I. SYNOPSIS: Protocol 1 blinded - Amazon Web Servicessurveygizmolibrary.s3.amazonaws.com/library/55348/... · I. SYNOPSIS: Protocol 1 blinded Date and Version # of Protocol Synopsis:

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