summarized and listed for the seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will be performed for the FAS. For absence seizure analyses, this analysis population will be further restricted to the subset of subjects who reported a history of absence seizures or reported absence seizures during baseline or the 24-week treatment period. For myoclonic seizure analyses, this analysis population will be further restricted to the subset of subjects who reported a history of myoclonic seizures or reported myoclonic seizures during baseline or the 24-week treatment period.
REDACTED COPY l PGTCS data (ie, all reported events after the
REDACTED COPY l PGTCS data (ie, all reported events after the
event) through each subject’s first 166 days of treatment, on the FAS.
REDACTED COPY
event) through each subject’s first 166 days of treatment, on the FAS.
Section 8.1.4, the following sensitivity analysis was added:
REDACTED COPY
Section 8.1.4, the following sensitivity analysis was added:
Repeat the primary efficacy analysis using the FAS, except
REDACTED COPY
Repeat the primary efficacy analysis using the FAS, exceptPGTCS will be analyzed as treatment failures.
REDACTED COPY
PGTCS will be analyzed as treatment failures.
e following sentence was clarified fromREDACTED COPY
e following sentence was clarified from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
proportionality is not expected when using
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
proportionality is not expected when using
varying coefficient, restricted mean survival)
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
varying coefficient, restricted mean survival)
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group.
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events) through
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events) through
l PGTCS data (ie, all reported events after the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
l PGTCS data (ie, all reported events after the event) through each subject’s first 166 days of treatment, on the FAS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
event) through each subject’s first 166 days of treatment, on the FAS.
Section 8.1.4, the following sensitivity analysis was added:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.1.4, the following sensitivity analysis was added:
Repeat the primary efficacy analysis using the FAS, except
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Repeat the primary efficacy analysis using the FAS, exceptPGTCS will be analyzed as treatment failures.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
PGTCS will be analyzed as treatment failures.
e following sentence was clarified from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
e following sentence was clarified from
The assumptions of proportional hazards will also be checked.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The assumptions of proportional hazards will also be checked.
assumptions of proportional hazards will also be checked using the same approach as for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
assumptions of proportional hazards will also be checked using the same approach as for the primary efficacy endpoint.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
primary efficacy endpoint.
Section 8.3, was revised from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.3, was revised from:
All seizure data recorded during the treatment period will be summarized and listed for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All seizure data recorded during the treatment period will be summarized and listed for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
d other efficacy variables. Analyses of seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
d other efficacy variables. Analyses of seizurebe performed for the FAS.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be performed for the FAS.
Was revised to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Was revised to:
All seizure data recorded during the treatment period will be summarized and listed for the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
All seizure data recorded during the treatment period will be summarized and listed for the seizure related other efficacy varia
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizure related other efficacy variabe performed for the FAS. For absence seizure analyses, this analysis population will be further
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
be performed for the FAS. For absence seizure analyses, this analysis population will be further restricted to the subset of subjects who reported a history of absence seizures or reported abs
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
restricted to the subset of subjects who reported a history of absence seizures or reported abs
![Page 119: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/119.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Section 8.3.1.1, the following text was removed:
The percent change in log-transformed (PCHL) PGTCS frequency per 28 days from the Combined Baseline (CB) to the appropriate analysis period (T) is defined as:
PCHL = [(ln(SFT) – ln(SFCB)) / ln(SFCB)] x 100
where SFT corresponds to the 28-day PGTCS frequency during the relative period and SFCB corresponds to the 28-day Combined Baseline PGTCS frequency.
Section 8.3.1.2, paragraphs 3, 4, and 5 were revised from:
The percent change (PCH) in days with absence seizures per 28 days from the appropriate Baseline (B) to the appropriate analysis period (T) is defined as:
PCH = [(DT – DB) / DB] x 100
where DT corresponds to the number of days with absence seizures per 28 days during the relative period and DB corresponds to the number of days with absence seizures per 28 days during the Baseline Period. If DB is zero, then PCH will be missing and any such subjects will be excluded from the percent change summary. PCH will be calculated for the 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from the appropriate Baseline Period will be calculated.
Were revised to:
The percent change (PCH) in days with absence seizures per 28 days from the Prospective Baseline (B) to the appropriate analysis period (T) is defined as:
PCH = [(DT – DB) / DB] x 100
where DT corresponds to the number of days with absence seizures per 28 days during the relative period and DB corresponds to the number of days with absence seizures per 28 days during the Prospective Baseline Period. If DB is zero, then PCH will be missing and any such subjects will be excluded from the percent change summary. PCH will be calculated for the 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from the Prospective Baseline Period will be calculated.
Section 8.3.1.8, Variable: Days with absence and myoclonic seizures – worsening is new:
Safety of the LCM treatment will be based on the percent change in days with absence seizure per 28 days and days with myoclonic seizure per 28 days. The increase in days with absence seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period. The increase in days with myoclonic seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period.
Section 8.3.1.9, Variable: Absence and myoclonic seizure frequencies per 28 days is new:
In order to account for potential differences in the durations of the study periods for individuals, absence and myoclonic seizure data will be normalized to 28 days.
REDACTED COPY Similarly, the percent change in the number of days with myoclonic seizures per 28 days from
REDACTED COPY Similarly, the percent change in the number of days with myoclonic seizures per 28 days from
The percent change (PCH) in days with absence seizures per 28 days from the Prospective
REDACTED COPY
The percent change (PCH) in days with absence seizures per 28 days from the Prospective Baseline (B) to the appropriate analysis period (T) is defined as:
REDACTED COPY
Baseline (B) to the appropriate analysis period (T) is defined as:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
rcent change (PCH) in days with absence seizures per 28 days from the appropriate
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
rcent change (PCH) in days with absence seizures per 28 days from the appropriate
where DT corresponds to the number of days with absence seizures per 28 days d
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where DT corresponds to the number of days with absence seizures per 28 days during the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
uring the relative period and DB corresponds to the number of days with absence seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
relative period and DB corresponds to the number of days with absence seizures per 28 days during the Baseline Period. If DB is zero, then PCH will be missing and any such subjects will
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the Baseline Period. If DB is zero, then PCH will be missing and any such subjects will culated for the 6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
culated for the 6week Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period.
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from
The percent change (PCH) in days with absence seizures per 28 days from the Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The percent change (PCH) in days with absence seizures per 28 days from the Prospective Baseline (B) to the appropriate analysis period (T) is defined as:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline (B) to the appropriate analysis period (T) is defined as:
where DT corresponds to the number of days with abse
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
where DT corresponds to the number of days with abserelative period and DB corresponds to the number of days with absence seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
relative period and DB corresponds to the number of days with absence seizures per 28 days
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the Prospective Baseline Period. If DB is zero, then PCH will be missing and any such
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the Prospective Baseline Period. If DB is zero, then PCH will be missing and any such subjects will be excluded from the p
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
subjects will be excluded from the pweek Titration Period, first 12 weeks of the Treatment Period and the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titration Period, first 12 weeks of the Treatment Period and the 24
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from tive Baseline Period will be calculated.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tive Baseline Period will be calculated.
Section 8.3.1.8, Variable: Days with absence and myoclonic seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.3.1.8, Variable: Days with absence and myoclonic seizures
Safety of the LCM treatment will be based on the percent change in days with absence seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Safety of the LCM treatment will be based on the percent change in days with absence seizure per 28 days and days with myocloni
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days and days with myocloni
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period. The increase in days with myoclonic seizures
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>50 to 75%, and >75% for the Treatment Period. The increase in days with myoclonic seizures per 28 days fr
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days fr75%, and >75% for the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
75%, and >75% for the Treatment Period.
![Page 120: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/120.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The 28-day absence SF will be calculated for the Prospective Baseline and Treatment Periods as:
SF =
(# absence seizures in the relative period/# days in relative period with evaluable absence seizure data)*28
The PCH in Absence seizure frequency per 28 days from the Prospective Baseline (PB) to the appropriate analysis period (T) is defined as:
PCH = [(SFT – SFPB) / SFPB] x 100
where SFT corresponds to the 28-day absence seizure frequency during the relative period and SFPB corresponds to the 28-day Prospective Baseline absence frequency; if subjects had no absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calculated for 6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period.
SF and PCH are calculated for subjects with myoclonic seizures using the same algorithm described above.
Section 8.3.1.10, Variable: Responder status – reduction in absence and myoclonic seizure frequencies is new:
Response to treatment will be based on the percent change in absence and myoclonic seizure frequencies, calculated as described in Section 8.3.1.9. A 50% responder is defined as a subject experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period).
Section 8.3.1.11, Variable: Absence and myoclonic seizure frequency - worsening is new:
Safety of the LCM treatment will be based on the percent change in absence seizure frequency per 28 days and myoclonic seizure frequency per 28 days. The increase in absence seizure frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period. The increase in myoclonic seizure frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period.
Section 8.3.2.5, the following last bullet was changed from:
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for reduction in days with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
Was revised to:
A histogram of ≥50% and ≥75% responder status for reduction in days with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
REDACTED COPY Response to treatment will be based on the percent change in absence and myoclonic seizure
REDACTED COPY Response to treatment will be based on the percent change in absence and myoclonic seizure
8.3.1.9
REDACTED COPY
8.3.1.9. A 50% responder is defined as a subject
REDACTED COPY . A 50% responder is defined as a subject
experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the
REDACTED COPY
experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the Prospective Baseline to the period of interest (6
REDACTED COPY
Prospective Baseline to the period of interest (6-
REDACTED COPY
-week Titr
REDACTED COPY
week Titrweek Treatment Period). A 75% responder is defined as a subject
REDACTED COPY
week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from
REDACTED COPY
experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from Prospective Baseline to the period of inREDACTED C
OPY
Prospective Baseline to the period of interest (6REDACTED COPY
terest (6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day absence seizure frequency during the relative period and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day absence seizure frequency during the relative period and day Prospective Baseline absence frequency; if subjects had no
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
day Prospective Baseline absence frequency; if subjects had no absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calcu
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calculated for
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lated for week Treatment
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment
SF and PCH are calculated for subjects with myoclonic seizures using the same algorithm
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
SF and PCH are calculated for subjects with myoclonic seizures using the same algorithm
reduction in absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in absence and myoclonic seizure
Response to treatment will be based on the percent change in absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment will be based on the percent change in absence and myoclonic seizure . A 50% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. A 50% responder is defined as a subject experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the week Titr
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Titrweek Treatment Period). A 75% responder is defined as a subject
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period). A 75% responder is defined as a subject experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from terest (6
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
terest (6week Treatment Period).
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
week Treatment Period).
, Variable: Absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
, Variable: Absence and myoclonic seizure
Safety of the LCM treatment will be based on the percent chang
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Safety of the LCM treatment will be based on the percent changper 28 days and myoclonic seizure frequency per 28 days. The increase in absence seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days and myoclonic seizure frequency per 28 days. The increase in absence seizure frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Per
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
>50 to 75%, and >75% for the Treatment Perper 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 75%, and >75% for the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
75%, and >75% for the Treatment Period.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.3.2.5, the following last bullet was changed from:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section 8.3.2.5, the following last bullet was changed from:
A histogram of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
A histogram of with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24Treatment Period by treatment group will be provided.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Treatment Period by treatment group will be provided.
Was revised to:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Was revised to:
![Page 121: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/121.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Section 8.3.2.6, the following bullet was inserted:
A histogram of ≥50% and ≥75% responder status for reduction in days with myoclonic seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by treatment group will be provided.
Section 8.3.2.7, Analysis: Percent change in absence and myoclonic seizure frequency per 28 days from Prospective Baseline is new:
Descriptive statistics will be provided on the percent change in absence and myoclonic seizure frequencies for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.
All absence and myoclonic seizure frequency per 28 days data will be listed.
Section 8.3.2.8, Analysis: Responder status – reduction in absence and myoclonic seizure frequency is new:
The following data will be summarized with descriptive statistics only:
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure frequency during the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency during the Treatment Period compared to the Prospective Baseline
REDACTED COPY least a 50% reduction in myoclonic seizure frequency
REDACTED COPY least a 50% reduction in myoclonic seizure frequency
during the first 6 weeks (Titration Period) compared to the Prospective Baseline
REDACTED COPY
during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure frequency during
REDACTED COPY
Percentage of subjects with at least a 50% reduction in absence seizure frequency during ent Period compared to the Prospective Baseline
REDACTED COPY
ent Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency
REDACTED COPY
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
REDACTED COPY
during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least REDACTED COPY
Percentage of subjects with at least
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics will be provided on the percent change in absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Descriptive statistics will be provided on the percent change in absence and myoclonic seizure Period), first 12 weeks of, and the entire
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Period), first 12 weeks of, and the entire
reduction in absence and myoclonic seizure
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
reduction in absence and myoclonic seizure
Percentage of subjects with at least a 50% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 6 weeks (Titration Period) compared to the Prospective Baseline
least a 50% reduction in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
least a 50% reduction in myoclonic seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure frequency during ent Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ent Period compared to the Prospective Baseline
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the first 12 weeks of the Treatment Period compared to the Prospective Baseline
Percentage of subjects with at least
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
a 50% reduction in absence seizure frequency during the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency during the Treatment Period compared to the Prospective Baseli
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
during the Treatment Period compared to the Prospective Baseli
Percentage of subjects with at least a 75% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in absence seizure frequency during the first 6 weeks (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency the first 6 weeks (Titration Period) compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 6 weeks (Titration Period) compared to the Prospective Baseline
Percentage of subjects with at least a 75% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage of subjects with at least a 75% reduction in absence seizure frequency during
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
the first 12 weeks of the Treatment Period compared to the Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage o
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Percentage o
![Page 122: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/122.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Section 10.2, the following TEAE summary was added:
Incidence of common TEAEs for EU labeling (above or equal to reporting threshold of 1% (prior to rounding) of subjects in the total LCM group) and occurring >1% than in the placebo group
Section 10.4.4.4, Increase in absence seizure frequency is new:
Response to treatment regarding absence seizures will also be based on the percent change in the absence seizure frequency per 28 days, calculated as described in Section 8.3.1.9 . The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in absence seizure frequency per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
Section 10.4.4.5, Increase in myoclonic seizure frequency is new:
Response to treatment regarding myoclonic seizures will also be based on the percent change in the myoclonic seizure frequency per 28 days, calculated as described in Section 8.3.1.9. The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in myoclonic seizure frequency per 28 days during the Treatment Period compared to the Prospective Baseline Period will be presented.
References were revised from:
Cox DR. Regression models and life-tables. J R Stat Soc Series B Methodol. 1972;34(2):187-220.
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of lamotrigine as adjunctive therapy in subjects with primary generalized tonic-clonic seizures. Epilepsia. 2007;48(S6):77-78.
LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods for the analysis of multicentre trials. Stat Methods Med Res. 2005;14:281-301.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered analysis of variance. Biometrika. 1976;63:655-60.
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study. Epilepsy & Behavior. 2010; 19: 352-8.
Was revised to the following:
Allison, PD. Survival Analysis Using SAS®: A Practical Guide. 2nd ed. Cary: SAS Institute; 2010
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study. Epilepsy & Behavior. 2010; 19: 352-8.
Collett D. Modelling survival data in medical research. 3rd ed. London: CRC Press; 2015
Cox DR. Regression models and life-tables. J R Stat Soc Series B Methodol. 1972;34(2):187-220.
REDACTED COPY
tables. J R Stat Soc Series B Methodol.
REDACTED COPY
tables. J R Stat Soc Series B Methodol.
ammer AE, VanLandingham KE. Time to nth seizure analysis of
REDACTED COPY
ammer AE, VanLandingham KE. Time to nth seizure analysis of lamotrigine as adjunctive therapy in subjects with primary generalized tonic
REDACTED COPY
lamotrigine as adjunctive therapy in subjects with primary generalized tonic
LaVange LM, Durham TA, Koch GG. RandomizationREDACTED COPY
LaVange LM, Durham TA, Koch GG. Randomization
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment regarding absence seizures will also be based on the percent change in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment regarding absence seizures will also be based on the percent change in the . The number
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
. The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in absence seizure frequency per 28 days during the Treatment Period compared to the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
and >75% in absence seizure frequency per 28 days during the Treatment Period compared to the
Response to treatment regarding myoclonic seizures will also be based on the percent change in
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Response to treatment regarding myoclonic seizures will also be based on the percent change in Secti
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Section
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
onnumber and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50%
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% cy per 28 days during the Treatment Period
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
cy per 28 days during the Treatment Period
tables. J R Stat Soc Series B Methodol.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
tables. J R Stat Soc Series B Methodol.
ammer AE, VanLandingham KE. Time to nth seizure analysis of
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ammer AE, VanLandingham KE. Time to nth seizure analysis of lamotrigine as adjunctive therapy in subjects with primary generalized tonic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lamotrigine as adjunctive therapy in subjects with primary generalized tonic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
LaVange LM, Durham TA, Koch GG. Randomization
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
LaVange LM, Durham TA, Koch GG. Randomizationanalysis of multicentre trials. Stat Methods Med Res. 2005;14:281
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
analysis of multicentre trials. Stat Methods Med Res. 2005;14:281
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered analysis of variance. Biometrika. 1976;63:655
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
analysis of variance. Biometrika. 1976;63:655
Biton V, Di Memmo J, Shukla R,
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Biton V, Di Memmo J, Shukla R,lamotrigine XR for primary generalized tonic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lamotrigine XR for primary generalized toniccontrolled study. Epilepsy & Behavior. 2010; 19: 352
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
controlled study. Epilepsy & Behavior. 2010; 19: 352
Was revised to the following:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Was revised to the following:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Allison, PD. Survival Analysi
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Allison, PD. Survival Analysi
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive lamotrigine XR for primary generalized tonic
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
lamotrigine XR for primary generalized toniccontrolled study.
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
controlled study.
Collett D. Modelling survival data in medical research. 3
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Collett D. Modelling survival data in medical research. 3
![Page 123: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/123.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of lamotrigine as adjunctive therapy in subjects with primary generalized tonic-clonic seizures. Epilepsia. 2007;48(S6):77-78.
LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods for the analysis of multicentre trials. Stat Methods Med Res. 2005;14:281-301.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered analysis of variance. Biometrika. 1976;63:655-60.
SAS®/Stat 9.4: User’s Guide. Cary: SAS Institute Inc; 2015
Section 12.3.3, Table 10 was updated with the post-treatment vital sign abnormalities requested in the Type C Written Response.
Section 12.3.4, Table 11 was updated with the post-treatment QTc abnormalities requested in the Type C Written Response.
Appendix 5: Registry Required Tables was revised from:
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or Article 46 (European Pediatric Regulation). These tables will be produced at the same time as the CSR required Tables.
Disposition and Discontinuation Reasons by Development
Discontinuation due to AEs
Demographics by Development
Baseline Characteristics by Development
LCM Overall Exposure by Development
Study Medication Duration by Development
Incidence of TEAEs by Development – Overview
Incidence of TEAEs by Development
Incidence of Serious TEAEs by Development
Incidence of Non-serious TEAEs
Incidence of TEAEs by Relationship and Development
Incidence of TEAEs Leading to Discontinuation by Development
Incidence of Serious TEAEs by Relationship
Incidence of Non-serious TEAEs by Relationship
Incidence of Fatal TEAEs by Relationship
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
Was revised to:
REDACTED COPY Disposition and Discontinuation Reasons by Development
REDACTED COPY Disposition and Discontinuation Reasons by Development
Baseline Characteristics by Development
REDACTED COPY
Baseline Characteristics by Development
LCM Overall Exposure by DevelopmentREDACTED COPY
LCM Overall Exposure by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment vital sign abnormalities requested
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment vital sign abnormalities requested
treatment QTc abnormalities requested in the
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
treatment QTc abnormalities requested in the
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or Article 46 (European Pediatric Regulation). These tables will be produced at the same time as
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Article 46 (European Pediatric Regulation). These tables will be produced at the same time as
Disposition and Discontinuation Reasons by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Disposition and Discontinuation Reasons by Development
Study Medication Duration by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Study Medication Duration by Development
Incidence of TEAEs by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs by Development –
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
–
Incidence of TEAEs by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs by Development
Incidence of Serious TEAEs by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of Serious TEAEs by Development
serious TEAEs
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serious TEAEs
Incidence of TEAEs by Relationship and Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs by Relationship and Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs Leading to Discontinuation by Dev
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of TEAEs Leading to Discontinuation by Dev
Incidence of Serious TEAEs by Relationship
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of Serious TEAEs by Relationship
Incidence of Non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of Non
Incidence of Fatal TEAEs by Relationship
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of Fatal TEAEs by Relationship
Incidence of Non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Incidence of Non
![Page 124: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/124.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or Article 46 (European Pediatric Regulation). These tables will be produced at the same time as the CSR required Tables.
Disposition and Discontinuation Reasons by Development
Discontinuation due to AEs
Demographics by Development
Baseline Characteristics by Development
ILAE Seizure Classification History by Development
Classification of Epileptic Syndrome by Development
AEDs and Benzodiazepines at Study Entry by Development
Summary of Time to Second PGTCS by Development
Proportion of Subjects with Seizure Freedom at Day 166 by Development
PGTCS Frequency Observed Results and Percent Changes from Combined Baseline by Development
Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline by Development
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline by Development
Responder Status for PGCTS by Development
Responder Status for Absence Seizure Frequency by Development
Responder Status for Myoclonic Seizure Frequency by Development
Seizure-free Status for PGTCS by Development
Days with Absence Seizures Observed Results and Percent Changes from Prospective Baseline by Development
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective Baseline by Development
Increase in Absence Seizure Frequency During the Treatment Period Compared to Prospective Baseline by Development
Responder Status and Seizure Worsening for Days with Absence Seizures by Development
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective Baseline by Development
Increase in Days with Myoclonic Seizures During the Treatment Period Compared to Prospective Baseline by Development
Increase in Myoclonic Seizure Frequency During the Treatment Period Compared to Prospective Baseline by Development
Responder Status and Seizure Worsening for Days with Myoclonic Seizures by Development
REDACTED COPY Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
REDACTED COPY Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
REDACTED COPY
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
nder Status for PGCTS by Development
REDACTED COPY
nder Status for PGCTS by Development
Responder Status for Absence Seizure Frequency by DevelopmentREDACTED COPY
Responder Status for Absence Seizure Frequency by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Proportion of Subjects with Seizure Freedom at Day 166 by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Proportion of Subjects with Seizure Freedom at Day 166 by Development
es from Combined Baseline by
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
es from Combined Baseline by
Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline
nder Status for PGCTS by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
nder Status for PGCTS by Development
Responder Status for Absence Seizure Frequency by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Responder Status for Absence Seizure Frequency by Development
Responder Status for Myoclonic Seizure Frequency by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Responder Status for Myoclonic Seizure Frequency by Development
free Status for PGTCS by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
free Status for PGTCS by Development
Days with Absence Seizures Observed Results and
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Days with Absence Seizures Observed Results and
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective Baseline by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline by Development
Increase in Absence Seizure Frequency During the Treatment Period Compared to Prospe
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Increase in Absence Seizure Frequency During the Treatment Period Compared to ProspeBaseline by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline by Development
Responder Status and Seizure Worsening for Days with Absence Seizures by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Responder Status and Seizure Worsening for Days with Absence Seizures by Development
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Baseline by Development
Increase in Days with Myoclonic Se
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Increase in Days with Myoclonic SeProspective Baseline by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Prospective Baseline by Development
![Page 125: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/125.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
Incidence of Absence Seizure Emergence or Worsening by Development
Incidence of Myoclonic Seizure Emergence or Worsening by Development
Seizure-free Status for All Generalized Seizure Types by Development
Study Medication Duration by Development
Cumulative Study Medication Duration by Development
Study Medication Daily Dosing by Development
Incidence of TEAEs by Development – Overview
Incidence of TEAEs by Development
Incidence of Serious TEAEs by Development
Incidence of Non-serious TEAEs
Incidence of TEAEs by Relationship and Development
Incidence of TEAEs Leading to Discontinuation by Development
Incidence of Serious TEAEs by Relationship
Incidence of Non-serious TEAEs by Relationship
Incidence of Fatal TEAEs by Relationship
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
12-Lead ECG Summary by Development
Treatment-Emergent Abnormal 12-Lead ECG Findings for Subjects by Development
Section 12.6 was revised from:
The following subgroup variable will also be programmed:
Subjects enrolled at Japanese study sites (Japanese, non-Japanese)
Was revised to:
The following subgroup variable will also be programmed:
Subjects enrolled at Japanese study sites (Japanese, non-Japanese)
Subjects enrolled at Asian study sites (Asian, non-Asian) – Asian sites are those in Taiwan, South Korea, China and Japan
REDACTED COPY
serious TEAEs Above Reporting Threshold of 5% of Subjects
REDACTED COPY
serious TEAEs Above Reporting Threshold of 5% of Subjects
serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
REDACTED COPY
serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
Lead ECG Summary by DevelopmentREDACTED C
OPY
Lead ECG Summary by Development
Le REDACTED COPY
Lead ECG Findings for Subjects by DevelopmentREDACTED COPY
ad ECG Findings for Subjects by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serious TEAEs Above Reporting Threshold of 5% of Subjects
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serious TEAEs Above Reporting Threshold of 5% of Subjects
serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship
ad ECG Findings for Subjects by Development
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
ad ECG Findings for Subjects by Development
The following subgroup variable will also be programmed:
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following subgroup variable will also be programmed:
Subjects enrolled at Japanese study sites (Japanese, non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects enrolled at Japanese study sites (Japanese, non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following subgroup variable will also
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
The following subgroup variable will also
Subjects enrolled at Japanese study sites (Japanese, non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects enrolled at Japanese study sites (Japanese, non
Subjects enrolled at Asian study sites (Asian, non
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
Subjects enrolled at Asian study sites (Asian, nonSouth Korea, China and Japan
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
South Korea, China and Japan
![Page 126: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/126.jpg)
UCB 28 Mar 2019 Statistical Analysis Plan SP0982
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
This document has been reviewed and approved per the Review and Approval of Clinical Documents Standard Operating Procedures. Signatures indicate that the final version of the Statistical Analysis Plan (SAP) or amended SAP is released for execution.
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.
![Page 127: STATISTICAL ANALYSIS PLAN - ClinicalTrials.govFinal SAP 09 Aug 2016 Amendment #1 24 Feb 2017 Amendment #2 14 Mar 2017 Amendment #3 4 Jan 2019 Amendment #4 28 Mar 2019 &RQILGHQWLDOLW](https://reader036.vdocuments.net/reader036/viewer/2022071300/60891f9ae0be4f34ac10af35/html5/thumbnails/127.jpg)
REDACTED COPY
This do
cumen
t can
not b
e use
d to s
uppo
rt any
mark
eting
autho
rizati
on ap
plica
tion a
nd an
y exte
nsion
s or v
ariati
ons t
hereo
f.