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I. SYNOPSIS: Protocol 1 blinded
Date and Version # of
Protocol Synopsis:
6 December 2012
Sponsor: Sponsor name blinded
Protocol Number: Protocol 1 blinded
Name of Study Drug: IMP (combination Drug A
and Drug B)
Phase of Development: Phase 3
Title of Study A randomized, double-blind, parallel-group, placebo and active
controlled, multicenter study to evaluate the efficacy, safety and
tolerability of combinations of Drug A and Drug B x dose and 2x
dose compared to Drug A and Drug B monotherapy in the
treatment of overactive bladder (Protocol 1 blinded)
Planned Study Period First subject in: Q4 2013
Last subject out: Q4 2014
Study Objective(s) Primary objective:
To evaluate the efficacy of 2 dose combinations of Drug A and
Drug B compared to Drug A and Drug B monotherapy
Secondary objectives:
To evaluate the efficacy of 2 dose combinations of Drug A and
Drug B compared to placebo
To evaluate the safety and tolerability of 2 dose combinations of
Drug A and Drug B compared to Drug A and Drug B monotherapy
and placebo
To evaluate the HEOR outcomes of 2 dose combinations of
Drug A and Drug B compared to Drug A and Drug B monotherapy
and placebo
To investigate the population pharmacokinetics and
pharmacokinetic/pharmacodynamic relationship of 2 dose
combinations of Drug A and Drug B with Drug B and Drug A
monotherapies
Planned Total Number
of Study Centers and
Location
Approximately 350 centers in approximately 45 countries
worldwide (North and South America, Europe, Africa and Asia
Pacific).
Design and Methodology
This is a multinational, multicenter, randomized, double-blind,
parallel-group, placebo and active controlled phase 3 study.
The study will comprise a single-blind, 4-week placebo run-in
period followed by a randomized, double-blind, placebo and active
controlled, 12-week treatment period followed by a single-blind, 2-
week placebo run-out period. Subjects will visit the clinic at
screening (Visit 1), at the end of the placebo run-in period (Visit
2), after 4, 8 and 12 weeks of double-blind treatment (Visit 3, 4
and 5) and 2 weeks after end of double-blind treatment, for a
follow-up visit (Visit 6).
Screening
Informed consent will be obtained before performing any study
related procedures. Subjects will undergo eligibility screening,
including safety labs, physical examination, pregnancy test (female
subjects of childbearing potential), post-void residual volume
(PVR), vital signs, ECG and urinalysis.
Run-in Period
Subjects meeting the screening inclusion/exclusion criteria will
begin a 4-week placebo run-in period. During this period, subjects
will be asked to complete a micturition diary (including 5
consecutive days prior to the next visit for vital signs). The first
two weeks will serve as a wash-out period for subjects previously
treated with OAB medication and a training diary will be
completed to check willingness and ability to complete diaries.
The micturition diary that is completed during the second two
weeks will be used to establish baseline data.
Randomization
Following the completion of the run-in phase, eligible subjects will
be randomized 2:2:1:1:1:1 to one of the following treatment arms
respectively:
Drug A + Drug B x mg
Drug A + Drug B 2x mg Placebo
Drug A
Drug B x mg
Drug B 2x mg
Randomization will be stratified by gender, age group (<65 years,
≥65 years), previous OAB treatment (yes, no) and geographic
region.
Treatment Period
The duration of the double-blind treatment phase is 12 weeks.
Follow-up Period
Following the completion (or the early termination) of the
treatment phase, subjects will enter the single blind, 2-week
placebo run-out period (follow-up period). Subjects will not take
any OAB treatment during the follow-up period. Safety
assessments will be performed at the follow-up visit.
Study Committees
Two adjudication committees for the independent evaluation of
cardiovascular SAEs (including deaths) and potential neoplasms
that have occurred during the study will be installed.
Number of Subjects
Planned
3392 randomized subjects
No more than 25% of subject should be treatment naïve, i.e.
have not received previous pharmacological treatment for OAB.
Selection Criteria
Inclusion/Exclusion Criteria:
Inclusion:
At screening (visit 1):
1. Subject is male or female and at least 18 years of age;
2. Institutional Review Board (IRB)-/Independent Ethics
Committee (IEC)-approved written Informed Consent (IC) and
privacy language as per national regulations has been obtained
from the subject or legally authorized representative prior to any
study-related procedures (including discontinuation of prohibited
medication, if applicable);
3. Subject is willing and able to complete the micturition diary and
questionnaires correctly and able to measure his/her vital signs at
home at stipulated time points, using the device provided by the
study personnel, and to adequately record the readings;
4. Subject has symptoms of “wet” OAB (urinary frequency and
urgency with incontinence) for at least 3 months;
At randomization (visit 2):
5. Subject continues to meet all inclusion criteria of visit 1;
6. Subject has a micturition frequency of on average ≥ 8 times per
24-hour period during the last 7 days of the micturition period
(incontinence episode should not be counted as a micturition);
7. Subject has experienced at least 3 incontinence episodes during
the last 7 days of the micturition diary period;
8. Subject has experienced at least 1 urgency episode (grade 3 or 4
on Patient Perception of Intensity of Urgency Scale [PPIUS]) per
24-hour period during the 7-day micturition diary period.
Exclusion:
Subjects will be excluded from participation if any of the
following apply:
At screening (visit 1):
1. Female subject is either not:
• post-menopausal (defined as at least 1 year without any menses)
prior to Screening or
• premenarchal prior to Screening or
• documented surgically sterile or status post hysterectomy (at least
1 month prior to Screening) or
• if of childbearing potential, must have a negative urine pregnancy
test at Screening and must be using highly effective
contraception1. All females of childbearing potential will be
required to use highly effective contraception consisting of two
forms of birth control (one of which must be a barrier method)
starting at Screening and throughout the study period and for 28
days after final study drug administration;
2. Female subject is breastfeeding at Screening or during the study
period and for 28 days after final study drug administration;
3. Female subject is donating ova starting at Screening and
throughout the study period and for 28 days after final study drug
administration;
4. Male subjects and their female spouses/partners who are of
childbearing potential are not using highly effective contraception1
consisting of two forms of birth control (one of which must be a
barrier method) starting at Screening and continue throughout the
study period and for 28 days after final study drug administration;
5. Male subject is donating sperm starting at Screening and
throughout the study period and for at least 28 days after final
study drug administration;
6. In the opinion of the investigator the subject has clinically
significant bladder outflow obstruction at risk of urinary retention;
7. Subject has significant PVR volume (> 150 mL);
8. Subject has significant stress incontinence or mixed
stress/urgency incontinence where stress is the predominant factor
as determined by the Investigator (for female subjects confirmed
by a cough provocation test [Appendix 7);
9. Subject has an indwelling catheter or practices intermittent self-
catheterization;
10. Subject has evidence of urinary tract infection, chronic
inflammation such as interstitial cystitis, bladder stones, previous
pelvic radiation therapy or previous or current malignant disease of
the pelvic organs;
11. Subject has had intravesical treatment in the past 12 months
with e.g., botulinum toxin, resiniferatoxin, capsaicin;
12. Subject has uncontrolled narrow angle glaucoma, urinary or
gastric retention, severe ulcerative colitis or Crohn’s Disease, toxic
megacolon, myasthenia gravis or any contraindications against the
use of anticholinergics;
13. Subject has clinically significant cardiovascular or
cerebrovascular diseases within 6 months prior to Screening, such
as myocardial infarction, uncontrolled angina, significant
ventricular arrhythmias, heart failure, stroke and severe cardiac
failure (NYHA class > 3);
14. Subject has a QTcF interval > 450 msecs for males or > 470
msecs for females or is at risk of QT prolongation (e.g., family
history of long QT syndrome, hypokalaemia);
15. Subject has clinically significant abnormal 12-lead ECG;
16. Subject has severe hypertension which is defined as a sitting
average systolic blood pressure ≥ 180 mm Hg and/or an average
diastolic blood pressure ≥ 110 mm Hg;
17. Subject has moderate to severe hepatic impairment (Child-
Pugh class B or C)
18. Subject has severe renal impairment or end stage renal disease
defined as eGFR<30 ml/min/1.73 m2
19. Subject has a concurrent malignancy or history of cancer (with
the exception of completely excised basal cell or squamous cell
carcinoma of the skin) within the last 5 years prior to screening.
Subjects with a history of cancer are considered eligible if the
subject has undergone therapy and the subject has been considered
disease free for at least 5 years;
20. Subject is receiving current non-drug treatment for OAB
including electrostimulation therapy (with the exception of a
bladder training program or pelvic floor exercises which started
more than 30 days prior to Screening);
21. Subject is using medications intended to treat OAB or
prohibited medications. Subject is excluded if using restricted
medications under conditions different to those specified in section
Concomitant Medication (Section 5.1.3.2);
22. Subject has known or suspected hypersensitivity to Drug A,
Drug B or any of their excipients;
23. Subjects with current or history of alcohol and/or drug abuse;
24. Subject has any clinically significant condition which in the
opinion of the investigator makes the subject unsuitable for the
study;
25. Subject who has participated in any interventional clinical
study or has been treated with any investigational drugs within 30
days prior to the initiation of Screening. If local regulations
stipulate a longer period, such local regulations should take
precedence;
26. Subject is an employee of the Sponsor Group, third parties
associated with the study or the clinical study site team.
At randomization (visit 2):
27. Subject fulfills any exclusion criteria of Visit 1;
28. Subject has evidence of a UTI (urine culture containing >
100,000 cfu/ml). The subject can be rescreened after successful
treatment of the UTI (confirmed by a laboratory result of negative
urine culture);
29. Subject had an average total daily urine volume > 3000 mL as
recorded in the micturition diary period;
30. Subject has serum creatinine > 150 umol/L, AST and/or ALT >
2x upper limit of normal range (ULN), or γ-GT > 3x ULN),
or total bilirubin > 2 ULN as assessed in screening visit (V1)
samples;
31. Subject has severe hypertension which is defined as a sitting
average systolic blood pressure ≥ 180 mmHg and/or an average
diastolic blood pressure ≥ 110 mmHg.
1 Highly effective contraception is defined as:
• Established use of oral, injected or implanted hormonal methods of
contraception.
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
Discontinuation Criteria There are no discontinuation criteria that mandate discontinuation
of a subject. Potential discontinuation criteria are specified in
section 3.4.
Test Drug Dose:
Mode of Administration:
Duration of Treatment:
Combination of Drug A + 2x mg Drug B
Oral tablets, QD
12 weeks
Reference Therapy
Dose:
Mode of Administration:
Duration of Treatment:
Placebo (3 different tablets; matching Drug A, matching Drug
B x mg and matching Drug B 2x mg)
Drug A
Drug B x mg
Drug B 2x mg
Oral tablets, QD
12 weeks (+ 4 weeks placebo run-in + 2 weeks placebo run-out)
Concomitant Medication Prohibited medications
Medications prohibited during the placebo run-in period and
double-blind treatment period include drugs used for the treatment
of OAB other than the study drugs (including intravesical
treatment) and other drugs that influence efficacy or act as
CYP2D6 substrates with a narrow therapeutic margin.
The subject must stop taking prohibited medications at least 2
weeks prior to the start of the placebo run-in period.
Restricted medications
Medications restricted during the placebo run-in period and
double-blind treatment period include medications on a long-term
base which may not be stopped, started or changed in dose within
this time period, because they may affect efficacy and/or safety
variables. Use of these medications is permitted provided the
subject has been taking the medication on a long-term basis, i.e.,
has not stopped, started or changed dose within the 30 days prior
to entering the study, the subject remains on the medication at the
same dose during the course of the placebo run-in period and the
double-blind treatment period and the subject is monitored
carefully for adverse events (AEs) possibly resulting from drug
interactions.
Primary Variables
Rate of incontinence episodes at End of Treatment
Secondary Variables
Key Secondary Efficacy Variables
Change from baseline to end of treatment in:
-VAS)
Questionnaire (OAB-q)
Other Secondary Efficacy Variables
after 4, 8 weeks of treatment)
uritions at
secondary time points (i.e., after 4, 8 weeks of treatment)
(grade 3 and/or 4)/24h (PPIUS scale)
used
incontinence episodes compared to baseline and MID reached
(improvement by at least 10 points) on the Symptom Bother scale
of the OAB-q questionnaire
n in number of
incontinence episodes compared to baseline and MID reached
(improvement by at least 10 points) on the HRQL Total score of
the OAB-q questionnaire
incontinence episodes compared to baseline and more than 1 point
improvement from baseline in PPBC
incontinence episodes compared to baseline, MID reached
(improvement by at least 10 points) on the Symptom Bother scale
of the OAB-q questionnaire, and more than 1 point improvement
from baseline in PPBC
incontinence episodes compared to baseline, MID reached
(improvement by at least 10 points) on the HRQL Total score of
the OAB-q questionnaire, and more than 1 point improvement
from baseline in PPBC
responder is defined as a subject with 0 incontinence episodes
post-baseline
Episodes: A responder is defined as a subject with a ≥ 50%
decrease from baseline in mean number of incontinence episodes
per 24 hours
a subject who had more than 8 micturitions per 24 hours at
baseline and at most 8 micturitions per 24 hours post-baseline
HEOR Variables
Condition (PPBC)
in PPBC
baseline in PPBC
OAB-q at other time points
assessed by the OAB-q (including subscales)
bother and health related quality of life scores as assessed by
OAB-q: A responder is defined as a subject with at least 10 points
improvement from baseline to End of Treatment
Quality of Life in 5 Dimensions (EQ-5D) questionnaire (including
subscales)
rk
Productivity and Activity Impairment: Specific Health Problem
(WPAI:SHP) questionnaire
-VAS at
other time points
Safety Variables
Incidence and severity of treatment emergent adverse events
Vital signs: sitting systolic and diastolic blood pressure and
pulse rate
Physical examination
Laboratory tests: hematology, biochemistry and urinalysis
ECG parameters
Post-void residual volume (PVR)
Pharmacokinetics /
Pharmacodynamics
PK and PK/PD analysis will be performed to study the relationship
between Drug A/Drug B exposures and efficacy and safety
Statistical Methods Sample Size Justification Using a 2:1 randomization ratio, a number of 558 subjects in each
combination treatment arm and 279 subjects in each of the
monotherapy and placebo arms provides 90% power to detect a
reduction of the rate of incontinence episodes over each
monotherapy component in the Drug A + Drug B combination
groups by at least 25% at a two-sided significance level of 0.05.
This sample size calculation is based on an analysis by Poisson
regression, using an over-dispersion factor of 2.75 and an expected
rate of 4.00 incontinence episodes in the comparator arm at End of
Treatment. Since the combination treatment groups will be
compared vs. both components, the combined power for both tests
will be at least 81% (assuming independence and a similar effect
size of the combination groups over each monotherapy).
Using a 2:1 randomization ratio, a number of 762 subjects in each
combination treatment arm and 381 subjects in each of the
monotherapy and placebo arms provides 90 % power to detect a
reduction of 0.55 in the mean number of micturitions/24 h over
each monotherapy component in the Drug A + Drug B
combination groups at a two-sided significance level of 0.05. A
standard deviation of 2.7 was assumed. Since the combination
treatment groups will be compared vs. both components, the
combined power for both tests will be at least 81% (assuming
independence and a similar effect size of the combination groups
over each monotherapy).
Since change from baseline in mean number of micturitions is a
key secondary variable, the sample size (762/381 subjects per arm)
is chosen to ensure sufficient power to test this endpoint. This
results in a power of more than 90% for the testing of the primary
efficacy variable.
If one of the combination dose groups is not superior to
monotherapy for mean volume voided per micturition, then the
trial has more than 80% power to test the change from baseline in
mean number of micturitions at a two-sided 0.025 significance
level.
Assuming a drop-out of 10% after randomization, approximately
3392 subjects need to be randomized.
Efficacy The primary analysis set for efficacy analyses will be the Full
Analysis Set (FAS) which comprises randomized subjects who
took at least one dose of study drug and who have a micturition
measurement at baseline, at least one post-baseline micturition
measurement, and at least one incontinence episode at baseline.
The rate of incontinence episodes from the continuous micturition
diary period will be analyzed in a mixed effect Poisson regression
model with treatment group, age group, gender, previous OAB
treatment, and geographic region as factors and rate of
incontinence episodes at baseline as covariate. Rate ratios of the
combination treatment groups vs. each component (primary
comparisons) and the rate ratios between the active treatment
groups and placebo (secondary comparisons) will be calculated
together with 95% confidence intervals (CI) and p-values.
Change from baseline in mean volume voided per micturition,
mean number of micturitions per 24 hours, subject’s assessment of
TS-VAS, and symptom bother as assessed by OAB-q will be
analyzed in an Analysis of Covariance (ANCOVA) model with
treatment group, gender, age group, previous OAB treatment, and
geographic region as fixed factors and baseline value as covariate.
The ANCOVA will present Least Square (LS) means and two-
sided 95% CIs for mean changes from baseline within each
treatment group. Differences in LS means between the
combination treatment groups and their components (primary
comparisons) and the differences in LS means between the active
treatment groups and placebo (secondary comparisons) will be
derived together with 95% CIs and p-values.
Adjustment for multiplicity within the primary variable of rate of
incontinence episodes from the micturition diary will be done at
the 0.05 level using a hierarchical testing procedure. In stage 1, the
Drug A + Drug B 2x mg combination group will be tested vs.
each component. If Drug A + Drug B 2x mg is superior to each
component, the Drug A + Drug B x mg combination group will be
tested vs. each component.
If Drug A + Drug B 2x mg is not superior vs one of the
components, the Drug A + 25 mg Drug B x mg combination will
be tested vs. each component at the 0.025 level.
If at least one combination group is superior vs. both components,
then a hierarchical testing procedure will be utilized to control the
type 1 error rate for the key secondary variables at 0.05. Only
those combination groups reaching statistical significance for the
primary variable will be further tested. In stage 1, mean volume
voided will be tested first for the Drug A + Drug B 2x mg
combination group vs. each component, followed by Drug A +
Drug B x mg combination group vs. each component if applicable.
If both combination groups demonstrate superiority to each
component at the 0.05 level, both will proceed to the next stage. If
only one group reaches statistical significance, only this group will
proceed to the next stage and will be tested there at an 0.025 level.
If no combination group reaches statistical significance, then no
further testing will be performed.
In stage 2, first the Drug A + Drug B 2x mg combination group,
followed by the Drug A + Drug B x mg combination group (as
applicable) will be tested vs. each component for mean number of
micturitions per 24 hours in the same way as in stage 1. In stages 3
and 4, change from baseline in symptom bother as assessed by the
OAB-q and change from baseline in subject’s assessment of TS-
VAS will be tested as described for stage 1.
Other secondary variables will be analyzed using the same
ANCOVA model as for change from baseline in mean number of
micturitions per 24 hours except variables based on incontinence
or nocturia episodes and pad use which will be analyzed using the
mixed effect Poisson regression model as described above.
Responder analyses will be performed using a logistic regression
model including the same factors as the ANCOVA model.
A Last Observation Carried Forward (LOCF) approach will be
used to impute missing values for efficacy assessments at Week
12. No multiplicity adjustments will be made for the comparisons
vs placebo.
Safety Safety analyses will be performed for the Safety Analysis Set
which comprises all subjects who received at least one dose of
double-blind study medication.
Change from baseline in vital sign variables will be analyzed using
the same ANCOVA model as described for the analysis of change
from baseline in mean number of micturitions per 24 hours. 95%
CIs will be presented for differences between active treatment
groups and placebo. No p-values will be calculated. All other
safety data will be analyzed descriptively.
Interim Analyses Not applicable.
Table 1: Schedule of Assessments
Placebo run-in (1)
Screening
Randomization
Double-blind
treatment
Follow up / Placebo
run-out (2)
Visit 1 Telephone
Visit
Day -14
2 3 4 5 6
Week -4/-2 0 4 8 12 14
Day -28 1 29 57 85 99
Permissible range relative to Visit 2 -35 to
-28 Baseline 26 to
32
54 to
60
82 to 88 99-106
Procedures
Subject information and informed consent
(3)
X
Demographics / Medical history / OAB
history
X
Medication history and OAB treatment
history (drug & non-drug)
X
Cough provocation test (women only) X
Inclusion/exclusion criteria check X X
Study medication dispensing X X X X
Study drug compliance check X X X X
Concomitant medication X X X X X X
Instruction on diary completion X X X X X
Diary and questionnaire review with subject
X X X X X
Safety
Assessment of adverse events X X X X X X
Hematology & biochemistry X X X X X X
Urinalysis (4) X X X X X X
Physical examination X X
Pregnancy test (β-HCG in serum) X X X X X X
Vital signs on site (5) X X X X X X
Vital signs at home (6) X X X X X X
PVR (ultrasonography or bladder scan) X X X X X X
12-lead ECG X X X X X X
Efficacy and pharmacokinetics
Micturition diary to be completed prior to
the visit (7)
X X X X X
OAB-q questionnaire X X X X
PGI C X
PPBC questionnaire X X X X
TS-VAS X X X X
EQ-5D questionnaire X X X X
WPAI:SHP questionnaire X X
Blood sampling for population PK X X X
(1) A training diary will be completed during the first two weeks of the placebo run-in period to allow the subject to get
acquainted to the electronic diary. At the end of the training diary completion a telephone visit will take place during
which the completion of the micturition diary will be evaluated. In the second two weeks of the placebo run-in period, after the telephone visit has taken place, the baseline micturion diary will be completed.
(2) A follow-up (FU) visit will be performed at least 2 weeks after Visit 5 (or earlier, i.e. 2 weeks after last medication
intake, if subjects terminate the treatment phase early). For subjects that terminate the treatment phase early, the
placebo run-out is not applicable. (3) Written informed consent should be obtained ultimately at the Screening Visit (Visit 1) and prior to the execution of
any study–related assessments.
(4) Urinalysis will be performed with a dipstick. If positive for nitrite, then sediment will be performed. If the sediment
results indicate a possible urinary tract infection (UTI), then a urine culture will be performed. If a UTI is seen at Screening, the subject cannot be randomized. If the UTI is successfully treated rescreening is allowed.
(5) Vital signs (blood pressure [BP] and pulse rate [PR]) will be measured on site with the site's standard office measuring
device.
(6) Vital signs (BP and PR) will be recorded by the subject at home during 5 consecutive days prior to the visit. (7) The micturition diary should be completed on a continuous basis:
The number of incontinence episodes should be recorded every day
The number of micturitions and urgency scores should be recorded for 7 consecutive days prior to the next visit
The volume voided should be recorded for 3 consecutive days prior to the next visit