statistical analysis plan (sap)laboratory tests (blood chemistry, hematology, and urinalysis) vital...

UCB 24 June2016Statistical Analysis Plan Brivaracetam 01315

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STATISTICAL ANALYSIS PLAN (SAP)

Study: N01315

Product: Brivaracetam

An open-label, multinational, multicenter, follow-up study to evaluate the long-term safety and efficacy of brivaracetam used at a flexible dose up to a maximum of 200mg/day in

subjects aged 16 years or older suffering from epilepsy

SAP/Amendment Number DateFinal SAPSAP Amendment 1

27 January 201424 June 2016

Confidentiality Material

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.

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TABLE OF CONTENTS

LIST OF ABBREVIATIONS.................................................................................................... 6

1 INTRODUCTION ............................................................................................................. 8

2 PROTOCOL SUMMARY................................................................................................. 8

2.1 Study Objectives ...................................................................................................... 8

2.1.1 Primary objective........................................................................................... 8

2.1.2 Secondary objectives ..................................................................................... 8

2.1.3 Exploratory objectives ................................................................................... 8

2.2 Study Variables........................................................................................................ 8

2.2.1 Safety variables.............................................................................................. 8

2.2.1.1 Primary safety variables....................................................................... 8

2.2.1.2 Other safety variables........................................................................... 8

2.2.2 Efficacy variables .......................................................................................... 8

2.2.2.1 Secondary efficacy variables ............................................................... 8

2.2.2.2 Other efficacy variables ....................................................................... 9

2.2.3 Pharmacoeconomic variables ........................................................................ 9

2.2.4 Pharmacokinetic variables ............................................................................. 9

2.3 Study Design and Conduct....................................................................................... 9

2.4 Determination of Sample Size ............................................................................... 11

2.5 Changes from the Analysis Planned in the Protocol.............................................. 11

3 DATA ANALYSIS CONSIDERATIONS ...................................................................... 11

3.1 General Presentation of Summaries and Analyses ................................................ 11

3.2 Analysis Time Points ............................................................................................. 12

3.2.1 First and last dose of BRV........................................................................... 12

3.2.2 Relative day ................................................................................................. 12

3.2.3 Summaries at Study Entry ........................................................................... 12

3.2.4 Study periods ............................................................................................... 13

3.2.5 Monthly time intervals................................................................................. 14

3.2.6 Last value on BRV treatment....................................................................... 14

3.2.7 Exposure duration and exposure duration cohorts....................................... 14

3.2.8 Study visit cohorts ....................................................................................... 15

3.3 Definition of Baseline Values................................................................................ 15

3.4 Protocol deviations................................................................................................. 15

3.5 Analysis Sets.......................................................................................................... 15

3.5.1 Safety Analysis Set ...................................................................................... 15

3.5.2 Efficacy Analysis Set................................................................................... 16

3.6 Treatment Assignment and Treatment Groups ...................................................... 16

3.7 Coding dictionaries ................................................................................................ 16

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3.8 Definitions of Study-specific Derived Variables ................................................... 16

3.8.1 Calculation of seizure frequency/days......................................................... 16

3.8.1.1 Initial seizure data processing............................................................ 16

3.8.1.2 Calculation of adjusted seizure frequency ......................................... 16

3.8.2 QOLIE-31-P................................................................................................. 17

3.8.3 HADS........................................................................................................... 17

3.8.4 Subject site transfers .................................................................................... 18

4 STATISTICAL/ANALYTICAL ISSUES ....................................................................... 18

4.1 Adjustments for Covariates.................................................................................... 18

4.2 Handling of Dropouts or Missing Data.................................................................. 18

4.3 Interim Analyses and Data Monitoring.................................................................. 18

4.4 Multicenter Studies ................................................................................................ 18

4.5 Multiple Comparisons/Multiplicity ....................................................................... 19

4.6 Use of an “Efficacy Subset” of Subjects................................................................ 19

4.7 Active-Control Studies Intended to Show Equivalence......................................... 19

4.8 Examination of Subgroups..................................................................................... 19

5 STUDY POPULATION CHARACTERISTICS............................................................. 20

5.1 Subject Disposition ................................................................................................ 20

5.2 Protocol Deviations................................................................................................ 21

6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 21

6.1 Demographics ........................................................................................................ 21

6.2 Medical and Procedure History ............................................................................. 22

6.2.1 Medical history diseases .............................................................................. 22

6.2.2 Procedure history and concomitant procedures ........................................... 22

6.3 History of Epilepsy ................................................................................................ 22

6.3.1 Etiology of epilepsy ..................................................................................... 22

6.3.2 Epileptic seizure profile ............................................................................... 23

6.3.3 Classification of epileptic syndrome............................................................ 23

6.3.4 Focus localization ........................................................................................ 23

6.3.5 History of epileptic seizures ........................................................................ 23

6.3.6 Seizure types experienced during baseline of the previous study ............... 23

6.4 Medications............................................................................................................ 23

6.4.1 Non-AEDs taken at study entry ................................................................... 24

6.4.2 Number of previous AEDs .......................................................................... 24

6.4.3 History of previous AED use....................................................................... 24

6.4.4 AEDs taken at study entry ........................................................................... 24

7 MEASUREMENTS OF TREATMENT COMPLIANCE............................................... 24

8 EFFICACY ANALYSES ................................................................................................ 25

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8.1 Statistical Analysis of the Secondary Efficacy Variables...................................... 25

8.1.1 Percentage of subjects on continuous BRV monotherapy........................... 25

8.2 Analyses of Other Efficacy Variables.................................................................... 25

8.2.1 Partial onset seizure frequency .................................................................... 25

8.2.2 Percent reduction in POS frequency............................................................ 25

8.2.3 Specified Month seizure freedom................................................................ 25

8.2.4 QOLIE-31-P................................................................................................. 26

8.2.5 EQ-5D.......................................................................................................... 27

8.2.6 Direct cost parameters ................................................................................. 27

8.2.7 Indirect cost parameters ............................................................................... 27

8.2.8 Socio-professional data................................................................................ 27

9 PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 27

10 IMMUNOLOGICAL PROCEDURES............................................................................ 27

11 SAFETY ANALYSES..................................................................................................... 27

11.1 Extent of Exposure................................................................................................. 28

11.1.1 Number of subjects exposed and subject-years of exposure ....................... 28

11.2 Adverse Events ...................................................................................................... 28

11.2.1 Definition of treatment-emergent AE .......................................................... 28

11.2.2 General summaries of TEAEs ..................................................................... 29

11.3 Clinical Laboratory Evaluations ............................................................................ 30

11.3.1 Hematology and blood chemistry parameters ............................................. 30

11.3.2 Macroscopic urinalysis ................................................................................ 31

11.3.3 Microscopic urinalysis ................................................................................. 31

11.4 Vital Signs, Physical Findings, and Other Observations Related to Safety........... 32

11.4.1 Vital signs .................................................................................................... 32

11.4.2 Electrocardiograms ...................................................................................... 32

11.4.3 Physical examination ................................................................................... 32

11.4.4 Neurological examination............................................................................ 33

11.4.5 Psychiatric and mental status....................................................................... 33

11.4.6 HADS........................................................................................................... 33

11.4.7 Columbia-Suicide Severity Rating Scale..................................................... 33

12 REFERENCES ................................................................................................................ 34

13 APPENDICES ................................................................................................................. 35

13.1 QOLIE-31-P Total and Subscale Score Calculations ............................................ 35

13.2 Subject site transfers .............................................................................................. 37

13.3 PCST criteria.......................................................................................................... 38

13.3.1 Hematology parameters ............................................................................... 38

13.3.2 Blood chemistry parameters ........................................................................ 39

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13.3.3 Urinalysis ..................................................................................................... 41

13.3.4 Vital signs and body weight......................................................................... 41

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LIST OF ABBREVIATIONS

AE adverse eventAED antiepileptic drugALP Alkaline phosphataseALT alanine aminotransferaseAST aspartate aminotransferaseATC Anatomic Therapeutic ClassBMI body mass indexBpm Beats per minuteBRV brivaracetamBUN blood urea nitrogenCHMP Committee for Medicinal Products for Human UseCR CL creatinine clearanceCRF case report formC-SSRS Columbia-Suicide Severity Rating ScaleDBP diastolic blood pressureECG electrocardiogramEDV Early Discontinuation VisitEQ-5D EuroQol 5 DimensionsER emergency roomEU European UnionF FemaleFDA Food and Drug AdministrationFEV Full Evaluation VisitFV Final VisitGGT Gamma-glutamyl transpeptidase HADS Hospital Anxiety and Depression ScaleHDL High-density lipoprotein HRQoL Health-Related Quality of LifeILAE International League Against EpilepsyLDL low-density lipoproteinMedDRA Medical Dictionary for Regulatory ActivitiesM MaleMEV Minimal Evaluation VisitN/A Not applicablePCST potentially clinically significant treatment-emergentPOS partial onset seizurePT preferred term QOLIE-31-P Patient Weighted Quality of Life in Epilepsy

QuestionnaireRBC Red Blood CellSAE serious adverse eventSAP statistical analysis planSBP systolic blood pressureSD standard deviation

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SGOT serum glutamic oxaloacetic transaminaseSGPT serum glutamic pyruvic transaminaseSOC system organ classTEAE treatment-emergent adverse eventULN Upper Limit of NormalV VisitVAS visual analog scaleWBC White Blood CellWHO-DRL World Health Organization Drug Reference ListYEV Yearly Evaluation Visit

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1 INTRODUCTION

This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a detailed description of statistical methodology for the statistical analyses to support the final clinical study report for N01315.

2 PROTOCOL SUMMARY

2.1 Study Objectives

2.1.1 Primary objective

To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses with a maximum of 200mg/day in subjects suffering from epilepsy.

2.1.2 Secondary objectives

To evaluate the maintenance of efficacy over time of BRV.

2.1.3 Exploratory objectives

To explore impact on health-related quality of life, anxiety and depression.

To obtain a description of patient’s self-reported health status.

To collect data on medical resources used and on indirect cost parameters.

2.2 Study Variables

2.2.1 Safety variables

2.2.1.1 Primary safety variables

Occurrence of a treatment-emergent adverse event (TEAE)

Withdrawal due to adverse event (AE)

Occurrence of a serious adverse event (SAE)

2.2.1.2 Other safety variables

Laboratory tests (blood chemistry, hematology, and urinalysis)

Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and body weight

Electrocardiogram (ECG)

Physical and neurological examination

Change in Hospital Anxiety and Depression Scale (HADS) scores from the Baseline of the previous study to each assessment for the first 2 years and to the last Evaluation Period assessment during the first 2 years

2.2.2 Efficacy variables

2.2.2.1 Secondary efficacy variables

Percentage of subjects on continuous BRV monotherapy for at least 3 months, at least 6 months, and at least 12 months of the Evaluation Period

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2.2.2.2 Other efficacy variables

Partial onset seizure (POS) (type I) frequency per 28 days during the Evaluation Period

Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous study to the Evaluation Period

Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 6 months and at least 12 months during the Evaluation Period

Change in Patient Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) scores from Baseline of the previous study to each assessment for the first 2 years and tothe last Evaluation Period assessment during the first 2 years

EuroQol-5 Dimensions (EQ-5D) questionnaire response for each assessment for the first 2 years for the Evaluation Period and for the last assessment during the first 2 years of the Evaluation Period

2.2.3 Pharmacoeconomic variables

Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent medical procedures, concomitant medications, hospitalizations, and emergency room [ER] visits) during the first 2 years of the Evaluation Period

Indirect costs (workdays or schooldays lost by the subject and days subject received help from a caregiver) during the first 2 years of the Evaluation Period

Socio-professional data for each assessment for the first 2 years and for the last assessment during the first 2 years of the Evaluation Period

2.2.4 Pharmacokinetic variables

Brivaracetam (parent compound only) plasma levels

Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levels

2.3 Study Design and Conduct

This is an open-label, long-term follow-up, multicenter, multinational, noncomparative, single-arm study of BRV. The primary objective is to evaluate the long-term safety and tolerability of BRV at individualized doses up to a maximum of 200mg/day in subjects suffering from epilepsy. The secondary objective is to evaluate the maintenance of efficacyover time of BRV. Exploratory objectives are to assess the effects of BRV on subjects’ Health-Related Quality of Life (HRQoL), obtain information on the direct and indirect costs and subjects’ self-reported health status.

At the time of development of this SAP, the enrollment into N01315 had completed. Study N01315 enrolled subjects 16 years of age and older who had completed N01276 or N01306.

Subjects who enrolled in the study entered an Evaluation Period at a recommended starting dose of 100mg/day. The dose of BRV could then be adjusted based on the individual subject’s seizure control and tolerability. Dose increases could be made in increments of a maximum 50mg/day on a weekly basis and up to a maximum dose of 200mg/day; dose decreases could be made in steps of maximum 50mg/day on a weekly basis with a last down-

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ort

label, long-

supp

ort

-term follow

supp

ort

term followarm study of BRV. The primarysu

pport

arm study of BRV. The primary of BRV at individualized doses up to a maximum of 200mg/day

supp

ort

of BRV at individualized doses up to a maximum of 200mg/day

any Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levels

any Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levels

Design and Conductany

Design and Conduct

marketi

ng Pharmacokinetic variables

marketi

ng Pharmacokinetic variables

Brivaracetam (parent compound only

marketi

ng

Brivaracetam (parent compound only) plasma levels

marketi

ng

) plasma levels

Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levelsmarketi

ng

Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levels

autho

rizati

on the subject and day

autho

rizati

on the subject and day


autho

rizati

on


professional data for each assessment for the first 2 y

autho

rizati

on

professional data for each assessment for the first 2 years of the Evaluation Period

autho

rizati

on


Pharmacokinetic variablesau

thoriz

ation

Pharmacokinetic variables

appli

catio

n Direct costs (healthcare provider consultations not foreseen b

appli

catio

n Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent

appli

catio

n y the protocol, concurrent medical procedures, concomitant medications, hospitalizations, and emergency

appli

catio

n medical procedures, concomitant medications, hospitalizations, and emergency

ion Period

appli

catio

n

ion Period

the subject and dayappli

catio

n

the subject and day

and

y the protocol, concurrent an

d y the protocol, concurrent

any e

xtens

ions

y to each assessment for the first 2 years and to

exten

sions

y to each assessment for the first 2 years and to

5D) questionnaire response for each assessment for the first

exten

sions

5D) questionnaire response for each assessment for the first ears for the Evaluation Period and for the last assessment during the first 2 yex

tensio

ns

ears for the Evaluation Period and for the last assessment during the first 2 y

or y to each assessment for the first 2 years and toor y to each assessment for the first 2 years and tova

riatio

ns th

ereof.


Confidential of 43

titration step at 20mg/day for 1 week. Subjects who completed the Down-Titration Period or subjects who discontinued during the Evaluation Period without entering the Down-Titration Period enter a Study Drug-Free Period for a minimum of 2 weeks and a maximum of 4 weeks. The maximum allowable daily dose for this study was increased from 150mg/day to 200mg/day based on integrated amendment 2 to the protocol. The daily dose should have been administered in 2 equal intakes (morning and evening), taken with or without food.

Subjects entering N01315 on BRV monotherapy could have converted to adjunctive BRV treatment during the N01315 study. In this case, as well as for subjects entering N01315 taking BRV and a concomitant AED, the Investigator may have adapted the concomitant AED drug/dosage for safety or efficacy reasons. In case of excellent efficacy and tolerability of BRV, withdrawal of concomitant AED(s) resulting in monotherapy with BRV may have been re-attempted by the Investigator.

Study visits at Months 2, 6, 12, 18, 24, etc., are either Full Evaluation Visits (FEVs) or Yearly Evaluation Visits (YEVs) at which a greater number of assessments are performed. Study visits at Months 1, 3, 9, 15, 21, etc. are Minimal Evaluation Visits (MEVs) at which few assessments are performed. If a subject elected to end their study participation prior to study completion, then an Early Discontinuation Visit was conducted and subjects wereprogressively down-titrated from study medication. Once study medication down-titration was completed, a telephone call was conducted for subjects who discontinued taking more than BRV 20 mg/day. A Study Drug Free Period was initiated after down titration of study medication was completed. The Final Visit was conducted after the Study Drug Free Period. The Visit schedule described is displayed in Table 2‒1.

Table 2‒1: Visit Schematic Diagram

1st, 2nd and subsequent years follow-up

Month Visit Type of Visit

M0 V1 Entry Visit (EV)

M1 V2 MEV

M2 V3 FEV

M3 V4 MEV

M4

M5

M6 V5 FEV

M7

M8

Table 2‒1: Visit Schematic Diagram (Continued)



M9 V6 MEV

REDACTED was

REDACTED was conduct

REDACTED conducted in

REDACTED ed in Table

REDACTED Table

Visit Schematic Diagram

REDACTED

Visit Schematic Diagram

upREDACTED

upREDACTED COPY conducted for subjects who discontinue

COPY conducted for subjects who discontinuewasCOPY

was initiated after COPY

initiated after conductCOPY

conduct

This do

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t M8

docu

ment M8

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ment

docu

ment

docu

ment

docu

ment c

anno

t

cann

ot

cann

ot

cann

ot be

be

used

us

ed to

to su

pport

supp

ort

supp

ort

supp

ort an

y V1

any V1

V2any

V2any

any m

arketi

ng

marketi

ng

marketi

ng

Visit

marketi

ng

Visit

marketi

ng

marketi

ng

V1 marketi

ng

V1 marketi

ng au

thoriz

ation

initiated after

autho

rizati

on initiated after

conduct

autho

rizati

on

conducted after the Study

autho

rizati

on

ed after the StudyTable

autho

rizati

on

Table 2

autho

rizati

on

2‒

autho

rizati

on

‒1

autho

rizati

on

1

autho

rizati

on ap

plica

tion to end their study

appli

catio

n to end their studyto end their study participation prior to to end their study

appli

catio

n to end their study participation prior to to end their studyconducted

appli

catio

n conductedOnce stud

appli

catio

n

Once study

appli

catio

n

y medication down

appli

catio

n

medication downconducted for subjects who discontinue

appli

catio

n

conducted for subjects who discontinueinitiated after ap

plica

tion

initiated after

and

y Evaluation Visits (YEVs) at which a greater number of assessments are performed.

and

y Evaluation Visits (YEVs) at which a greater number of assessments are performed. are Minimal Evaluation Visits (M

and are Minimal Evaluation Visits (M

to end their study and

to end their study participation prior to and

participation prior to to end their study participation prior to to end their study and

to end their study participation prior to to end their study

any are either Full Evaluation Visits (FEVs) or

any are either Full Evaluation Visits (FEVs) or

y Evaluation Visits (YEVs) at which a greater number of assessments are performed. any y Evaluation Visits (YEVs) at which a greater number of assessments are performed.

are Minimal Evaluation Visits (Man

y are Minimal Evaluation Visits (M

exten

sions

and tolerabilit

exten

sions

and tolerability with BRV may

exten

sions

y with BRV may have

exten

sions

have y with BRV may have y with BRV may

exten

sions

y with BRV may have y with BRV may

are either Full Evaluation Visits (FEVs) or exten

sions

are either Full Evaluation Visits (FEVs) or

or and tolerabilitor and tolerabilit

varia

tions

there

of.


Confidential of 43



M10

M11

M12 V7 YEV

M15 V8 MEV

M18 V9 FEV

M21 V10 MEV

M24 V11 YEV

M… V… …

FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month; V=visit; YEV=Yearly Evaluation Visit

Visit 1 will correspond to the last visit from the previous study and should be the visit at which study drug is dispensed for N01315.

This study will run throughout the duration of the clinical development period of BRV, and will continue until a marketing authorization is granted by any Health Authority in an indication for the adjunctive treatment in adults with refractory POS, whether or not secondarily generalized, until the Sponsor decides to close the study, or until BRV development is stopped by the Sponsor.

2.4 Determination of Sample Size

No sample size calculation was done. Sample size was dependent upon recruitment into and completion of preceding studies. At the time of development of this SAP, the enrollment into this study has been completed and a total of 108 subjects have been enrolled into N01315.

2.5 Changes from the Analysis Planned in the Protocol

Percentage of subjects remaining on continuous BRV monotherapy from the start of the study through 3, 6, and 12 months will not be done because it would be limited to subjects entering on monotherapy and it was expected that this rate would be low due to the parent studies being stopped prematurely. Instead of this analysis, the cumulative proportion of subjects able to achieve BRV monotherapy for 3, 6, and 12 months during the Evaluation Period will be summarized

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 carried out using SAS® Version 9.1 or higher.

Descriptive statistics, such as the mean, standard deviation (SD), median, 25th percentile, 75th

percentile, minimum value, and maximum value for quantitative variables, and counts and percentages for categorical variables, will be provided. Denominators for percentages will

REDACTED generalized, until the Sponsor decides to close the study

REDACTED generalized, until the Sponsor decides to close the study

Determination of Sample Size

REDACTED


No sample size calculation was done. Sample size REDACTED

No sample size calculation was done. Sample size completion of preceding studies. At the time of development of this SAP, the enrollment into

REDACTED

completion of preceding studies. At the time of development of this SAP, the enrollment into

COPY will continue until a marketing authorization is granted b

COPY will continue until a marketing authorization is granted bindication for the adjunctive treatment in adults with refractory

COPY indication for the adjunctive treatment in adults with refractory

generalized, until the Sponsor decides to close the studyCOPY

generalized, until the Sponsor decides to close the study

This do

cumen

t Statistical analy

docu

ment

Statistical analyoutput will be carried out using SAS

docu

ment

output will be carried out using SAS

cann

ot be

be summarized

be be summarizedus

ed stopped prematurely

used

stopped prematurelyable to achieve BRV monotherap

used

able to achieve BRV monotherapbe summarizedus

ed

be summarized

to y and it was expected that this rate would be low due to the parent studies

to y and it was expected that this rate would be low due to the parent studies

stopped prematurelyto stopped prematurelysu

pport

remaining on

supp

ort remaining on

months will not be done

supp

ort

months will not be doney and it was expected that this rate would be low due to the parent studies su

pport

y and it was expected that this rate would be low due to the parent studies stopped prematurely

supp

ort

stopped prematurely

any Changes from the A

any Changes from the A

remaining on any

remaining on

marketi

ng No sample size calculation was done. Sample size

marketi

ng No sample size calculation was done. Sample size

completion of preceding studies. At the time of development of this SAP, the enrollment into

marketi

ng

completion of preceding studies. At the time of development of this SAP, the enrollment into has been completed and a total of 108 subjects have been enrolled into N01315.

marketi

ng

has been completed and a total of 108 subjects have been enrolled into N01315.

Changes from the Amarketi

ng

Changes from the A

autho

rizati

on indication for the adjunctive treatment in adults with refractory

autho

rizati

on indication for the adjunctive treatment in adults with refractory


autho

rizati

on


Determination of Sample Sizeau

thoriz

ation


No sample size calculation was done. Sample size autho

rizati

on

No sample size calculation was done. Sample size

appli

catio

n will run throughout the duration of the clinical development period of BRV, and

appli

catio

n will run throughout the duration of the clinical development period of BRV, and

y anap

plica

tion

y any Health Authorityap

plica

tion

y Health Authorityindication for the adjunctive treatment in adults with refractoryap

plica

tion

indication for the adjunctive treatment in adults with refractory

and and should be the visit at and and should be the visit at

any

any FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month; V=visit; YEV=Yearly Evaluation Visitany FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month; V=visit; YEV=Yearly Evaluation Visitex

tensio

ns

exten

sions

exten

sions

exten

sions

or or va

riatio

ns

varia

tions

varia

tions

varia

tions

varia

tions

varia

tions

there

of.


Confidential of 43

generally be based on the set of subjects with at least 1 assessment at the time point or at least 1 assessment during the time interval being summarized.

All summaries will be descriptive; no statistical hypothesis testing is planned.

Unless otherwise noted, summaries will present BRV overall, which will include all subjects exposed to BRV during the study.

Subject data listings will be provided and will present source data and key derived variables for statistical analyses.

3.2 Analysis Time Points

3.2.1 First and last dose of BRV

Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first dose of BRV during N01315. Unless otherwise noted, all references to the last known dose of BRV in this SAP refer to the last dose of BRV taken across any study periods (ie, not necessarily the last dose of BRV during the Evaluation Period).

3.2.2 Relative day

Relative day will be calculated as the current date minus the date of first dose of study drug for days prior to the first dose of study drug, and the current date minus the date of first dose of study drug plus 1 for days on or after the day first dose of study drug and prior to or on the day of last study drug dose (eg, the day of first dose will be Day 1 and the day prior to first dose will be Day -1), ie, Day 1 representing the day of first dose of BRV, the previous day is Day -1 and each day prior to that is Day -2, Day -3, etc; subsequent relative days to Day 1 will be Day 2, Day 3, etc. For days after the last dose of BRV, relative day will be calculated as the current date minus the date of last dose of BRV and including a ‘+’ to denote post treatment days (eg, the day after the last dose of BRV will be Day +1). Relative day will not be calculated for partial or missing dates.

3.2.3 Summaries at Study Entry

The study Entry Visit (EV) corresponds to assessments performed at the time of entry into N01315. There are 2 groups of subjects to consider:

1. Subjects who immediately entered N01315 after completing the Evaluation Period or meeting the protocol defined exit criteria for N01276 and N01306

2. Subjects who did not immediately enter N01315 and had a gap in treatment with study drug between the previous study and N01315

Subjects in category 1 will generally not have any interruption in study drug dosing during the transition to N01315. Subjects in category 2 had minimal gaps in treatment, which will not change how the data are analyzed. For subjects in both categories, selected assessments from Visit 8 of the previous study will be summarized at EV. Subjects who met exit criteria in the prior study will have data from EDV used as EV for N01315.

For the assessments that were performed for all subjects at Visit 8/EDV of the previous study, the following assessments will be summarized at EV: vital signs, weight, physical examination, neurological examination, ECGs, recording of seizures, and laboratory parameters.

REDACTED of first dose will be Day

REDACTED of first dose will be Day 1 representing the day

REDACTED 1 representing the day

2, Day

REDACTED 2, Day

s after the last dose of BRV, relative day

REDACTED

s after the last dose of BRV, relative dayas the current date minus the date of last doREDACTED

as the current date minus the date of last do after the last dose of BRV will be DayREDACTED

after the last dose of BRV will be Day

COPY drug, and the current date minus the date of first dose

COPY drug, and the current date minus the date of first dose first dose of study

COPY first dose of study

of first dose will be DayCOPY

of first dose will be Day

This do

cumen

t not change how the data

docu

ment not change how the data

from

docu

ment

from

cann

ot drug between the previous study

cann

ot drug between the previous study

Subjects in category

cann

ot Subjects in categorythe transition to ca

nnot

the transition to

be 2. Subjects who di

be 2. Subjects who di

drug between the previous studybe

drug between the previous studyus

ed meeting the protocol defined exit criteria

used

meeting the protocol defined exit criteria

2. Subjects who diused

2. Subjects who di

to Subjects who immediately entered

to Subjects who immediately entered meeting the protocol defined exit criteria to meeting the protocol defined exit criteria

supp

ort Visit (EV) corresponds to assess

supp

ort Visit (EV) corresponds to assess

groups of subjects to consider:

supp

ort

groups of subjects to consider:

Subjects who immediately entered supp

ort

Subjects who immediately entered

any Summaries at Study

any Summaries at Study

Visit (EV) corresponds to assessany

Visit (EV) corresponds to assess

marketi

ng as the current date minus the date of last do

marketi

ng as the current date minus the date of last dose of BRV and including a ‘+’ to denote post

marketi

ng se of BRV and including a ‘+’ to denote post

after the last dose of BRV will be Day

marketi

ng

after the last dose of BRV will be Daybe calculated for partial or missing dates.

marketi

ng

be calculated for partial or missing dates.

Summaries at Studymarketi

ng

Summaries at Study

autho

rizati

on first dose of study

autho

rizati

on first dose of study

of first dose will be Day

autho

rizati

on

of first dose will be Day 1 representing the day

autho

rizati

on

1 representing the day of first dose of BR

autho

rizati

on

of first dose of BR 1 representing the day of first dose of BR 1 representing the day

autho

rizati

on

1 representing the day of first dose of BR 1 representing the day2, Day

autho

rizati

on

2, Day -

autho

rizati

on

-2, Day -2, Day

autho

rizati

on

2, Day -2, Day 3, etc; subsequent relative day

autho

rizati

on

3, etc; subsequent relative days after the last dose of BRV, relative dayau

thoriz

ation

s after the last dose of BRV, relative dayse of BRV and including a ‘+’ to denote post au

thoriz

ation

se of BRV and including a ‘+’ to denote post

appli

catio

n will be calculated as the current date minus the date of first dose of study

appli

catio

n will be calculated as the current date minus the date of first dose of study

drug, and the current date minus the date of first dose

appli

catio

n

drug, and the current date minus the date of first dose first dose of studyap

plica

tion

first dose of study

and a

ny dose of BRV during N01315. Unless otherwise noted, all references to the last

any

dose of BRV during N01315. Unless otherwise noted, all references to the last periods

any periodsex

tensio

ns

the first dose of BRV in this SAP refer to the first

exten

sions

the first dose of BRV in this SAP refer to the first dose of BRV during N01315. Unless otherwise noted, all references to the last ex

tensio

ns

dose of BRV during N01315. Unless otherwise noted, all references to the last known exten

sions

known

or va

riatio

ns th

ereof.


Confidential of 43

3.2.4 Study periods

The study is divided into 3 periods: Evaluation Period, Down-Titration Period, and Post-Treatment Period. A subject is classified as “discontinued” if the subject has a termination case report form (CRF) or has an early discontinuation visit (EDV). A subject is classified as “completed” if this subject completes the full extent of the study as defined in the protocol at database lock.

A “discontinued” subject can be potentially slotted into the 3 periods of the study. The following algorithms will be used to slot the subject appropriately into the Evaluation Period, Down-Titration Period, and Post-Treatment Period.

For Evaluation Period, the start date is the date of first dose of BRV, and the following algorithm is used to determine the end date:

If the subject enters the Down-Titration Period, then the date of EDV is the end date;

If the subject does not enter the Down-Titration Period but meets 1 of the following criteria, the Evaluation Period ends on date of last dose of BRV:

Without an EDV but having a termination CRF,

With an EDV and having a termination CRF,

With an EDV and the date of EDV prior to the database lock date and having no termination CRF.

A subject is considered entering Down-Titration Period only if the subject has an EDV and at least 1 dose of study drug after the date of EDV, the start date of Down-Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period ends on date of last dose of BRV. A subject without an EDV but having a termination CRF or with an EDV but without any dosing of study drug after the EDV will not have the Down-Titration Period, and no artificial Down-Titration Period will be created for analysis.

A subject is considered entering the Post-Treatment Period if the subject has at least 1 contact (scheduled visit, unscheduled visit, or telephone contact) after the date of last dose of BRV. The Post-Treatment Period starts 1 day after date of last dose of BRV irrespective of entering the Down-Titration Period, and there is no end date.

A “completed” subject can potentially have Evaluation Period, Down-Titration Period, or Post-Treatment Period. At the time of study termination by the Sponsor, subjects will discontinue the study drug following the down titration process or will be converted without titration to commercial BRV where available; alternatively, subjects may be initiated without down-titration in a managed access program, named patient program, compassionate use program, or similar type of access program as allowed per country specific requirements in addition to legal and regulatory guidelines.

REDACTED With an EDV and the date of EDV prior to the database lock date and

REDACTED With an EDV and the date of EDV prior to the database lock date and having no termination CRF.

REDACTED having no termination CRF.

considered entering Down

REDACTED

considered entering Downdose of study

REDACTED

dose of study drug after the date of EDV, the start date of Down-REDACTED

drug after the date of EDV, the start date of Down-dose of study drug after the date of EDV, the start date of Down-dose of studyREDACTED

dose of study drug after the date of EDV, the start date of Down-dose of studyTitration Period is set as 1 dayREDACTED

Titration Period is set as 1 day after the date of EDV, and the Down-REDACTED

after the date of EDV, and the Down-Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period is set as 1 dayREDACTED

Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period is set as 1 day

COPY With an EDV and having a termination CRF,

COPY With an EDV and having a termination CRF,

With an EDV and the date of EDV prior to the database lock date and COPY

With an EDV and the date of EDV prior to the database lock date and

This do

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t titration to commercial BRV where available

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ment titration to commercial BRV where available

down

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downprogram, or similar t

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program, or similar t

cann

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reatment

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ot discontinue the studytitration to commercial BRV where availableca

nnot

titration to commercial BRV where available

be A “completebe A “completed” subject can potentiallybe d” subject can potentiallyus

ed of BRV

used

of BRVirrespective of entering the Down

used

irrespective of entering the Down

to t (scheduled visit, unscheduled visit, or telephone contact) after the date of last

to t (scheduled visit, unscheduled visit, or telephone contact) after the date of last

of BRV to of BRV. The Postto . The Postsu

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A subject is considered entering the Post

supp

ort

A subject is considered entering the Postt (scheduled visit, unscheduled visit, or telephone contact) after the date of last su

pport

t (scheduled visit, unscheduled visit, or telephone contact) after the date of last

any Titration Period, and no artificial Down

any Titration Period, and no artificial Downmark

eting

drug after the date of EDV, the start date of Down-

marketi

ng drug after the date of EDV, the start date of Down-

after the date of EDV, and the Down-

marketi

ng

after the date of EDV, and the Down-ends on date of last dose of BRV. A subject without an EDV but having a termination

marketi

ng

ends on date of last dose of BRV. A subject without an EDV but having a termination ut without anymark

eting

ut without anyTitration Period, and no artificial Down

marketi

ng

Titration Period, and no artificial Down

autho

rizati

on With an EDV and having a termination CRF,

autho

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on With an EDV and having a termination CRF,

With an EDV and the date of EDV prior to the database lock date and

autho

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on

With an EDV and the date of EDV prior to the database lock date and having no termination CRF.

autho

rizati

on

having no termination CRF.

considered entering Downau

thoriz

ation

considered entering Down-au

thoriz

ation

-Titration Period onlyau

thoriz

ation

Titration Period only drug after the date of EDV, the start date of Down-au

thoriz

ation

drug after the date of EDV, the start date of Down-

appli

catio

n following criteria, the Evaluation Period ends on date of last dose of BRV

appli

catio

n following criteria, the Evaluation Period ends on date of last dose of BRV

a termination CRF,

appli

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With an EDV and having a termination CRF,appli

catio

n

With an EDV and having a termination CRF,

and Period and Period but meets 1 of the and but meets 1 of the

following criteria, the Evaluation Period ends on date of last dose of BRVan

d following criteria, the Evaluation Period ends on date of last dose of BRV

any

Titration Period, then the date of EDV is the

any

Titration Period, then the date of EDV is the exten

sions

For Evaluation Period, the start date is the date of first dose of BRV, and the

exten

sions

For Evaluation Period, the start date is the date of first dose of BRV, and the

Titration Period, then the date of EDV is the exten

sions

Titration Period, then the date of EDV is the

or va

riatio

ns

to slot the subject appropriately into the Evaluation Period, varia

tions

to slot the subject appropriately into the Evaluation Period,

thereo

f.


Confidential of 43

3.2.5 Monthly time intervals

A month is defined as 30 days and time intervals based on monthly durations are defined as a multiple of 30 days (eg, 12 months is defined as 360 days). The following definitions of 3-month and 6-month intervals are based on 30-day months where the date of first dose of BRV is Day 1:

Interval Duration DefinitionMonths 1-3 Days 1-90Months 4-6 Days 91-180Months 7-9 Days 181-270Months 10-12 Days 271-360

Months 1-6 Days 1-180Months 7-12 Days 181-360Months 13-18 Days 361-540Months 19-24 Days 541-720

Subsequent 3- and 6-month intervals are defined in a similar manner.

Six-month intervals are defined for the evaluation of direct and indirect cost parameters. Statistical summaries for direct and indirect cost parameters will only present results through the first 2 years of treatment. Three-month intervals will be used for analysis of efficacy outcomes and AEs.

End date is the date of last dose of BRV.

For the analysis of efficacy outcomes, a subject is included in the analysis for a 3-month interval if the end date is on or after the last day of the 3-month interval and the subject diary was completed for at least 1 day during the 3-month interval.

For the analysis of AEs, a subject is included in the analysis for a 3-month interval if the end date is on or after the first day of the 3-month interval.

3.2.6 Last value on BRV treatment

Last Value for QOLIE-31-P, HADS, EQ-5D, and socio-professional data is the last assessment strictly after the date of first dose of BRV and up to and including the YEV at the end of the second year and any EDVs for subjects who did not complete through the YEV at the end of the second year.

Last Value for clinical laboratory parameters, vital signs, and ECGs is the last available result obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All scheduled and unscheduled assessments within this time period will be considered. Last Value will be determined separately for each laboratory parameter for hematology, chemistry, and urinalysis assessments.

3.2.7 Exposure duration and exposure duration cohorts

At the final analysis, the overall duration of exposure (or On Treatment Period) will be calculated as the date of last dose of BRV minus the date of first dose of BRV plus 1 day.

REDACTED

outcomes, a subject is included in the anal

REDACTED

outcomes, a subject is included in the analinterval if the end date is on or after the

REDACTED

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Confidential of 43

Each subject will be classified into one or more of the following exposure duration cohorts based on the duration of BRV exposure as calculated above:

All subjects ≥1 day

≥3 months ≥90 days



This categorization will continue in 6-month increments past 12 months up to a time point that will be determined based on cumulative exposure at the time of the database lock.

3.2.8 Study visit cohorts

Study visit cohorts are defined for summaries of QOLIE-31-P, HADS, and EQ-5D. Six-month, 12-month, 18-month, and 24-month cohorts are defined. Subjects will be classified into a study visit cohort if they attend the scheduled visit at the time point defined by the cohort. For example, subjects will be included in the 18-month study visit cohort if they attend the scheduled visit at 18 months (ie, FEV at Month 18). Subjects may be classified in more than 1 cohort. Generally, subjects included in a cohort for a later visit will be included in all earlier study visit cohorts (eg, 6-month and 12-month study visit cohorts for subjects in the 18-month study visit cohort), although this may not be the case in the event of a missed visit or if an unscheduled visit is conducted in lieu of a scheduled visit.

3.3 Definition of Baseline Values

Baseline for all study outcomes will be based on baseline from the previous studies. For assessments performed at scheduled and unscheduled visits, Baseline will generally be the last result obtained or prior to the randomization visit of the previous study. Baseline will be defined separately for each hematology, blood chemistry, and urinalysis parameter.

Baseline for the evaluation of seizure frequency and seizure days will be calculated from the core study seizure diary based on the rules defined in Section 3.8.1.

3.4 Protocol deviations

The criteria for identifying important protocol deviations and the classification of important protocol deviations will be defined separately in the Specification of Protocol Deviations document. 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.

3.5 Analysis Sets

3.5.1 Safety Analysis Set

The Safety Analysis Set will consist of all subjects who took at least 1 dose of study drug.

Summaries of demographics and baseline characteristics, medical history, AEDs, non-AEDs, HADS, direct and indirect cost parameters, socio-professional data, study drug exposure, and safety outcomes will be provided for the Safety Analysis Set.

REDACTED Definition of Baseline Values

REDACTED Definition of Baseline Values

Baseline for all study outcomes will be based on baseline from the previous studies. For

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Confidential of 43

3.5.2 Efficacy Analysis Set

Efficacy Analysis Set will consist of all subjects who took at least 1 dose of study drug and have at least 1 seizure diary day during the Evaluation Period.

Summaries of seizure outcomes, epilepsy history, QOLIE-31-P, and EQ-5D will be provided for the Efficacy Analysis Set.

3.6 Treatment Assignment and Treatment Groups

This is an uncontrolled study in which all subjects receive BRV in doses that are optimally adjusted for each subject. Generally, statistical summaries will present all subjects combined as a single treatment arm unless otherwise indicated.

3.7 Coding dictionaries

Medical history, AEs, and concurrent medical procedures will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be coded using the World Health Organization Drug Reference List (WHO-DRL). Prior medical procedures will not be coded.

3.8 Definitions of Study-specific Derived Variables

3.8.1 Calculation of seizure frequency/days

3.8.1.1 Initial seizure data processing

Each seizure code in the clinical database will be mapped to exactly 1 of the following codes based on the 1981 International League Against Epilepsy (ILAE) classification: I, IA, IA1, IA2, IA3, IA4, IB, IB1, IB2, IC, II, IIA, IIB, IIC, IID, IIE, IIF, or III.

Seizures reported as “too frequent to count” will not have a reported frequency; the count of 1 will be used for analyses.

3.8.1.2 Calculation of adjusted seizure frequency

Baseline POS frequency for seizure types I, IA, IB, IC, and for all seizure types (I+II+III) will be obtained from the Baseline Period of the previous study.

The total number of seizures for seizure types I, IA, IB, and IC, and the total number of seizures for all seizure types (I+II+III) will be calculated overall, by 3-month time intervals, and over the cohort interval for each exposure duration cohort. Allseizure diary on or after the date of first dose of BRV and prior to or on the date of last dose of BRV will be considered for these calculations.

Twenty-eight day adjusted seizure frequency for seizure types I, IA, IB, and IC, and for all seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and over each exposure duration cohort interval by dividing the total number of seizures for each seizure type by the number of days for which the diary was completed overall, within each 3-month interval, and within each exposure duration cohort interval, and multiplying the resulting value by 28.

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Confidential of 43

3.8.2 QOLIE-31-P

The QOLIE-31-P is an adaptation of the original QOLIE-31 (Cramer et al, 1998). The QOLIE-31-P includes 30 items grouped into 7 multi-item subscales (seizure worry [5 items], overall quality of life [2 items], emotional well-being [5 items], energy/fatigue [4 items], cognitive functioning [6 items], medication effects [3 items], and social function [5 items]) and a health status item. The QOLIE-31-P total score, subscale scores, and health status item score are calculated according to the scoring algorithm described below, with scores ranging from 0 to 100 and higher scores indicating better functioning. In addition to these 31 items, the QOLIE-31-P includes 7 items assessing the degree of “distress” associated with the topic of each subscale (ie, distress items) and 1 item asking about the relative importance of each subscale topic (ie, prioritization item).

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 13.1. Each subscale score is then calculated by summing the rescaled responses for that subscale and dividing by the number of items without a 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 13.1. 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

Responses 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.

3.8.3 HADS

The HADS assessment consists of 14 items that are each scored on a 4-point scale ranging from 0 to 3, with a higher score corresponding to worse anxiety or depression. The depression and anxiety scores will be calculated by summing the scores for the items corresponding to each subscale, as described in the Hospital Anxiety and Depression Scale Manual (Snaith and Zigmond, 1994): the depression score is calculated as the sum of all even-numbered items; the anxiety score is calculated as the sum of all odd-numbered items.

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Confidential of 43

Scores for each subscale range from 0 to 21, with higher scores corresponding to a greater level of anxiety or depression.

Missing items will be replaced by the mean of non missing items from the same subscale when calculating the above, provided at least 50% of the items (ie, at least 4 of 7 items) within the subscale are present. A subscale score will not be calculated if more than 50% of the items are missing within a subscale. This rule applies separately to the subscale scores for anxiety and depression; for example, it may be possible to calculate the depression score in cases where the anxiety score is not calculated due to non response.

3.8.4 Subject site transfers

Subjects may have transferred from one site to another through the course of participation in the study. Subjects that transferred from one site to another site, for whatever reason, have generally retained their subject number. However, in some cases, the subject number changed. When this is true, the most recently assigned subject number will be used for analyses and subject data listings. A record of any change in subject numbers will be presented in the Section 13.2.

4 STATISTICAL/ANALYTICAL ISSUES

4.1 Adjustments for Covariates

No statistical testing is planned; therefore, this section is not applicable.

4.2 Handling of Dropouts or Missing Data

Seizure frequency will be calculated over non missing diary days during each study period or time interval as described in Section 3.8.1; diary days for which seizure data were not obtained will not be considered in the calculation of seizure frequency. Because the evaluation of efficacy is not the primary objective of this study, and because this is an uncontrolled study in a variable setting which allows individualized optimization of dosing of BRV and concomitant AEDs, no summaries assessing the impact of missing seizure diary days are planned.

For subjects who prematurely discontinue during the Evaluation Period, the calculation of seizure frequency will be based on available seizure diary data while the subject was receiving BRV. The presence of dropouts may influence the evaluation of the long-term outcomes for subjects who either do not discontinue or do not discontinue early in the study. Therefore, as described below, selected summaries will be produced by exposure duration cohorts to allow an assessment of long-term outcomes without the potentially confounding influence of earlier discontinuations.

4.3 Interim Analyses and Data Monitoring

Interim summaries may be produced to support regulatory submissions for marketing authorization while this study is ongoing. There are no statistical concerns with such interim assessments for this study design.

4.4 Multicenter Studies

Efficacy and safety outcomes will not be assessed for individual investigator sites due to the low expected number for enrollment within each investigator site.

REDACTED Handling of Dropouts or Missing Data

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exten

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have transferred from one site to another through the course of participation in

ever reason, have

exten

sions

ever reason, have y retained their subject number. However, in some cases, the subject number ex

tensio

ns

y retained their subject number. However, in some cases, the subject number assigned subject number will be used for ex

tensio

ns

assigned subject number will be used for

or va

riatio

ns th

ereof.


Confidential of 43

4.5 Multiple Comparisons/Multiplicity

No statistical testing is planned; therefore, this section is not applicable.

4.6 Use of an “Efficacy Subset” of Subjects

All subjects who receive at least 1 dose of study drug and have at least 1 diary record during the Evaluation Period will be included in efficacy summaries. No additional efficacy subsets are defined for the study.

4.7 Active-Control Studies Intended to Show Equivalence

This section is not applicable for this study.

4.8 Examination of Subgroups

Selected summaries will be provided for the following subgroups as specified within each of the following sections:

Two mappings of countries to regions are defined, 1 based on the classification requested by Food and Drug Administration (FDA), and 1 based on the regional classification for the CHMP (Committee for Medicinal Products for Human Use).

Countries will be mapped to geographic regions as follows for the FDA:

Geographic Region (FDA) Country

Countries will be mapped to geographic regions as follows for the CHMP:

Geographic Region (CHMP) Country

REDACTED COPY Countries will be mapped to geographic regions as follows for the FDA:

COPY Countries will be mapped to geographic regions as follows for the FDA:

CountryCOPY

CountryCOPY

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be (CHMP)

be us

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pport

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ort

Countries will be mapped to geographic regions as follows for the CHMP:supp

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d Two mappings of countries to regions are defined, 1 based on the classification Food and Drug Administration (FDA), and 1 based on the regional an

d Food and Drug Administration (FDA), and 1 based on the regional

any

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exten

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roups as specified within each of exten

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roups as specified within each of

or va

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Confidential of 43

* .

Subject’s exit status in the prior trial (eg., =1 if met exit criteria in prior trial, =0 otherwise)

5 STUDY POPULATION CHARACTERISTICS

5.1 Subject Disposition

Due to differences in data format across studies, in order to facilitate summary of subject disposition, the reasons for discontinuation for individual studies will be collapsed as follows for summaries:

LTFU Category CRF ReasonADVERSE EVENT ADVERSE EVENTLACK OF EFFICACY LACK OF EFFICACY

LOSS OF EFFICACYLOST TO FOLLOW-UP LOST TO FOLLOW-UPSUBJECT CHOICE CONSENT WITHDRAWN

WITHDRAWAL OF CONSENT FOR PERSONAL REASONS NOT RELATED TO AESWITHDRAWAL OF CONSENT FOR PERSONAL REASONS NOT RELATED TO AES OR LACK OF EFFICACY

OTHER PROTOCOL VIOLATIONOTHER REASONOTHER

MISSING If subject discontinued the study and the termination CRF is not available

Only 1 primary reason for discontinuation should have been reported. In the event that more than 1 reason is specified in the clinical database, both reasons will be summarized and a footnote will be added to the summary table to indicate that at least 1 subject is counted for multiple reasons for discontinuation.

An overall summary of disposition will be provided for all enrolled subjects (ie, all subjects who signed informed consent). The following will be summarized:

The number of subjects in the Safety Analysis Set

The number of subjects excluded from the Safety Analysis Set

The number of subjects completed the study

The number of subjects who have discontinued from the study, including the reason for discontinuation. If subject discontinued the study and the termination CRF is not available, the reason for discontinuation will be reported as “MISSING”.

REDACTED VIOLATION

REDACTED VIOLATION

REDACTED OTHER REASON

REDACTED OTHER REASON

REDACTED

OTHER

REDACTED

OTHER

REDACTED

If subject discontinued the studyREDACTED

If subject discontinued the studyREDACTED COPY THDRAWAL OF CONSENT FOR PERSONAL

COPY THDRAWAL OF CONSENT FOR PERSONAL REASONS NOT REL

COPY REASONS NOT RELATED TO

COPY ATED TO

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The number of subjects ca

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The number of subjects

be The number of subjects in the Safet

be The number of subjects in the Safet

The number of subjects excluded from the Safetbe

The number of subjects excluded from the Safetus

ed who signed informed consent). The following will be summarized:

used

who signed informed consent). The following will be summarized:

used

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to An overall summary

to An overall summary of disposition wil

to of disposition wilAn overall summary of disposition wilAn overall summary

to An overall summary of disposition wilAn overall summarywho signed informed consent). The following will be summarized:to who signed informed consent). The following will be summarized:

supp

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supp

ort footnote will be added to the summary

multiple reasons for discontinuation.

supp

ort

multiple reasons for discontinuation.

of disposition wilsupp

ort

of disposition wilwho signed informed consent). The following will be summarized:

supp

ort

who signed informed consent). The following will be summarized:

any 1 reason is specified in the clinical database, both reasons will be summarized and a

any 1 reason is specified in the clinical database, both reasons will be summarized and a

footnote will be added to the summaryany

footnote will be added to the summary

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not available

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not available

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reason for discontinuation should have been reported. In the event that more marketi

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reason for discontinuation should have been reported. In the event that more 1 reason is specified in the clinical database, both reasons will be summarized and a

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autho

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VIOLATION

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VIOLATION

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OTHER REASON

autho

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OTHER REASON

autho

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If subject discontinued the studyau

thoriz

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If subject discontinued the studyau

thoriz

ation

appli

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n THDRAWAL OF CONSENT FOR PERSONAL

appli

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n THDRAWAL OF CONSENT FOR PERSONAL ATED TO AES

appli

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n ATED TO AES

appli

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THDRAWAL OF CONSENT FOR PERSONAL ap

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THDRAWAL OF CONSENT FOR PERSONAL ATED TO ap

plica

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ATED TO appli

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d any

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s

exten

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exten

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exten

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exten

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or the reasons for discontinuation for individual studies will be collapsed as follows

or the reasons for discontinuation for individual studies will be collapsed as follows va

riatio

ns

the reasons for discontinuation for individual studies will be collapsed as follows varia

tions

the reasons for discontinuation for individual studies will be collapsed as follows

thereo

f.


Confidential of 43

Additionally, an overall summary of disposition will present the following for subjects in the Safety Analysis Set:

The number of subjects completing the study The overall number of subjects discontinuing and the number of subjects discontinuing by primary reason for discontinuation. If subject discontinued the study and the termination CRF is not available, the reason for discontinuation will be reported as “MISSING”.

Overall subject disposition will also be summarized by geographic region for the Safety Analysis Set.

The number of subjects within each geographic region will be summarized for the Safety Analysis Set.

Kaplan-Meier estimates of the percentage of subjects completing 3, 6, 12, 24, 36, 48, and 60 months of treatment with BRV will be provided. This analysis will be based on the duration of exposure to BRV as defined in Section 3.2.7. Subjects who have permanently discontinued will be analyzed as events on the last day of treatment with study drug; subjects who complete the study will be censored on the last day of treatment with study drug.

The date of first subject in (date of earliest Visit 1), date of last subject out (date of last scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in each analysis set or indication will be summarized overall and by investigator site. Subjects who transferred sites will be summarized according to their original site.

5.2 Protocol Deviations

The number and percentage of subjects with at least 1 important protocol deviation will be summarized overall and by category of protocol deviation for the Safety Analysis Set.

6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS

6.1 Demographics

Demographics summaries will be based on demographic data from follow-up studies for subjects who enrolled in a follow-up study that collected demographic data. Otherwise, demographics summaries will be based on demographic data collected in the previous double-blind study.

Age, age category (<17, 17 to <65, and ≥65 years), gender, racial group and overall racial group (see below), body weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI category (<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40) will be summarized for the Safety Analysis Set. Demographic data will be summarized overall and by subgroup for geographic region.

Racial group was not collected in a consistent manner across studies. For this reason, racial group will be collapsed as follows for statistical summaries:

REDACTED who transferred sites will be summarized according to their orig

REDACTED who transferred sites will be summarized according to their orig

The number and percentage of subjects with at least 1 important protocol deviation will be

REDACTED

The number and percentage of subjects with at least 1 important protocol deviation will be of protocol deviation for the SafetyREDACTED

of protocol deviation for the Safety

PHICS AND OTHREDACTED

PHICS AND OTH

COPY scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in

COPY scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in is set or indication will be summarized overall and by

COPY is set or indication will be summarized overall and by

who transferred sites will be summarized according to their origCOPY who transferred sites will be summarized according to their orig

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Racial group was not collected in a consistent manner across studies. For this reason, racial

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Racial group was not collected in a consistent manner across studies. For this reason, racial

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cann

ot Analysis Set. Demographic data will be summarized overall and by

cann

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region.cann

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region.

be Age, age category

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to demographics summaries will be based on demographic data collected in the previous

to demographics summaries will be based on demographic data collected in the previous su

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supp

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supp

ort

subjects who enrolled in a follow-demographics summaries will be based on demographic data collected in the previous su

pport

demographics summaries will be based on demographic data collected in the previous

any Demographics

any Demographics

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Demographics summaries will be based on demographic data from follow

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The number and percentage of subjects with at least 1 important protocol deviation will be au

thoriz

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The number and percentage of subjects with at least 1 important protocol deviation will be of protocol deviation for the Safetyau

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of protocol deviation for the Safety

appli

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appli

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The date of first subject in (date of earliest Visit 1), date of last subject out (date of

appli

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exten

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exten

sions

y

Meier estimates of the percentage of subjects completing 3, 6, 12, 24, 36, 48, and

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Confidential of 43

Category CRF Racial GroupAmerican Indian/Alaskan Native

American Indian/Alaskan Native

Asian Asian, Asian/Pacific Islander, Indian/PakistaniBlack Black, African-AmericanNative Hawaiian or Other Pacific Islander

Native Hawaiian or Other Pacific Islander

White White, Caucasian, HispanicOther/Mixed Other, Other/Mixed, Mixed Race

moreover, the overall racial group will be collapsed as follows for statistical summaries:

Category Racial Group from Previous StudyWhite White, Caucasian, HispanicBlack Black, African-AmericanAsian Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander,

Indian/PakistaniOther American Indian/Alaskan Native, Other, Other/Mixed

All subjects should be classified into one of the above categories.

Racial group, ethnicity (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup (Indian/Pakistani, Japanese, Other) will be provided in subject data listings.

6.2 Medical and Procedure History

6.2.1 Medical history diseases

The summary of medical history will be based on the medical history at the time of entry into the previous studies.

The number and percentage of subjects with a medical history condition, including both resolved and ongoing conditions at the time of entry into the previous study, will be summarized overall and by primary MedDRA system organ class (SOC) and preferred term (PT) for the Safety Analysis Set.

6.2.2 Procedure history and concomitant procedures

Medical procedures are not coded and will only be provided in subject data listings.

6.3 History of Epilepsy

All of the following are summarized using data collected at the time of entry into the previous studies or from the Baseline Period of the previous studies.

6.3.1 Etiology of epilepsy

The number and percentage of subjects with each type of etiology as specified on the CRF (genetic, congenital, etc) from the previous studies will be summarized for the Efficacy Analysis Sets. A subject will be counted as having a particular etiology if that etiology was either confirmed or suspected based on the investigator's assessment.

REDACTED Medical and Procedure History

REDACTED Medical and Procedure History

diseases

REDACTED diseases

will be based on the medical historyREDACTED

will be based on the medical history

COPY y (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup

COPY y (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup (Indian/Pakistani, Japanese, Other) will be provided in subject data listings.

COPY (Indian/Pakistani, Japanese, Other) will be provided in subject data listings.

Medical and Procedure HistoryCOPY


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The number and percentage of subjects with each ty

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supp

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resolved and ongoing conditions at the time of entry

autho

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will be based on the medical history

appli

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one of the above categories.

appli

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y (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup ap

plica

tion

y (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup (Indian/Pakistani, Japanese, Other) will be provided in subject data listings.ap

plica

tion

(Indian/Pakistani, Japanese, Other) will be provided in subject data listings.

and

Indian/Alaskan Native, Other, Other/Mixedand

Indian/Alaskan Native, Other, Other/Mixed

any Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander, any Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander, ex

tensio

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exten

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moreover, the overall racial group will be collapsed as follows for statistical summaries: or va

riatio

ns th

ereof.


Confidential of 43

6.3.2 Epileptic seizure profile

The number and percentage of subjects experiencing each seizure type at any time prior to study entry will be summarized for the Efficacy Analysis Sets. The following seizure types will be summarized: I, IA, IA1 through IA4, IB, IB1, IB2, IC, II, IIA through IIF, III, and IV. A subject with a history of a more specific seizure type will be counted in all higher levels of seizure types (eg, a subject with a history of IB1 seizures will be counted for seizure types I, IB, and IB1).

6.3.3 Classification of epileptic syndrome

The number and percentage of subjects with each epileptic syndrome will be summarized for the Efficacy Analysis Sets. This summary will include the number and percentage of subjects within the following categories: localization-related epilepsy; idiopathic, symptomatic, and cryptogenic localization-related epilepsy; generalized epilepsy; and idiopathic, symptomatic, and cryptogenic generalized epilepsy.

6.3.4 Focus localization

The number and percentage of subjects with each category of focus localization (frontal, temporal, parietal, occipital) will be summarized for the Efficacy Analysis Set. Subjects may be counted in more than 1 category of focus localization.

6.3.5 History of epileptic seizures

History of epileptic seizures, including the number and percentage of subjects with a history of status epilepticus and quantitative summaries of epilepsy duration, age at onset of first seizure, and percent of life with epilepsy, will be summarized for the Efficacy Analysis Set.

6.3.6 Seizure types experienced during baseline of the previous study

The number and percentage of subjects experiencing each seizure type during the Baseline Period will be summarized for the Efficacy Analysis Set based on the Baseline seizure diary data from the previous studies. The following seizure types will be summarized: I, IA, IB, IC, II, and IIA through IIF.

Subjects will be counted for all higher levels of seizure type categories corresponding to the seizure types or seizure sub-types reported on the CRF.

6.4 Medications

Medications recorded on the Concomitant Medications CRF and the Concomitant Medications (AEDs only) CRF will be classified as either AEDs or non-AEDs based on the preferred drug name search criteria, which are documented outside of the SAP.

The medication is not an AED if it does not meet the search criteria based on preferred drug name, regardless of which CRF is used for reporting the medication. However, further review will be performed for medications that are recorded on the Concomitant Medications (AEDs only) CRF but are not included in the AEDs search criteria;

For non-benzodiazepine medications, if the medication meets the search criteria for an AED based on preferred drug name, then the medication will be classified as an AED regardless of indication and regardless of which CRF the medication is recorded on;

REDACTED of epileptic seizures, including the number and percentage of subjects with a history

REDACTED of epileptic seizures, including the number and percentage of subjects with a historystatus epilepticus and quantitative summaries of epileps

REDACTED status epilepticus and quantitative summaries of epileps

seizure, and percent of life with epilepsy

REDACTED

seizure, and percent of life with epilepsy, will be summarized for the Efficacy

REDACTED

, will be summarized for the Efficacy

Seizure types experienced during baseline of the previous studyREDACTED

Seizure types experienced during baseline of the previous study

COPY localization.

COPY localization.

of epileptic seizures, including the number and percentage of subjects with a historyCOPY

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nnot

Medications (AEDs only) CRF will be classified as either AEDs or non

cann

ot Medications (AEDs only) CRF will be classified as either AEDs or nonpreferred drug name search criteria, which are documented outside of the SAP.

cann

ot preferred drug name search criteria, which are documented outside of the SAP.

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ot

The medication is not an AED if it does not meet the search criteria bacann

ot

The medication is not an AED if it does not meet the search criteria ba

be Medications recorded on the Concomitant Medications CRF

be Medications recorded on the Concomitant Medications CRF

Medications (AEDs only) CRF will be classified as either AEDs or nonbe

Medications (AEDs only) CRF will be classified as either AEDs or nonus

ed Medications

used

Medications

Medications recorded on the Concomitant Medications CRF used

Medications recorded on the Concomitant Medications CRF

to Medicationsto Medicationssu

pport

Subjects will be counted for all higher levels of seizure ty

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data from the previous studies. The following seizure ty

autho

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of epileptic seizures, including the number and percentage of subjects with a history

autho

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of epileptic seizures, including the number and percentage of subjects with a historystatus epilepticus and quantitative summaries of epileps

autho

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status epilepticus and quantitative summaries of epileps, will be summarized for the Efficacy

autho

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, will be summarized for the Efficacy

Seizure types experienced during baseline of the previous studyautho

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appli

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appli

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n localization (frontal, ipital) will be summarized for the Efficacy

appli

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appli

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and

localization (frontal, and

localization (frontal,

any e

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exten

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exten

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will include the number and percentage of subjects

ymptomatic, and

exten

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ymptomatic, and ; and idiopathic, syex

tensio

ns

; and idiopathic, symptomatic, exten

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; and idiopathic, symptomatic, ; and idiopathic, sy

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Confidential of 43

For benzodiazepines (identified using the search criteria), if the benzodiazepine is recorded on the Concomitant Medications (AEDs only) CRF, then the benzodiazepine will be classified as an AED;

For benzodiazepines (identified using the search criteria), if the benzodiazepine is recorded on the Concomitant Medications CRFs, then the benzodiazepine will not be classified as an AED.

After medications are classified as AEDs or non-AEDs, the standard date imputation algorithms for start and stop date of the medication and first dose and last dose of BRV in the study will be applied. If an AED was taken at any time during dosing with BRV, then the AED is classified as a concomitant AED.

6.4.1 Non-AEDs taken at study entry

The number and percentage of subjects taking non-AED medications at study entry for the previous double-blind study will be summarized by WHO-DRL primary therapeutic group (Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and preferred drug name for the Safety Analysis Set.

6.4.2 Number of previous AEDs

The number and percentage of subjects taking an AED prior to entry into the previous study will be summarized by WHO-DRL preferred drug name for the Efficacy Analysis Set based on the following categorization: 0-1 AEDs, 2-4 AEDs, and ≥5 AEDs.

6.4.3 History of previous AED use

The number and percentage of subjects who had taken at least 1 AED prior to entry into the previous study will be summarized overall and by WHO-DRL preferred drug name for the Efficacy Analysis Set.

6.4.4 AEDs taken at study entry

The number and percentage of subjects taking AEDs at study entry for the previous double-blind study will be summarized by WHO-DRL preferred drug name for the Efficacy Analysis Set.

6.4.5 Concomitant AEDs

A concomitant AED is an AED which was taken during administration of BRV, regardless of the start and stop date of the AED. The number and percentage of subjects taking concomitant AEDs will be summarized by WHO-DRL preferred drug name for the Efficacy Analysis Set.

7 MEASUREMENTS OF TREATMENT COMPLIANCE

Study drug compliance will not be assessed due to the complexities associated with the calculation and interpretation of study drug compliance for this study. Study drug dosing will be provided in subject data listings.

REDACTED AEDs, and

REDACTED AEDs, and

AED use

REDACTED AED use

The number and percentage of subjects who had taken at least 1

REDACTED

The number and percentage of subjects who had taken at least 1previous study will be summarized overall and byREDACTED

previous study will be summarized overall and by

COPY The number and percentage of subjects taking an AED prior to entry

COPY The number and percentage of subjects taking an AED prior to entry preferred drug name for the Efficacy

COPY preferred drug name for the Efficacy

AEDs, and COPY

AEDs, and

This do

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AED use

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plica

tion

The number and percentage of subjects taking an AED prior to entry preferred drug name for the Efficacyap

plica

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and (Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and

and (Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and

any

AED medications at study

any

AED medications at study therapeutic group an

y therapeutic group (Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and

any

(Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and

exten

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ime during dosing with BRV, then the

exten

sions

ime during dosing with BRV, then the

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sions

AED medications at study entryexten

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entryAED medications at study entryAED medications at study exten

sions

AED medications at study entryAED medications at study

or algorithms for start and stop date of the medication and first dose and last dose of BRV in the

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tions

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thereo

f.


Confidential of 43

8 EFFICACY ANALYSES

Unless otherwise noted, all efficacy outcomes will be summarized for the Efficacy Analysis Set. The derivations of 28-day adjusted seizure frequency are described in detail in Section 3.8.1.2.

All summaries of efficacy data are descriptive; no statistical testing will be performed.

8.1 Statistical Analysis of the Secondary Efficacy Variables

8.1.1 Percentage of subjects on continuous BRV monotherapy

The cumulative proportion of subjects able to achieve BRV monotherapy for 3, 6, and 12 months during the Evaluation Period will be summarized. BRV monotherapy is defined as continuous treatment with BRV only (ie, no treatment with another AED). Use of rescue AED medications for a duration of no more than 2 consecutive days will not disqualify a subject from being defined as on continuous monotherapy provided the use of rescue AED medication does not exceed more than 1 time per week.

8.2 Analyses of Other Efficacy Variables

8.2.1 Partial onset seizure frequency

Twenty-eight day adjusted POS frequency will be summarized with quantitative descriptive statistics for all subjects for the Baseline Period, the On Treatment Period, and by 3-month time intervals over the On Treatment Period. The summary over the On Treatment Period will include all subjects in the Efficacy Analysis Set. Similar summaries will be provided for the full cohort interval and by 3-month time intervals for each exposure duration cohort.

8.2.2 Percent reduction in POS frequency

Percent reduction in POS frequency from Baseline to the On Treatment Period will be calculated as follows, where On Treatment Period Frequency is the 28-day adjusted POS frequency during On Treatment Period and Baseline Period Frequency is the 28-day adjusted POS frequency during the Baseline Period of the previous study.

FrequencyPeriodBaseline

FrequencyPeriodTreatment On FrequencyPeriodBaseline100Reduction%

A similar calculation applies to each 3-month time interval over the On Treatment Period and for the cohort interval for each exposure duration cohort.

Percent reduction from Baseline for POS frequency will be summarized with quantitative descriptive statistics for the On Treatment Period, and by 3-month time intervals over the On Treatment Period. The summary over the On Treatment Period will include all subjects in the Efficacy Analysis Set. Similar summaries will be provided for the full cohort interval and by 3-month time intervals for each exposure duration cohort. Percent reduction from Baseline for POS frequency will be summarized in the same manner by geographic region.

8.2.3 Specified Month seizure freedom

The numbers and percentages of subjects who are seizure free for all seizure types for any continuous 6-month interval, 12-month interval, 18-month interval, and so forth will be summarized overall for the period of time that subjects are being treated with BRV and by

REDACTED er the On Treatment Period. The summary

REDACTED er the On Treatment Period. The summaryys

REDACTED ysis Set. Similar summaries will be provided for

REDACTED is Set. Similar summaries will be provided for

month time intervals for each exposure duration cohort

REDACTED month time intervals for each exposure duration cohort

rcent reduction in POS frequencyREDACTED

rcent reduction in POS frequency

from Baseline to the On Treatment Period will be REDACTED

from Baseline to the On Treatment Period will be

COPY will be summarized with quantitative descriptive

COPY will be summarized with quantitative descriptive statistics for all subjects for the Baseline Period, the On Treatment Period, and by

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and a

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exten

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3, 6, and 12 is defined as

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varia

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of.


Confidential of 43

Exposure Duration Cohort. The overall summary will present the number and percentage of subjects who reported no seizures for the specified duration of seizure freedom and the seizure diary was completed for at least 90% of days within the seizure-free interval. Subjects whose duration of BRV treatment was less than the specified duration of seizure freedom will be considered failures for seizure-freedom. Summaries by exposure duration cohort will present the number and percentage of subjects who reported no seizures for the specified duration of seizure freedom at any time during the cohort interval (eg, through the end of Month 6 for the 6-month cohort) and the seizure diary was completed for at least 90% of days within the seizure-free interval. Percentages are relative to the number of subjects within each Exposure Duration Cohort.

A subject is seizure free for a 6-month interval if the subject did not report any seizures in the 6-month interval and the seizure diary was completed for at least 90% of days within the seizure-free interval. The percentage of days for which seizure diary was completed within a given 6-month interval will be calculated as follows based on a 30-day month:

%ofdaysdiarywasdone=100 × �180 − numberofdaysdiarywasnotdoneintheinterval

180�

A similar calculation applies for 12-month seizure freedom based on 360 days, 18-month seizure freedom based on 540 days, and so forth.

8.2.4 QOLIE-31-P

The scoring algorithm for QOLIE-31-P is described in Section 3.8.2 and Section 13.1.

QOLIE-31-P is assessed at the following time points: Month 2, Month 6, Month 12, Month 18, and Month 24. QOLIE-31-P is also assessed at EDVs for subjects who discontinue prior to the YEV at the end of the second year.

Observed values for QOLIE-31-P total score and subscale scores for Seizure Worry, Daily Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, Overall Quality of Life, and Health Status will be summarized for Baseline and Last Value for the Efficacy Analysis Set. Additionally, observed values will be summarized for Baseline, EV, and by visit for each study visit cohort. For summaries of observed values at each time point, only subjects with a change from Baseline value at that time point will be summarized. Additionally, the mean and SD for each Baseline score will be provided at each post-Baseline time point for subjects included in the summary of change from Baseline.

Similar summaries will be provided for QOLIE-31-P distress items Seizure Worry, Daily Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, and Overall Quality of Life.

The rankings of prioritization items (Seizure Worry, Daily Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, and Overall Quality of Life) will be summarized by visit for the first 2 years of the Evaluation Period, and for Last Value for the first 2 years of the Evaluation Period for the Efficacy Analysis Set. Only observed values will be summarized and only the number of non missing values and the means for each item will be presented.

REDACTED P is described in Section

REDACTED P is described in Section

P is assessed at the following time points: Month 2, Month 6, Month 12, Month

REDACTED P is assessed at the following time points: Month 2, Month 6, Month 12, Month

-P is also assessed at EDVs for subjects who discontinue prior

REDACTED

-P is also assessed at EDVs for subjects who discontinue prior yeREDACTED

year. REDACTED

ar.

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P is assessed at the following time points: Month 2, Month 6, Month 12, Month

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appli

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appli

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and numberofdaysdiarywasnotdoneintheinterval

and numberofdaysdiarywasnotdoneintheinterval

and a

ny month:

any month:

numberofdaysdiarywasnotdoneintheintervalany

numberofdaysdiarywasnotdoneintheinterval

exten

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exten

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exten

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tensio

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was completed within a month:

exten

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or free interval. Percentages are relative to the number of subjects within each

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riatio

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was completed for at least 90% of day

varia

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thereo

f.


Confidential of 43

8.2.5 EQ-5D

EQ-5D (EuroQol Group, 2000) is assessed at the following time points: Month 2, Month 6, Month 12, Month 18, and Month 24. EQ-5D is also assessed at EDVs for subjects who discontinue prior to the YEV at the end of the second year.

Qualitative EQ-5D items will be summarized for Baseline and Last Value for the Efficacy Analysis Set. Additionally these parameters will be summarized for Baseline and by visit for each study visit cohort. Percentages will be relative to the number of subjects with a response to each item at each time point.

Observed values for the visual analog scale (VAS) score for general health state will be summarized for Baseline and Last Value for the Efficacy Analysis Set. Additionally observed values will be summarized for Baseline and by visit for each study visit cohort. Change from Baseline will be summarized at each visit during the Evaluation Period.

For summaries of observed values for VAS at each time point, only subjects with a change from Baseline value at that time point will be summarized.

8.2.6 Direct cost parameters

Direct costs will be assessed based on concurrent medical procedures, healthcare provider consultations not foreseen by protocol, hospital stays, and ER visits.

Direct cost parameters will not be summarized but will be provided in subject data listings.

8.2.7 Indirect cost parameters

The number of school or working days lost will not be summarized but will be provided in subject data listings.

8.2.8 Socio-professional data

Socio-professional data are collected at the following time points: Month 12 and Month 24. Socio-professional data are also collected at EDVs for subjects who discontinue prior to the YEV at the end of the second year. These additional assessments will not be summarized but will be provided in subject data listings.

9 PHARMACOKINETICS AND PHARMACODYNAMICS

Plasma samples to analyze BRV and concomitant AED plasma concentrations will no longer be obtained, as directed by the integrated protocol amendment 2.

No summaries of BRV or concomitant AED plasma levels will be provided; plasma levels will only be provided in subject data listings.

10 IMMUNOLOGICAL PROCEDURES

This section is not applicable for this study.

11 SAFETY ANALYSES

Safety is assessed with AEs, laboratory tests (blood chemistry, hematology, urinalysis, and pregnancy test), vital signs, body weight, ECGs, physical examination, neurological

REDACTED

arameters

REDACTED

arameters

The number of school or working dayREDACTED

The number of school or working days lost will REDACTED

s lost will

COPY s, and ER visits.

COPY s, and ER visits.

but COPY

but wCOPY will be provided in subject data listings.COPY

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docu

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10ca

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be obtained, as directed by the integrated protocol amendment 2.

cann

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cann

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cann

ot No summaries of BRV or concomitant AED plasma levels will be provided; plasma levels will onlyca

nnot

will only

be Plasma samples to

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supp

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any collected at the following time points: Month 12 and Mont

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Confidential of 43

examination, mental status, and psychiatric status. Summary tables will be provided for AEs; blood chemistry, hematology, and urinalysis; vital signs; body weight; and ECGs. No summary tables will be provided for pregnancy testing, physical examination, neurological examination, or psychiatric and mental status.

All safety summaries will be based on the Safety Analysis Set.

11.1 Extent of Exposure

11.1.1 Number of subjects exposed and subject-years of exposure

A daily dose will be calculated for each study day from the day of first dose of BRV to the day of last dose of BRV for the purposes of calculating modal dose. Daily dose will be calculated as the sum of the AM and PM dose for each day.

Modal daily doses will be calculated across all study days on or after the day of first dose of BRV and up to and including the day of last dose of BRV. Modal daily dose is the most frequently taken daily dose during this period. In the event of a tie, the modal dose will be set to the lower of the tied doses. Modal daily dose will be categorized as follows:

Category Definition

5 mg/day <20mg/day20mg/day ≥20mg/day to <50mg/day 50mg/day ≥50mg/day to <100mg/day100mg/day ≥100mg/day to <150mg/day150mg/day ≥150mg/day to <200mg/day200mg/day ≥200mg/day

Subject years of exposure will be calculated by summing the exposure duration in days for all subjects being summarized, and dividing the resulting value by 365.25.

Subject years of exposure will be presented overall and by modal dose for the Safety Analysis Set. The subject years of exposure presented by modal dose will be the total subject years of exposure of subjects with that modal dose.

The number and percentage of subjects exposed to BRV will be summarized overall and by modal dose category. The number and percentage of subjects in each Exposure Duration Cohort (≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.

The number and percentage of subjects within each modal dose category will be summarized for each Exposure Duration Cohorts; percentages will be relative to the total number of subjects in each Exposure Duration Cohort.

In addition to the overall summaries of the above, the above will also be summarized by subgroup for region.

11.2 Adverse Events

11.2.1 Definition of treatment-emergent AE

AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined as AEs which had onset prior to the date of the first dose of BRV for N01315. TEAEs are defined as AEs that had onset on or after the day of first BRV dose. AEs with an incomplete

REDACTED to <150mg/day

REDACTED to <150mg/day to <200mg/day

REDACTED to <200mg/day

ears of exposure will be calculated by summing the exposure duration in dayREDACTED

ears of exposure will be calculated by summing the exposure duration in daysubjects being summarized, and dividing the resulting value b

REDACTED

subjects being summarized, and dividing the resulting value b

COPY to <50mg/day

COPY to <50mg/day

50mg/day ≥50mg/day to <100mg/dayCOPY 50mg/day ≥50mg/day to <100mg/day

to <150mg/dayCOPY

to <150mg/day

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11.2

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cann

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cann

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In addition to the overall summaries of the above, the above will also be summarized byca

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be for each Exposure Durati

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subjects in each Exposure Duration Cohort.

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used


The number and percentage of subjects within each modal dose categoryus

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ed

for each Exposure Durati

to modal dose category. The number and percentage of subjects in each Exposure Duration

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≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.to ≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.su

pport

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supp

ort ars of exposure of subjects with that modal dose.

supp

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supp

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ears of exposure will be calculated by summing the exposure duration in dayautho

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appli

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y dose during this period. In the event of a tie, the modal dose will be set

and

y dose during this period. In the event of a tie, the modal dose will be set dose will be categorized as follows:an

d dose will be categorized as follows:an

y y dose is the most

any y dose is the most

y dose during this period. In the event of a tie, the modal dose will be set any

y dose during this period. In the event of a tie, the modal dose will be set

exten

sions

dose will be

exten

sions

dose will be

of first dose of ex

tensio

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Confidential of 43

onset date will be classified as TEAEs if the month and year of onset (when only the month and year are specified) is the same as the month and year of the first BRV dose or the year of onset (when only year is specified) is the same as the year of first BRV dose.

11.2.2 General summaries of TEAEs

Pre-treatment AEs will be provided in a subject data listing; no summaries of pre treatment AEs are planned.

An overall summary of AEs will provide the overall number of TEAEs and the numbers and percentages of subjects with at least 1 TEAE, with a TEAE that led to permanent discontinuation of study drug, with a drug-related TEAE, with a severe TEAE, with a treatment-emergent SAE, and with a drug-related treatment-emergent SAE. The number and percentage of subjects who died will also be summarized. This summary will be provided for all subjects in the Safety Analysis Set and also by subgroup for geographic region.

The following summaries of TEAEs will be provided by MedDRA SOC and PT. All summaries are for the combined Evaluation, Down-Titration, and Post-Treatment Periods unless otherwise indicated.

Overall Incidence Summaries

Incidence of TEAEs

Incidence of TEAEs by 3-month time interval

Incidence of TEAEs by study period (Evaluation, Down-Titration, Post-Treatment)

Incidence of TEAEs for TEAEs occurring in at least 5% of subjects

Incidence of TEAEs by 3-month time intervals for TEAEs occurring in at least 5% of subjects overall

Incidence of non-serious TEAEs occurring in at least 5% of subjects

The incidence of TEAEs occurring in at least 5% of subjects will be summarized overall as noted above and also by subgroup for geographic region.

A subject is included in a 3-month interval if the subject was receiving BRV at any time during that interval based on their duration of exposure to BRV (eg, a subject with exposure for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of AEs by 3-month intervals will include all subjects who are classified into each time interval as defined above. TEAEs which had onset prior to or on the date of the last dose of BRV (or the date of last scheduled or unscheduled visit for subjects who are ongoing at the time of the clinical cutoff) are included in summaries by 3-month time intervals.

Maximum Intensity and Causality

Incidence of TEAEs by maximum intensity

Incidence of drug-related TEAEs

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Incidence of treatment-emergent SAEs

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Confidential of 43

Discontinuations due to TEAE

Incidence of TEAEs leading to permanent discontinuation of study drug

TEAEs of interest

AEs of interest will be identified based on MedDRA search criteria, which are documented outside of the SAP. The following summaries will be provided for AEs of interest:

Incidence of TEAEs of interest

Incidence of TEAEs of interest by 3-month time interval

For the summary by maximum intensity, each subject will be counted at most once per SOC or PT according to the maximum intensity of all AEs within that SOC or PT. Severe intensity will be assumed for AEs for which intensity is not specified.

Drug-related AEs are AEs for which the relationship to study drug is specified as Related or AEs for which relationship is not specified.

11.3 Clinical Laboratory Evaluations

Clinical laboratory parameters (blood chemistry, hematology, urinalysis) are assessed at all FEVs, YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits.

11.3.1 Hematology and blood chemistry parameters

Observed values for each planned hematology and blood chemistry parameter will be summarized for Baseline, Study Entry, and each scheduled visit during the Evaluation Period for which laboratory parameters were assessed, Last Value, EDV, and FV. Change from Baseline will be summarized for all post-Baseline time points including EV. Only laboratory parameters planned per protocol will be summarized; results for laboratory parameters not planned per the protocol will only be provided in subject data listings.

The number and percentage of subjects with an on-treatment potentially clinically significant treatment-emergent (PCST) value, PCST low value, and PCST high value will be summarized. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the number of subjects with an on-treatment assessment.

Additionally, the number and percentage of subjects with a PCST value, PCST low value, and PCST high value will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages for each parameter and time point will be relative to the number of subjects with a value at that time point.

PCST (Sections 13.3.1, 13.3.2, and 13.3.3) criteria are based on FDA Division of Neuropharmacologic Drug Products guidelines with some UCB-defined additions.

Creatinine clearance, when available from the central laboratory, will be provided in subject data listings only and will not be summarized.

REDACTED Observed values for each planned hematology

REDACTED Observed values for each planned hematology and blood chemistry

REDACTED and blood chemistryObserved values for each planned hematology and blood chemistryObserved values for each planned hematology

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Confidential of 43

11.3.2 Macroscopic urinalysis

Quantitative urinalysis parameters will be summarized in the same manner as hematology and blood chemistry parameters. Response categories are negative, 1+, 2+, and 3+ for the qualitative urinalysis parameters occult blood, leukocytes, glucose, protein, and ketones and negative and positive for nitrates. Outcome values for these parameters are mapped to the levels Negative, 1+, 2+, and 3+ as follows for purposes of summary tables and the determination of PCST:

Category Definition

Negative “Negative”, “NEGATIVE”, or other outcomes that clearly reflect a negative finding

1+ “1+”, “+” , “Trace”, “TRACE”, or other outcomes that clearly reflect trace amount

2+ “2+” or “++”

3+ “3+”, “+++”, or other outcomes that clearly reflect the data above 3+ (eg, “4+”, “5+” etc) or more than 4 plus signs (eg, “++++”, “+++++”etc)

For qualitative urinalysis parameters (occult blood, leukocytes, glucose, protein, ketones, and nitrates), the number and percentage of subjects with each response category will be summarized for Baseline, Study Entry, each scheduled visit during the Evaluation Period for which urinalysis parameters were scheduled to be assessed, Last Value, EDV, and FV. Percentages for each parameter will be relative to the number of subjects with a result at each time point.

For occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number and percentage of subjects with an on-treatment PCST value, PCST low value, and PCST high value will be summarized. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the number of subjects with an on-treatment assessment.

Additionally, for occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number and percentage of subjects with a PCST value, PCST low value, and PCST high value will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages for each parameter and time point will be relative to the number of subjects with a value at that time point.

11.3.3 Microscopic urinalysis

In microscopic urinalysis, a small sample of urine is centrifuged to remove the liquid. The sediment is then examined under a microscope. In the urinalysis laboratory test group, other than urinalysis parameters such as Bilirubin, Blood, Glucose, Ketone, Nitrite, pH, Protein, Specific Gravity, Total protein, Occult Blood, and Leukocytes, a listing of microscopic analysis parameters will be provided; no summaries of microscopic analysis findings are planned.

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Confidential of 43

11.4 Vital Signs, Physical Findings, and Other Observations Related to Safety

11.4.1 Vital signs

Vital signs are assessed at all FEVs, MEVs, YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits. Body weight is assessed at all FEVs, YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits.

Observed values for SBP, DBP, pulse rate, and body weight will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which vital signs or body weight were assessed, EDV, Last Value, and FV. Changes from Baseline for SBP, DBP, pulse rate, and body weight will be summarized for all post-Baseline time points.

The number and percentage of subjects with an on-treatment PCST value, PCST low value, and PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV.

Additionally, the number and percentage of subjects with a PCST value, PCST low value, and PCST high value will be summarized for the above parameters for Study Entry, each visit during the Evaluation Period for which vital signs or body weight were scheduled to be assessed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects with a value at each time point.

PCST criteria (Section 13.3.4) are based on FDA Division of Neuropharmacologic Drug Products guidelines with some UCB-defined additions

11.4.2 Electrocardiograms

ECGs are assessed at all YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits.

The number and percentage of subjects with no abnormality, an abnormal but not clinically significant finding, and a clinically significant finding will be summarized overall. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV.

Additionally, the number and percentage of subjects with no abnormality, an abnormal but not clinically significant finding, and a clinically significant finding will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which an ECG is scheduled to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects with an ECG assessment at each time point. Subjects are counted at most once at each time point based on the worst observed outcome across all abnormalities reported at that time point.

A subject number listing will be provided that identifies subjects with a clinically significant finding after the first dose of BRV for each type of ECG abnormality.

11.4.3 Physical examination

A listing of abnormal physical examination findings will be provided; no summaries of physical examination findings are planned.

REDACTED are based on FDA Division of Neuropharmacologic Drug

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Confidential of 43

11.4.4 Neurological examination

A listing of abnormal neurological examination findings will be provided; no summaries of neurological examination findings are planned.

11.4.5 Psychiatric and mental status

A listing of abnormal Psychiatric and Mental Status findings will be provided; no summaries of Psychiatric and Mental Status findings are planned.

11.4.6 HADS

The scoring algorithm for HADS is described in Section 3.8.3.

During the first 2 years, HADS was assessed at Month 2, Month 6, Month 12, Month 18, and Month 24 and at EDV for subjects who discontinued the study prior to the YEV at the end of the second year for all subjects, and was also assessed at Month 4 and Month 9 for some subjects from N01114. HADS was not assessed for subjects from N01187 and N01236. Prior to integrated protocol amendment 25, HADS was being assessed for time points beyond the YEV at the end of the second year. These additional assessments will not be summarized but will be provided in subject data listings.

Observed values for HADS depression and anxiety scores will be summarized for Baseline and Last Value for the Safety Analysis Set. Additionally, observed values will be summarized for Baseline and by visit for each study visit cohort. Change from Baseline will be summarized at each visit during the Evaluation Period.

For summaries of observed values at each time point, only subjects with a change from Baseline value at that time point will be summarized. Additionally, the mean and SD for each Baseline score will be provided at each post-Baseline time point for subjects included in the summary of change from Baseline.

11.4.7 Columbia-Suicide Severity Rating Scale

With global amendment 2 to the protocol, the Columbia-Suicide Severity Rating Scale (C-SSRS) was added as an assessment at all study visits. Specific rules are provided to the study sites with regard to the identification of AEs or SAEs based on the outcome of this assessment. Because clinical events of interest will be recorded as AEs or SAEs, no study variable is defined for this assessment and no analyses are planned for the C-SSRS within the context of this study. However, subject data listings of the data for the C-SSRS will be provided. Additional listings will be provided for the subset of subjects with suicidal ideation and the subset of subject with actual suicide attempts.

Suicide ideation includes a “yes” answer to any 1 of the 5 suicidal ideation questions:

REDACTED be summarized at each visit during the Evaluation Period.

REDACTED be summarized at each visit during the Evaluation Period.

For summaries of observed values at each time point, only

REDACTED For summaries of observed values at each time point, onlyBaseline value at that time point will be summarized.

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and to integrated protocol amendment 25, HADS was being assessed for time points bey

and to integrated protocol amendment 25, HADS was being assessed for time points bey

ssessments will not be summarized but and

ssessments will not be summarized but

any subjects from N01114. HADS was not assessed for subjects from N01187 and N01236. Prior

any subjects from N01114. HADS was not assessed for subjects from N01187 and N01236. Prior

to integrated protocol amendment 25, HADS was being assessed for time points beyany

to integrated protocol amendment 25, HADS was being assessed for time points bey

exten

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12, Month

exten

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12, Month 18, and

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18, and

24 and at EDV for subjects who discontinued the study prior to the YEV at the end of

exten

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24 and at EDV for subjects who discontinued the study prior to the YEV at the end of 4 and Month ex

tensio

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4 and Month 9 for some exten

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9 for some

or va

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ereof.


Confidential of 43

Suicide attempt includes response of a “yes” answer to any 1 of the 3 suicide attempt questions:

12 REFERENCES

Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. Epilepsia 1998, 39(1): 81-88.

EuroQol Group. EQ-5D. A measure of health-related quality of life developed by the EuroQol group. User guide. 8th issue. April 2000.

Snaith RP, Zigmond AS. The hospital anxiety and depression scale manual. London: nferNelson Publishing Company Ltd. 1994.

REDACTED COPY

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t can

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tion and depression scale manual. London:

appli

catio

n and depression scale manual. London: an

d of life developed by

and

of life developed by

and depression scale manual. London: an

d and depression scale manual. London:

any of life developed byany of life developed byex

tensio

ns

of life in epilepsy

exten

sions

of life in epilepsy inventory

exten

sions

inventory of life in epilepsy inventory of life in epilepsy

exten

sions

of life in epilepsy inventory of life in epilepsy

or or va

riatio

ns

varia

tions

there

of.

thereo

f.


Confidential of 43

13 APPENDICES

13.1 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.

Response Final ScoreScale/Item Numbers 1 2 3 4 5 6 Subtotal 0-100 point scale

Seizure Worry30. 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 = _____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 = _____

REDACTED

20 40 60 80 100

REDACTED

20 40 60 80 10020 40 60 80 100

REDACTED

20 40 60 80 100100 80 60 40 20REDACTED

100 80 60 40 20

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100 80 60 40 20

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and _____

and _____

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any e

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Final Score100 point scale

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Confidential of 43

Medication Effects28. 0 33.3 66.7 100 –– –– _____26. 100 75 50 25 0 –– _____27. 100 75 50 25 0 –– _____

TOTAL : _____ ÷ 3 = _____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 ScaleFinal 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 (c)

REDACTED (c)(d)

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(d)(e)

REDACTED

(e)

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(f)

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activities/Social functioning (g)

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appli

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appli

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shown below. Total score will be missing if at least 1 subscale score is missing. Total score

and 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.and will range from 0 to 100 with a higher score reflecting better functioning.

any Total score is calculated as a weighted sum of the subscale scores based on

any Total score is calculated as a weighted sum of the subscale scores based on the weighting

any the weighting

shown below. Total score will be missing if at least 1 subscale score is missing. Total score any

shown below. Total score will be missing if at least 1 subscale score is missing. Total score

exten

sions

_____

exten

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_____

the weighting exten

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the weighting

or va

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Confidential of 43

13.2 Subject site transfers

CRF# Initial Site Subject # Transfer Site Subject #

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Confidential of 43

13.3 PCST criteria

13.3.1 Hematology parametersParameter UCB Conventional Units SI Units CF

Hematocrit For 1 m to < 6 m: 25% For 1 m to < 6 m: 0.25 0.01

For 6 m to < 2 y: 27% For 6 m to < 2 y: 0.27

For 2 y to < 4 y: 29% For 2 y to < 4 y: 0.29

For 4 y to < 12 y: 32% (Female[F]); 35% (Male [M]) For 4 y to < 12 y: 0.32 (F); 0.35 (M)

For 12 y: 32% (F); 37% (M) For 12 y: 0.32 (F); 0.37 (M)Hemoglobin For 6 m: 9.7 g/dL For 6 m: 97 g/L 10

For 6 m to < 12 y: 10.0 g/dL For 6 m to < 12 y: 100 g/L

For 12 y: 9.5 g/dL (F); 11.5 g/dL (M) For 12 y: 95 g/L (F); 115 g/L (M)Platelets 75 x 109/L or 700 x 109/L 75 x 109/L or 700 x 109/L Not applicable (N/A)

White Blood Cell (WBC)

For 17 y: < 3.0 x 109/L or > 20 x 109/L; For 17 y: < 3.0 x 109/L or > 20 x 109/L; N/A

For 17 y: < 2.8 x 109/L or > 16 x 109/L; For 17 y: < 2.8 x 109/L or > 16 x 109/L;Red Blood Cell (RBC)

For 17 y: < 2.5 x 106/mm3 For 17 y: < 2.5 x 1012/L 1

For 17 y: < 2.0 x 106/mm3 (F); < 2.5 x 106/mm3 (M) For 17 y: < 2.0 x 1012/L (F); < 2.5 x 1012/L (M)Eosinophils 10% or 0.7 x 109/L 0.10 or 0.7 x 109/L 0.01 or N/A

Neutrophils 15% or 1.0 x 109/L 0.15 or 1.0 x 109/L 0.01 or N/A

Basophils 5% or 0.4 x 109/L 0.05 or 0.4 x 109/L 0.01 or N/A

Monocytes 20% or 1.5 x 109/L 0.20 or 1.5 x 109/L 0.01 or N/A

Lymphocytes For 1 m to < 6 m: 22% or 80% For 1 m to < 6 m: 0.22 or 0.80 0.01

2.1 x 109/L or 8.5 x 109/L 2.1 x 109/L or 8.5 x 109/L N/A

For 6 m to < 2 y: 15% or 80% For 6 m to < 2 y: 0.15 or 0.80 0.01

1.5 x 109/L or 7.5 x 109/L 1.5 x 109/L or 7.5 x 109/L N/A

For 2 y to < 12 y: 12% or 80% For 2 y to < 12 y: 0.12 or 0.80 0.01

1.0 x 109/L or 7.5 x 109/L 1.0 x 109/L or 7.5 x 109/L N/A

For 12 y to 17 y: 10% or 80% For 12 y to 17 y: 0.10 or 0.80 0.01

0.5 x 109/L or 5.5 x 109/L 0.5 x 109/L or 5.5 x 109/L N/A

For 17 y: 10% or 80% For 17 y: 0.10 or 0.80 0.01

0.5 x 109/L or 4.5 x 109/L 0.5 x 109/L or 4.5 x 109/L N/A

REDACTED

REDACTED

/mm

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/mm3

REDACTED

3 (M)

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Confidential of 43

13.3.2 Blood chemistry parameters

Parameter UCB Conventional Units SI Units CFAST (SGOT) > 3 times of ULN > 3 times of ULN N/AALT (SGPT) > 3 times of ULN > 3 times of ULN N/AALP For 17 y: > 2 times of ULN, if normal range

adjusted to the age range; For 17 y: > 2 times of ULN, if normal range

adjusted to the age range; N/A

For 17 y: > 3 times of ULN For 17 y: > 3 times of ULNGGT > 3 times of ULN, if baseline value < 3 times of ULN > 3 times of ULN, if baseline value < 3 times of ULN N/ABUN > 30 mg/dL > 10.71 mmol/L 0.357Urea > 60 mg/dL > 10.02 mmol/L 0.167Creatinine For 17 y: > 1.5 mg/dL; For 17 y: > 132.6 umol/L; 88.4

For 17 y: > 2.0 mg/dL For 17 y: > 176.8 umol/LCreatinine clearance (calc)

For 12 y: 70 ml/min (Schwartz)(a) For 12 y: 70 ml/min (Schwartz)(a) N/A

For 12 y: 70 ml/min (Cockroft)(b) For 12 y: 70 ml/min (Cockroft)(b)

Total bilirubin

> 2.0 mg/dL > 34.2 umol/L 17.1

Glucose 50 mg/dL or 180 mg/dL 2.775 mmol/L or 9.99 mmol/L 0.0555

Total Protein For 1 m to 6 m: 3.6 g/dL or 7.8 g/dL For 1 m to 6 m: 36 g/L or 78 g/L 10

For 6 m to 17 y: 4.7 g/dL or 9.5 g/dL For 6 m to 17 y: 47 g/L or 95 g/L

For 17 y: 4.5 g/dL or 9.0 g/dL For 17 y: 45 g/L or 90 g/LAlbumin For 17 y: 2.4 g/dL or 6.5 g/dL For 17 y: 24 g/L or 65 g/L 10

For 17 y: 2.5 g/dL or 6.5 g/dL For 17 y: 25 g/L or 65 g/LGlobulin For 17 y: 1.2 g/dL or 5.0 g/dL For 17 y: 12 g/L or 50 g/L 10

For 17 y: 1.5 g/dL or 5.0 g/dL For 17 y: 15 g/L or 50 g/LSodium For 17 y: 120 mEq/L or 155 mEq/L For 17 y: 120 mmol/L or 155 mmol/L 1

For 17 y: 115 mEq/L or 155 mEq/L For 17 y: 115 mmol/L or 155 mmol/LPotassium For 17 y: 3.0 mEq/L or 6.5 mEq/L For 17 y: 3.0 mmol/L or 6.5 mmol/L 1

For 17 y: 3.0 mEq/L or 5.8 mEq/L For 17 y: 3.0 mmol/L or 5.8 mmol/LCalcium For 17 y: 7 mg/dL or 11.5 mg/dL For 17 y: 1.75 mmol/L or 2.875 mmol/L 0.25

For 17 y: 7 mg/dL or 15.5 mg/dL For 17 y: 1.75 mmol/L or 3.875 mmol/L

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adjusted to the age range;

and adjusted to the age range;

>an

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d any

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Confidential of 43

Uric Acid For < 12 y: 8 mg/dL For < 12 y: 475.84 umol/L 59.48

For 12 y: 8 mg/dL (F); 9.5 mg/dL (M) For 12 y: 475.84 umol/L (F); 565.06 umol/L (M)

Cholesterol 300 mg/dL 7.77 mmol/L 0.0259

HDL 25 mg/dL 0.65 mmol/L 0.0259

LDL 200 mg/dL 5.18 mmol/L 0.0259

Triglycerides 300 mg/dL 3.42 mmol/L 0.0114(a) Schwartz equation (patients <12): Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine (b) Cockroft equation (patients >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 0.85ALT=alanine aminotransferase; ALP=Alkaline phosphatase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CR CL=creatinine clearance; GGT=Gamma-glutamyl transpeptidase; HDL=High-density lipoprotein; LDL=low-density lipoprotein; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; ULN=Upper Limit of Normal.

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age) x body weight (kg)] / (72 x serum creatinine),

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Confidential of 43

13.3.3 Urinalysis

Qualitative urine parameters are generally reported by a descriptive score, which differs among laboratories. For data analysis purpose, a four-point scale is used. Five-point, six-point, or seven-point scales will be collapsed into a four-point scale first. A value is considered possibly clinically significant treatment emergent abnormal if an upward shift of at least 2 degrees from the baseline occurs under investigational treatment. To collapse the results in a five-point scale into a four-point scale, the lowest two positive results will be combined (see example below). For results reported with a scale of more than five-point, please consult your study physician for how to collapse into four-point scale.

Original Five-point Scale Four-point Scale

Negative/None Negative/NoneTrace/Rare/Mild/A Few Trace/1+/Rare/Mild/A Few1+2+/Mod 2+/Mod3+/Sev 3+/Sev

13.3.4 Vital signs and body weight

Pulse rate For 1 m to 12 m: <110 bpm and a decrease of > 20 bpm from baseline or > 180 bpm and an increase of > 20 bpm from baseline

For 12 m to 3 y: < 90 bpm and a decrease of > 20 bpm from baseline or > 150 bpm and an increase of > 20 bpm from baseline

For 3 y to 12 y: < 65 bpm and a decrease of > 20 bpm from baseline or > 130 bpm and an increase of > 20 bpm from baseline

For 12 y to 17 y: < 60 bpm and a decrease of > 20 bpm from baseline or > 120 bpm and an increase of > 20 bpm from baseline

For 17 y: < 50 bpm and a decrease of > 30 bpm from baseline or > 120 bpm and an increase of > 30 bpm from baseline

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Systolic blood pressure For 1 m to 12 m: < 60 mmHg and a decrease of > 20 mmHg from baseline or > 110 mmHg and an increase of > 30 mmHg from baseline

For 12 m to 6 y: < 70 mmHg and a decrease of > 20 mmHg from baseline or > 120 mmHg and an increase of > 30 mmHg from baseline

For 6 y to 13 y: < 70 mmHg and a decrease of > 20 mmHg from baseline or > 130 mmHg and an increase of > 30 mmHg from baseline

For 13 y and 17 y: < 90 mmHg and a decrease of > 20 mmHg from baseline or > 140 mmHg and an increase of > 30 mmHg from baseline

For 17 y: < 90 mmHg and a decrease of > 30 mmHg from baseline or > 180 mmHg and an increase of > 40 mmHg from baseline

Diastolic blood pressure For 1 m to 12 m: < 40 mmHg and a decrease of > 15 mmHg from baseline or > 60 mmHg and an increase of > 20 mmHg from baseline

For 12 m to 6 y: < 45 mmHg and a decrease of > 15 mmHg from baseline or > 80 mmHg and an increase of > 20 mmHg from baseline



For 17 y: < 50 mmHg and a decrease of > 20 mmHg from baseline or > 105 mmHg and an increase of > 30 mmHg from baseline

Weight For 17 y: < 3% or 97% of the normal body weight growth curve ranges for the age at date of weight assessment (a) and gender;

For 17 y: change of 7% of baseline weight(a) Once the subject reaches 17 years of age use the body curve criteria of a 17 year old regardless of their age in the study.

REDACTED 6 y

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14 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN

Rational for the amendment

The primary purpose for the amendment is (1) remove rules and definitions based on data cutoffs for interim analyses; (2) remove the summary analysis for direct cost parameter and indirect cost parameters, and as well as Socio-professional data.

Change #1 (global)

Removed all rules and definitions based on data cutoffs for interim analyses throughout SAP.

Change #2

Section 8.2.6 Direct cost parameters, Section 8.2.7 Indirect cost parameters, Section 8.2.8 Socio-professional data

Removed all direct/indirect cost parameters and socio-professional data summary analysis.

Change #3

Removed signature page. Using e-signature approval process through Mikado.

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statistical analysis plan (sap)laboratory tests (blood chemistry, hematology, and urinalysis) vital...

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