Clinical trial NCT03492281
Conditions: Overactive Bladder
Keywords: Beta-3 adrenergic receptor (β3-AR) agonists Incontinence OAB Vibegron Urge urinary incontinence Urinary bladder, overactive Urologic Diseases Lower Urinary Tract Symptoms Urological Agents
Sponsor: Urovant Sciences GmbH
Start date: 2018-03-26; Completion date: 2019-02-04
Enrollment: 1530 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the safety, tolerability, and efficacy of vibegron administered once daily in patients with OAB.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: vibegron intervention 2: Vibegron placebo intervention 3: Tolterodine Tartrate ER intervention 4: Tolterodine placebo
Intervention descriptions: intervention 1: single daily oral dose of vibegron 75 mg for 12 weeks intervention 2: placebo to match vibegron (experimental drug) intervention 3: single daily oral dose of tolterodine tartrate ER 4 mg for 12 weeks intervention 4: placebo to match tolterodine (active comparator)

Protocol documents:
Prot_000.pdf: 
Confidential 
Page | 1 
CLINICAL STUDY PROTOCOL 
Study Title: 
An International Phase 3, Randomized, Double-Blind, Placebo- and Active 
(Tolterodine)-Controlled Multicenter Study to Evaluate the Safety and 
Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder 
Protocol Number: 
RVT-901-3003 
Compound Name and/or 
Number: 
Vibegron 
Indication 
Treatment of Overactive Bladder 
Sponsor: 
Urovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Development Phase: 
3 
Regulatory Identifier(s): 
IND# 106,410 
EudraCT# 2017-003293-14 
Current Version and 
Effective Date: 
Version 3.0; 15 NOV 2018 
Previous Version(s) and 
Effective Date(s): 
Version 2.1; 12 FEB 2018 
Version 2.0; 30 JAN 2018 
Version 1.2; 01 NOV 2017 
Version 1.1; 05 OCT 2017 
Version 1.0; 29 SEP 2017 
Study Director: 
, 
 
, Clinical Development 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under 
control of Urovant Sciences GmbH, and is provided to you in confidence as an investigator, potential 
investigator or consultant, for review by you, your staff, and an applicable Institutional Review Board or 
Independent Ethics Committee.  The information is only to be used by you in connection with authorized 
clinical studies of the investigational drug described in the protocol.  You will not disclose any of the 
information to others without written authorization from Urovant Sciences GmbH. except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 
NCT Number: NCT03492281
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
Confidential 
Page | 2 
SUMMARY OF CHANGES 
Version
Location 
Description of Change 
3.0 
Global 
Minor typographical/formatting errors were corrected. 
3.0 
1; 3; 9.3.1 
The key secondary efficacy endpoints were reordered.  The 
following one key secondary efficacy endpoint was added: 
 Percent of OAB Wet patients with a 100% reduction from 
baseline in UUI episodes per 24 hours at Week 12 
The following four key secondary efficacy endpoints were 
removed (moved to and combined under exploratory endpoints): 
3.0 
1; 3; 9.3.1 
The following additional secondary endpoint was removed: 
3.0 
1; 3; 9.3.1 
Exploratory endpoints were reordered and analysis timepoints 
were updated for some endpoints.  The following endpoints were 
added: 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
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Page | 3 
Version
Location 
Description of Change 
The following exploratory endpoints were removed: 
3.0 
1.1 
Removed the phrase “and adverse events deemed related to 
Study Procedures” from footnote #15 (all adverse events are 
recorded). 
3.0 
7.8; 8.3.1 
For consistency with the adverse collection window, removed 
language indicating that adverse events from time of informed 
consent to first dose of study treatment should be recorded as 
medical history. 
3.0 
9.2.2 
For consistency with the updated key secondary endpoints, one 
objective/hypothesis was added, four key secondary 
objectives/hypotheses were deleted, and the 
objectives/hypotheses were reordered and renumbered 
accordingly. 
2.1 
Global 
Minor typographical/formatting errors were corrected. 
2.0 
Cover page 
Add Basel address; changed study director contact. 
2.0 
Global 
Minor typographical/grammatical errors were corrected. 
2.0 
Global 
Tables were renumbered sequentially without a chapter number 
included as part of the table number in the main body, and an 
appendix letter was added as part of the table numbering within 
the appendices. 
2.0 
Medical Contact / 
Sponsor Information Page 
Change 
 email to 
; change 
 to 
, to reflect new company 
names. 
2.0 
Table of Contents 
Updated all page numbers; edited Section 5.4 and 5.4.1 from 
“Discontinuation” to “Interruption”, deleted “Withdrawal from 
the Study”. 
2.0 
1; 3; 9.3.1 


Clinical Study Protocol 
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Version
Location 
Description of Change 
2.0 
1; 3; 9.2.2; 9.3.1; 9.5.1 
Change of 5% in response efficacy endpoint (70 to 75%; Percent 
of OAB Wet patients with a 75% reduction from baseline in UUI 
episodes per 24 hours at Week 12). 
2.0 
1; 2.1 
Addition of (RVT-901) after Vibegron to align with Certificate 
of Analysis for product. 
2.0 
1; 3; 9.5.1 
2.0 
1.1 
Updated Schedule of Activities and visit events to reflect 
protocol text; updated and realigned footnotes accordingly. 
2.0 
1.1; 8.3.1 
Update language around timing of data collection for AE and 
SAE. 
2.0 
1; 5.1.1; 7.10 
Change days of screening compliance from 6 to 5. 
2.0 
5.4; 5.4.1 
Replaced “discontinued” with “interrupted”; reversed order of 
sentences. 
2.0 
6.6 
Removed study medication rechallenge in patients with a grade 
3 or higher drug-related AE reported.   
2.0 
7.3 
Moved Visit Reminders to 7.12. 
2.0 
7.10; 7.10.1 
Updates to Patient Voiding Diary instructions, training, and 
description. 
2.0  
7.11; 7.11.1; 7.11.2 
Updates to Urine Volume Collection instructions, training, and 
description. 
2.0 
7.12 
Update to instructions on Reminders for Diary Collection. 
2.0 
7.13; 7.13.1; 7.13.2 
Updates to Electronic Diary instructions and training. 
2.0 
7.26.1 
Deletion of data collection of food/meal intake prior to 
PK sampling. 
2.0 
8.6 
Updated MACCE language to match CAC Charter. 
2.0 
8.7 
Addition of timeframe around pregnancy and infant outcome. 
1.2 
Global 
Minor typographical/grammatical errors were corrected. 
1.2 
Sponsor Signature Page 
Minor wording update to sentence:  This protocol has been 
approved by a representative of Urovant Sciences GmbH. 
1.2 
1; 5.1.1 
Inclusion criterion updated:  #4 updated for OAB Wet criteria 
from “Screening diary” to “previous visit diary”; #5 updated to 
reflect wording in Section 5.2.1. 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
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Version
Location 
Description of Change 
1.2 
1; 5.1.2 
-powered field in a 
spun specimen and/” was removed from Exclusion criterion #8. 
1.2 
1; 5.1.2 
Exclusion added for narrow angle glaucoma. 
1.2 
1.1 
Footnotes were updated to include:  a note that paper diaries may 
be used; clarification that pelvic exams may be part of the 
physical exam; clarification that urinalysis will be performed if 
there is a positive dipstick result; FSH removed from chemistry.  
1.2 
1.1; 7.5 
The timing for collection of paper diaries (if used) was added. 
1.2 
1.1; 7.5.2; 7.5.3 
References to the Week 2 timepoint as a visit were reworded to 
clarify that a study visit does not occur at Week 2. 
1.2 
6.1 
“Tablet” or “capsule” descriptors were added to Table 3 
(formerly numbered as Table 6-1). 
1.2 
6.2 
Wording was added to indicate the study treatment should be 
swallowed whole; Wording was added to require a witnessed 
dose at the clinic at Run-In and Baseline Visits; PK sub-study 
language was changed to collect pre-dose; dispense study 
medication was language was combined.   
1.2 
7.5.4 
PK sub-study language was changed to hold dose on morning of 
study visit to collect pre-dose PK. 
1.2 
7.18.1 
PK sub-study language was changed to collect pre-dose PK. 
1.2 
7.12.1 
The Follicle Stimulating Hormone test was removed from the list 
of laboratory tests performed. 
1.2 
7.16 
Clarified that tablet/capsule count will be recorded in the 
interactive voice or web response system rather than case report 
form. 
1.2 
8.6 
Added adverse events suggestive of cystitis or urinary tract 
infection and moved liver test values to end of list. 
1.1 
5.2.1 
Changes were made to description of contraception requirements 
and methods for female patients. 
1.1 
7.5 
Plan to use a paper diary as backup was added. 


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SPONSOR SIGNATURE PAGE 
Study Title:  An International Phase 3, Randomized, Double-Blind, Placebo- and Active 
(Tolterodine)-Controlled Multicenter Study to Evaluate the Safety and Efficacy of Vibegron in 
Patients with Symptoms of Overactive Bladder 
Protocol Number:  RVT-901-3003 
This protocol has been approved by a representative of Urovant Sciences GmbH.  The following 
signature documents this approval. 
 
 
 
 
 Clinical Development 
 
 
 


Clinical Study Protocol 
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Urovant Sciences GmbH 
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MEDICAL CONTACT/SPONSOR INFORMATION PAGE 
Sponsor Medical Contact/Serious Adverse Event Contact Information: 
Role 
Name 
Day Time 
After-Hours 
Primary 
Medical 
Monitor 
Office:
Mobile:
Fax:
E-mail:  
Office: 
Mobile: 
Fax: 
E-mail:  
Secondary 
Medical 
Monitor 
Office: 
Mobile:
Fax: 
E-mail: 
Office: 
Mobile:
Fax:
E-mail:  
 
Contact for Serious 
Adverse Events (SAEs) 
Email:  
 
Phone:  
 
Fax:  
 
 
Study Sponsor: 
This study is sponsored by Urovant Sciences GmbH. 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
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INVESTIGATOR STATEMENT 
 I confirm agreement to conduct the study in compliance with the protocol. 
 I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
 I agree to ensure that all associates, colleagues, and employees assisting in the 
conduct of the study understand their obligations and will comply with the study 
protocol.  Mechanisms are in place to ensure that site staff receives the appropriate 
training and information throughout the study. 
 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
Date 
 
Site 
 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES ...........................................................................................................2 
SPONSOR SIGNATURE PAGE ....................................................................................................6 
MEDICAL CONTACT/SPONSOR INFORMATION PAGE ........................................................7 
INVESTIGATOR STATEMENT ...................................................................................................8 
1. 
SYNOPSIS .................................................................................................................15 
1.1. 
Schedule of Activities .................................................................................................25 
2. 
INTRODUCTION ......................................................................................................31 
2.1. 
Indication ....................................................................................................................31 
2.2. 
Background .................................................................................................................31 
2.3. 
Non-clinical Safety Summary .....................................................................................32 
2.4. 
Summary of Relevant Clinical Experience with Vibegron ........................................33 
2.4.1. 
Efficacy .......................................................................................................................33 
2.4.2. 
Safety and Tolerability ...............................................................................................34 
2.4.3. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism .....................................36 
2.5. 
Study Rationale ...........................................................................................................36 
2.6. 
Dose Rationale ............................................................................................................36 
2.7. 
Information on Other Study-Related Therapies .........................................................37 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................38 
4. 
INVESTIGATIONAL PLAN .....................................................................................42 
4.1. 
Overall Study Design ..................................................................................................42 
4.2. 
Treatment Arms and Duration ....................................................................................44 
4.3. 
Number of Participants ...............................................................................................44 
4.4. 
Definition of Study Completion by a Patient .............................................................44 
4.5. 
End of Study Definition ..............................................................................................44 
5. 
STUDY POPULATION .............................................................................................45 
5.1. 
Eligibility Criteria .......................................................................................................45 
5.1.1. 
Inclusion Criteria ........................................................................................................45 
5.1.2. 
Exclusion Criteria .......................................................................................................46 
5.2. 
On-Study Restrictions .................................................................................................48 
5.2.1. 
Contraception ..............................................................................................................48 
5.2.1.1. 
Female Patients ...........................................................................................................48 


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5.2.2. 
Meals and Dietary Restrictions ...................................................................................49 
5.3. 
Screen Failure .............................................................................................................49 
5.4. 
Interruption of Study Treatment .................................................................................50 
5.4.1. 
Temporary Interruption ..............................................................................................50 
5.4.2. 
Rechallenge .................................................................................................................50 
5.5. 
Withdrawal from the Study ........................................................................................50 
5.6. 
Lost to Follow Up .......................................................................................................50 
5.7. 
Early Study Termination .............................................................................................51 
6. 
STUDY TREATMENT ..............................................................................................52 
6.1. 
Study Treatments Description ....................................................................................52 
6.2. 
Administration of Study Treatments ..........................................................................52 
6.3. 
Study Treatment Assignment .....................................................................................53 
6.4. 
Blinding ......................................................................................................................53 
6.4.1. 
Unblinding ..................................................................................................................53 
6.5. 
Dose Modification ......................................................................................................54 
6.6. 
Treatment Discontinuation and Rechallenge ..............................................................54 
6.7. 
Packaging and Labeling ..............................................................................................54 
6.8. 
Preparation/Handling/Storage/Accountability ............................................................54 
6.9. 
Study Treatment Compliance .....................................................................................55 
6.10. 
Study Treatment Overdose .........................................................................................55 
6.11. 
Treatment after the End of the Study ..........................................................................55 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................56 
7.1. 
Order of Assessments .................................................................................................56 
7.2. 
Scheduling Visits ........................................................................................................56 
7.3. 
Unscheduled Visits .....................................................................................................56 
7.4. 
Assignment of Patient Number ...................................................................................56 
7.5. 
Screening/Washout .....................................................................................................56 
7.6. 
Informed Consent .......................................................................................................57 
7.7. 
Inclusion/Exclusion Criteria .......................................................................................57 
7.8. 
Medical History ..........................................................................................................58 
7.9. 
Prior and Concomitant Medications ...........................................................................58 
7.9.1. 
Prior Medications ........................................................................................................58 
7.9.2. 
Concomitant Medications ...........................................................................................58 


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7.9.3. 
Prohibited Medications and Non-Drug Therapies ......................................................58 
7.9.4. 
Permitted Medications and Non-Drug Therapies .......................................................60 
7.9.5. 
Requirements for Use of Stable Therapies .................................................................60 
7.9.6. 
Washout of Prior Medications ....................................................................................61 
7.10. 
Patient Voiding Diary .................................................................................................61 
7.10.1. 
Patient Voiding Diary Training/Re-Training..............................................................62 
7.11. 
Urine Volume Diary ...................................................................................................62 
7.11.1. 
Urine Volume Collection Training/Re-Training ........................................................63 
7.11.2. 
Dispense Urine Collection and Measurement Supplies ..............................................63 
7.12. 
Reminders for Diary Collection ..................................................................................63 
7.13. 
Electronic Diary ..........................................................................................................64 
7.13.1. 
eDiary Device Set-Up and Training ...........................................................................64 
7.13.2. 
Device Training/Re-Training ......................................................................................64 
7.14. 
Patient-Reported Outcomes ........................................................................................64 
7.15. 
Post-Void Residual Volume .......................................................................................65 
7.16. 
Physical Examination .................................................................................................65 
7.17. 
Electrocardiogram .......................................................................................................65 
7.18. 
Vital Signs ..................................................................................................................65 
7.19. 
Adverse Events ...........................................................................................................66 
7.20. 
Clinical Laboratory Assessments ...............................................................................66 
7.20.1. 
Chemistry, Hematology, and Urinalysis (Laboratory Safety Evaluations) ................66 
7.20.2. 
-hCG ...............................................................................................................68 
7.21. 
Dispense Single-Blind Run-in Study Treatment ........................................................68 
7.22. 
IxRS Randomization to Study Treatment ...................................................................68 
7.23. 
Dispense Double-Blind Study Treatment ...................................................................68 
7.24. 
Study Treatment Return/Accountability Review ........................................................68 
7.25. 
Administer Witnessed Dose of Study Treatment .......................................................68 
7.26. 
Pharmacokinetic (PK) Sampling (PK Subset Only) ...................................................69 
7.26.1. 
Pharmacokinetic Sample Collection ...........................................................................69 
7.27. 
Follow-up Visit ...........................................................................................................69 
8. 
SAFETY CONSIDERATIONS ..................................................................................70 
8.1. 
Definition of an Adverse Event ..................................................................................70 
8.2. 
Definition of a Serious Adverse Event .......................................................................71 


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8.3. 
Adverse Event Reporting ............................................................................................72 
8.3.1. 
Period for Reporting Adverse Events .........................................................................73 
8.3.2. 
Reporting Serious Adverse Events .............................................................................73 
8.3.3. 
Study Treatment Overdose Management ...................................................................74 
8.4. 
Assigning Causal Relationship to Study Treatment ...................................................74 
8.5. 
Assigning Severity Rating for Adverse Events ..........................................................75 
8.6. 
Adverse Events of Clinical Interest ............................................................................75 
8.6.1. 
Criteria for Temporary Withholding of Study Treatment in Association with 
Liver Test Abnormalities ............................................................................................76 
8.6.2. 
Criteria for Permanent Discontinuation of Study Treatment in Association 
with Liver Test Abnormalities ....................................................................................77 
8.7. 
Pregnancy Management and Reporting to the Sponsor ..............................................78 
8.8. 
Benefit/Risk Assessment ............................................................................................78 
9. 
STATISTICAL CONSIDERATIONS .......................................................................79 
9.1. 
Responsibility for Analyses/In-House Blinding .........................................................79 
9.2. 
Hypotheses ..................................................................................................................79 
9.2.1. 
Primary Objective and Hypotheses ............................................................................79 
9.2.2. 
Key Secondary Objectives and Hypotheses ...............................................................79 
9.3. 
Analysis Endpoints .....................................................................................................81 
9.3.1. 
Efficacy Endpoints ......................................................................................................81 
9.3.2. 
Safety Endpoints .........................................................................................................83 
9.4. 
Analysis Populations ..................................................................................................83 
9.4.1. 
Efficacy Analysis Populations ....................................................................................83 
9.4.2. 
Safety Analysis Populations .......................................................................................84 
9.4.3. 
Pharmacokinetic Population .......................................................................................84 
9.5. 
Statistical Methods ......................................................................................................84 
9.5.1. 
Statistical Methods for Efficacy Analyses ..................................................................84 
9.5.1.1. 
Primary Efficacy Endpoints ........................................................................................84 
9.5.1.2. 
Sensitivity Analyses ....................................................................................................85 
9.5.1.3. 
Secondary Efficacy Endpoints ....................................................................................85 
9.5.1.4. 
Exploratory Efficacy Endpoints .................................................................................86 
9.5.2. 
Statistical Methods for Safety Analyses .....................................................................86 
9.5.3. 
PK Analysis ................................................................................................................86 


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9.6. 
Multiplicity .................................................................................................................86 
9.7. 
Sample Size Determination ........................................................................................87 
9.8. 
Subgroup Analyses and Effect of Baseline Factors ....................................................87 
9.9. 
Interim Analyses .........................................................................................................88 
10. 
STUDY GOVERNANCE CONSIDERATIONS .......................................................89 
10.1. 
Financial Disclosure ...................................................................................................89 
10.2. 
Pre-Initiation Visit ......................................................................................................89 
10.3. 
Data Management .......................................................................................................89 
10.4. 
Monitoring ..................................................................................................................90 
10.5. 
Auditing or Inspections ...............................................................................................90 
10.6. 
Study Oversight Committees ......................................................................................90 
10.6.1. 
Clinical Adjudication Committee ...............................................................................90 
10.6.2. 
Steering Committee ....................................................................................................90 
10.7. 
Protocol Modifications ...............................................................................................91 
10.8. 
Study Discontinuation ................................................................................................91 
10.9. 
Publications .................................................................................................................91 
10.10. 
Investigator-Specific Responsibilities ........................................................................92 
10.10.1. 
Compliance with Regulations and Ethical Standards .................................................92 
10.10.2. 
Protocol Compliance ..................................................................................................92 
10.10.3. 
Institutional Review Board/Independent Ethics Committee Requirements ...............92 
10.10.4. 
Informed Consent .......................................................................................................93 
10.10.5. 
Confidentiality ............................................................................................................93 
10.10.6. 
Study Files and Retention of Records ........................................................................93 
10.10.7. 
Electronic Case Report Forms ....................................................................................95 
10.10.8. 
Investigational Product Accountability ......................................................................95 
10.11. 
Sponsor-Specific Responsibilities ..............................................................................95 
10.11.1. 
Study Report ...............................................................................................................95 
10.11.2. 
Posting of Information on Publicly Available Clinical Trial Registers ......................95 
11. 
REFERENCES ...........................................................................................................96 
APPENDICES ...............................................................................................................................98 
APPENDIX A. LIST OF ABBREVIATIONS ...........................................................................98 
APPENDIX B. ALGORITHM FOR ASSESSING LABORATORY VALUES .....................101 


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APPENDIX C. APPROXIMATE BLOOD/TISSUE VOLUMES 
DRAWN/COLLECTED BY SAMPLE TYPE ........................................................102 
APPENDIX D. GUIDELINES FOR ELEVATIONS IN HEPATIC ENZYMES ....................103 
 
LIST OF TABLES 
Table 1: 
RVT-901-3003 Schedule of Activities .......................................................................25 
Table 2: 
Summary of Phase 2b Study 008 and Preliminary Phase 3 Study 
301 Efficacy Results ...................................................................................................34 
Table 3 
RVT-901-3003 Study Treatments ..............................................................................52 
Table 4: 
Listing of Prohibited Medications ..............................................................................59 
Table 5: 
Laboratory Tests .........................................................................................................67 
Table 6 
Criteria for Determining the Grade/Severity of Adverse Event Terms ......................75 
 
LIST OF FIGURES 
Figure 1: 
RVT-901-3003 Study Schematic ................................................................................43 
 


Clinical Study Protocol 
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1. 
SYNOPSIS 
Study Title 
An International Phase 3, Randomized, Double-Blind, Placebo- and 
Active (Tolterodine)-Controlled Multicenter Study to Evaluate the 
Safety and Efficacy of Vibegron in Patients with Symptoms of 
Overactive Bladder 
Protocol Number 
RVT-901-3003 
Study Center 
Location(s) 
International 
Number of Study 
Centers Planned 
~330 
Study Phase 
3 
Target Population 
Adult men and women with either: 
 Overactive bladder (OAB) Wet; or 
 OAB Dry 
Number of Patients 
Planned 
~1400 
Study Objectives 
 
Primary Efficacy 
Objective 
 To evaluate the efficacy of vibegron (RVT-901) compared to 
placebo in patients with symptoms of overactive bladder (OAB), 
specifically the frequency of micturitions and frequency of urge 
urinary incontinence episodes 
Secondary Efficacy 
Objective 
 To evaluate the overall efficacy of vibegron compared to placebo 
in patients with symptoms of OAB 
Safety Objectives 
 To evaluate the safety and tolerability of treatment with vibegron 
Pharmacokinetic / 
Pharmacodynamic 
Objectives 
 To evaluate the pharmacokinetic profile of vibegron in patients 
with symptoms of OAB 
 To assess relationships between exposure and efficacy/safety in 
patients with symptoms of OAB receiving vibegron 
Exploratory 
Objectives 


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Study Design 
This is an international, Phase 3, randomized, double-blind, placebo-
controlled with active control (tolterodine), parallel-group, multicenter 
study to evaluate the safety, tolerability, and efficacy of vibegron 75 mg
in men and women with symptoms of overactive bladder (OAB). 
Approximately 1,400 men and women with overactive bladder will be 
enrolled at approximately 330 study sites. 
At Baseline, patients who meet all eligibility criteria are randomized 
5:5:4 to receive either vibegron 75 mg, placebo, or tolterodine ER 4 mg 
in a double-blind fashion.  Between the Baseline and Week 12 Visits, 
patients will attend Visits at Weeks 4 and 8. 
This study consists of a Screening Period (1 to 5 weeks), a single-blind 
Run-in Period (2 weeks), a randomized double-blind Treatment Period 
(12 weeks), and a Safety Follow-up Period (4 weeks).  Patients who 
complete the Week 12 Visit may be offered the opportunity to enroll in 
a 40-week double-blind extension study RVT-901-3004 (which will be 
conducted under a separate protocol), until enrollment in that study is 
complete.  Patients who do not enroll into the optional extension study 
will have a Follow-up Visit approximately 28 days after the patient’s 
last dose of Study Treatment (i.e., at Week 16 for patients who 
complete the Week 12 Visit, or approximately 4 weeks after withdrawal 
for patients who discontinue the study early).  Additionally, 
Unscheduled Visit(s) may be arranged for patients with study-related 
safety concerns as needed. 
Study Treatments 
All treatments are dosed orally, once daily (QD).  Patients are 
randomized to one of the following blinded treatments: 
 Vibegron 75 mg tablet + placebo capsule to match tolterodine ER 
4 mg capsule (N = 500) 
 Placebo tablet to match vibegron 75 mg tablet + placebo capsule to 
match tolterodine ER 4 mg capsule (N = 500) 
 Tolterodine ER 4 mg capsule + placebo tablet to match vibegron 
75 mg tablet (N = 400) 
Duration of 
Treatment 
12 weeks 
Eligibility Criteria 
 
Inclusion Criteria 
1. Willing and able to provide written informed consent. 
2. 
8 years of age.  Note:  Up to 15% of patients 
can be male. 
3. Has a history of OAB (as diagnosed by a physician) for at least 
3 months prior to the Screening Visit.  Note:  OAB is defined as 
urgency, with or without urge urinary incontinence (UUI), usually 
associated with frequency and nocturia.  Urodynamic evaluation is 
not required. 


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4. Meets either the OAB Wet or OAB Dry criteria described below, 
based on the Patient Voiding Diary returned both at the Run-in 
Visit and Baseline Visit (all Complete Diary Days must be used in 
determining eligibility).  A minimum of 5 Complete Diary Days 
rned at 
the Run-in Visit, and 4 Complete Diary Days are required for the 
diary returned at the Baseline Visit.  Averages should not be 
rounded up to the whole number: 
 OAB Wet criteria: 
 
0 micturitions per Diary Day; and 
 An average of  1.0 UUI episodes per Diary Day; and 
 If stress urinary incontinence is present, the total number 
of UUI episodes must be greater than the total number of stress 
urinary incontinence episodes from the previous visit diary. 
 OAB Dry criteria: 
 
0 micturitions per Diary Day; and, 
 
0 urgency episodes per Diary Day; and 
 An average of < 1.0 UUI episodes per Diary Day; and 
 If stress urinary incontinence is present, the total number of 
UUI episodes must be greater than the total number of stress 
urinary incontinence episodes from the previous visit diary. 
Note:  Up to 25% of patients that meet OAB Dry criteria may 
be enrolled. 
5. For females of reproductive potential:  Agrees to remain abstinent 
or use (or have their male partner use) an acceptable method of 
birth control (as defined in Section 5.2.1) each time the patient 
has intercourse from the Screening Visit until completion of 
the Follow-up Visit. 
6. For females of reproductive potential:  Agrees not to donate 
ova (eggs) until at least 1 month after the last dose of Study 
Treatment. 
7. 
 80% compliance with self-administration 
of Study Treatment during the Run-in Period. 
8. Is ambulatory and in good general physical and mental health 
as determined by the Investigator. 
9. In the opinion of the Investigator, is able and willing to comply 
with the requirements of the protocol, including completing 
electronic versions of questionnaires, the Patient Voiding Diary, 
and the Urine Volume Diary (will require ability to collect, 
measure, and record voided volume by herself/himself using a 
 


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Exclusion Criteria 
Urology Medical 
History 
1. Patient has a history of 24-hour urine volume greater than 
3,000 mL in the past 6 months, or a Urine Volume Diary day 
measurement greater than 3,000 mL during the Run-in Period. 
2. Has lower urinary tract pathology that could, in the opinion of the 
Investigator, be responsible for urgency, frequency, or 
incontinence; including, but not limited to, urolithiasis, interstitial 
cystitis, prostate cancer, gastrointestinal (GI) cancer, tuberculosis, 
stone disease, urothelial tumor, prostatitis, and clinically relevant 
benign prostatic hypertrophy (BPH) or bladder outlet obstruction, 
as judged by the Investigator.  Note:  Male patients with mild to 
moderate BPH without evidence of bladder obstruction as 
determined by the Investigator may be included as long as they 
have been taking a medication for the treatment of BPH for at a 
least 1-year prior to Screening, with no change in dose of herbal 
medications, alpha antagonist medications or other symptomatic 
treatments or medications within 3 months prior to Screening, and 
no change in dose of 5 alpha reductase inhibitors within 6 months 
of Screening. 
3. Has a history of surgery to correct stress urinary incontinence, 
pelvic organ prolapse, or procedural treatments for BPH within 
6 months of Screening. 
4. Has current history or evidence of Stage 2 or greater pelvic organ 
prolapse (prolapse extends beyond the hymenal ring). 
5. Patient is currently using a pessary for the treatment of pelvic organ 
prolapse. 
6. Has a known history of elevated post-void residual volume defined 
as greater than 150 mL. 
7. Has undergone bladder training or electrostimulation within 
28 days prior to Screening or plans to initiate either during 
the study. 
8. Has an active or recurrent (> 3 episodes per year) urinary tract 
 5 white 
ulture, defined as 
 105 
 specimen).  Patients 
diagnosed with a urinary tract infection (UTI) at the Screening Visit 
may be treated and re-screened once the infection has resolved. 
9. Has a requirement for an indwelling catheter or intermittent 
catheterization. 
10. Has received an intradetrusor injection of botulinum toxin within 
9 months prior to Screening. 


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Other Medical History 11. Has uncontrolled hyperglycemia (defined as fasting blood glucose 
> 150 mg/dL or 8.33 mmol/L and/or non-fasting blood glucose 
> 200 mg/dL or 11.1 mmol/L) or, if in the opinion of the 
Investigator, is uncontrolled. 
12. Has evidence of diabetes insipidus. 
13. Is pregnant, breast-feeding, or is planning to conceive within 
the projected duration of the study. 
14. Has a concurrent malignancy or history of any malignancy within 
5 years prior to signing informed consent, except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical 
cancer. 
15. Has uncontrolled hypertension (systolic blood pressure of 
 180 
 100 mmHg) 
or has a resting heart rate (by pulse) > 100 beats per minute. 
16. 
 160 mmHg but 
< 180 mmHg are excluded, unless deemed by the Investigator 
and/or Medical Monitor as safe to proceed in this study and able to 
complete the study per protocol; these patients must be on stable 
hypertension medication for at least 90 days. 
17. All patients with signs and symptoms of uncontrolled hypertension, 
regardless of blood pressure measurement, are excluded from the 
study.  These include, but are not limited to neurological symptoms 
or findings, hematuria, proteinuria, retinopathy, unstable angina, 
and acute heart failure. 
18. Has narrow angle glaucoma (primary open angle glaucoma is 
not excluded). 
19. Has a history of cerebral vascular accident, transient ischemic 
attack, unstable angina, myocardial infarction, coronary artery 
interventions (e.g., coronary artery bypass grafting or percutaneous 
.g., 
neurovascular interventions (e.g., carotid artery stenting) within 
6 months prior to the Screening Visit.  Patients with these 
conditions should be on stable medical therapy for at least 3 months 
prior to the Screening Visit. 
20. Has a known history of liver disease. 
21. Has a history of injury, surgery, or neurodegenerative diseases 
(e.g., multiple sclerosis, Parkinson’s) that could affect the lower 
urinary tract or its nerve supply. 


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Laboratory/Procedure 
History 
22. Has hematuria, including microscopic hematuria (> 5 red blood 
hematuria may participate.  Documentation must be obtained 
indicating an unremarkable upper urinary tract (kidneys and 
ureters) imaging study (e.g., 
with and without contrast, renal ultrasound, magnetic resonance 
etc.) and cystoscopy.  Patients whose hematuria has not been 
previously evaluated may not be enrolled. 
23. Has clinically significant electrocardiogram (ECG) abnormality 
that, in the opinion of the Investigator, exposes the patient to risk 
by participating in the study. 
24. Has alanine aminotransferase or aspartate aminotransferase 
> 2.0 times the upper limit of normal (ULN), or bilirubin (total 
bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert 
syndrome or pattern consistent with Gilbert syndrome). 
25. Has clinically significant laboratory abnormality (from the 
Screening Visit results) that remains unresolved after repeat testing 
(Refer to Algorithm for Laboratory Testing Appendix B) or that 
could confound the results of the study or indicate that it is not in 
the best interest of the patient to participate. 
26. Has an estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2. 
Medication History 
27. Use of any prohibited medications as detailed in Section 7.9.3 
(suitable washout periods from these medications are also described 
therein). 
28. Had changed the dose of any medications listed in Section 7.9.5 
within 4 weeks prior to the Baseline Visit, or plans to initiate or 
change the dosing of any of these medications during the study. 
29. Has an allergy, intolerance, or a history of a significant clinical or 
laboratory adverse experience associated with any of the active or 
inactive components of the vibegron formulation or tolterodine 
formulation. 
Other 
30. Is currently participating or has participated in a study with an 
investigational compound or device within 28 days prior to signing 
informed consent. 
31. Is currently participating in or has participated in a study with 
vibegron. 
32. Has a history of significant drug or alcohol abuse/dependence 
within a year prior to informed consent, as assessed by the 
investigator. 
33. Has a varying sleep schedule anticipated during times when the 
voiding diaries are to be completed. 


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34. Has coronary or neurovascular interventions planned during the
duration of the study.
35. Has a history or current evidence of any condition, therapy, lab
abnormality, or other circumstance that might, in the opinion of the
Investigator, confound the results of the study, interfere with the
patient’s ability to comply with study procedures, or make
participation in the study not in the patient’s best interest.
Endpoints 
Co-Primary Efficacy 
Endpoints 
 Change from baseline (CFB) at Week 12 in average number of 
micturitions per 24 hours in all OAB patients 
 CFB at Week 12 in average number of urge urinary incontinence 
(UUI) episodes per 24 hours in OAB Wet patients 
Key Secondary 
Efficacy Endpoints 
 CFB at Week 12 in average number of urgency episodes (need to 
urinate immediately) over 24 hours in all OAB patients 
 Percent of OAB Wet patients with at least a 75% reduction from 
baseline in UUI episodes per 24 hours at Week 12 
 Percent of OAB Wet patients with a 100% reduction from baseline 
in UUI episodes per 24 hours at Week 12 
 Percent of all OAB patients with at least a 50% reduction from 
baseline in urgency episodes (need to urinate immediately) per 
24 hours at Week 12 
 CFB at Week 12 in average number of total incontinence episodes 
over 24 hours in OAB Wet patients 
 CFB at Week 12 in Coping Score from the Overactive Bladder 
Questionnaire Long Form (OAB-q LF, 1-week recall) in all OAB 
patients 
 CFB at Week 12 in average volume voided per micturition in all 
OAB patients 
Additional Secondary 
Efficacy Endpoints 
 CFB at Week 12 in Health-related Quality of Life (HRQL) Total 
Score from the OAB-q LF (1-week recall) in all OAB patients 
 CFB at Week 12 in Symptom Bother Score from the OAB-q-LF 
(1-week recall) in all OAB patients 
 Percent of all OAB patients with average number of micturitions 
< 8 per 24 hours at Week 12 
 Percent of OAB Wet patients with at least a 50% reduction from 
baseline in total incontinence episodes per 24 hours at Week 12 
 CFB at Week 12 in overall bladder symptoms based on Patient 
Global Impression of Severity (PGI-Severity) in all OAB patients 
 CFB at Week 12 in overall control over bladder symptoms based 
on Patient Global Impression of Control (PGI-Control) in all OAB 
patients 


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Safety Assessments 
 Incidence of adverse events 
 Clinical laboratory assessments 
 Vital signs and physical examinations 
Pharmacokinetic / 
Pharmacodynamic 
Endpoints 
 AUC and C24 estimated from population PK modeling 
Exploratory 
Endpoints 


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Statistical Methods 
 
Efficacy Analyses 
For the analysis of the co-primary endpoints (change from baseline in 
average number of daily micturitions at Week 12 and change from 
baseline in average number of daily UUI episodes at Week 12), a mixed 
model for repeated measure (MMRM) with restricted maximum 
likelihood estimation will be used.  The analysis model for each 
efficacy endpoint will include terms for treatment, visit, OAB Type 
(Wet vs Dry), Sex (Female vs Male), Region (US vs Rest of World), 
baseline score, and interaction of visit by treatment.  An unstructured 
covariance matrix will be used to model the correlation among repeated 
measurements.  The Kenward-Roger adjustment will be used with 
restricted (or residual) maximum likelihood (REML) to make statistical 
inference. 
Other change from baseline endpoints will be analyzed using the same 
MMRM model. 
Response efficacy endpoints (proportion of patients with at least 75% 
reduction or 100% reduction in the average number of daily UUI 
episodes at Week 12 and proportion of patients with at least 50% 
reduction in the average number of daily urgency episodes at Week 12) 
will be analyzed using the Cochran-Mantel-Haenszel risk difference 
estimate.  Missing Week 12 data will be analyzed using multiple 
imputation.  For each imputed dataset, the estimated difference in the 
proportion of responders and 95% confidence interval for the difference 
will be calculated using the Cochran-Mantel-Haenszel risk difference 
estimate stratified by OAB Type (Wet vs Dry) and Sex (Female vs 
Male), with weights proposed by Greenland and Robins. 
Multiplicity Adjustment 


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The key secondary endpoints will be tested using a hierarchical testing 
strategy using two-
multiplicity is needed. 
Safety Analyses 
Safety assessments (e.g., adverse events, clinical laboratory 
assessments, vital signs) will be summarized using descriptive statistics. 
No formal statistical comparisons will be performed. 
Power and Sample 
Size 
Approximately 1,400 patients will be randomized in a 5:5:4 ratio to 
receive one of the following Study Treatments: 
 Vibegron 75 mg tablet + placebo capsule to match tolterodine ER 
4 mg capsule (N = 500) 
 Placebo tablet to match vibegron 75 mg tablet + placebo capsule to 
match tolterodine ER 4 mg capsule (N = 500) 
 Tolterodine ER 4 mg capsule + placebo tablet to match vibegron 
75 mg tablet (N = 400) 
Approximately 500 patients will be assigned to the vibegron and 
placebo treatment groups, and approximately 400 patients will be 
assigned to the tolterodine treatment group.  Assuming a total of 10% 
patients will discontinue prior to Week 12 (for any reason), there will 
be approximately 450 evaluable patients in the vibegron and placebo 
treatment groups at the end of Week 12.  Assuming 75% of the 
population will have OAB Wet, there will be approximately 
337 evaluable patients in the vibegron and placebo treatment groups for 
the incontinence endpoints.  The study has: 
 Approximately 98% power to detect a true underlying between-
group treatment difference of 0.6 in change from baseline in 
micturitions at a two-sided 0.05 level assuming a variability 
estimate of 2.20 based on vibegron Study 008 data. 
 Approximately 98% power to detect a true underlying between-
group treatment difference of 0.51 in change from baseline in UUI 
episodes at a two-sided 0.05 level assuming a variability estimate 
of 1.68 based on vibegron Study 008 data. 
Assuming that these endpoints are uncorrelated, then this study has 
96% power to reject both co-primary hypotheses. 


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1.1. 
Schedule of Activities 
Table 1: 
RVT-901-3003 Schedule of Activities 
Study Period: Screening/ 
Washout 
Run-in 
Treatment 
Safety Follow-up/ 
Unscheduled 
Visit Number: 
Visit #1 
Visit #2 
Visit #3 
Diary 
Only 
Visit #4 
Visit #5 
Visit #6 
UNS # 
Visit #7 
Visit Name: Screening1 
Run-in 
Baseline 
Week 2 
Week 4 
Week 8 
Week 12 
or Early 
WD 
Unsch-
eduled25 
Follow-
up26 
Study Day: 
-49 to -15 
-14 
1 
15 
29 
57 
85 or 
Early WD 
 
113 or 
Early WD + 
28 
Permitted Visit Window: 
 
± 3 Days 
 
 
± 3 Days ± 3 Days 
± 3 Days 
 
± 3 Days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Eligibility Review 
X 
X 
X 
 
 
 
 
 
 
Medical and Medication History 
X 
X 
X 
 
 
 
 
 
 
Electronic Diary (eDiary)2: 
 
 
 
 
 
 
 
 
 
eDiary Device: 
 
 
 
 
 
 
 
 
 
Device Setup/Function Check3 
X 
X 
X 
 
X 
X 
X 
X 
 
Device Training/Re-Training4 
X 
X 
X 
 
X 
X 
 
X 
 
Dispense/Collect eDiary Device 
X 
 
 
 
 
 
X 
 
 
Patient Voiding Diary: 
 
 
 
 
 
 
 
 
 
Patient Voiding Diary Training/Re-Training5 
X 
X 
X 
 
X 
X 
 
X 
 
Patient Completes Patient Voiding Diary6 
X 
X 
 
X 
X 
X 
X 
 
 
Urine Volume Diary: 
 
 
 
 
 
 
 
 
 
Urine Volume Diary Training/Re-Training5 
X 
X 
X 
 
X 
X 
 
X 
 
Dispense Urine Collection/Measurement 
Supplies 
X 
 
 
 
 
 
 
 
 
Patient Completes Urine Volume Diary7 
X 
X 
 
X 
X 
X 
X 
 
 
Diary and Visit Reminders 
 
 
 
 
 
 
 
 
 
         Phone Calls / Optional SMS reminders8 
X 
X 
 
X 
X 
X 
X 
 
 


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Study Period: Screening/ 
Washout 
Run-in 
Treatment 
Safety Follow-up/ 
Unscheduled 
Visit Number: 
Visit #1 
Visit #2 
Visit #3 
Diary 
Only 
Visit #4 
Visit #5 
Visit #6 
UNS # 
Visit #7 
Visit Name: Screening1 
Run-in 
Baseline 
Week 2 
Week 4 
Week 8 
Week 12 
or Early 
WD 
Unsch-
eduled25 
Follow-
up26 
Study Day: 
-49 to -15 
-14 
1 
15 
29 
57 
85 or 
Early WD 
 
113 or 
Early WD + 
28 
Permitted Visit Window: 
 
± 3 Days 
 
 
± 3 Days ± 3 Days 
± 3 Days 
 
± 3 Days 
Patient Reported Outcomes9: 
 
 
 
 
 
 
 
 
 
Global Impression Items (PGI-Severity, PGI-
Control, PGI-Frequency, PGI-Leakage, and 
PGI-Change) 
 
 
X 
 
X 
X 
X 
 
 
Overactive Bladder Questionnaire (OAB-q LF) 
 
 
X 
 
 
 
X 
 
 
Work Productivity and Activity Impairment 
Questionnaire-Urinary Symptoms (WPAI-US) 
 
 
X 
 
 
 
X 
 
 
EQ-5D 
 
 
X 
 
 
 
X 
 
 
Post-Void Residual (PVR) Volume10 
 
X 
 
 
 
 
X 
 
 
Physical Exam11 
X 
X 
 
 
 
 
 
X 
X 
ECG12 
X 
 
 
 
 
 
 
X 
 
Vital Signs13 
X 
X 
X 
 
X 
X 
X 
X 
X 
Adverse Events14 
==============================================================================
 
Serious Adverse Events15 
==============================================================================
 
Concomitant Medication Review16 
==============================================================================
 
Clinical Laboratory Assessments: 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
 
X 
 
X 
 
X 
X 
X 
Hematology 
X 
 
X 
 
X 
 
X 
X 
X 
Urinalysis Dipstick17,18 
X 
 
X 
 
X 
 
X 
X 
X 
-hCG (women)19 
X 
X 
X 
 
X 
X 
X 
X 
X 
IxRS Randomization to Study Treatment 
 
 
X 
 
 
 
 
 
 
Dispense Study Treatment20 
 
X 
X 
 
X 
X 
 
X 
 


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Study Period: Screening/ 
Washout 
Run-in 
Treatment 
Safety Follow-up/ 
Unscheduled 
Visit Number: 
Visit #1 
Visit #2 
Visit #3 
Diary 
Only 
Visit #4 
Visit #5 
Visit #6 
UNS # 
Visit #7 
Visit Name: Screening1 
Run-in 
Baseline 
Week 2 
Week 4 
Week 8 
Week 12 
or Early 
WD 
Unsch-
eduled25 
Follow-
up26 
Study Day: 
-49 to -15 
-14 
1 
15 
29 
57 
85 or 
Early WD 
 
113 or 
Early WD + 
28 
Permitted Visit Window: 
 
± 3 Days 
 
 
± 3 Days ± 3 Days 
± 3 Days 
 
± 3 Days 
Study Treatment Return/Accountability Review21 
 
 
X 
 
X 
X 
X 
 
 
Administer Witnessed Dose of Study Treatment22 
 
X 
X 
 
 
 
 
 
 
Pharmacokinetic Sampling (PK Subset Only): 
 
 
 
 
 
 
 
 
 
PK Sample Collection23 
 
 
 
 
X 
X 
X 
 
 
Collect Date/Time of Prior Dose24 
 
 
 
 
X 
X 
X 
 
 
Abbreviations:  IxRS, interactive voice or web response system, PK
-h
-human chorionic gonadotropin 


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Table Footnotes: 
Screening 
1. The time between the Screening and Run-in Visits may be up to 5 weeks, to allow for washout of prior OAB medications (if needed) and 
completion of the Patient Voiding Diary and Urine Volume Diary. 
Electronic Diary (eDiary) 
2. The Electronic Diary (eDiary) for this study includes both the Patient Voiding Diary and the Urine Volume Diary, and will be implemented 
via an eDiary device (provisioned smartphone).  A paper diary will be provided to all patients to be used as a back-up when necessary.  If 
a back-up paper diary is used, it should be collected at each study visit. 
eDiary Device 
3. At Screening, site personnel will setup the eDiary Device, confirm proper functioning, and dispense the eDiary Device to the patient.  At 
each subsequent visit during the Treatment Period, site personnel will confirm that the eDiary Device is functioning properly. 
4. Specific training on device operation will be provided to the patient at Screening, with re-training provided at each subsequent visit. 
Patient Voiding Diary and Urine Volume Diary 
5. Specific training on completion of the Patient Voiding Diary and Urine Volume Diary will be provided to the patient at Screening, with re-
training provided at each subsequent visit. 
6. The Patient Voiding Diary should be completed by the patient on all of the 7 Diary Days prior to the Run-in Visit (days -21 to -15), 
Baseline Visit (days -7 to -1), Week 2 Visit (days 8 to 14), Week 4 Visit (days 22 to 28), Week 8 Visit (days 50 to 56), and Week 12 Visit 
(days 78 to 84).  Patient will receive SMS text alerts and/or phone call reminders to complete the Diary. 
7. The Urine Volume collection and Urine Volume Diary completion should be performed by the patient on one (1) of the 7 Diary Days prior 
to the Run-in, Baseline, and Weeks 2, 4, 8, and 12 Visits. 
Diary and Visit Reminders 
8. Patient will receive phone call reminders from the site to complete the Diary on approximately the first day and third day of each diary 
collection period (or next business day). Patient may consent to additional SMS Text reminders (where available). 
Patient Reported Outcomes 
9. Vital signs, followed by PRO Questionnaires will be the first procedure performed at visits that include PRO administration.  
Questionnaires will be administered at the site in the order listed in the Schedule of Activities. 
Post Void Residual Volume 
10. All efforts will be made to ensure the same device and operator are used for all PVR volume measurements for individual patients. 
 
 


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Physical/ECG/Vitals 
11. A Complete Physical Exam will be performed at the Screening Visit and will include a digital rectal exam for all males.  Focused physical 
examinations will be performed at the Run-in and Follow-up Visits, which will include a pelvic exam for women only as needed to confirm 
prolapse. 
12. A single 12-lead ECG will be obtained at Screening. 
13. Vital Signs includes Blood Pressure (average of three measurements taken 1-2 minutes apart after sitting for 5 minutes), Heart Rate, 
Temperature, Respiration Rate and Weight.  Height will be measured only at Screening. 
Adverse Events 
14. Adverse events will be collected from the time a patient provides informed consent to participate in the study until the Follow-up Visit is 
completed. 
15. Serious adverse events will be collected from the time a patient provides informed consent to participate in the study until the Follow-up 
Visit is completed. 
Prior and Concomitant Medications 
16. Concomitant medications will be reviewed and recorded at each study visit from the Screening through the Week 12 and at any 
Unscheduled Visits.  Medications taken within 1 year of the Screening Visit for the treatment of OAB will also be recorded. 
Labs 
17. At Week 8, the Urine Dipstick will only be performed if clinically indicated (e.g., symptoms of urinary retention or urinary tract infection). 
18. Urinalysis will be performed only if the urine dipstick tests positive for the presence of leukocytes, nitrites, or blood cells, and will be 
performed by the central lab. 
19. Urine beta-
-hCG) will be tested for women of childbearing potential only. 
Dosing/Drug 
20. Dosing will occur every day from the Witnessed Dose on the day of the Run-in Visit through the day before the Week 12 Visit. 
21. Study Treatment bottles should be returned by the patient at each visit.  Clinic staff will perform accountability and review any 
discrepancies with the patient during the visit. 
22. All patients will take their dose of Study Treatment on the day of the Run-in and Baseline Visits at the site as a witnessed dose.  The date 
and time of Study Treatment dosing will be recorded 
Pharmacokinetics Subset Only 
23. PK samples for Population PK Analysis will be collected from a subset of patients (approximately 30% of enrolled patients) at selected 
sites.  Pre-dose blood samples will be collected at Week 4, Week 8, and Week 12.  PK samples should be collected during the clinic visit 
after all other study assessments have been completed. 
24. The date and time of the last dose of Study Treatment prior to PK sampling will be recorded. 


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Follow-up/Unscheduled 
25. Unscheduled Visits and the specific procedures performed at these visits will be determined by the Investigator, as clinically indicated.  
The procedures indicated in the Schedule of Activities will be performed at these visits, as clinically indicated, based on the purpose of the 
visit (e.g., follow-up for an adverse event or abnormal laboratory test, study treatment dispensation).  The reason for the visit will be 
captured in the source documents. 
26. For Patients who do not enroll into the optional extension study (RVT-901-3004) or patients who Withdraw from the study for any reason, 
a Follow-up Visit should be performed approximately 28 days after the last dose of Study Treatment on Study Day 113 or approximately 
28 days after a patient’s Withdrawal from the study.  When a patient withdraws from the study prior to study completion, all applicable 
activities scheduled for the Week 12 Visit should be performed at the time of withdrawal. 
 
 


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2. 
INTRODUCTION 
2.1. 
Indication 
Vibegron (RVT-901) is currently in development to reduce urge urinary incontinence, urgency, 
and urinary frequency in patients with overactive bladder (OAB). 
2.2. 
Background 
OAB affects approximately 16% of the population in the US and EU.  Prevalence increases with 
age, affecting approximately 1/3 of people 75 y
Stewart, 2003; Milsom, 2001 .  
The International Continence Society (ICS) defines OAB as urgency, with or without urge 
Abrams, 2002 .  Urgency is 
defined as a sudden compelling desire to void which is difficult to defer.  Urge urinary 
incontinence (UUI) is the involuntary loss of urine accompanied by urgency (referred to as OAB 
Wet) and is present in approximately one-
Stewart, 2003; 
Milsom, 2001 .  In the absence of incontinence, OAB is referred to as OAB Dry.  UUI is 
distinguished from stress urinary incontinence, which is the involuntary loss of urine on effort or 
physical exertion (e.g., sporting activities), or on sneezing or coughing.  When both components 
are present, the classification is mixed urinary incontinence and the Investigator will make a 
determination of either urgency or stress specified as the predominant component. 
Currently, the predominant class of drugs used to treat OAB is antimuscarinics.  The clinical use 
of antimuscarinics is limited by modest efficacy and poor tolerability due to mechanism-based 
side effects including dry mouth, constipation, and the potential for CNS adverse effects 
(e.g., cognitive impairment).  High discontinuation rates have been observed for both tolterodine 
and oxybutynin, two commonly prescribed antimuscarinics, in both clinical trials and marketed 
D’Souza, 2008; Lawrence, 2000 .  In a study evaluating the discontinuation rate of new 
prescriptions for tolterodine ER or oxybutynin, the mean time to discontinuation was 45 to 
60 
Lawrence, 2000 .  At 
six months, less than 1/3 of patients were still refilling their prescriptions.  The lack of efficacy 
or inability to tolerate antimuscarinics leaves patients with few alternative treatment options.  As 
such, there is a clear unmet medical need for better treatment options for patients with OAB.  In 
addition, recent evidence from observational studies suggests that higher cumulative 
anticholinergic use is associated with an increased 
Gray, 2015; Gray, 2016 . 
Beta-3 adrenergic receptor ( 3-AR) agonists demonstrated efficacy in alleviating symptoms of 
Chapple, 2009; Chapple, 2010; Chapple, 2012 .  
3-AR agonist, mirabegron 
(Astellas Pharma Global Development, Inc.), has received marketing approval in Japan and the 
United States for the treatment of OAB.  Reductions in micturition frequency, urinary 
incontinence and urgency episodes, and increases in mean volume voided per micturition were 
Chapple, 2009; Chapple, 2010; Chapple, 2012 .  Cross-study 
3-AR agonists with the antimuscarinic, DETROL® LA 
3-AR 
agonists possess similar efficacy for the treatment of OAB with an improved tolerability profile 
Chapple, 2009; Van Kerrebroeck, 2001 .  A recent publication demonstrated that patients 
prescribed mirabegron remained on treatment longer and showed greater adherence than those 


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prescribed traditional antimuscarinics, and mirabegron was associated with a favorable safety 
Chapple, 2017  
3-AR agonist demonstrating > 9,000 fold 
selectivity for activation of 3-AR over 2-AR and 1-AR in cell based in vitro assays.  
-
-AR) are prototypic G-protein coupled receptors expressed on the 
surface of cells and mediate intracellular signaling via coupling to G proteins and increasing 
levels of intracellular cyclic adenosine monophosphate (cAMP).  3-ARs are widely distributed 
-AR subtype expressed on human detrusor smooth 
Takeda, 2000 .  In 
3-AR using 
subtype-
3-AR 
Yamaguchi, 2002; Biers, 2006 .  In 
3-AR agonists relax bladder smooth muscle and suppress 
non-
Takeda, 2000; Woods, 2001; 
Takeda, 2002; Kaidoh, 2002 .  In rhesus monkeys, dose-dependent increases in bladder capacity 
and decreases in micturition pressure were observed with vibegron.  Bladder capacity was further 
increased by vibegron in combination with tolterodine or darifenacin. 
2.3. 
Non-clinical Safety Summary 
Nonclinical safety evaluation of vibegron included a comprehensive package of safety 
pharmacology, repeat-dose oral toxicity up to the chronic duration, genetic toxicology, 
carcinogenicity, reproductive developmental, and special safety studies to support the continued 
evaluation of long-term oral administration of vibegron in humans. 
Cardiovascular safety pharmacology findings consisted of increased heart rates, decreased QT 
interval, and increased corrected QT (QTc) 
 2.5 mg/kg); the QRS interval and diastolic 
blood pressure were increased in monkeys at 135 mg/kg.  At 2.5 mg/kg in monkeys, the 
maximum concentration (Cmax) level was less than the estimated human exposure at 75 mg.  All 
safety pharmacology changes were transient, and QT changes in the nonclinical model did not 
translate to humans.  A clinical thorough QT (tQT) study did not identify clinically meaningful 
effects on QTc interval or blood pressure when evaluated up to the supratherapeutic dose of 
400 mg. 
Additional findings included neurobehavioral effects of reduced mobility with abnormal posture 
0 mg/kg (34-fold of Cmax at the 75 mg); and increased respiration rates and 
 2.5 mg/kg. 
In chronic toxicity studies, findings were limited to a transient clinical sign of salivation, a 
decreased body weight gain in rats, and a higher incidence of abdominal distension in monkeys.  
In monkeys, histopathology changes consisted of a slight cellular infiltration in the liver, which 
correlated with hepatic enzyme elevation in the 3-month study.  Systemic exposures at no-
observed-adverse-effect levels (NOAELs) in rats were 3- and 32-fold higher in males and 
females, respectively, compared to the gender-specific human exposures.  In monkeys, the 
NOAEL was 21-fold higher than human exposure. 
Vibegron was not phototoxic, genotoxic, or carcinogenic.  The carcinogenicity NOAELs were at 
least 27- and 23-fold higher in mice and rats, respectively, compared to the human exposure.  
Fertility and embryo-fetal developmental findings consisted of reduced fertility in female rats 


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and an increased incidence of delayed skeletal ossification in fetuses of rabbits at a maternally 
toxic dose.  The reproductive developmental NOAELs were greater than 349-fold of the human 
exposure.  The nonclinical safety data supports the Phase 3 clinical studies of the proposed dose 
of 75 mg/day. 
2.4. 
Summary of Relevant Clinical Experience with Vibegron 
As of 03 February 2017, approximately 2,300 patients and healthy volunteers (including 
approximately 1,840 patients with OAB and 460 healthy volunteers) have received at least one 
dose of vibegron in 19 completed studies.  Vibegron has been evaluated in 16 Phase 1 studies, 
one large international Phase 2 dose-ranging study in patients with OAB (Study 008), and two 
completed Phase 3 studies in Japanese patients with OAB (Study 301 and 302).  A summary of 
available clinical data is included below.  Refer to the vibegron Clinical Investigator’s Brochure 
for additional information. 
2.4.1. 
Efficacy 
The efficacy of vibegron in the treatment of OAB has been assessed in one international Phase 2 
(008) and 2 Phase 3 studies (301 and 302).  A brief summary of these studies is included below. 
Study 008 was an international, randomized, placebo- and active-controlled Phase 2 dose-
ranging study conducted in 1,395 patients with OAB.  Patients were equally randomized in a 
double-blind fashion to 8 weeks of treatment in the following study arms:  vibegron 3 mg, 
15 mg, 50 mg, or 100 mg once daily, tolterodine ER 4 mg once daily, or placebo once daily.  An 
optional extension study for eligible patients continued vibegron (50 and 100 mg) and tolterodine 
treatment for a total duration of 52 weeks.  Treatment of patients with OAB with vibegron 
resulted in a dose-dependent reduction in the average daily number of micturitions, total urinary 
incontinence episodes, UUI episodes, and urgency episodes.  At doses of 50 and 100 mg of 
vibegron, statistically and clinically relevant lowering of important OAB endpoints was observed 
(Table 2). 
Kyorin Pharmaceutical Company (Kyorin) has conducted a development program in Japan, 
consisting of two large Phase 3 clinical trials (Studies 301 and 302).  Overall, 908 patients were 
treated with vibegron in the Kyorin Phase 3 program. 
Study KRP114V-T301 (Study 301) was a double-blind, randomized, placebo controlled, multi-
center, Phase 3 study designed to evaluate the safety and efficacy of vibegron in Japanese males 
and females with OAB.  Upon completion of the placebo Run-in period, 1,232 patients were 
randomized to receive blinded study treatment for 12 weeks including:  vibegron 50 mg 
(N=370), vibegron 100 mg (N=369), placebo (N=369), or imidafenacin 0.2 mg (comparator; 
N=117).  Study 301 results demonstrate that once daily vibegron produced statistically 
significant reductions in efficacy parameters including:  micturitions, UUI episodes, total 
incontinence episodes, and urgency episodes (Table 2). 
Study KRP114V-T302 (Study 302) was an open-label, uncontrolled, multi-center, Phase 3 study 
designed to evaluate the long-term (52-week) safety and efficacy of vibegron in Japanese males 
and females with OAB.  Upon completion of a 1-week observation period, 169 patients initiated 
vibegron 50 mg once daily.  After eight weeks, the dose could be increased to 100 mg once daily 
as clinically indicated.  Patients continued vibegron at a dose of 50 mg or 100 mg through 


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Week 52.  Once daily vibegron reduced episodes of micturitions, UUI episodes, total 
incontinence episodes, and urgency episodes over a 52-week treatment period. 
Table 2: 
Summary of Phase 2b Study 008 and Preliminary Phase 3 Study 301 Efficacy 
Results 
 
Merck (Study 008) Week 8 Kyorin (Study 301) Week 12
50 mg 
100 mg 
50 mg 
100 mg 
Micturitions 
(Merck N~140, Kyorin N~370) 
-0.64 
(-1.11, -0.18) 
p = 0.007 
-0.91 
(-1.37, -0.44) 
p < 0.001 
-0.86 
(-1.12, -0.60) 
p < 0.0001 
-0.81 
(-1.07, -0.55) 
p < 0.0001 
Urge Urinary Incontinence 
Episodes 
(Merck N~115, Kyorin N~260) 
-0.72 
(-1.11, -0.33) 
p < 0.001 
-0.71 
(-1.10, -0.32) 
p < 0.001 
-0.27 
(-0.44, -0.10) 
p = 0.0015 
-0.39 
(-0.55, -0.22) 
 p < 0.0001 
Total Incontinence Episodes 
(Merck N~115, Kyorin N~260) 
-0.60 
(-1.02, -0.18) 
p = 0.005 
-0.58 
(-1.01, -0.16) 
p = 0.007 
-0.30 
(-0.49, -0.12) 
p = 0.0015 
-0.43 
(-0.61, -0.24) 
p < 0.0001 
Urgency Episodes 
(Merck N~140, Kyorin N~370) 
-0.76 
(-1.43, -0.10) 
p = 0.024 
-1.24 
(-1.90, -0.58) 
p < 0.001 
-0.51 
(-0.76, -0.25) 
p = 0.0001 
-0.67 
(-0.93, -0.42) 
p < 0.0001 
Volume Voided (mL) 
(Merck N~140, Kyorin N~370) 
29.05 
(14.36, 43.74)
p < 0.001 
23.36 
(8.66, 38.06) 
p = 0.002 
25.76 
(20.02, 31.46)
p < 0.0001 
22.16 
(16.44, 27.89) 
p < 0.0001 
Note:  Results presented as least squares mean placebo adjusted change from baseline (95% 
confidence interval CI ), p-value.  Sample sizes vary slightly by treatment arm and endpoint. 
 
2.4.2. 
Safety and Tolerability 
The safety of vibegron has been evaluated in 19 clinical studies.  Over 450 subjects have 
received vibegron in Phase 1 clinical trials and over 1,900 patients have received vibegron in 
Phase 2 and 3 trials for overactive bladder.  In addition to this overview, please refer to the 
Clinical Investigator’s brochure for an in-depth review of the safety profile. 
In 16 Phase 1 clinical studies, vibegron was well-tolerated following single dose administration 
of doses up to 600 mg and following multiple dose administration of doses up to 400 mg for 
14 days and 150 mg for 28 days.  In healthy volunteers, at doses  100 mg, vibegron was 
associated with increases in heart rate and blood pressure and occasional orthostatic symptoms.  
There were no serious adverse events in the Phase 1 program and most adverse events (AEs) 
were mild or moderate in intensity and transient.  There were no clinically meaningful changes in 
laboratory safety or ECG parameters with vibegron alone or when co-administered with 
tolterodine.  A clinical tQT/QTc study did not identify clinically meaningful effects on QTc 
interval or blood pressure. 


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There have been two large placebo-controlled studies with vibegron, as well as two 52-week 
long-term safety studies.  The first placebo controlled trial, conducted by Merck, was a 2-part 
Phase 2 clinical study (Study 008); this also included an open-label 1-year extension in which 
1,395 patients were enrolled, of whom 976 received treatment with vibegron.  This study was 
designed to assess the safety, tolerability, and efficacy of vibegron, and to provide proof-of-
concept for concomitant dosing with tolterodine ER 4 mg.  Part 1 evaluated once-daily doses of 
vibegron ranging from 3 to 100 mg, tolterodine ER 4 mg, or placebo for 8 weeks and 
concomitant dosing of vibegron 50 mg with tolterodine ER 4 mg for 4 weeks.  Part 2 evaluated 
once daily doses of vibegron 100 mg, tolterodine ER 4 mg, vibegron 100 mg with tolterodine ER 
4 mg, or placebo once daily for 4 weeks.  The most common adverse events for vibegron were 
dry mouth, headache, urinary tract infection, and nasopharyngitis, all of which were reported at 
< 5.5%.  These AE rates were similar to the placebo and tolterodine ER 4 mg treatment groups.  
Assessment of safety laboratory parameters and mean vital sign values over time, including heart 
rate and blood pressure, showed no meaningful differences for any active treatment group 
relative to placebo. 
Vibegron was generally well-tolerated during 52 weeks of treatment in the extension phase of 
Study 008 when administered alone or when co-administered with tolterodine, with no 
meaningful differences in the overall incidence or severity of adverse events observed among the 
treatment groups compared to placebo or in the combination treatment groups compared to either 
monotherapy. 
Results from the Kyorin Study 301 demonstrated that both the 50 and 100 mg vibegron dose 
levels were well-tolerated in these 12-week studies.   The incidence of AEs in vibegron treatment 
groups was similar to the placebo group, and the data showed a similar safety profile as observed 
in Study 008.  Nasopharyngitis was the most commonly reported adverse event (7.3% in the 
placebo group; 8.6 and 9.5% of patients in the 50 and 100 mg vibegron dose groups, 
respectively).  Dry mouth occurred in 0.5% of patients in the placebo group, and in 1.4% and 
0.5% of patients in the 50 and 100 mg vibegron dose groups, respectively.  Cystitis was reported 
in 0.8% of patients in the placebo group, and in 2.4% and 2.2% of patients in the 50 and 100 mg 
vibegron dose groups, respectively. 
In a 52-week long term administration open-label study (Study 302), where patients had the 
option to increase their treatment dose from 50 to 100 mg, there were no trends toward increased 
frequency of AEs in 51 of the 169 vibegron-treated patients who elected to increase their dose. 
In summary, data from Phase 1 through 3 clinical trials suggest that vibegron is generally safe 
and well- tolerated, when administered alone or when co-administered with the following drugs:  
antimuscarinics (imidafenacin or tolterodine); metoprolol (a representative beta-blocker); or 
amlodipine (a representative vasodilator).  Assessment of safety laboratory parameters and mean 
vital sign values over time, including heart rate and blood pressure, showed no clinically 
meaningful differences for any active treatment group relative to placebo or anti-muscarinic 
comparators.  Discontinuation rates due to adverse events were low (less than 5%) in all clinical 
studies. 
These data support the ongoing evaluation of vibegron monotherapy in clinical safety and efficacy 
studies for the treatment of patients with symptoms of overactive bladder. 


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2.4.3. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Results of Phase 1 absorption distribution metabolism and excretion study 011, which evaluated 
a single-dose of 14C-vibegron 100 mg in 6 subjects suggested that, found that the majority of 
vibegron was eliminated as parent indicating minimal metabolism.  Approximately 30% and 
50% of the absorbed dose was eliminated through renal and hepatic routes, respectively.  Based 
on preclinical and preliminary clinical data, vibegron is metabolically stable and while 
CYP3A4 is likely the predominant cytochrome P450 (CYP) responsible for in vitro metabolism, 
metabolism appears to only play a minor role (< 10%) in the elimination of vibegron. 
Pharmacokinetic (PK) data in young, middle-aged and elderly males and females with vibegron 
suggest good absorption with non-linear pharmacokinetics.  Vibegron time to reach maximum 
concentration (tmax) values are generally similar across age groups and across genders, ranging 
from 1 to 3 hours.  Preliminary data suggest that the area under the concentration-time curve 
from time 0 to 24 hours (AUC0-24hr) and Cmax increase in a greater than dose-proportional manner 
as a result of an increase in bioavailability with increasing dose, possibly due to saturable 
P-glycoprotein (P-gp)-mediated efflux in the gut.  Vibegron plasma concentrations are higher in 
females compared to males, in Japanese compared to non-Japanese and in elderly compared to 
middle aged and young.  Exposures are similar in middle-aged males when compared to young 
males.  The harmonic mean apparent terminal half-life (t½) values following multiple-dose 
administration range from 59 to 94 hours, with accumulation half-lives of 25 hours and 38 hours 
in young and elderly subjects, respectively.  Steady state trough concentrations appeared to have 
been approached by Day 7 across age groups.  The steady state area under the concentration-time 
curve (AUC) geometric mean accumulation ratios were ~2 in young males and ~2.8 in the elderly 
(males and females).  Food and ethnicity do not meaningfully alter the pharmacokinetic profile 
of vibegron. 
2.5. 
Study Rationale 
The use of vibegron in a large Phase 2b study (Study 008) in patients with OAB has 
demonstrated encouraging safety, tolerability, and efficacy results.  Furthermore, Phase 3 data in 
Japan (Studies 301 and 302) have demonstrated that vibegron is a safe, well tolerated, and 
effective therapy for OAB patients.  Given there are still OAB patients that do not reach their 
treatment goals with currently approved therapies, there remains an unmet need for new OAB 
therapies with a favorable safety, tolerability, and efficacy profile.  This study is designed to 
evaluate the safety, tolerability, and efficacy of vibegron 75 mg administered once daily in 
patients with OAB. 
2.6. 
Dose Rationale 
Clinical and non-clinical data support selection of a Phase 3 dose of vibegron 75 mg 
administered once daily in patients with OAB.  This pivotal Phase 3 study is designed to 
establish the safety, tolerability, and efficacy profile of vibegron 75 mg administered once daily 
in patients with OAB. 
Several lines of evidence support evaluating a once daily 75 mg vibegron dose:  1) Study 008, a 
large Phase 2b dose ranging study, and two Phase 3 studies (Study 301 and Study 302) 
demonstrated that doses up to 100 mg for 52 weeks are safe and well tolerated in patients with 


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OAB; 2) Study 008 demonstrated dose-dependent efficacy across multiple clinical endpoints in 
OAB patients with the maximal effect generally estimated between 50 and 100 mg; 75 mg of 
vibegron is expected to capture approximately 90% of the efficacy of 100 mg; 3) slight increases 
in mean maximum heart rate and infrequent increases in systolic or diastolic blood pressure in 
patients with OAB were difficult to detect relative to placebo and were not readily 
distinguishable between 50 and 100 mg of vibegron; these effects appear similar to, or less than, 
marketed agents tolterodine ER 4 mg and mirabegron 50 mg; and 4) vibegron exhibits greater 
than dose-proportional increases in exposures with mean Cmax increasing ~4-fold when dose 
increases from 50 to 100 mg.  A simulated dose of 75 mg decreases Cmax by approximately 40% 
and reduces extremes of exposure compared to 100 mg.  Lowering Cmax should maximize the 
benefit-risk profile for patients with OAB by minimizing the potential for heart rate or blood 
pressure increases. 
2.7. 
Information on Other Study-Related Therapies 
Placebo 
The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use 
(CHMP) Note for Guidance on the Clinical Investigation of Medicinal Products for the 
Treatment of Urinary Incontinence recommends that OAB trials include a placebo arm to 
account for the recognized large placebo responses commonly observed in these studies 
EMA, 2002 .  To accurately demonstrate and measure the true efficacy of vibegron, a placebo 
arm will be included in this study.  Furthermore, a single-blind Run-in Period will be used to 
assess the early placebo response and to ensure that patients have adequate experience with the 
Patient Voiding Diary prior to starting the blinded Treatment Period of the study. 
Tolterodine ER 
Tolterodine ER is an antimuscarinic approved for the treatment of overactive bladder and will be 
administered at the recommended labeled dose of 4 mg once daily (QD) orally.  In this study, 
tolterodine ER 4 mg will be used as an active control. 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Efficacy Endpoints 
Primary Efficacy 
To evaluate the efficacy of 
vibegron compared to placebo 
in patients with symptoms of 
OAB, specifically the frequency 
of micturitions and frequency of 
urge urinary incontinence 
episodes 
Co-primary Efficacy Endpoints: 
 Change from baseline (CFB) at Week 12 in average 
number of micturitions per 24 hours in all OAB 
patients 
 CFB at Week 12 in average number of urge urinary 
incontinence (UUI) episodes per 24 hours in OAB Wet 
patients 
Secondary Efficacy 
To evaluate the overall efficacy 
of vibegron compared to 
placebo in patients with 
symptoms of OAB 
Key Secondary Efficacy Endpoints: 
 CFB at Week 12 in average number of urgency 
episodes (need to urinate immediately) over 24 hours in 
all OAB patients 
 Percent of OAB Wet patients with at least a 75% 
reduction from baseline in UUI episodes per 24 hours 
at Week 12 
 Percent of OAB Wet patients with a 100% reduction 
from baseline in UUI episodes per 24 hours at Week 12 
 Percent of all OAB patients with at least a 50% 
reduction from baseline in urgency episodes (need to 
urinate immediately) per 24 hours at Week 12 
 CFB at Week 12 in average number of total 
incontinence episodes over 24 hours in OAB Wet 
patients 
 CFB at Week 12 in Coping Score from the Overactive 
Bladder Questionnaire Long Form (OAB-q LF, 1-week 
recall) in all OAB patients 
 CFB at Week 12 in average volume voided per 
micturition in all OAB patients 


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Objectives 
Efficacy Endpoints 
 
Additional Secondary Endpoints: 
 CFB at Week 12 in Health-related Quality of Life 
(HRQL) Total Score from the OAB-q LF (1-week 
recall) in all OAB patients 
 CFB at Week 12 in Symptom Bother Score from the 
OAB-q-LF (1-week recall) in all OAB patients 
 Percent of all OAB patients with average number of 
micturitions < 8 per 24 hours at Week 12 
 Percent of OAB Wet patients with at least a 50% 
reduction from baseline in total incontinence episodes 
per 24 hours at Week 12 
 CFB at Week 12 in overall bladder symptoms based on 
Patient Global Impression of Severity (PGI-Severity) in 
all OAB patients 
 CFB at Week 12 in overall control over bladder 
symptoms based on Patient Global Impression of 
Control (PGI-Control) in all OAB patients 
Safety 
To evaluate the safety and 
tolerability of treatment with 
vibegron 
 Incidence of adverse events 
 Clinical laboratory assessments 
 Vital signs and physical examinations 
Pharmacokinetic/Pharmacodynamic 
To evaluate the 
pharmacokinetic profile of 
vibegron in patients with 
symptoms of OAB 
To assess relationships between 
exposure and efficacy/safety in 
patients with symptoms of OAB 
receiving vibegron 
 AUC and C24 estimated from population PK modeling 
Exploratory 


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Objectives 
Efficacy Endpoints 


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Objectives 
Efficacy Endpoints 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an international, Phase 3, randomized, double-blind, placebo-controlled with active 
control (tolterodine), parallel-group, multicenter study in men and women with overactive 
bladder, to be conducted in conformance with International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice.  Enrollment of patients will include individuals with OAB Wet (those with 
UUI, the involuntary loss of urine accompanied by urgency) and OAB Dry (those without UUI). 
The study consists of a Screening Period (1 to 5 weeks), a single-blind Run-in Period (2 weeks), 
a randomized double-blind Treatment Period (12 weeks), and a Follow-up Period (4 weeks).  
Patients who complete the Week 12 Visit may be offered the opportunity to enroll in a 40-week 
double-blind extension study (RVT-901-3004), which will be conducted under a separate 
protocol, until enrollment in that study is complete.  Patients who do not enroll into the optional 
extension study will have a Follow-up Visit approximately 28 days after the patient’s last dose of 
Study Treatment (i.e., at Week 16 for patients who complete the Week 12 Visit, or 
approximately 4 weeks after withdrawal for patients who withdraw early from study 
participation).  Additionally, Unscheduled Visit(s) may be arranged at any time during the study 
for patients with study-related safety concerns, as needed. 
The study will assess the safety, tolerability, and efficacy of 75 mg vibegron versus placebo.  
Tolterodine ER 4 mg is the active control.  Patients will be randomized 5:5:4 in a double-blind 
fashion to one of three treatment arms:  vibegron 75 mg, placebo, or tolterodine ER 4 mg, all 
administered once daily for 12 weeks during the Treatment Period.  Between the Baseline and 
Week 12 Visits, patients will have study assessments at Week 4 and Week 8.  A schematic of the 
study design is shown as Figure 1. 
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (Table 1).  Details of study 
procedures are provided in Section 7. 
A schematic of the study design is shown as Figure 1. 


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Figure 1: 
RVT-901-3003 Study Schematic 
 


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4.2. 
Treatment Arms and Duration 
Refer to Section 6 for full details of Study Treatments.  Patients will be randomized 5:5:4 to one 
of the following blinded treatments during this study: 
 Vibegron 75 mg tablet + placebo capsule to match tolterodine ER 4 mg capsule; both 
oral and administered once daily 
 Placebo tablet to match vibegron 75 mg tablet + placebo capsule to match tolterodine 
ER 4 mg capsule; both oral and administered once daily 
 Tolterodine ER 4 mg capsule + placebo tablet to match vibegron 75 mg tablet; both 
oral and administered once daily 
Dosing will begin at the Baseline Visit (Day 1), and once daily dosing of the Study Treatment 
will continue through Study Day 84, the day before the Week 12 Visit. 
Patients who complete the Week 12 Visit may be offered the opportunity to enroll in a 40-week 
double-blind extension study RVT-901-3004 (which will be conducted under a separate 
protocol), until enrollment in that study is complete. 
4.3. 
Number of Participants 
Approximately 1,400 patients will be enrolled at approximately 330 study sites. 
4.4. 
Definition of Study Completion by a Patient 
A patient is considered to have completed the study if she/he completes the Week 12 Visit. 
4.5. 
End of Study Definition 
End of study is defined as the date when the last patient has either completed the study 
(see Section 4.4 for definition of completion), has discontinued from the study, or is lost to 
follow-up (i.e., the patient is unable to be contacted by the Investigator). 


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5. 
STUDY POPULATION 
5.1. 
Eligibility Criteria 
To be eligible for participation in this study, a patient must meet all the Inclusion Criteria, and 
none of the Exclusion Criteria. 
5.1.1. 
Inclusion Criteria 
1. Willing and able to provide written informed consent. 
2. 
8 years of age.  Note:  Up to 15% of patients can be male. 
3. Has a history of OAB (as diagnosed by a physician) for at least 3 months prior to the 
Screening Visit.  Note:  OAB is defined as urgency, with or without urge urinary 
incontinence (UUI), usually associated with frequency and nocturia.  Urodynamic 
evaluation is not required. 
4. Meets either the OAB Wet or OAB Dry criteria described below, based on the Patient 
Voiding Diary returned both at the Run-in Visit and Baseline Visit (all Complete Diary 
Days must be used in determining eligibility).  A minimum of 5 Complete Diary Days 
-in Visit, and 
4 Complete Diary Days are required for the diary returned at the Baseline Visit.  
Averages should not be rounded up to the whole number: 
 OAB Wet criteria: 
 
0 micturitions per Diary Day; and 
 An average of  1.0 UUI episodes per Diary Day; and 
 If stress urinary incontinence is present, the total number of UUI episodes must be 
greater than the total number of stress urinary incontinence episodes from the 
previous visit diary. 
 OAB Dry criteria: 
 
0 micturitions per Diary Day; and, 
 
0 urgency episodes per Diary Day; and 
 An average of < 1.0 UUI episodes per Diary Day; and 
 If stress urinary incontinence is present, the total number of UUI episodes must be 
greater than the total number of stress urinary incontinence episodes from the 
previous visit diary. 
Note:  Up to 25% of patients that meet OAB Dry criteria may be enrolled. 
5. For females of reproductive potential:  Agrees to remain abstinent or use (or have their 
male partner use) an acceptable method of birth control (as defined in Section  5.2.1) 
each time the patient has intercourse from the Screening Visit until completion of the 
Follow-up Visit. 
6. For females of reproductive potential:  Agrees not to donate ova (eggs) until at least 
1 month after the last dose of Study Treatment. 
7. 
 80% compliance with self-administration of Study Treatment during 
the Run-in Period. 


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8. Is ambulatory and in good general physical and mental health as determined by the 
Investigator. 
9. In the opinion of the Investigator, is able and willing to comply with the requirements 
of the protocol, including completing electronic versions of questionnaires, the Patient 
Voiding Diary, and the Urine Volume Diary (will require ability to collect, measure, 
and record voided volume by herself/himself using a graduated urine collection and 
 
5.1.2. 
Exclusion Criteria 
Urology Medical History 
1. Patient has a history of 24-hour urine volume greater than 3,000 mL in the past 6 months, 
or a Urine Volume Diary day measurement greater than 3,000 mL during the Run-in 
Period. 
2. Has lower urinary tract pathology that could, in the opinion of the Investigator, be 
responsible for urgency, frequency, or incontinence; including, but not limited to, 
urolithiasis, interstitial cystitis, prostate cancer, gastrointestinal (GI) cancer, tuberculosis, 
stone disease, urothelial tumor, prostatitis, and clinically relevant benign prostatic 
hypertrophy (BPH) or bladder outlet obstruction, as judged by the Investigator.  Note:  
Male patients with mild to moderate BPH without evidence of bladder obstruction as 
determined by the Investigator may be included as long as they have been taking a 
medication for the treatment of BPH for at a least 1-year prior to Screening, with no 
change in dose of herbal medications, alpha antagonist medications or other symptomatic 
treatments or medications within 3 months prior to Screening, and no change in dose of 
5 alpha reductase inhibitors within 6 months of Screening. 
3. Has a history of surgery to correct stress urinary incontinence, pelvic organ prolapse, or 
procedural treatments for BPH within 6 months of Screening. 
4. Has current history or evidence of Stage 2 or greater pelvic organ prolapse (prolapse 
extends beyond the hymenal ring). 
5. Patient is currently using a pessary for the treatment of pelvic organ prolapse. 
6. Has a known history of elevated post-void residual volume defined as greater than 
150 mL. 
7. Has undergone bladder training or electrostimulation within 28 days prior to Screening or 
plans to initiate either during the study. 
8. Has an active or recurrent (> 3 episodes per year) urinary tract infection by clinical 
symptoms or laboratory criteria 
5 w
 105 
 specimen).  Patients diagnosed 
with a urinary tract infection (UTI) at the Screening Visit may be treated and re-screened 
once the infection has resolved. 
9. Has a requirement for an indwelling catheter or intermittent catheterization. 
10. Has received an intradetrusor injection of botulinum toxin within 9 months prior to 
Screening. 


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Other Medical History 
11. Has uncontrolled hyperglycemia (defined as fasting blood glucose > 150 mg/dL or 
8.33 mmol/L and/or non-fasting blood glucose > 200 mg/dL or 11.1 mmol/L) or, if in the 
opinion of the Investigator, is uncontrolled. 
12. Has evidence of diabetes insipidus. 
13. Is pregnant, breast-feeding, or is planning to conceive within the projected duration of the 
study. 
14. Has a concurrent malignancy or history of any malignancy within 5 years prior to signing 
informed consent, except for adequately treated basal cell or squamous cell skin cancer or 
in situ cervical cancer. 
15. Has 
0 mmHg and/or diastolic 
 100 mmHg) or has a resting heart rate (by pulse) > 100 beats per 
minute. 
16. 
 160 mmHg but < 180 mmHg are excluded, 
unless deemed by the Investigator and/or Medical Monitor as safe to proceed in this study 
and able to complete the study per protocol; these patients must be on stable hypertension 
medication for at least 90 days. 
17. All patients with signs and symptoms of uncontrolled hypertension, regardless of blood 
pressure measurement, are excluded from the study.  These include, but are not limited to 
neurological symptoms or findings, hematuria, proteinuria, retinopathy, unstable angina, 
and acute heart failure. 
18. Has narrow angle glaucoma (primary open angle glaucoma is not excluded). 
19. Has a history of cerebral vascular accident, transient ischemic attack, unstable angina, 
myocardial infarction, coronary artery interventions (e.g., coronary artery bypass grafting 
e.g., 
neurovascular interventions (e.g., carotid artery stenting) within 6 months prior to the 
Screening Visit.  Patients with these conditions should be on stable medical therapy for at 
least 3 months prior to the Screening Visit. 
20. Has a known history of liver disease. 
21. Has a history of injury, surgery, or neurodegenerative diseases (e.g., multiple sclerosis, 
Parkinson’s) that could affect the lower urinary tract or its nerve supply. 
Laboratory/Procedure History 
22. Has hematuria, including microscopic hematuria (> 5 r
.  
Patients with known, fully evaluated, benign hematuria may participate.  Documentation 
must be obtained indicating an unremarkable upper urinary tract (kidneys and ureters) 
imaging study (e.g., 
 with and without contrast, intravenous 
pyelogram, etc.) and cystoscopy.  Patients whose hematuria has not been previously 
evaluated may not be enrolled. 
23. Has clinically significant electrocardiogram (ECG) abnormality that, in the opinion of the 
Investigator, exposes the patient to risk by participating in the study. 


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24. Has alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of 
normal (ULN), or bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to 
Gilbert syndrome or pattern consistent with Gilbert syndrome). 
25. Has clinically significant laboratory abnormality (from the Screening Visit results) that 
remains unresolved after repeat testing (Refer to Algorithm for Laboratory Testing 
Appendix B) or that could confound the results of the study or indicate that it is not in the 
best interest of the patient to participate. 
26. Has an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. 
Medication History 
27. Use of any prohibited medications as detailed in Section 7.9.3 (suitable washout periods 
from these medications are also described therein). 
28. Had changed the dose of any medications listed in Section 7.9.5 within 4 weeks prior to 
the Baseline Visit, or plans to initiate or change the dosing of any of these medications 
during the study. 
29. Has an allergy, intolerance, or a history of a significant clinical or laboratory adverse 
experience associated with any of the active or inactive components of the vibegron 
formulation or tolterodine formulation. 
Other 
30. Is currently participating or has participated in a study with an investigational compound 
or device within 28 days prior to signing informed consent. 
31. Is currently participating in or has participated in a study with vibegron. 
32. Has a history of significant drug or alcohol abuse/dependence within a year prior to 
informed consent, as assessed by the investigator. 
33. Has a varying sleep schedule anticipated during times when the voiding diaries are to be 
completed. 
34. Has coronary or neurovascular interventions planned during the duration of the study. 
35. Has a history or current evidence of any condition, therapy, lab abnormality, or other 
circumstance that might, in the opinion of the Investigator, confound the results of the 
study, interfere with the patient’s ability to comply with study procedures, or make 
participation in the study not in the patient’s best interest. 
5.2. 
On-Study Restrictions 
5.2.1. 
Contraception 
5.2.1.1. 
Female Patients 
In this study, female patients must agree to use (or have their male partner use) a highly effective 
contraception, unless any of the following apply: 
 has reached natural menopause, defined as at least 12 months of spontaneous 
amenorrhea without an alternative medical cause; 
 is permanently sterile, following hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. 


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The highly effective methods of contraception include the following: 
 combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation, which may be oral intravaginal or 
transdermal  
 progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injectable, or implantable intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™ at least 6 months prior to the initial Screening Visit 
Essure must have prior confirmation of tubal occlusion by hysterosalpi
 
 sexual partner(s) who was vasectomized at least 6 months prior to the Screening 
Visit 
 sexual abstinence from heterosexual intercourse, as a preferred lifestyle; periodic 
abstinence is not acceptable 
Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm when they sign a consent form they understand the 
requirements for avoidance of pregnancy during the course of the study. 
These methods of contraception are only effective when used consistently, correctly, and in 
accordance with the product label.  The Investigator is responsible for ensuring that patients 
understand how to properly use these methods of contraception. 
5.2.2. 
Meals and Dietary Restrictions 
Patients may consume a normal, regular diet and take their Study Treatment daily without regard 
to food or other medications. 
Patients do not need to fast prior to laboratory draws. 
5.3. 
Screen Failure 
After obtaining informed consent, study site personnel will access the interactive voice or web 
response system (IxRS) to assign a unique patient number to a potential study participant. 
For patients who provide informed consent and subsequently do not meet eligibility criteria or 
withdraw consent, study site personnel should document the screen failure in the patients' source 
documents.  The documentation should include demographics and medical history, the reason for 
screen failure, the eligibility criteria reviewed, procedures performed, etc. 
For patients excluded during Screening and Run-in, the screen failure should be reported 
promptly to IxRS. 


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5.4. 
Interruption of Study Treatment 
5.4.1. 
Temporary Interruption 
The medical monitor should be contacted for Study Treatment interruption of >7 days in 
duration.  Study treatment may be temporarily interrupted for up to 21 consecutive days if 
required for adverse event management, as described in Section 6.6. 
5.4.2. 
Rechallenge 
See Section 6.6. 
5.5. 
Withdrawal from the Study 
Patients may withdraw consent at any time for any reason or be withdrawn from the study at the 
discretion of the Investigator should any untoward effect occur.  Every effort should be made to 
establish and document the possible reasons for withdrawal.  A patient may be withdrawn by the 
Investigator or the Sponsor if enrollment into the study is inappropriate, the study plan is 
violated, or for administrative and/or other safety reasons.  The patient may be discontinued from 
further study participation after discussion between the Investigator and the Sponsor clinical 
monitor (or designee) if the patient requires therapy with any excluded medication.  Medications 
that may cause a patient to be discontinued have been described in Section 7.9.3. 
A patient must be discontinued from the study for any of the following reasons: 
 The patient or legal representative (such as a legal guardian) withdraws consent. 
 Study treatment administration is interrupted for more than 21 consecutive days. 
 The patient has a medical condition or personal circumstance which, in the opinion of 
the Investigator and/or Sponsor, places the patient at unnecessary risk through 
continued participation in the study or does not allow the patient to adhere to the 
requirements of the protocol. 
 The patient has a confirmed positive serum pregnancy test. 
 The patient is unable to complete the study procedures successfully, including 
completion of the Patient Voiding Diary. 
 When a patient withdraws from the study prior to study completion, all applicable 
activities scheduled for the Week 12 Visit should be performed at the time of 
withdrawal.  Any adverse events that are present at the time of withdrawal should be 
followed in accordance with the safety requirements outlined in Section 8. 
 Once a patient is withdrawn, he/she shall not be allowed to enroll again. 
5.6. 
Lost to Follow Up 
Should a patient fail to attend a required study visit, the site should attempt to contact the patient 
and re-schedule the missed visit as soon as possible.  The site should also counsel the patient on 
the importance of maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study based on previous non-compliance.  In cases where 
the patient does not return for the rescheduled visit or cannot be reached to reschedule the missed 
visit, the site should make every effort to regain contact with the patient so that they can 


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appropriately be withdrawn from the study with a primary reason of “Lost to Follow-up”.  
Including at least three documented attempts to contact the patient (i.e., phone, email, or certified 
letter).  Efforts to establish the possible reason for discontinuation should be documented. 
5.7. 
Early Study Termination 
The study may be terminated early if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the study population as a whole is 
unacceptable.  In addition, further recruitment in the study overall or at a particular study site 
may be stopped due to insufficient compliance with the protocol, Good Clinical Practice (GCP) 
and/or other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high. 


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6. 
STUDY TREATMENT 
6.1. 
Study Treatments Description 
Study treatment is defined as vibegron, tolterodine, or matching placebo for vibegron or 
tolterodine.  All Study Treatments will be provided by the Sponsor. 
Each Study Treatment is described in Table 3. 
Table 3 
RVT-901-3003 Study Treatments 
Study Treatment 
Dose 
Frequency; Route of 
Administration; 
Description 
Use 
Vibegron 
75 mg 
Once daily; oral; 
tablet 
Experimental 
Tolterodine ER 
4 mg 
Once daily; oral; 
capsule 
Active control 
Placebo to match vibegron 75 mg 
NA 
Once daily; oral; 
tablet 
Placebo control and 
Blinding 
Placebo to match tolterodine ER 
4 mg 
NA 
Once daily; oral; 
capsule 
Placebo control and 
Blinding 
 
6.2. 
Administration of Study Treatments 
Throughout the study, all Study Treatments will be taken by mouth once daily in the morning 
with 8 ounces of water and should be swallowed whole.  Study treatment may be taken without 
regard to meals. 
During the Run-in Period, all patients will take placebo (1 tablet and 1 capsule) once daily for 
2 weeks prior to the Baseline Visit.  The Investigator will be aware that the Study Treatment 
during this period is placebo, however, the patient will NOT be told that the treatment 
administered during this period is placebo or that the patient needs to qualify to enter the 
randomized Treatment Period. 
Study treatments will be taken either at the site or at home as follows: 
 All patients will take their dose of Study Treatment on the day of the Run-in and 
Baseline Visits at the site as a witnessed dose. 
 Patients in the population PK subset will hold their dose of Study Treatment on the 
day of the Week 4 and Week 8 Visits. 
 All other doses of Study Treatment will be taken by the patient at home. 
If a patient forgets to take Study Treatment in the morning, the missed dose should be taken as 
soon as possible on the same calendar day.  However, if a dose is missed for an entire calendar 


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day, the missed dose should NOT be taken on the following calendar day.  This will be recorded 
as a missed dose. 
6.3. 
Study Treatment Assignment 
Randomization will occur centrally using an interactive voice or web response system (IxRS) 
using central, stratified randomization.  There are three treatment arms to which patients will be 
randomized in a 5:5:4 ratio: 
 Vibegron 75 mg + placebo to match tolterodine ER 4 mg 
 Placebo to match vibegron 75 mg + placebo to match tolterodine ER 4 mg 
 Tolterodine ER 4 mg + placebo to match vibegron 75 mg 
Randomization will be stratified based on baseline category of OAB Wet or OAB Dry and Sex 
(Female vs Male). 
Enrollment will be capped based on OAB Dry criteria and sex as follows: 
 Up to 25% of the patients enrolled may meet OAB Dry criteria. 
 Up to 15% of the patients enrolled may be male. 
Note:  The proportion of OAB Dry patients and male patients during Screening will 
be monitored in IxRS.  The final proportion of OAB Dry and male patients will 
depend on both number of OAB Dry or male patients in the Screening queue at the 
time the stratum is closing and on total study enrollment. 
6.4. 
Blinding 
A single-blind (Run-in only) and double-blind/masking technique will be used:  vibegron and its 
matching placebo and tolterodine ER and its matching placebo will be packaged identically so 
that treatment blind/masking is maintained.  The patient, the Investigator, and Sponsor personnel 
or delegate(s) who are involved in the treatment or clinical evaluation of the patients are unaware 
of the treatment group assignments. 
At the end of the study (including the 28-day Follow-up Period), the official, final database will 
be frozen and unblinded after medical/scientific review has been performed, and data have been 
declared final and complete.  The Sponsor will be granted access to the unblinded database in 
order to analyze the data.  A clinical study report will be prepared after all patients complete the 
study. 
6.4.1. 
Unblinding 
All efforts should be made to contact the Medical Monitor immediately if the need for emergent 
unblinding of treatment assignment is desired.  In consultation with the Medical Monitor, IxRS 
should be used for emergency unblinding treatment assignment in the event that this is required 
for patient safety. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date and 
reason) must be documented promptly, and the Sponsor notified as soon as possible.  Only the 
Principal Investigator or delegate and the respective patient’s code should be unblinded.  Site 


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personnel and Sponsor personnel directly associated with the conduct of the study should not be 
unblinded. 
6.5. 
Dose Modification 
No dose modifications are allowed. 
6.6. 
Treatment Discontinuation and Rechallenge 
Refer to Section 8.6.1 and Section 8.6.2, respectively, for information regarding temporary 
withholding or permanent discontinuation of Study Treatment in association with liver test 
abnormalities. 
Patients who experience a grade 3 or greater toxicity that is considered related to Study 
Treatment should have their treatment discontinued permanently. 
Patients who experience an adverse event grade 3 or 4 adverse event that is not related to Study 
Treatment may have their Study Treatment interrupted for a period of up to 21 consecutive days 
if the Investigator believes it is in the best interest of the patient.  (Refer to Table 6 for Criteria 
for Determining the Grade/Severity of Adverse Event Terms).  Prior to restarting study drug, the 
adverse event must have improved to grade 0, 1, or 2. 
If the adverse event that is not related to Study Treatment remains grade 3 or grade 4 after 
treatment interruption or the Investigator believes it is in the best interest of the patient, Study 
Treatment should be discontinued permanently. 
6.7. 
Packaging and Labeling 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.  
During the Run-in Period, patients will receive a single-blind supply of Study Treatment bottles 
to support a 2-week Run-in Period and overage.  Once randomized into the study, patients will 
receive a double-blind supply of Study Treatment bottles at each study visit during the Treatment 
Period. 
6.8. 
Preparation/Handling/Storage/Accountability 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. 
Receipt and dispensing of Study Treatment must be recorded by an authorized person at the 
study site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
The Investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the patients, and the 
amount remaining at the conclusion of the study.  These records will be monitored throughout 
the study. 
For all sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return. 


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6.9. 
Study Treatment Compliance 
If a patient is persistently noncompliant with the Study Treatment, it may be appropriate to 
withdraw the patient from the study.  Interruptions from the protocol specified treatment plan for 
compliance (  75% or > 125%) require consultation between the Investigator and the Sponsor 
and written documentation of the collaborative decision on patient management. 
6.10. 
Study Treatment Overdose 
Refer to Section 8.3.3 for Overdose Management.  An overdose is defined as a known deliberate 
or accidental administration of Study Treatment, to or by a study patient, at a dose above that 
assigned to that individual patient according to the study protocol. 
For this study, any dose of vibegron or placebo > 2 tablets and any dose of tolterodine or placebo 
> 2 capsules within a 24-hour window (i.e., > 2 tablets and/or > 2 capsules of blinded Study 
Treatment within a 24-hour window) is an overdose.  There is no known antidote for an 
overdose. 
6.11. 
Treatment after the End of the Study 
Other than patients who participate in the RVT-901-3004 extension study, patients will not 
receive any additional treatment with the Study Treatment from the Sponsor after completion of 
the study because the indication being studied is not life-threatening or seriously debilitating 
and/or other treatment options are available.  The Investigator is responsible for ensuring that 
consideration has been given to the post-study care of the patient’s medical condition. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
The Schedule of Activities (Table 1) summarizes the study assessments/procedures to be 
performed at each visit.  Individual assessments and procedures are described below. 
It may be necessary to perform these procedures at unscheduled time points if deemed clinically 
necessary by the Investigator.  Furthermore, additional evaluations/testing may be deemed 
necessary by the Investigator and/or the Sponsor for reasons related to patient safety.  In some 
cases, such evaluation/testing may be potentially sensitive in nature, and thus local regulations 
may require that additional informed consent be obtained from the patient.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1. 
Order of Assessments 
Vital signs, followed by PRO questionnaires, will be the first procedures performed at visits that 
include PRO administration.  Blood draws should be performed after PRO administration.  A 
urine pregnancy test (with a negative result) must be done prior to randomization. 
7.2. 
Scheduling Visits 
To the extent possible, all visits should occur at the same time across the study between the hours 
of 8 am and 12 pm.  At the end of each visit, the next visit should be scheduled/confirmed.  
Every effort should be made to adhere to the visit scheduling window as described in the 
Schedule of Activities (Table 1) to ensure the patient has an adequate amount of Study 
Treatment to comply with protocol dosing instructions.  Patients will be reminded to complete 
the Patient Voiding Diary and Urine Volume Diary within the 7 days prior to their next visit. 
7.3. 
Unscheduled Visits 
Unscheduled Visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on adverse events, at the patient’s request, or as deemed necessary by the 
Investigator.  The date and reason for the Unscheduled Visit should be recorded in the source 
documentation.  The specific procedures performed at these visits will be determined by the 
Investigator, as clinically indicated.  The recommended minimum procedures are indicated in the 
Schedule of Activities (Table 1). 
7.4. 
Assignment of Patient Number 
All consented patients will be issued a unique patient number that will be used to identify the 
patient for all procedures that occur.  Each patient will be assigned only one unique patient 
number.  Unique patient numbers must not be re-used for different patients.  Any patient who is 
re-screened will obtain a new original unique patient number assigned at the repeated Screening 
Visit. 
7.5. 
Screening/Washout 
 Patients requiring washout of medications (see Section 7.9.3), can begin washout 
immediately following the Screening Visit.  After the 28-day washout period, site 
staff should contact patients to begin completion of the 7-day eDiary (Patient Voiding 


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Diary and Urine Volume Diary).  Patients not requiring washout can begin the 7-day 
eDiary the day after the Screening Visit. 
 After laboratory results from the Screening Visit are reviewed and found to be 
clinically acceptable, patients will be eligible to continue to the Run-in Visit.  An 
algorithm for assessing out-of-range laboratory results is in Appendix B. 
 Patients that fail Screening may be re-screened only one time when the reason for 
exclusion has resolved, such as a resolved urinary tract infection.  If a patient is 
rescreened, a unique patient number must be used.  Patients cannot be re-screened 
after receiving placebo-run in Study Treatment.  During the Screening or Run-in 
Periods, or after re-screening, if it is determined that a patient does not qualify for the 
study, he/she will be excluded.  Patients excluded during Screening should be 
reported as a screen failure promptly to IxRS. 
7.6. 
Informed Consent 
Documented consent must be obtained from each potential patient prior to participating in study 
procedures.  Consent must be documented by the patient’s dated signature on a consent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the patient before participation 
in the study. 
The initial informed consent form, any subsequent revised written informed consent form, and 
any written information provided to the patient must receive institutional review board 
(IRB)/research ethics board (REB)/institutional ethics committee (IEC) approval/favorable 
opinion in advance of use.  The patient should be informed in a timely manner if new 
information becomes available that may be relevant to the patient’s willingness to continue 
participation in the study.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures 
the patient’s dated signature. 
Specifics about a study and the study population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB/REB/IEC requirements, applicable laws and 
regulations and Sponsor requirements. 
7.7. 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee at 
the Screening, Run-in, and Baseline Visits to ensure that the patient qualifies for the study. 
All inclusion criteria must be met and none of the exclusion criteria may apply.  No eligibility 
waivers will be granted. 
Patients found ineligible during review of inclusion/exclusion will not proceed through the 
remaining Screening process. 


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Inclusion/Exclusion criteria for the eDiary completion parameters will be applied to both the 
Screening eDiary (7-day eDiary period prior to the Run-in Visit), and the Run-in eDiary (7-day 
eDiary period prior to the Baseline Visit). 
Results from the Screening Visit will be used as a basis to confirm eligibility for glucose, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and eGFR.  Urine pregnancy 
test and average blood pressure measure will be confirmed at Screening Visit and Baseline Visit 
(prior to randomization).  Concomitant medications will be reviewed at Baseline to ensure 
required stability. 
7.8. 
Medical History 
A medical history will be obtained by the Investigator or qualified designee.  Medical history 
from the 5 years prior to the Screening Visit will be collected, including all chronic and ongoing 
conditions, regardless of year diagnosed.  Medical history will include a review of any 
concurrent malignancy or history of any malignancy to confirm eligibility criteria. 
Pelvic floor physiotherapy history will be collected. 
7.9. 
Prior and Concomitant Medications 
7.9.1. 
Prior Medications 
The Investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the patient within 28 days 
prior to beginning completion of the Screening eDiary. 
All medications for the treatment of OAB taken within 1 year of the Screening Visit will also be 
recorded.  Specific details on a patient’s use of prior antimuscarinic therapy including the reason 
for discontinuation will be collected. 
Medication history will be assessed for male patients with history of mild to moderate BPH to 
ensure a stable treatment regimen that meets eligibility criteria. 
7.9.2. 
Concomitant Medications 
Concomitant medications will be reviewed and recorded at each study visit from Screening 
through Week 12 and at any Unscheduled Visits.  Patients will be informed at the study start 
regarding permissible medications during the study.  The Investigator or qualified designee will 
record all medications, if any, taken by the patient during the study.  This will include initiation 
of new medications, or changes to existing/ongoing medications. 
Upon entry into the study, patients will be instructed to report the possible need for any 
prescription or nonprescription medications immediately (and before use) to the Investigator. 
7.9.3. 
Prohibited Medications and Non-Drug Therapies 
Table 4 provides a listing of specific restrictions for concomitant therapy use during the study, 
with any necessary washout periods described.  This table provides examples of prohibited drug 
categories; however, it is not a comprehensive list of all restricted medications. 


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Use of other concomitant therapies that are listed in Section 7.9.5 are also prohibited if the 
patient’s dose has changed in the 4 weeks prior to the Baseline Visit or if the patient plans to 
initiate or change any of these therapies during the study. 
If there is a clinical indication for any therapy that is specifically prohibited during the study, 
discontinuation from Study Treatment may be required.  The Investigator should discuss any 
questions regarding this with the medical monitor.  The final decision on any supportive therapy 
rests with the Investigator and/or the patient's primary physician.  However, the decision to 
continue the patient on Study Treatment requires the mutual agreement of the Investigator, the 
Sponsor, and the patient. 
Consult the medical monitor if there is any uncertainty regarding patient use of a particular drug 
or drug class. 
Table 4: 
Listing of Prohibited Medications 
Class 
Examples 
Washout Period/Comments 
Anticholinergics 
darifenacin, fesoterodine, 
hyoscyamine, 
oxybutynin, 
propantheline, 
solifenacin, tolterodine, 
and trospium 
Patient must discontinue use at least 28 days 
prior to beginning completion of the 
Screening Patient Voiding Diary and remain 
off this therapy during the study 
Smooth muscle 
relaxants 
flavoxate, dicyclomine, 
propiverine 
Patient must discontinue use at least 28 days 
prior to beginning completion of the 
Screening Patient Voiding Diary and remain 
off this therapy during the study 
Beta-2 adrenergic 
agonists used for the 
treatment of stress 
urinary incontinence 
clenbuterol 
Patient must discontinue use at least 28 days 
prior to beginning completion of the 
Screening Patient Voiding Diary and remain 
off this therapy during the study 
Systemic beta-
2 adrenergic agonist 
terbutaline 
No washout period; patient must remain off 
this therapy during the study 
Synthetic antidiuretic 
hormones 
desmopressin 
Patient must discontinue use at least 28 days 
prior to beginning completion of the 
Screening Patient Voiding Diary and remain 
off this therapy during the study 
Beta-3 adrenergic 
agonists 
mirabegron 
Patient must discontinue use at least 28 days 
prior to beginning completion of the 
Screening Patient Voiding Diary and remain 
off this therapy during the study 
Medications with a 
narrow therapeutic 
index 
Warfarin, digoxin, 
lithium, phenytoin, 
theophylline 
Patient must not have taken this therapy 
within 28 days prior to the Screening Visit 
and remain off this therapy during the study 


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Class 
Examples 
Washout Period/Comments 
Intradetrusor 
botulinum toxins 
intradetrusor injection of 
botulinum toxin 
Patient must not have received an injection 
within 9 months prior to the Screening Visit 
and must not receive this therapy during the 
study 
7.9.4. 
Permitted Medications and Non-Drug Therapies 
Consult the medical monitor if there is any uncertainty regarding patient use of a particular drug 
or drug class. 
7.9.5. 
Requirements for Use of Stable Therapies 
Patients who are receiving any of the therapies from the list below must have been on a stable 
 28 days prior to Baseline to be eligible to enroll in the study.  Additionally, patients 
who plan to initiate or change any of the following therapies during the study are not eligible to 
enroll in the study: 
 Tricyclic antidepressants or combinations, including, but not limited to, amitriptyline, 
imipramine, and doxepin. 
 Alpha-1-antagonists, unless used for BPH treatment, in which case, stable dosing for 
3 months is required. 
 Serotonin and/or norepinephrine reuptake inhibitors, including, but not limited to, 
fluoxetine, paroxetine, and duloxetine. 
 Alpha-adrenergic agonists, including nonspecific sympathomimetic amines, such as, 
but not limited to, ephedrine, pseudoephedrine, and phenylephrine. 
 Diuretic therapy, including, but not limited to, furosemide and hydrochlorothiazide. 
 Inhaled anticholinergic, including, but not limited to, tiotropium bromide and 
ipratropium bromide. 
 Regular use of phosphodiesterase type 5 (PDE 5) inhibitors, including, but not limited 
to, tadalafil, sildenafil, and vardenafil. 
Note:  Occasional use of PDE 5 inhibitors (e.g., for the treatment of erectile 
dysfunction) is allowed throughout the study. 
Male patients with mild to moderate BPH without evidence of bladder obstruction as determined 
by the Investigator may be included as long as they have been taking a medication for the 
treatment of BPH for at a least 1-year prior to Baseline, with no change in dose of herbal 
medications, alpha antagonist medications, or other symptomatic treatments or medications 
within 3 months prior to Baseline.  To be eligible for the study, these BPH medication/s must be 
stable from Screening until Baseline Visit. 
Patients with a history of hypertension must be on a stable blood pressure treatment regimen for 
90 days prior to the Baseline Visit and must be deemed by the Investigator and/or Medical 
Monitor as safe to proceed in this study and able to complete the study per protocol. 
Patients with a history of cerebral vascular accident, transient ischemic attack, unstable angina, 
myocardial infarction, coronary artery interventions (e.g., coronary artery bypass grafting or 


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e.g., angioplasty, stent ins
interventions (e.g., carotid artery stenting) should be on stable medical therapy for at least 
3 months prior to the Screening Visit until the Baseline Visit and anticipated to be stable 
throughout the study. 
7.9.6. 
Washout of Prior Medications 
All consented patients meeting the Screening Visit entry criteria that are taking certain 
medications (as outlined in Section 7.9.3) will be required to begin wash-out of these 
medications following the Screening Visit for a minimum of 28 days prior to beginning 
completion of the Screening Patient Voiding Diary.  These medications must not be used from 
the point of initiation of washout following the Screening Visit, through the Week 12 Visit. 
7.10. 
Patient Voiding Diary 
The Patient Voiding Diary is used by participants (via the eDiary or paper Diary) to record the 
frequency of daily OAB symptoms including all micturitions, urgency, incontinence, and main 
reason for incontinence by selecting the respective box for each symptom occurring during the 
course of a given day and night. 
The Patient Voiding Diary should be completed by the patient on all of the 7 days prior to the 
Run-in Visit, Baseline Visit, Week 2 (diary only; no clinic visit), and the Weeks 4, 8, and 12 
Visits. 
Patients will complete the Patient Voiding Diary between the Screening Visit and Run-in Visit 
(over the 7 days prior to the Run-in Visit).  After the Screening Visit, patients not requiring 
wash-out can begin the Patient Voiding Diary the morning after the Screening Visit (upon 
getting up for the day).  Patients requiring wash-out of medications can begin completing the 
Patient Voiding Diary after the 28-day wash-out period. 
Patients will also complete the Patient Voiding Diary between the Run-in Visit and the Baseline 
Visit (over the 7 days prior to the Baseline Visit, while the patient is taking Run-in Study 
Treatment). 
A “Diary Day” is defined as the time between when the patient gets up for the day each morning 
(i.e., the time the patient got up for the day yesterday to the time the patient got up for the day 
today; approximately a 24-hour period). 
A “Complete Diary Day” is defined as a Diary Day for which the patient indicates that they 
have recorded all urinations and any leakages that occurred during that Diary Day.  Specifically, 
on the eDiary the patient will respond Yes to the corresponding item in the Begin Day 
Questionnaire to indicate that their data are complete for the preceding Diary Day. On the paper 
Patient Voiding Diary the patient will check Yes in response to the question “Did you record 
each time you urinated or leaked during this diary day?”  
If a subject completes more than the required 7 days of entry in the Diary, only “Complete” 
Diary Days within 10 days prior to the current visit are used to calculate eligibility.   
To be eligible for the study, patients must have a minimum of: 


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 5 Complete Diary Days (not necessarily consecutive) during the Screening Period 
(over the 7 days prior to the Run-in Visit), and  
 4 Complete Diary Days (not necessarily consecutive) during the Run-in Period (over 
the 7 days prior to the Baseline Visit), and  
 be capable in the Investigator’s opinion of maintaining compliance with the diary 
requirements, including the measurement and recording of urine volume, as required, 
at Baseline and throughout the course of the study.  
To meet eligibility, patients must meet either the OAB Wet or OAB Dry criteria at the Run-in 
Visit and then the Baseline Visit, based on their Patient Voiding Diary data.  Patients will be 
randomized to the appropriate stratum based on which criteria are met at the Baseline Visit.  
When both components are present, the classification is specified as the predominant component. 
7.10.1. 
Patient Voiding Diary Training/Re-Training 
All Visits 
The site staff should inquire whether patients had any difficulties with the diary and address any 
questions patients may have. 
Instructions for proper completion of the Patient Voiding Diary should be re-reviewed, and, if 
available, patients may view an instructional video to reinforce their understanding of Patient 
Voiding Diary instructions. 
Patients will be trained to enter data immediately following each event (in real time) and to input 
data from any “missed” events as soon as they are able. They will review and confirm that data 
from all events occurring within the preceding Diary Day (approximately 24 hours) have been 
entered at a consistent time each morning (e.g., upon getting up for the day). 
Run-in and Baseline Visits 
Responses to the Patient Voiding Diary will be reviewed by the site staff to assess whether 
patients are capable of completing the diary and if patients meet eligibility criteria.  The daily 
averages for micturitions, urgency episodes, and UUI episodes will be calculated as average of 
the total by the number of events on Complete Diary Days.  Patients who do not meet the OAB 
entry criteria will be excluded from the study. 
7.11. 
Urine Volume Diary 
Urine volume data are collected separately by patients using the Urine Volume component of the 
eDiary, or the paper Urine Volume Chart.  The Urine Volume Chart is a tool routinely used in 
clinical practice and clinical investigation to assess voiding functions over a 24-hour period and 
is regarded as a useful instrument in the investigation of patients with voiding symptoms. Urine 
volume may be collected during any one (1) of the 7 Diary Days prior to the visit, and it should 
be recorded for ~24-hours starting from the time the patient gets up for the day and continues 
until the time the patient gets up for the day on the next day.   
Patients will be asked to complete the Urine Volume Diary to record their urine volume passed 
during that day. The Urine Volume collection and Urine Volume Diary completion should be 
performed by the patient on a day that they choose for one (1) complete day of the 7 days prior to 


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the Run-in Visit, Baseline Visit, and Week 2 (Diary only; no cinic visit), and the Weeks 4, 8, and 
12 Visits. The definition of a Diary Day and data entry instructions will be the same as for the 
Patient Voiding Diary (i.e., the data should be recorded in real time, morning to morning). 
7.11.1. 
Urine Volume Collection Training/Re-Training 
At the Screening Visit, all patients will receive detailed instructions on urine volume collection 
and measurement and/or be provided and review instructions with site staff.  The site staff should 
demonstrate how to measure a volume of water in a sample collection supplies before asking 
patients to demonstrate their ability to measure a volume of water as practice.  At each 
subsequent visit the site staff should confirm the patient’s understanding and ability to measure a 
volume of water as practice. 
Patients should be instructed that on the days the paper Urine Volume Chart Diary is completed: 
 Every micturition recorded on the Patient Voiding Diary must have a corresponding 
entry recorded on the Urine Volume Chart (this is automatically done on the eDiary). 
 Every entry recorded on the Urine Volume Chart must have a corresponding 
micturition recorded on the Patient Voiding Diary (this is automatically done on the 
eDiary). 
Site staff should reinstruct the patient on Urine Volume collection procedures as needed. 
Instructions for proper completion of the Urine Volume Chart should be re-reviewed, and, if 
available, patients may view an instructional video to reinforce their understanding of the Urine 
Volume Chart and collection instructions. 
7.11.2. 
Dispense Urine Collection and Measurement Supplies 
The urine collection and measurement container (if needed) are reusable and should be rinsed by 
patients and reused for the days that they will be collecting their urine volume throughout the 
study.  Patients should be reminded to keep the urine collection container with them during the 
period of time when urine volume is being collected. 
7.12. 
Reminders for Diary Collection 
The site will phone the patient on approximately the first day and the third (or next business 
days) of the 7 Diary collection days. Patients will be reminded to enter data immediately 
following each micturition (in real time); they will also be asked to input data from any “missed” 
events and confirm that data from all micturitions occurring within the preceding 24 hours have 
been entered at a consistent time each morning (e.g., upon getting up for the day). Patients 
participating in the PK subset will be reminded to withhold Study Treatment on the morning of 
the study visit for PK sampling (patients in population PK subset only). 
Patients may consent to receive additional reminders via SMS text to their personal mobile 
phone. In addition to visit reminders, these diary completion reminders will be sent the day 
before each diary collection period begins (to remind patients to start diary completion) and two 
days prior to the end of each diary collect window (to ensure urine volume collection has been 
completed prior to the visit).   


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7.13. 
Electronic Diary 
The Electronic Diary (eDiary) for this study includes both the Patient Voiding Diary, and the 
Urine Volume Diary, and will be implemented via an eDiary device (provisioned smartphone).  
Paper diaries will be provided to all patients to be used when necessary.  When a paper diary is 
used, it should be collected at each visit.  
7.13.1. 
eDiary Device Set-Up and Training 
Device Setup/Function Check 
The eDiary device will be set-up by the site at the Screening Visit and dispensed to the Patient.  
At each subsequent visit, site personnel will check that the device is functioning correctly.  
Instructions on how to perform the set-up task will be provided by the Sponsor. 
7.13.2. 
Device Training/Re-Training 
Prior to study initiation, site staff will be trained on how to instruct patients on the use of the 
eDiary.  Training materials for site staff, including general instructions and specific questions 
relating to completion of the eDiary, will be provided to each site and should be used as a guide 
on how to instruct patients. 
At the Screening Visit, site staff will carefully explain the collection of the Patient Voiding Diary 
and Urine Volume Diary on the eDiary device to patients and will clearly demonstrate how to 
record the occurrence of urinating in the toilet (micturition), episodes of needing to urinate 
immediately (urgency), and episodes of accidental urine leakage (incontinence) along with the 
main reason for leakage.  Site staff will answer any questions that patients may have and will 
instruct patients to call the site with any questions they may have about the eDiary after they 
have left the clinic.  Patients will complete the eDiary for several example situations prior to 
taking the eDiary home. 
At subsequent visits, patients will be reinstructed as needed. Instructions for proper completion 
of the eDiary should be re-reviewed, and, if available, patients may view an instructional video 
to reinforce their understanding. 
7.14. 
Patient-Reported Outcomes 
Patients will complete paper questionnaires at the site at the start of each required study visit to 
assess patient-perceived symptom relief, symptom bother, and health-related quality of life at the 
study visits.  These include the following questionnaires: 
 Global Impression Items include Patient Global Impression of Severity 
(PGI-Severity), Patient Global Impression of Control (PGI-Control), Patient Global 
Impression of Frequency (PGI-Frequency), Patient Global Impression of Leakage 
(PGI-Leakage), and Patient Global Impression of Change (PGI-Change). 
 Overactive Bladder Questionnaire (OAB-q long form 
-q L
, 1-week recall) 
is a multi-item questionnaire that was developed to assess symptom bother and the 
impact of overactive bladder on health-related quality of life.  The instrument was 
developed and validated in both continent and incontinent OAB patients, including 
both men and women. 


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 Work Productivity and Activity Impairment Questionnaire-Urinary Symptoms 
(WPAI-US), version 2.0, is a 6-item questionnaire that assesses health-related work 
productivity loss due to urinary symptoms with a 1-week recall period. 
 The EQ-5D health questionnaire is a standardized instrument for use as a measure of 
Rabin, 2014 .  It is applicable to a wide range of health conditions 
and treatments; it provides a simple descriptive profile and a single index value for 
health status. 
The Investigator should not provide any additional information to patients prior to completing 
the questionnaires which might influence responses. 
7.15. 
Post-Void Residual Volume 
The risk of acute urinary retention or morbidities related to an increase in Post-Void Residual 
(PVR) is a concern with antimuscarinic therapy that promotes smooth muscle relaxation by 
inhibiting acetylcholine-induced smooth muscle contraction.  If, during contraction, the bladder 
cannot generate enough pressure to overcome the outlet resistance in the urethra, either because 
of poor detrusor contractility or profound obstruction (most commonly from BPH), acute urinary 
retention or incomplete emptying of the bladder may result. 
The volume of urine that remains in the bladder after voiding (PVR) is an objective measurement 
that may serve as a proxy for impaired ability to void.  The physician should assess patients with 
an increase in PVR for an adverse event. 
PVR will be performed via ultrasound at the visits indicated in the Schedule of Activities 
(Table 1).  All efforts will be made to ensure the same device and operator are used for all PVR 
volume measurements for individual patients. 
7.16. 
Physical Examination 
Complete physical examinations will include a digital rectal examination for men at the 
Screening Visit to confirm entry criteria. 
Focused physical examinations will be performed at the Run-in and Follow-up Visit and will 
include examination of heart, lungs, abdomen, and pelvic exam (only as needed to confirm 
prolapse), as well as any other organ system in which a previous abnormality was noted at 
Baseline or relates to a patient complaint of an adverse event. 
7.17. 
Electrocardiogram 
A single twelve-lead ECG will be performed at the Screening Visit and may be performed, as 
clinically indicated, at an Unscheduled Visit. 
ECG should be performed after 10 minutes of rest in a semi-recumbent position. 
7.18. 
Vital Signs 
Vital signs including blood pressure, heart rate, respiration rate, and temperature (oral or 
tympanic) will be obtained at all visits after patients have rested quietly in a sitting position for 
5 minutes. 


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Three blood pressure measurements will be taken in a sitting position and performed on the same 
arm and by the same site staff, if possible, for each patient throughout the study.  The following 
instructions should be followed: 
 Sitting systolic and diastolic blood pressures will be determined by averaging 
3 replicate measurements obtained 1 to 2 minutes apart.  The average of the 
3 replicate blood pressure measurements will be used for eligibility and safety 
assessments (not an individual value). 
The same method for assessing temperature should be used at all visits for a particular patient. 
Body weight will be measured with patients in street clothing with jacket/coat and shoes 
removed. 
Standing height will be measured without shoes at Screening only. 
7.19. 
Adverse Events 
Spontaneously reported adverse events will be recorded at each visit.  The Investigator or site 
staff is responsible for detecting, documenting, and reporting events that meet the definition of 
an adverse event or serious adverse event.  See Section 8 for details on adverse event definitions 
and reporting. 
7.20. 
Clinical Laboratory Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this study are 
provided below.  The total amount of blood/tissue to be drawn/collected over the course of the 
study (from pre-study to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per patient can be found in Appendix C. 
Please refer to the Schedule of Activities (Table 1) for specific laboratory tests performed at each 
study visit. 
7.20.1. 
Chemistry, Hematology, and Urinalysis (Laboratory Safety Evaluations) 
Laboratory tests for chemistry, hematology, and urinalysis are specified in Table 5.  Patients do 
not need to fast prior to laboratory safety tests. 
Analysis of hematology and chemistry will be performed by the central laboratory chosen by the 
Sponsor.  A urine dipstick and urine pregnancy test (for women of childbearing potential) will be 
performed at the site (supplied by the central laboratory).  A sample for urinalysis (including 
e 
central laboratory only if the urine dipstick tests positive for the presence of leukocytes, nitrites, 
or blood cells.  If a patient reports symptoms that are suggestive of a uriary tract infection at any 
visit, a urine dipstick should be performed and a sample sent for urinalysis and culture, as 
needed. 
If all laboratory values are within the normal reference range, the patient may continue to be 
evaluated for study entry.  If one or more values fall outside the normal range, the Investigator 
may either exclude the patient from the study or investigate further to determine clinical 


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relevance.  Please refer to Appendix B for an algorithm for assessing out-of-range laboratory 
values. 
Table 5: 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysisa 
Other 
Hematocrit 
Albumin 
Blood 
-human 
chorionic gonadotropin 
-hCG)b  
Hemoglobin 
Alkaline phosphatase 
Glucose 
 
Platelet count
Alanine aminotransferase 
(ALT) 
Protein 
 
WBC (total 
and 
differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity 
 
RBC 
Bicarbonate 
Microscopic exam, 
(RBCs, WBCs, epithelial 
cells, and bacteria) 
 
 
Calcium 
pH 
 
 
Chloride 
Color 
 
 
Creatininec 
-
hCG) 
 
 
Glucose (fasting or non-
fasting) 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubind 
 
 
 
Blood Urea Nitrogen 
 
 
 
Total Cholesterol 
 
 
a. 
A sample for urinalysis and urine culture will be sent to the central laboratory only if the urine dipstick 
performed at the site tests positive for the presence of leukocytes, nitrites, or blood cells. 
b. 
-hCG will be tested for women of childbearing potential only.  
-hCG is 
-
hCG must be performed. 
c. 
eGFR will be calculated and reported by the central lab. 
d. If total bilirubin is elevated above the upper limit of normal. 


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7.20.2. 
-hCG 
-hCG pregnancy test at each study 
visit indicated on the Schedule of Activities (Table 1).  A urine pregnancy test (supplied by the 
central laboratory) will be performed at the site.  
-hCG test must be followed 
-hCG pregnancy test.  A positive pregnancy test prior to randomization 
requires exclusion.  A positive 
-hCG test after randomization requires immediate 
interruption of Study Treatment 
-hCG is performed and found to be negative.  
Patient must be discontinued from the study and followed if pregnancy is confirmed by a 
-hCG. 
7.21. 
Dispense Single-Blind Run-in Study Treatment 
At the Run-in Visit, single-blind Study Treatment will be dispensed to patients, as described in 
Section 6. 
7.22. 
IxRS Randomization to Study Treatment 
A unique 
 patient number will be allocated to each subject during the Screening Visit 
using the IxRS.  The identifier will consist of 
 
.  The patient number identifies the patient for all procedures occurring 
after screening.  Once a patient number is assigned to a patient, it can never be re-assigned to 
another patient. 
At the Baseline Visit, all eligible patients will be randomly allocated to double-blind Study 
Treatment using IxRS. 
7.23. 
Dispense Double-Blind Study Treatment 
At the Baseline, Week 4, and Week 8 Visits, double-blind Study Treatment will be dispensed to 
patients, as described in Section 6, and according to their randomized treatment assigned per 
IxRS. 
7.24. 
Study Treatment Return/Accountability Review 
Patients should bring all unused study drug to each study visit.  A complete tablet/capsule count 
will be performed, and results will be recorded as the primary source of patient Study Treatment 
compliance.  Tablet/capsule counts will also be recorded in the IxRS.  All patients should be 
reinstructed regarding dosing compliance during study visits.  The authorized study personnel 
conducting the re-education must document the process in the patient’s source records. 
7.25. 
Administer Witnessed Dose of Study Treatment 
Study treatments will be taken as a witnessed dose as described in Section 6.2. 


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7.26. 
Pharmacokinetic (PK) Sampling (PK Subset Only) 
7.26.1. 
Pharmacokinetic Sample Collection 
PK sampling will be conducted in a sub-population of patients (approximately 30% of the total 
study population) at selected sites for assessment of the effect of demographic covariates by 
population PK analysis.  The patient must consent to participate in PK sampling. 
PK samples should be collected during the clinic visit after all other study assessments have been 
completed. 
Pre-dose PK samples will be collected at three visits:  Week 4, Week 8, and Week 12.  The time 
of last dose of study medication (taken the day prior to the visit) should be recorded. 
Details regarding the collection procedure, handling, storage, and shipment of these samples will 
be provided by the central laboratory. 
Continuation into Extension Study 
Patients who complete the Week 12 Visit may be offered the opportunity to enroll in a 40-week 
double-blind extension study (RVT-901-3004), which will be conducted under a separate 
protocol, until enrollment in that study is complete. 
Participation in the extension study is separate from this study and is optional.  Patients will 
provide separate informed consent to participate in the extension study. 
7.27. 
Follow-up Visit 
For patients who do not enroll in the optional extension study (RVT-901-3004), the Follow-up 
Visit should be performed 28 days after the patient’s last dose of Study Treatment to collect 
information about any serious adverse events that occurred during this period.  For a patient who 
discontinues Study Treatment early, the Follow-up Visit should occur 28 days after the last dose 
of Study Treatment.  
28 days after the patient’s 
last dose of Study Treatment, that visit will serve as the Follow-up Visit.  Safety labs may be 
collected for the evaluation of adverse experiences during discontinuation at the discretion of the 
Investigator. 


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8. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations, vital signs (and 
weight), and clinical laboratory tests. 
8.1. 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
patient, temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product or protocol-specified procedure, whether or not considered related to the 
medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the Sponsor’s product, is also an adverse event. 
Events meeting the definition of an adverse event include: 
 A worsening, excluding minor fluctuations, in the nature, severity, frequency, or 
duration of a pre-existing condition; 
 A new condition detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study; 
 Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate 
medical events (e.g., for a fall secondary to dizziness, both “dizziness” and “fall” 
should be recorded separately); 
 An investigational abnormality (e.g., laboratory parameter, vital sign, ECG) only if 
the abnormality is considered clinically significant by the Investigator based on at 
least one of the following criteria: 
 Induces clinical signs or symptoms; 
 Requires active intervention; 
 Requires interruption or discontinuation of Study Treatment. 
 Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication. 
 Events that do not meet the definition of an adverse event include: 
 The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the patient’s 
condition; 
 Medical or surgical procedure (e.g., endoscopy, appendectomy) should be entered 
into the eCRF.  If not planned prior to signing the informed consent, the condition 
that leads to the procedure is reported as an adverse or serious event, as appropriate.  


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Periodic procedures for routine maintenance of a medical device should not be 
considered associated with an adverse event (e.g., expected change of a stent); 
 Situations where an untoward medical occurrence did not occur (e.g., planned 
hospitalization for an elective procedure, with elective defined as known or planned 
at the time of signing of the informed consent; social and/or convenience admission 
to a hospital); 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
Adverse events that occur during the study should be evaluated by the Investigator and assessed 
for causal relationship to Study Treatment and severity, as described in Section 8.4 and 
Section 8.5.  Episodic adverse events, such as vomiting, or those that occur repeatedly over a 
period of consecutive days are “intermittent”.  All other events are “continuous”.  Additional 
information on detecting, documenting, and reporting adverse events and serious adverse events 
are provided below.  No toxicity-related dose reductions of Study Treatment are permitted; 
however, Study Treatment can be held for a period of up to 21 days for evaluation and treatment 
of an adverse event.  The Study Treatment may be restarted if deemed safe for the patient by the 
Investigator. 
8.2. 
Definition of a Serious Adverse Event 
If an event is not an adverse event per Section 8.1, then it cannot be a serious adverse event if 
serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc.).  A serious adverse event is any untoward medical 
occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the patient was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the patient has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred 
or was necessary, the adverse event should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 


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interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect 
f. Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
8.3. 
Adverse Event Reporting 
The Investigator or site staff is responsible for detecting, documenting, and reporting events that 
meet the definition of an adverse event or serious adverse event. 
The reporting of serious adverse events by the sponsor (Urovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the Investigator to report serious 
adverse events to their local IRB, REB, or IEC, as required by their local IRB/REB/IEC 
requirements. 
Care will be taken not to introduce bias when detecting adverse events and/or serious adverse 
events.  Open-ended and non-leading verbal questioning of the patient is the preferred method to 
inquire about adverse event occurrence.  Appropriate questions include: 
 “How are you feeling?” 
 “Have you had any (other) medical problems since your last visit/contact?” 
 “Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact? 
The patient’s eDiary entries and responses to questionnaires used in the study will not be used as 
a primary means to collect adverse events however, they should be reviewed by the study site 
personnel and the study monitors.  Should the Investigator or site staff become aware of a 
potential adverse event through the information collected with these instruments, proper follow-
up with the patient for medical evaluation should be undertaken.  Through this follow-up, if it is 
determined that an adverse event not previously reported has been identified, normal reporting 
requirements should be applied. 
All patients who experience an adverse event will be evaluated at appropriate time intervals and 
followed until the event resolves, becomes stable or chronic, or the patient is deemed lost to 
follow-up.  At the conclusion of the study, the Investigator and medical monitor will assess 
unresolved adverse events and determine if additional/continued follow-up is warranted. 
All adverse events, whether related to the Study Treatment or not, must be fully and completely 
documented on the adverse event case report form and in the patient’s source documents.  In 
addition, any adverse event resulting in permanent treatment discontinuation must be recorded 


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on the appropriate case report form as well as documented in the patient’s source documents.  
Adverse event terms should include a diagnosis, as available, in preference to listing the 
individual signs and symptoms.  If the diagnosis is not known, the Investigator should record 
each sign and symptom as an individual adverse event. 
Reporting for overdose and for pregnancy in the patient or patient’s partner will be reported as 
described in Section 8.3.3 and Section 8.7, respectively. 
8.3.1. 
Period for Reporting Adverse Events 
Adverse events and serious adverse events will be collected from the time a patient provides 
informed consent to participate in the study until the Follow-up Visit is completed approximately 
28 days after the last dose of Study Treatment or the date of initiation of another investigational 
agent, an alternate therapeutic drug for overactive bladder, or surgical intervention for overactive 
bladder, whichever occurs first.  Serious adverse events reported to the Investigator after the 
safety reporting period should be reported to the sponsor if the Investigator assesses the event as 
related to the Study Treatment. 
Reporting instructions for serious adverse events are provided in Section 8.3.2. 
8.3.2. 
Reporting Serious Adverse Events 
All serious adverse events must be reported in the eCRF within 24 hours of the study site 
personnel’s knowledge of the event, regardless of the Investigator assessment of the 
relationship of the event to Study Treatment. 
The event term, start date, severity, and initial causality assessment must be entered in the 
Adverse Event eCRF page and the event must be marked as “Serious”.  This will activate 
additional assessment fields including “action taken with study drug”, “seriousness criteria”, and 
“brief description” which should be completed as soon as information is available.  Marking the 
event as “serious” will automatically send required notifications for Sponsor review. 
The initial serious adverse event report should include: 
 The date of the report; 
 A description of the serious adverse event (event term, seriousness of the event, date 
of onset, intensity); and 
 Causal relationship to the Study Treatment. 
A discharge summary should be provided for all hospitalizations.  If the patient died, the report 
should include the cause of death as the event term (with death as the outcome) and whether the 
event leading to death was related to Study Treatment, as well as the autopsy findings, if 
available. 
Do not delay reporting a suspected serious adverse event to obtain additional information.  Any 
additional information, if collected, can be reported as a follow-up to the initial report. 
All patients who experience a serious adverse event will be evaluated at appropriate time 
intervals and followed until the event resolves, becomes stable or chronic, or the patient is 
deemed lost to follow-up.  Serious adverse events reported to the Investigator after the safety 


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reporting period should be reported to the sponsor if the Investigator assesses the event as related 
to the Study Treatment. 
8.3.3. 
Study Treatment Overdose Management 
The medical monitor must be contacted in the event of any Study Treatment overdose. 
An overdose is defined as a known deliberate or accidental administration of Study Treatment, to 
or by a study patient, at a dose above that assigned to that individual patient according to the 
study protocol. 
For this study, any dose of vibegron or placebo > 2 tablets and any dose of tolterodine or placebo 
> 2 capsules within a 24-hour window (i.e., > 2 tablets and/or > 2 capsules of blinded Study 
Treatment within a 24-hour window) is an overdose.  There is no known antidote for an 
overdose. 
In the event of an overdose, the Investigator or treating physician should: 
 Contact the medical monitor immediately; 
 Closely monitor the patient for adverse events and laboratory abnormalities; 
 Report all overdose events within 24 hours of awareness by the study site, using a 
serious adverse event form according to Section 8.3.2, whether or not the overdose is 
associated with an adverse event; 
 If possible, obtain a plasma sample for PK analysis within 2 days from the date of the 
last dose of Study Treatment if requested by the medical monitor (determined on a 
case-by-case basis); 
 Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF. 
The medical monitor, in consultation with the Investigator, will make decisions regarding patient 
status and potential dose interruptions, based on the clinical evaluation of the patient. 
8.4. 
Assigning Causal Relationship to Study Treatment 
The reasonable possibility of the relationship of an adverse event to Study Treatment is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
following definitions are to be used for the relationship of the adverse event to Study Treatment: 
 Probably related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely attributed to 
concurrent disease or other drugs or chemicals, or that follows a clinically reasonable 
response on re-administration (rechallenge) or withdrawal (dechallenge). 
 Possibly related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug but that could also be 
explained by concurrent disease or other drugs or chemicals.  Information on drug 
withdrawal may be lacking or unclear. 
 Not related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable and/or 


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in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
All adverse events, whether related to Study Treatment or not, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, the primary reason for 
withdrawal (i.e., due to an adverse event) must be recorded on the eCRF as such. 
8.5. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as a 
severe headache.  This is not the same as “serious,” which is based on patient/event outcome or 
action taken. 
The Investigator must determine the severity of each adverse event according to the criteria in 
Table 6. 
Table 6 
Criteria for Determining the Grade/Severity of Adverse Event Terms 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically 
significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 
8.6. 
Adverse Events of Clinical Interest 
Selected non-serious and serious adverse events will be reported as Adverse Events of Clinical 
Interest (AECI) and must be reported within 24 hours of the study site personnel’s knowledge 
of the event as an AECI by marking the appropriate box on the AE eCRF form and assigning the 
most appropriate category.  Additional information requested should be provided as directed in 
the eCRF Completion Guidelines (eCCGs). 
AECIs that also meet the definition of a serious adverse event must be reported as a serious 
adverse event, as described in Section 8.3.2. 


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Adverse Events of Clinical Interest for this study include: 
 
Potential Major Adverse Cardiac and Cerebrovascular Events (MACCE), which will be 
adjudicated by an independent external expert clinical adjudication committee (CAC) 
into the following categories according to the definitions in the CAC Charter: 
 
Death or any event with fatal outcome 
 
Myocardial infarction / Heart Attack 
 
Cerebrovascular Accident / Stroke 
 
Hospitalization for Unstable Angina / Chest Pain 
 
Hospitalization for Heart Failure 
 
Coronary revascularization / Angioplasty / Stent 
 
Hypertension: 
An adverse event of hypertension should be reported and will be an AECI as follows: 
 
For patients without hypertension (average SBP <140 mmHg, DBP <90 mmHg) 
at baseline, at two consecutive visits, the average of three systolic blood 
pressure (SBP) 
 mmHg or diastolic blood pressure (DBP) 
 mmHg (or 
both); at 2 consecutive visits in patients who were not hypertensive at baseline; 
or, 
 
For patients with hypertension at baseline, an increase compared to baseline at 
2 consecutive visits in the average of three SBP by 
 mmHg OR DBP 
by 
 mmHg;  
 
Initiation of, or increase in dose of, medication for treatment of hypertension in 
any patient. 
 
Adverse events consistent with orthostatic hypotension as confirmed by orthostatic vital 
signs. 
 
Adverse events suggestive of cystitis or urinary tract infection. 
 
Elevated AST or ALT lab value requiring that study drug be temporarily withheld or 
permanently discontinued (see Section 8.6.1 and Section 8.6.2). 
Note:  These criteria are based upon available regulatory guidance documents.  The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  Study site guidance for assessment and follow up of these 
criteria can be found in the Study Reference Manual. 
8.6.1. 
Criteria for Temporary Withholding of Study Treatment in Association with 
Liver Test Abnormalities 
Elevated liver enzymes or bilirubin sufficient to require withholding study medication must be 
reported within 24 hours of the study site personnel’s knowledge of the event using AECI 
specific eCRFs/forms/worksheets provided for the study. 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
FDA, 2009  


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If the following liver test abnormalities develop, Study Treatment should be withheld 
immediately with appropriate clinical follow-up (including repeat laboratory tests, until a 
patient’s laboratory profile has returned to normal/baseline status), and the event reported as a 
serious adverse event: 
 ALT or AST > 8 x ULN; or 
 ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
 ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalized 
ratio (INR) > 1.5 
 ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The Investigator and sponsor must discuss and agree with any decision to rechallenge. 
Rechallenge should not occur when the etiology of the liver test abnormalities is considered 
possibly drug induced. 
8.6.2. 
Criteria for Permanent Discontinuation of Study Treatment in Association with 
Liver Test Abnormalities 
Study treatment should be discontinued permanently if all of the following 4 criteria are met (i.e., 
potential severe drug-induced liver injury/Hy’s law case): 
1. Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
2. 
3 x ULN; AND 
3. Alkaline phosphatase value does not reach 2 x ULN; AND 
4. No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to the following: 
 Hepatobiliary tract disease; 
 Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus); 
 Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms; 
 Alcoholic hepatitis; 
 Non-alcoholic steatohepatitis; or 
 Autoimmune hepatitis. 
If an alternative cause for hepatotoxicity is identified, then it should be determined (based on the 
severity of the hepatotoxicity or event) whether Study Treatment should be withheld or 
permanently discontinued as appropriate for the safety of the patient. 


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8.7. 
Pregnancy Management and Reporting to the Sponsor 
If any patient or female partner of a patient becomes pregnant during the study, the site must 
discontinue the patient from Study Treatment immediately and have the patient return for an 
Early Withdrawal Visit (Week 12 Visit activities).  The Investigator must inform the patient of 
their right to receive treatment information.  If the patient chooses to receive unblinded treatment 
information, the individual blind should be broken and the treatment assignment provided to the 
patient.  The study team will remain blinded to the patient’s treatment assignment. 
In the case of a pregnant patient, if she agrees, the Investigator should notify the patient’s 
primary care physician of the pregnancy and provide details of the patient’s participation in the 
study and treatment (blinded or unblinded, as applicable). 
In the case of a male patient with a pregnant partner, if the patient agrees, the patient’s pregnant 
partner should be notified and requested to sign a Release of Information form, permitting 
transfer of information regarding the pregnancy and outcome to the sponsor. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the pregnancy reporting forms and the contact information in Section 8.3.2.  
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result, neonatal data, etc. should be included in this 
information, as available. 
The Investigator will follow the medical status of the mother, the pregnancy, as well as the 
outcome of the infant at birth, and will report the outcome to the sponsor. 
8.8. 
Benefit/Risk Assessment 
Patients may not expect to receive direct benefit from treatment during participation, as this 
study is designed to provide information about the safety and effectiveness of an investigational 
medicine compared to placebo.  Some patients will receive tolterodine, an approved medication 
for treating overactive bladder with symptoms of urinary frequency, urgency, and leakage. 
Additional details about vibegron may be found in the current vibegron Investigator’s Brochure 
(IB) and Informed Consent documents. 


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9. 
STATISTICAL CONSIDERATIONS 
This section contains a brief summary of the statistical analyses for this study; full details shall 
be provided in the Reporting and Statistical Analysis Plan. 
9.1. 
Responsibility for Analyses/In-House Blinding 
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee of the Sponsor. 
The study will be conducted as a double-blind study.  The randomized allocation schedule will 
be generated by an external vendor, and implemented by the vendor of the study IxRS. 
At the end of the study (including the period of 28 days follow-up), the official, final database 
will be frozen and unblinded after medical/scientific review has been performed, and data have 
been declared final and complete.  A Reporting and Statistical Analysis Plan will be approved 
prior to data being unblinded.  A clinical study report will be prepared after all patients complete 
the study. 
9.2. 
Hypotheses 
9.2.1. 
Primary Objective and Hypotheses 
The primary objective will be to demonstrate superiority of vibegron 75 mg over placebo in 
patients with OAB based on the co-primary endpoints of the average change in daily micturitions 
and the average change in daily UUI episodes from baseline to Week 12.  The co-primary 
statistical hypotheses are listed below: 
 Co-Primary Hypothesis 1:  In patients with OAB, vibegron 75 mg will have a 
different average change from baseline (CFB) in the number of daily micturitions 
than placebo at Week 12. 
 Co-Primary Hypothesis 2:  In patients with OAB Wet, vibegron 75 mg will have a 
different average CFB in the number of daily UUI episodes than placebo at Week 12. 
9.2.2. 
Key Secondary Objectives and Hypotheses 
(1) Objective: 
To evaluate the efficacy of vibegron in reducing the average number 
of urgency episodes from baseline compared with placebo at 
Week 12 in all patients with OAB. 
Hypothesis: In patients with OAB, vibegron 75 mg will have a different average 
change from baseline in the number of urgency episodes than placebo 
at Week 12. 
(2) Objective: 
To evaluate the efficacy of vibegron in proportion of patients with at 
least 75% reduction from baseline in the average number of daily UUI 
episodes compared with placebo at Week 12 in patients with OAB 
Wet. 


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Hypothesis: In patients with OAB Wet, vibegron 75 mg will have a different 
proportion of patients attaining at least 75% reduction from baseline in 
the average number of daily UUI episodes than placebo at Week 12. 
(3) Objective: 
To evaluate the efficacy of vibegron in proportion of patients with at 
least 100% reduction from baseline in the average number of daily 
UUI episodes compared with placebo at Week 12 in patients with 
OAB Wet. 
Hypothesis: In patients with OAB Wet, vibegron 75 mg will have a different 
proportion of patients attaining at least 100% reduction from baseline 
in the average number of daily UUI episodes than placebo at Week 12. 
(4) Objective: 
To evaluate the efficacy of vibegron in proportion of patients with at 
least 50% reduction from baseline in the average number of daily 
urgency episodes compared with placebo at Week 12 in patients with 
OAB. 
Hypothesis: In patients with OAB, vibegron 75 mg will have a different proportion 
of patients attaining at least 50% reduction from baseline in the 
average number of daily urgency episodes than placebo at Week 12. 
(5) Objective: 
To evaluate the efficacy of vibegron in reducing the average number 
of total incontinence episodes from baseline compared with placebo at 
Week 12 in all patients with OAB Wet. 
Hypothesis: In patients with OAB Wet, vibegron 75 mg will have a different 
average change from baseline in the number of total incontinence 
episodes than placebo at Week 12. 
(6) Objective: 
To evaluate the efficacy of vibegron in improving quality of life from 
baseline, the average change from baseline in the Coping Score from 
the OAB-q LF (1-week recall) will be compared with placebo at 
Week 12 in all patients with OAB. 
Hypothesis: In patients with OAB, vibegron 75 mg will have a different average 
change from baseline in the Coping Score from the OAB-q LF (1-
week recall) than placebo at Week 12. 
(7) Objective: 
To evaluate the efficacy of vibegron in change in the average volume 
voided per micturition from baseline compared with placebo at 
Week 12 in all patients with OAB. 
Hypothesis: In patients with OAB, vibegron 75 mg will have a different average 
change from baseline in the average volume voided per micturition 
than placebo at Week 12. 
The assessments of superiority of vibegron 75 mg over placebo on the additional secondary 
endpoints will also be performed and details will be provided in the Reporting and Statistical 
Analysis Plan. 


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9.3. 
Analysis Endpoints 
Efficacy, safety, and exploratory endpoints that will be evaluated for within- and/or between-
treatment differences are listed below.  The descriptions of the endpoints and time points at 
which they are measured are described in Section 3 and Table 1 (Schedule of Activities), 
respectively. 
No formal comparisons of vibegron vs. tolterodine are planned; all between-treatment analyses 
between these two groups will be considered descriptive. 
9.3.1. 
Efficacy Endpoints 
In describing the efficacy variables of interest below, the descriptions are restricted to the 
primary time point of interest at Week 12 in the study.  However, many variables are measured 
at additional time points, as indicated in the Schedule of Activities, and will be analyzed at other 
time points. 
Co-Primary Efficacy Endpoints: 
 Change from baseline (CFB) at Week 12 in average number of micturitions per 
24 hours in all OAB patients 
 CFB at Week 12 in average number of UUI episodes per 24 hours in OAB 
Wet patients 
For the purpose of this study, the number of micturitions will be defined as the number of times a 
patient has voided in the toilet as indicated on the Patient Voiding Diary.  Average daily 
micturitions are calculated using the daily entries in the Patient Voiding Diary, which is 
completed over the 7 days prior to each study visit.  Average daily number of micturitions will 
be calculated as the total number of micturitions that occur on a Complete Diary Day divided by 
the number of Complete Diary Days in the Patient Voiding Diary.  A complete diary day 
requires confirmation by the patient in the Patient Voiding Diary that all voids and leakages have 
been recorded for the diary day.  Baseline is defined as the average number of micturitions 
occurring during the last evaluable diary prior to the Baseline Visit. 
The number of UUI episodes will be defined as the number of times a patient has checked "urge" 
as the reason for accidental urine leakage.  Average daily UUI episodes at each study visit will 
be calculated in the same manner as described above for the micturition endpoint.  The UUI 
endpoint will be analyzed using only OAB Wet patients. 
Key Secondary Efficacy Endpoints: 
 CFB at Week 12 in average number of urgency episodes (need to urinate 
immediately) over 24 hours in all OAB patients 
 Percent of OAB Wet patients with at least a 75% reduction from baseline in UUI 
episodes per 24 hours at Week 12 
 Percent of OAB Wet patients with a 100% reduction from baseline in UUI episodes 
per 24 hours at Week 12 
 Percent of all OAB patients with at least a 50% reduction from baseline in urgency 
episodes (need to urinate immediately) per 24 hours at Week 12 


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 CFB at Week 12 in average number of total incontinence episodes over 24 hours in 
OAB Wet patients 
 CFB at Week 12 in Coping Score from the Overactive Bladder Questionnaire Long 
Form (OAB-q LF, 1-week recall) in all OAB patients 
 CFB at Week 12 in average volume voided per micturition in all OAB patients 
Additional Secondary Efficacy Endpoints: 
 CFB at Week 12 in HRQL Total Score from the OAB-q LF (1-week recall) in all 
OAB patients 
 CFB at Week 12 in Symptom Bother Score from the OAB-q-LF (1-week recall) in all 
OAB patients 
 Percent of all OAB patients with average number of micturitions < 8 per 24 hours at 
Week 12 
 Percent of OAB Wet patients with at least a 50% reduction from baseline in total 
incontinence episodes per 24 hours at Week 12 
 CFB at Week 12 in overall bladder symptoms based on PGI-Severity in all OAB 
patients 
 CFB at Week 12 in overall control over bladder symptoms based on PGI-Control in 
all OAB patients 
Exploratory Endpoints: 


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9.3.2. 
Safety Endpoints 
Safety and tolerability will be assessed via clinical review of all relevant safety parameters 
including clinical adverse events, clinical laboratories, vital signs, and physical examinations that 
occurred during the respective study period. 
9.4. 
Analysis Populations 
9.4.1. 
Efficacy Analysis Populations 
The Full Analysis Set (FAS) population will serve as the primary population for the analysis of 
efficacy data in this study.  Since the endpoints related to incontinence would only apply to 
patients who meet the definition of incontinence at study entry, it is necessary to have a separate 
FAS definition with an additional criterion to define the primary analysis population for 
incontinence endpoints. 
The following FAS populations are defined in the study: 
 Full analysis set (FAS):  all randomized OAB patients who took at least one dose of 
double-blind Study Treatment and have at least one evaluable change from baseline 
micturition measurement 
 Full analysis set for incontinence (FAS-I):  all randomized OAB Wet patients who 
took at least one dose of double-blind Study Treatment and have at least one 
evaluable change from baseline UUI measurement 
The Per-Protocol population (PP) and Per-Protocol population for incontinence (PP-I) exclude 
patients due to important deviations from the protocol that may substantially affect the results of 


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the primary efficacy endpoints.  A supportive analysis using the Per-Protocol populations will be 
performed for the co-primary and key secondary efficacy endpoints.  The final determination on 
protocol violations, and thereby the composition of the Per-Protocol population, will be made 
prior to the unblinding of the database and will be documented in a separate memo. 
Patients will be included in the treatment group to which they are randomized for the analysis of 
efficacy data using the FAS and Per-Protocol populations. 
9.4.2. 
Safety Analysis Populations 
The Safety Set (SAF) will be used for the analysis of safety data in this study.  The SAF consists 
of all patients who received at least one dose of Study Treatment.  Patients will be included in 
the treatment group corresponding to the Study Treatment they actually received for the analysis 
of safety data using the SAF population.  For most patients this will be the treatment group to 
which they are randomized. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
Study Treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a Baseline measurement is also required. 
No imputation will be performed for missing safety data.  Baseline will be defined as the last 
non-missing value before treatment. 
9.4.3. 
Pharmacokinetic Population 
The PK population will include all subjects in the Safety Set who undergo plasma PK sampling 
and have evaluable PK assay results. 
9.5. 
Statistical Methods 
Statistical testing and inference methods for safety and efficacy analyses are described below.  
Efficacy results that will be considered statistically significant after consideration of the strategy 
for controlling the Type I error are described in Section 9.6, Multiplicity.  Nominal p-values may 
be computed for other efficacy analyses as a measure of the strength of association between the 
endpoint and the treatment effect rather than formal tests of hypotheses.  Unless otherwise stated, 
two-sided) level. 
9.5.1. 
Statistical Methods for Efficacy Analyses 
9.5.1.1. 
Primary Efficacy Endpoints 
For the analysis of the co-primary endpoints (change from baseline in average number of daily 
micturitions at Week 12 and change from baseline in average number of daily urge urinary 
incontinence episodes at Week 12), a mixed model for repeated measure (MMRM) with 
restricted maximum likelihood estimation will be used.  This model corrects for dropout and 
accounts for the fact that measurements taken on the same patient over time tend to be correlated 
by using all available information on patients within the same covariate set to derive an estimate 
of the treatment effect for a dropout-free population.  The analysis model for each efficacy 
endpoint will include terms for treatment, visit, OAB Type (Wet vs Dry), Sex (Female vs Male), 
Region (US vs Rest of World), baseline score, and interaction of visit by treatment. 


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Primary inferences will be drawn from treatment differences for the changes from baseline 
derived from the MMRM models at Week 12.  As part of secondary objectives, the treatment 
differences for each post baseline visit will also be derived using the same MMRM model.  The 
estimated treatment difference for at each visit will be displayed in the summary of statistical 
analysis together with the 95% confidence interval and the associated p-value. 
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements.  The Kenward-Roger adjustment will be used with restricted (or residual) 
maximum likelihood (REML) to make statistical inference.  If the unstructured covariance model 
fails to converge with the default Newton-Raphson algorithm, the Fisher scoring algorithm or 
other appropriate methods can be used to provide initial values of the covariance parameters.  In 
the rare event that none of the above methods yield convergence, a structured covariance will be 
used to model the correlation among repeated measurements. 
9.5.1.2. 
Sensitivity Analyses 
9.5.1.3. 
Secondary Efficacy Endpoints 
The change from baseline efficacy endpoints will be analyzed using the same MMRM model 
described for co-primary endpoints. 
Analysis of the efficacy endpoints of proportion of patients with at least 75% reduction or a 
100% reduction in the average number of daily UUI episodes at Week 12 and proportion of 
patients with at least 50% reduction in the average number of daily urgency episodes at 
Week 12 will be analyzed using the Cochran-Mantel-Haenszel risk difference estimate.  Missing 
Week 12 data will be analyzed using multiple imputation.  The estimated difference in the 
proportion of responders and 95% confidence interval for the difference will be calculated using 
the Cochran-Mantel-Haenszel risk difference estimate stratified by OAB Type (Wet vs Dry) and 
Sex (Female vs Male), with weights proposed by Greenland and Robins.  Further details will be 
provided in the SAP. 


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9.5.1.4. 
Exploratory Efficacy Endpoints 
9.5.2. 
Statistical Methods for Safety Analyses 
Safety analyses will be conducted using the SAF and summarized by treatment group as treated.  
The treatment-emergent period will be defined as the period of time from the first dose date of 
the double blinded Study Treatment through 28 days after the last dose of Study Treatment, or 
the date of initiation of another investigational agent or surgical intervention or rollover to the 
extension study, whichever occurs first.  Safety will be assessed through summaries of adverse 
events, the frequency of treatment discontinuations due to adverse events, and clinical laboratory 
evaluations. 
The severity of all adverse events will be evaluated by the Investigator as described in 
Section 8.5.  All adverse events will be coded to preferred term and system organ class using 
Medical Dictionary for Regulatory Activities (MedDRA) 20.0 or higher.  The incidence of 
adverse events will be presented by MedDRA system organ class and preferred term, 
relationship to Study Treatment, and severity. 
Laboratory data will consist of chemistry, hematology, and urinalysis data.  Only data collected 
by the central laboratory will be included in the analyses. 
Vital signs parameters, including temperature, will be listed and summarized by visit. 
9.5.3. 
PK Analysis 
Plasma concentrations will be listed and summarized by study visit and treatment group. 
Pharmacokinetic parameters for RVT-901 for each subject may be estimated via nonlinear mixed 
effect modeling using a population PK model and described in a separate report. 
9.6. 
Multiplicity 
A stepwise gate-keeping procedure will be used to control the overall Type-I error rate at 
5 level (two-sided) over the co-primary and key secondary hypotheses.  If both co-primary 
endpoints are achieved, then the key secondary endpoints will be tested sequentially in the 
predefined order given in Section 9.2.  If statistical significance is achieved at all previous key 
secondary endpoints, the next sequential key secondary endpoint will be tested.  Once a key 
secondary endpoint is found to be insignificant (i.e. p-
stop.  For all subsequent key secondary endpoints, nominal p-values will be provided. 
All other efficacy endpoints will be considered supportive and no multiplicity adjustments will 
be performed for these other efficacy endpoints.  Nominal p-values will be computed for other 
efficacy endpoints as a measure of the strength of association between the endpoint and the 
treatment effect rather than formal tests of hypotheses.  Unless otherwise stated, all statistical 
tests will be conducted at the (two-
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9.7. 
Sample Size Determination 
Approximately 1,400 patients will be randomized in a 5:5:4 ratio to receive one of the following 
Study Treatments: 
 Vibegron 75 mg + placebo to match tolterodine ER 4 mg; 
 Placebo to match vibegron 75 mg + placebo to match tolterodine ER 4 mg; or 
 Tolterodine ER 4 mg + placebo to match vibegron 75 mg 
Approximately 500 patients will be assigned to the vibegron and placebo treatment groups, and 
approximately 400 patients will be assigned to the tolterodine treatment group.  Assuming that a 
total of 10% patients will discontinue prior to Week 12 (for any reason), there will be 
approximately 450 evaluable patients in the vibegron and placebo treatment groups at the end of 
Week 12.  Assuming 75% of the population will have OAB Wet, there will be approximately 
337 evaluable patients in the vibegron and placebo treatment groups for the incontinence 
endpoints.  The study has: 
 Approximately 98% power to detect a true underlying between-group treatment 
difference of 0.6 in change from baseline in micturitions at a two-sided 0.05 level 
assuming a variability estimate of 2.20 based on vibegron Study 008 data. 
 Approximately 98% power to detect a true underlying between-group treatment 
difference of 0.51 in change from baseline in urge urinary incontinence at a two-sided 
0.05 level assuming a variability estimate of 1.68 based on vibegron Study 008 data. 
Assuming that these endpoints are uncorrelated, then this study has 96% power to reject both co-
primary hypotheses. 
9.8. 
Subgroup Analyses and Effect of Baseline Factors 
To determine whether the treatment effect is consistent across various subgroups, the estimate of 
the between-group treatment effect (with a nominal 95% confidence interval CI ) for the 
primary endpoint will be estimated and plotted within each category of the following 
classification variables: 
 Region (US vs. Rest of World) 
 Age category (< 
 40 to < 
 55 to < 
 65 to 75,  75 years) 
 Age category (< 65,  65 years) 
 Race (white vs. other) 
 Sex (female vs. male) 
 Prior OAB therapy (naïve vs. non-naïve) 
 OAB Type (OAB Wet vs. OAB Dry) 
For each subgroup, the primary MMRM model will be fit including a subgroup by treatment 
interaction term and model results will be presented.  The consistency of the treatment effect will 
be assessed descriptively via summary statistics by category for the classification variables listed 
above. 


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9.9. 
Interim Analyses 
There is no planned interim analysis for efficacy. 


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10. 
STUDY GOVERNANCE CONSIDERATIONS 
10.1. 
Financial Disclosure 
Financial disclosure requirements are outlined by the US Code of Federal Regulations Title 21, 
Part 54 (21 CFR 54), Financial Disclosure by Clinical Investigators.  It is the Sponsor's 
responsibility to determine, based on these regulations, whether a request for financial disclosure 
information is required.  It is the Investigator's and Sub-Investigator's responsibility to comply 
with any such request. 
This is a “covered clinical study”, defined under 21 CFR 54 as “any study of a drug or device in 
humans submitted in a marketing application or reclassification petition patient to this part that 
the applicant or FDA relies on to establish that the product is effective (including studies that 
show equivalence to an effective product) or any study in which a single Investigator makes a 
significant contribution to the demonstration of safety.”  As such, all Investigators and Sub-
Investigators must provide documentation of their financial interest or arrangements with the 
Sponsor, or proprietary interests in the drug being studied.  This documentation must be provided 
before participation of the Investigator and any Sub-Investigator.  The Investigator and Sub-
Investigator agree to notify the Sponsor of any change in reportable interests during the study 
and for 1 year following completion of the study. 
10.2. 
Pre-Initiation Visit 
Sponsor personnel or designee(s) may visit the study site as necessary prior to initiation of the 
study to review information about the Study Treatment, protocol requirements, eCRFs, 
monitoring requirements, reporting of serious adverse events, and to ensure a full understanding 
of the Study Reference Manual with the site personnel. 
10.3. 
Data Management 
Patient data will be entered into a Sponsor-approved electronic database and combined with data 
provided from other sources in validated datasets then transmitted electronically to the Sponsor 
or designee. 
Management of clinical data will be performed in accordance with applicable Sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (e.g., errors will be 
corrected and inconsistencies clarified). 
Adverse events and concomitant medications terms will be coded using the most current versions 
of the MedDRA (i.e., 20.0 or higher) and the World Health Organization Drug Dictionary 
Enhanced (WHO-DDE), respectively. 
The Investigator will retain original source documents and the Sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
Sponsor. 


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10.4. 
Monitoring 
This study will be monitored by the Sponsor (or designee) in accordance with current GCP 
regulations.  By signing this protocol, the Investigator grants permission to the Sponsor (or 
designee) and appropriate regulatory authorities to conduct on-site monitoring of all appropriate 
study documentation.  In order to verify the accuracy of data collected in the eCRF, the monitor 
will require direct access to original source documents (e.g., patient records, patient charts, and 
laboratory reports). 
During the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.  A study monitor will contact and visit the 
site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various 
records of the study.  It will be the study monitor’s responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
correctness, and accuracy of all eCRF entries, and to meet with the Investigator to discuss study 
progress and compliance with the protocol and GCP.  The study monitor should have access to 
laboratory test results and any other source records and data needed to verify the entries on the 
eCRF.  The Investigator agrees to cooperate with the study monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
10.5. 
Auditing or Inspections 
Representatives of regulatory authorities, health authorities, the Sponsor, or IRB/REB/IEC’s may 
conduct inspections or audits of the clinical study.  If the Investigator is notified of an inspection 
by a regulatory authority, the Investigator agrees to notify the Sponsor’s medical monitor 
immediately.  By signing this protocol, the Investigator agrees to provide to appropriately 
qualified personnel from such groups, access to records, facilities, and personnel for the effective 
conduct of any inspection or audit. 
10.6. 
Study Oversight Committees 
10.6.1. 
Clinical Adjudication Committee 
As noted in Section 8.6, MACCE event diagnosis will be adjudicated by an independent external 
expert committee. 
10.6.2. 
Steering Committee 
A Steering Committee may be formed, if deemed necessary.  If formed, the committee will be 
comprised of both Sponsor and non-Sponsor scientific experts who will participate in the design, 
conduct, analyses, and publication of the study.  Steering Committee members will remain 
blinded to patients’ treatment assignments and all unblinded data until the database is officially 
locked and unblinded. 


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10.7. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the Sponsor.  All protocol modifications must be submitted to the IRB/REB/IEC in 
accordance with local requirements.  Approval must be obtained before changes can be 
implemented.  The Investigator must not deviate from the protocol without first obtaining 
approval from the Sponsor and the IRB/REB/IEC, if required.  In medical emergencies, the 
Investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the Sponsor (or designee) and the IRB/REB/IEC immediately regarding the type of 
emergency and the course of action taken.  The Investigator must notify the Sponsor (or 
designee) of any inadvertent protocol deviations upon their discovery, and document the 
deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB/REB/IEC, and 
all patients on treatment will again provide informed consent. 
10.8. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, the 
Sponsor will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies) and IRB/REB/IEC.  In terminating the study, the Sponsor and the Investigator will 
assure that adequate consideration is given to the protection of the study participants’ interests. 
10.9. 
Publications 
After conclusion of the study and without prior written approval from the Sponsor, Investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
The results of the study in their entirety have been publicly disclosed by or with the consent of 
the Sponsor in an abstract, manuscript, or presentation form; or 
The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Urovant Sciences GmbH 
confidential information (see Section 10.10.5). 
The Investigator will submit to the Sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation.  The Investigator will comply with Sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary. 


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10.10. 
Investigator-Specific Responsibilities 
10.10.1. 
Compliance with Regulations and Ethical Standards 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), ICH guidelines, or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the study participant.  For studies 
conducted under a United States investigational new drug application, the Investigator will 
ensure that the basic principles of GCP, as outlined in 21 Code of Federal Regulations (CFR 
312), subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 
21 CFR, part 56, 1998, are adhered to.  These standards are consistent with the requirements of 
the European Community Directive 2001/20/EC. 
The Investigator will also comply with financial disclosure requirements as described in 
Section 10.1. 
10.10.2. 
Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.10.3. 
Institutional Review Board/Independent Ethics Committee Requirements 
The protocol, protocol amendments, informed consent form, IB, and any other relevant 
materials, including accompanying material to be provided to the patient (e.g., advertisements, 
patient information sheets, or descriptions of the study used to obtain informed consent) will be 
submitted by the Investigator to an IRB/REB/IEC.  Approval from the IRB/REB/IEC must be 
obtained before starting the study and should be documented in a letter to the Investigator 
specifying the following: 
 Protocol number; 
 Protocol version; 
 Protocol date; 
 Documents reviewed; and 
 Date on which the committee met and granted the approval. 
Any amendments to the protocol will require IRB/REB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/REB/IEC’s 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/REB/IEC; 
 Notifying the IRB/REB/IEC of serious adverse events or other significant safety 
findings as required by procedures established by the IRB/REB/IEC. 


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10.10.4. 
Informed Consent 
The Investigator (or designee) is responsible for obtaining written informed consent from each 
study participant prior to any study activities.  To help the individual make an informed decision 
about participating, the Investigator (or designee) shall discuss with the potential participant the 
purpose of the research, procedures, risks, benefits, alternative options to participating, 
confidentiality, how to contact study personnel, and the patient’s rights.  Potential participants 
must be informed that their participation is voluntary and must be given ample time to ask the 
Investigator questions and obtain clarifications regarding the study prior to providing consent. 
The Investigator must utilize an IRB/REB/IEC-approved informed consent form for 
documenting written informed consent that contains all elements required by national, state, 
local, and institutional regulations or requirements.  Each informed consent form will be 
appropriately signed and dated by the patient or the patient’s legally authorized representative 
and the person obtaining consent. 
As described in Section 10.7, patients must be re-consented to participate in the study if a 
protocol amendment is made that substantially alters the study design or the potential risks or 
burden to patients. 
10.10.5. 
Confidentiality 
The Investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number (i.e., not names) and 
date of birth (as allowed) should be recorded on any form or biological sample submitted to the 
Sponsor, IRB/REB/IEC, or laboratory.  The Investigator must keep a Screening log showing 
codes, names, and addresses for all patients screened and for all patients enrolled in the study. 
The Investigator agrees that all information received from the Sponsor, including, but not limited 
to, the IB, protocol, eCRFs and other study forms, the investigational drug, and any other study 
information, remain the sole and exclusive property of the Sponsor during the conduct of the 
study and thereafter.  This information is not to be disclosed to any third party (except employees 
or agents directly involved in the conduct of the study or as required by law) without prior 
written consent from the Sponsor.  The Investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
10.10.6. 
Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following two categories: 
Investigator’s study file.  The Investigator’s study file will contain the IB, protocol/amendments, 
IRB/REB/IEC and governmental approval with correspondence, informed consent forms, drug 
records, staff curriculum vitae, authorization and training forms, and other appropriate 
documents and correspondence. 


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Patient clinical source documents.  The required source data should include the following for 
each patient: 
 Patient identification (name, date of birth, sex); 
 Documentation that the patient meets eligibility criteria, (e.g., history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
 Participation in the study (including study number); 
 Study discussed and date of informed consent; 
 Dates of all visits; 
 Documentation that protocol-specific procedures were performed; 
 Results of efficacy parameters, as required by the protocol; 
 Start and end date (including dose regimen) of Study Treatment (drug dispensing and 
return should be documented as well); 
 Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the Investigator); 
 Concomitant medication (including start and end date); and 
 Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the Investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified.  
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with the Sponsor.  The Investigator must 
notify the Sponsor before destroying any clinical study records. 
Clinical study documentation includes the IB, signed protocol and amendments, signed informed 
consents, notification of serious adverse events and related reports, any dispensing and 
accountability logs, shipping records of investigational product and study-related materials, 
documentation of financial aspects of the study, insurance statement, and signed agreement 
between the involved parties, dated and documented IRB/REB/IEC approval, approval of 
regulatory authorities as applicable, decoding procedures for blinded studies, curriculum vitae 
and all training records of study site personnel, and all correspondence pertaining to the conduct 
of the study. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
Investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 


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10.10.7. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the Investigator or 
Sub-Investigator (as appropriate) listed on Food and Drug Administration Form 1572 and/or 
other appropriate local health authority documents within a reasonable time period after data 
collection.  This also applies to records for those patients who fail to complete the study (even 
during a pre-randomization Screening Period if an eCRF was initiated).  If a patient withdraws 
from the study, the reason must be noted on the eCRF.  If a patient is withdrawn from the study 
because of a treatment-limiting adverse event, thorough efforts should be made to clearly 
document the outcome. 
10.10.8. 
Investigational Product Accountability 
The Investigator or Investigator’s designee (e.g., pharmacist) is responsible for ensuring 
adequate accountability (including dates and lot numbers) of all used and unused Study 
Treatment (active and placebos).  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient dispensing records, and returned or destroyed 
study product.  Dispensing records will document quantities received from the Sponsor and 
quantities dispensed to patients, including lot number, date dispensed, Patient Number, and the 
initials of the person dispensing the Study Treatment. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
Sponsor requirements.  Drug may be returned (by the monitor) or destroyed on-site, if 
appropriate per site standard operating procedures (SOPs).  At the end of the study, following 
final drug inventory reconciliation by the monitor, the study site will dispose of and/or destroy 
all unused Study Treatment supplies, including empty containers, according to these procedures.  
If the site cannot meet the Sponsor’s requirements for disposal, arrangements will be made 
between the site and the Sponsor (or designee) for destruction or return of unused investigational 
medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
10.11. 
Sponsor-Specific Responsibilities 
10.11.1. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies).  The 
Sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be 
prepared in certain cases. 
10.11.2. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of patients begins.  Results will be posted as required. 


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adrenoceptor agonist, CL316, 243, and various smooth muscle relaxants.  J Pharm Exp 
Ther 2000;293:  939-45. 
18. Takeda H, Yamazaki Y, Igawa Y, Kaidoh K, Akahane S, Miyata H, Nishizawa O, 
Akahane M, Andersson KE.  
-adrenoceptor stimulation on prostaglandin E2-
induced bladder hyperactivity and on the cardiovascular system in conscious rats.  
Neurology and Urodynamics 2002;21:  558-65. 
19. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, and Wein A. tolterodine oncedaily:  
superior efficacy and tolerability in the treatment of the overactive bladder.  Urol 
2001;57:  414–21. 
20. Woods M, Carson N, Norton N, Wesley S, Jeffery H, Argentieri TM.  Efficacy of the 
-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia 
and detrusor instability in the rat.  J Urol 2001;166:  1142-7. 
21. Yamaguchi O.  
-adrenoceptors in human detrusor muscle.  Urology 2002;59 
(Supplement 5A):  25-29. 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
 
Confidential 
Page | 98 
 
APPENDICES 
APPENDIX A. LIST OF ABBREVIATIONS 
Term 
Description 
AE 
adverse event 
AECI 
Adverse Events of Clinical Interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AR 
adrenergic receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours
BP 
blood pressure 
BPH 
benign prostatic hypertrophy 
bpm 
beats per minute 
CAC 
clinical adjudication committee 
cAMP 
cyclic adenosine monophosphate 
CFB 
change from baseline 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval 
Cmax 
maximum concentration 
CT 
computerized tomography 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EQ-5D 
European Quality of Life-5 dimension 
ER 
extended release 
EU 
European Union 
FAS 
full analysis set 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
 
Confidential 
Page | 99 
 
Term 
Description 
FAS-I 
full analysis set for incontinence 
FDA 
(United States) Food and Drug Administration 
GCP 
good clinical practice 
GI 
gastrointestinal 
HRQL 
health-related quality of life 
IB 
Investigator's Brochure 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IEC 
institutional ethics committee 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IxRS 
interactive voice or web response system 
LF 
long form 
LFT 
liver function tests 
LOCF 
last observation carried forward 
MACCE 
major adverse cardiovascular and cerebrovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measure 
MRI 
magnetic resonance imaging 
NOAEL 
no-observed-adverse-effect level 
NVU 
nighttime voids associated with urgency 
OAB 
overactive bladder 
OAB-q 
Overactive Bladder Questionnaire 
OAB-q LF 
Overactive Bladder Questionnaire Long Form 
PD 
pharmacodynamic(s) 
PDE 5 
phosphodiesterase type 5 
PGI 
Patient Global Impression 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PP 
per-protocol population 
PP-I 
per-protocol population for incontinence 
PRO 
patient-reported outcome(s) 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
 
Confidential 
Page | 100 
 
Term 
Description 
PVR 
patient void residual 
QD 
once daily 
QTc 
corrected QT 
RBC 
red blood cell 
REB 
research ethics board 
REML 
restricted (or residual) maximum likelihood 
SAE 
serious adverse event 
SAF 
safety set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SOP 
standard operating procedures 
t1/2 
half-life 
TIA 
transient ischemic attack 
Tmax 
time to reach maximum concentration 
tQT 
thorough QT 
ULN 
upper limit of normal 
Urovant 
Urovant Sciences GmbH 
US 
United States 
UTI 
urinary tract infection 
UUI 
urge urinary incontinence 
WBC 
white blood cell 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
WPAI-US 
Work Productivity and Activity Impairment Questionnaire-
Urinary Symptoms 
-AR 
beta-3 adrenergic receptor 
-AR 
beta adrenergic receptor 
-hCG 
beta-human chorionic gonadotropin 
 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
 
Confidential 
Page | 101 
 
APPENDIX B. ALGORITHM FOR ASSESSING LABORATORY VALUES 
For all laboratory values obtained at pre-study evaluation: 
1. If all values are normal, the patient may enter the study. 
2. If a value is outside the normal range, the following choices are available: 
 The patient may be excluded from the study; 
 The abnormal test may be repeated. 
 The result may be deemed “Not Clinically Significant” and the patient may be 
enrolled in the study. 
3. If the Investigator decides to repeat an abnormal test and if it is within the normal range, 
the patient may enter the study. 
4. If the Investigator decides to repeat an abnormal test and if the repeat test is still 
abnormal, the Investigator will evaluate the potential patient with a complete history and 
physical examination, looking especially for diseases that could result in an abnormality 
in the laboratory value in question.  If such diseases can be excluded, and if the 
Investigator feels that the abnormal laboratory value is not clinically relevant, then the 
patient may enter the study.  The Urovant clinical monitor will be included in the 
decision of whether or not to enroll the patient in the study. 
5. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
patient will be excluded from the study. 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
 
Confidential 
Page | 102 
 
APPENDIX C. APPROXIMATE BLOOD/TISSUE VOLUMES 
DRAWN/COLLECTED BY SAMPLE TYPE 
 
Number of 
collections 
Approximate 
amount per 
collection 
Total Amount 
Hematology 
5 
10 mL 
50 mL 
Serum/Plasma Chemistry 
5 
10 mL 
50 mL 
Pharmacokinetic (Subset of the total 
population) 
3 
4 mL 
12 mL 
Total 
112 mL 
 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
 
Confidential 
Page | 103 
 
APPENDIX D. GUIDELINES FOR ELEVATIONS IN HEPATIC 
ENZYMES 
Study treatment should be withheld for any liver test abnormality listed in Section 8.6.1, pending 
investigation of alternative causes of liver injury.  Follow-up should continue until the liver test 
abnormalities resolve to baseline. 
Monitor liver tests per the applicable schedule in Table D-1, and per the investigations in 
Table D-2.  If close monitoring is not possible, Study Treatment should be withheld, even if the 
results do not meet the criteria for withholding in Section 8.6.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Table D-1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, 
Alkaline Phosphatase, and INR Testsa 
3 x ULN and total bilirubin > 2 x 
ULN or INR > 1.5 
Every 24 hours until laboratory 
abnormalities improve 
3 x ULN and total bilirubin and 
INR are normal 
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve AND the 
patient is asymptomatic 
Frequency may decrease 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized 
ratio; ULN, upper limit of normal 
a. Review frequency of monitoring with medical monitor for an individual patient, in case of questions 


Clinical Study Protocol 
RVT-901-3003 
Urovant Sciences GmbH 
Effective:  15 NOV 2018 
 
Confidential 
Page | 104 
 
Table D-2 
Investigations of Alternative Causes for Abnormal Liver Tests 
Obtain a detailed history and perform a physical examination: 
 Detailed history of symptoms (e.g., right upper quadrant pain, fatigue, nausea, vomiting, 
and fever); 
 Prior and concurrent disease or illnesses; 
 Exposure to environmental (e.g., travel, new sexual exposure, exposure to ill family 
members or coworkers, etc.) and/or industrial chemical agents; 
 Prior and concurrent use of alcohol, recreational drugs, and special diets; 
 Concomitant use of medications (including nonprescription medicines and herbal and 
dietary supplements), plants and mushrooms; 
 Physical examination. 
Recommended tests: 
 Also perform additional tests as clinically indicated or in consultation with a 
gastroenterologist or hepatologist. 
 Repeat liver tests as per Table D-1a; 
 Obtain gamma-glutamyl transferase, albumin, INR, and glucose in conjunction with 
repeat liver tests; 
 Complete blood count with differential to assess for eosinophilia; 
 Serum acetaminophen (paracetamol) concentration; 
 Obtain viral serologies for hepatitis A, B, C, D, and E; consider testing for Epstein Barr 
virus; 
 Evaluate for alcoholic hepatitis, nonalcoholic steatohepatitis, biliary tract disease, 
autoimmune hepatitis, etc.; 
 Serology for celiac disease; 
 Appropriate liver imaging; and 
 Hepatology consult (liver biopsy may be considered in consultation with a hepatologist 
or gastroenterologist). 
Abbreviations:  INR, international normalized ratio 
a. If the first follow-up testing does not confirm the initial abnormal liver test results, review any additional follow-
up monitoring with the medical monitor. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
Page 1 of 88 
Sponsor Name: Urovant Sciences GmbH
Protocol Number and Title: 
RVT-901-3003 
An International Phase 3, Randomized, Double-
Blind, Placebo- and Active (Tolterodine)-
Controlled Multicenter Study to Evaluate the 
Safety and Efficacy of Vibegron in Patients with 
Symptoms of Overactive Bladder 
Protocol Version and Date: 
RVT-901-3003 
<Protocol Amendment numbers 
and dates> 
v3.0, 15NOV2018 
v2.1, 12FEB2018 
v2.0, 30JAN2018 
v1.2, 01NOV2017 
v1.1, 05OCT2017 
v1.0, 29SEP2017 
 
 
Author(s): 
, 
, Biostats, Programming & 
Data Management, Urovant Sciences 
 
 
SAP Version: 
3.1 
SAP Version Date: 
06-MAR-2019
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Urovant Sciences Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or 
disclosed without prior written authorization from an official of Urovant Sciences.  However, this document 
may be disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, 
 should be notified 
promptly. 
1
NCT Number: NCT03492281
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
    
 
Page 2 of 88 
Revision History 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
1.0 
30APR2018 
Initial Release Version 
2.0 
20NOV2018 
Additions to the efficacy section to include Multiple 
imputation instead of LOCF 
Minor changes to content to be in line with protocol 
version 2.1 
3.0 
05MAR2019 
Updates to shells per Sponsor comments;  
Addition of section on deviations from Protocol;  
Minor changes to content to be in line with Protocol 
version 3.0. 
3.1 
06MAR2019 
Minor update to allow for the possibility to transform 
data prior to modeling for primary analyses if 
assumptions for the model are grossly violated. 
 
 
2


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
1 confirm that T have reviewed this document and agree with the content. 
 Biostatistics 
Sponsor Contact 
APPROVALS 
, Biostats, Programming & Data Management 
Date (dd-Mmm-yyyy) 
Date (dd-Mmm-yyyy) 
_
 
Date (dd-Mmm-yyyy) 
Page J of 88 
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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
  
 
Page 8 of 88 
LIST OF TABLES 
Table 3.11.1: 
Schedule of Activities ............................................................................. 16 
Table 6.5.1: Analysis Window ........................................................................................... 37 
Table 8.2.6.1 
OAB-q LF Domain Questions ............................................................... 54 
Table 9.4.1: Laboratory Tests and Scheduled Study Visits ........................................ 67 
 
8


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
 
Page 9 of 88 
1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
AIC 
Akaike’s Information Criteria 
ANCOVA 
Analysis of Covariance 
AR 
Autoregressive 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass index 
BP 
Blood Pressure 
BPH 
Benign Prostatic Hyperplasia 
BPM 
Beats Per Minute 
CI 
Confidence Interval 
CFB 
Change from Baseline 
CS 
Compound Symmetry 
ECDF 
Empirical Cumulative Distribution Function 
eCRF 
Electronic Case Report Form 
C24 
24h Concentration 
CV 
Coefficient of Variation 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
EQ-5D 
EuroQual 5 Dimension Questionnaire 
FAS 
Full Analysis Set 
FAS-I 
Full Analysis Set for Incontinence 
GPP 
Good Pharmacoepidemiology Practice 
HRQL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IP 
Investigational Product 
IxRS 
Interactive Voice/Web Response System 
LOCF 
Last Observation Carried Forward 
LF 
Long Form 
MAR 
Missing at Random 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
Min 
Minimum 
9


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
  
 
Page 10 of 88 
Abbreviation 
Description 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random 
N/A 
Not Applicable 
NA 
Not Applicable 
NVU 
Night Time Voids Associated with Urgency 
OAB 
Overactive Bladder 
OAB Dry 
OAB in the absence of Incontinence 
OAB Type 
Investigator-Defined Baseline OAB Categorization 
OAB Wet 
OAB with Incontinence 
OAB-d Type 
eCRF Derived Baseline OAB Categorization 
OAB-q 
Overactive Bladder Questionnaire 
PGI 
Patient Global Impression 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PPS 
Per-Protocol Set 
PPS-I 
Per-Protocol Set for Incontinence 
PT 
Preferred Term 
PVR 
Post-Void Residual (Volume) 
QC 
Quality Control 
QTc 
Corrected QT Interval 
REML 
Restricted (or Residual) Maximum Likelihood 
RVT-901 
Vibegron (Urovant Code Number) 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUI 
Stress Urinary Incontinence  
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
Urovant 
Urovant Sciences GmbH 
US 
United States 
UUI 
Urge Urinary Incontinence 
WHO 
World Health Organization 
WPAI-US 
Work Productivity and Activity Impairment Questionnaire-Urinary 
Symptoms 
 
 
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Table Footnotes:  
Screening  
1. The time between the Screening and Run-in Visits may be up to 5 weeks, to allow for washout of prior OAB medications (if 
needed) and completion of the Patient Voiding Diary and Urine Volume Diary.  
Electronic Diary (eDiary)  
2. The Electronic Diary (eDiary) for this study includes both the Patient Voiding Diary and the Urine Volume Diary, and will be 
implemented via an eDiary device (provisioned smartphone). A paper diary will be provided to all patients to be used as a back-up 
when necessary. If a back-up paper diary is used, it should be collected at each study visit.  
eDiary Device  
3. At Screening, site personnel will setup the eDiary Device, confirm proper functioning, and dispense the eDiary Device to the 
patient. At each subsequent visit during the Treatment Period, site personnel will confirm that the eDiary Device is functioning 
properly.  
4. Specific training on device operation will be provided to the patient at Screening, with re-training provided at each subsequent 
visit.  
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Patient Voiding Diary and Urine Volume Diary  
5. Specific training on completion of the Patient Voiding Diary and Urine Volume Diary will be provided to the patient at 
Screening, with re-training provided at each subsequent visit.  
6. The Patient Voiding Diary should be completed by the patient on all of the 7 Diary Days prior to the Run-in Visit (days -21 to -
15), Baseline Visit (days -7 to -1), Week 2 Visit (days 8 to 14), Week 4 Visit (days 22 to 28), Week 8 Visit (days 50 to 56), and 
Week 12 Visit (days 78 to 84). Patient will receive SMS text alerts and/or phone call reminders to complete the Diary.  
7. The Urine Volume collection and Urine Volume Diary completion should be performed by the patient on one (1) of the 7 Diary 
Days prior to the Run-in, Baseline, and Weeks 2, 4, 8, and 12 Visits.  
Diary and Visit Reminders  
8. Patient will receive phone call reminders from the site to complete the Diary on approximately the first day and third day of 
each diary collection period (or next business day). Patient may consent to additional SMS Text reminders (where available).  
Patient Reported Outcomes  
9. Vital signs, followed by PRO Questionnaires will be the first procedure performed at visits that include PRO administration. 
Questionnaires will be administered at the site in the order listed in the Schedule of Activities.  
Post Void Residual Volume  
10. All efforts will be made to ensure the same device and operator are used for all PVR volume measurements for individual 
patients.  
Physical/ECG/Vitals 
11. A Complete Physical Exam will be performed at the Screening Visit and will include a digital rectal exam for all males. 
Focused physical examinations will be performed at the Run-in and Follow-up Visits, which will include a pelvic exam for women 
only as needed to confirm prolapse. 
12. A single 12-lead ECG will be obtained at Screening. 
13. Vital Signs includes Blood Pressure (average of three measurements taken 1-2 minutes apart after sitting for 5 minutes), Heart 
Rate, Temperature, Respiration Rate and Weight. Height will be measured only at Screening. 
Adverse Events 
14. Adverse events will be collected from the time a patient provides informed consent to participate in the study until the Follow-
up Visit is completed. 
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15. Serious adverse events will be collected from the time a patient provides informed consent to participate in the study until the 
Follow-up Visit is completed. 
Prior and Concomitant Medications 
16. Concomitant medications will be reviewed and recorded at each study visit from the Screening through the Week 12 and at any 
Unscheduled Visits. Medications taken within 1 year of the Screening Visit for the treatment of OAB will also be recorded. 
Labs 
17. At Week 8, the Urine Dipstick will only be performed if clinically indicated (e.g., symptoms of urinary retention or urinary 
tract infection). 
18. Urinalysis will be performed only if the urine dipstick tests positive for the presence of leukocytes, nitrites, or blood cells, and 
will be performed by the central lab. 
19. Urine beta-human chorionic gonadotropin (β-hCG) will be tested for women of childbearing potential only. 
Dosing/Drug 
20. Dosing will occur every day from the Witnessed Dose on the day of the Run-in Visit through the day before the Week 12 Visit. 
21. Study Treatment bottles should be returned by the patient at each visit. Clinic staff will perform accountability and review any 
discrepancies with the patient during the visit. 
22. All patients will take their dose of Study Treatment on the day of the Run-in and Baseline Visits at the site as a witnessed dose. 
The date and time of Study Treatment dosing will be recorded 
Pharmacokinetics Subset Only 
23. PK samples for Population PK Analysis will be collected from a subset of patients (approximately 30% of enrolled patients) at 
selected sites. Pre-dose blood samples will be collected at Week 4, Week 8, and Week 12. PK samples should be collected during 
the clinic visit after all other study assessments have been completed. 
24. The date and time of the last dose of Study Treatment prior to PK sampling will be recorded. 
Follow-up/Unscheduled 
25. Unscheduled Visits and the specific procedures performed at these visits will be determined by the Investigator, as clinically 
indicated. The procedures indicated in the Schedule of Activities will be performed at these visits, as clinically indicated, based on 
the purpose of the visit (e.g., follow-up for an adverse event or abnormal laboratory test, study treatment dispensation). The reason 
for the visit will be captured in the source documents. 
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26. For Patients who do not enroll into the optional extension study (RVT-901-3004) or patients who withdraw from the study for 
any reason, a Follow-up Visit should be performed approximately 28 days after the last dose of Study Treatment on Study Day 
113 or approximately 28 days after a patient’s Withdrawal from the study. When a patient withdraws from the study prior to study 
completion, all applicable activities scheduled for the Week 12 Visit should be performed at the time of withdrawal. 
 
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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 29 of 88 
Other Major protocol deviation categories may include, but are not limited to the 
following: 
 Informed Consent Issues 
 IP Dispensation/Storage 
 Lab Sample Issues (Missing/Not Analyzed etc.) 
 AECI Not Reported 
All major protocol deviations related to efficacy will be discussed during the BDRM, and 
decisions relating to exclusion for the PPS(-I) will be documented in the BDRM Report, 
finalized prior to unblinding. 
29


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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 32 of 88 
A nighttime void is defined as “Urinated in Toilet” as indicated on the voiding diary, after 
going to bed but prior to getting up the next day. 
Nighttime UUI 
A nighttime UUI episode is defined as having "urge" as the main reason for the leakage as 
indicated on the voiding diary, regardless of whether more than one reason for leakage is 
checked, and occurring after going to bed, but prior to getting up the next day.    
OAB Categorization 
There will be two different definitions of OAB Categorization used for the study: OAB 
Type and OAB-d Type.  OAB Type will be based on the randomization strata and OAB-d 
Type will be derived based on the baseline diary data, defined below. Details on the 
derivation of baseline patient voiding diary endpoints are presented further below in this 
section (Definition of Baseline for Patient Voiding Diary Endpoints). 
OAB-d Type (Wet, Dry, Missing) will be categorized based on Baseline diary data, as 
follows: 
OAB Wet: Patients are considered OAB Wet according to the following criteria: 
 An average of ≥ 8.0 micturitions per Diary Day; and,  
 An average of ≥ 1.0 UUI episodes per Diary Day; and,  
 If stress urinary incontinence (SUI) is present, the total number of UUI episodes 
must be greater than the total number of SUI episodes.  
OAB Dry: Patients are considered OAB Dry according to the following criteria: 
 An average of ≥ 8.0 micturitions per Diary Day; and,  
 An average of ≥ 3.0 urgency episodes per Diary Day; and, 
 An average of < 1.0 UUI episodes per Diary Day 
OAB-d Type Missing: Patients are considered non-categorized for OAB if neither of the 
above criteria is achieved. 
Where OAB Wet is discussed in this document, it pertains to patients randomized under 
the strata of OAB Wet; where all OAB Patients are discussed, this relates to all patients 
randomized as either OAB Wet or OAB Dry. Under the randomization strata, all patients 
are categorized as OAB Wet or Dry; missing is not present. Unless otherwise stated, for 
the purposes of the analyses, OAB Type (i.e. as randomized) will be used.  
Diary Day 
32


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
  
 
Page 33 of 88 
A “Diary Day” is defined as the time between when the patient gets up for the day each 
morning and the time the patient gets up for the day the next morning as recorded in the 
patient voiding diary.   
Complete Diary Day   
A “Complete Diary Day” is defined as a Diary Day that includes input of micturition data 
by patients on the voiding diary. Unless a patient indicated “No” to the questions of “Did 
you record each time you urinated or leaked during this Diary Day” the Diary Day is 
considered complete. 
For post-baseline diaries at Weeks 4 and 8, only complete diary days within 10 days prior 
to the study visit will be included. For the Week 12/Early Termination diary, only 
complete diary days within 14 days prior to the study visit will be included. For the Week 
2 diary, complete diary days within 10 days prior to the target Week 2 day will be used. 
For diaries at all visits, if a patient has fewer than 4 complete diary days, that will be 
identified as a significant protocol deviation and that diary data will be excluded from all 
analysis.  
Definition of Baseline for Patient Voiding Diary Endpoints 
Baseline will be the data collected during the Run-in Period. If greater than 10 complete 
diary days are available in the Run-in diary, only the complete diary days within the 10 
days prior to the Baseline visit will be used; if 4 or more and less than 10 complete diary 
days are available, all complete diary days in the Run-in diary will be used to calculate 
Baseline. If less than 4 complete diary days are available, the Baseline will be regarded as 
missing. For a patient to have an evaluable change from baseline, the patient must have 
both a baseline diary and a post-baseline diary from any post-baseline timepoint, after 
analysis window has been applied (i.e., Week 2, Week 4, Week 8, or Week 12). 
Definition of Baseline for Endpoints not Derived from the Patient Voiding Diary 
Baseline value for all secondary efficacy, exploratory and safety endpoints will be defined 
as the last non-missing assessment before starting double-blind treatment. 
Screening/Washout Period 
The Screening/Washout Period covers Day -49 (Screening Visit) to Day -15 (the day 
before the start of the Run-in Period), which includes a 28-day washout period followed by 
7-days of Diary completion. Patients not requiring the 28-day washout period can begin 
the 7-day Diary the day after the Screening Visit. 
Run-in Period 
The Run-in Period covers the duration between screening (Day -14) and the day before 
baseline (Day 1). There is no day 0 included in the study. 
33


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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 35 of 88 
Incomplete/missing start and stop dates will be handled as follows:  
Incomplete AE/Concomitant Medication Start Date  
If only the start day is missing, then the start day will be imputed as the first day of the 
month that the event occurred with the following exceptions:  (1) if the partial date is the 
same month and year as the date of first dose of run-in single-blind medication (or double-
blind medication), then the partial date will be imputed as the date of first dose of single-
blind medication (or double-blind medication). However, if the date of first dose of single-
blind medication and date of first dose of double-blind medication occur in the same 
month, then the date of first dose of double-blind medication will be imputed. (2) if the 
partial date is before the date of first dose of run-in single-blind medication, then the start 
date will be sent as the date of informed consent.  
If the start date is missing both the day and month, then the day and month will be imputed 
as the first day of the year (i.e., 01-Jan) with the following exceptions:  if the partial date is 
in the same year as the first dose dose of run-in single-blind medication (or double-blind 
medication), then the partial date will be imputed as the date of first dose of single-blind 
medication (or double-blind medication). However, if the date of first dose of single-blind 
medication and date of first dose of double-blind medication occur in the same month, then 
the date of first dose of double-blind medication will be imputed. (2) if the start year is 
before the year of first dose of run-in single-blind medication, then the start date will be 
sent as the date of informed consent.  
Incomplete AE/Concomitant Medication or Treatment End Date 
If only the end day is missing, then the end day will be imputed as the last day 
(28/29/30/31) of the month of occurance. If the patient died in the same month, then set the 
imputed date as the death date. 
If the day and month are missing, then the end day will be imputed as the 31st of 
December of year occurance. If the patient died in the same year, then set the imputed date 
as the death date. 
Missing Wake/Bed Time 
For a patient with a complete diary day, if the wake and/or bed time is missing for that day 
then the missing time will be imputed as the average of the other wake and/or bed times 
from that diary.  E.g., for the Week 12 diary, if the patient has 4 complete diary days with 
4 wake times, but only 3 bed times of 10:00pm, 10:10pm, and 10:20pm, then the missing 
bed time will be imputed as the average of the observed data which is 10:10pm. 
Other Data 
35


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


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 38 of 88 
 Prior beta-3 agonist use in the last 12 months (yes vs. no) 
 OAB Type (OAB Wet vs. OAB Dry) 
 OAB-d Type (OAB Wet vs. OAB Dry) 
 
The details of the analysis of subgroups used for statistical inference of the co-primary 
endpoints are given in Section 8.1.4. 
A list of anticholinergics is given in the protocol in Table 4 of Section 7.9.3. 
38


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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 42 of 88 
Table 7.5.3: OAB Medication Selection 
Class 
Variable Selected 
Selection 
Anticholinergics 
Preferred Term 
darifenacin, fesoterodine, festoterodine 
fumarate hyoscyamine, oxybutynin, 
oxybutynin hydrochloride, propantheline, 
solifenacin, solifenacin succinate, tolterodine, 
tolterodine l-tartrate, trospium, and trospium 
chloride  
Beta-3 adrenergic 
agonists 
Preferred Term 
Mirabegron, vibegron 
 
42


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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 44 of 88 
estimate of the treatment effect for a MAR-free population.  No imputation of missing data 
is required for this analysis.  The analysis model will include terms for treatment, visit, 
OAB Type (Wet vs Dry), Sex (Female vs Male), Region (US vs non-US), baseline score, 
and interaction of visit by treatment. 
Primary inference will be drawn from the treatment difference between vibegron and 
placebo at Week 12. The comparisons between tolterodine and placebo will be reported 
with nominal p-values. The standard error and 95% CI for the differences will also be 
presented with the corresponding p-values.  Additionally, estimates of least-squares means, 
standard errors, and 95% CIs will be presented for each treatment group (placebo, vibegron 
and tolterodine).  The table output will also include treatment group estimates and 
treatment differences between vibegron and placebo, and tolterodine and placebo at Weeks 
2, 4, and 8 from this model. 
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements. The Kenward-Roger adjustment will be used with restricted (or residual) 
maximum likelihood (REML) to make statistical inference.  If the unstructured covariance 
model fails to converge with the default Newton-Raphson algorithm, the Fisher scoring 
algorithm will be used to provide initial values of the covariance parameters.  In the rare 
event that none of the above methods yield convergence, the following structures will be 
investigated:  heterogeneous Toeplitz, Toeplitz, heterogeneous First-Order Autoregressive 
[AR (1)], heterogeneous compound symmetry (HCS), and compound symmetry (CS).  The 
covariance structure converging to the best fit, as determined by Akaike’s information 
criterion (AIC), will be used. 
An example of the SAS code for the base procedure is given below: 
proc mixed data = datain method = reml ; 
 
class TRTP AVISITN USUBJID OABTYPE SEX REGION ; 
 
model CHG = TRTP AVISITN OABTYPE SEX REGION BASE TRTP*AVISITN   
 
 
/ ddfm=KR solution chisq ; 
 
REPEATED AVISITN / subject=USUBJID type=UN r rcorr ; 
 
LSMEANS TRTP*AVISITN / pdiff=all cl alpha=0.05 ;  
run ; 
Where TRTP is the planned treatment, AVISITN is the visit number, USUBJID is the unique 
patient identifier, OABTYPE indicates if the patient is Dry or Wet, SEX is female or male, 
REGION indicates if the patient is in the United States or in the non-US countries and BASE 
indicates baseline value.   
Model assumptions will be assessed through inspection of residual plots and normal 
probability plots.  Should gross violations of the assumptions occur, the change from 
baseline in average daily micturitions will be transformed prior to the modeling. 
44


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Urovant Protocol #3003 
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Page 45 of 88 
 
8.1.1.2. 
Sensitivity Analysis 
45


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
Page 46 of 88 
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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 49 of 88 
o The analysis model for CFB in micturitions will include terms for 
treatment, visit, OAB Type (Wet vs Dry), Region (US vs Non-US), baseline 
score, sex, interaction of sex by treatment, and interaction of visit by 
treatment. 
o The analysis model for CFB in UUI endpoint will exclude the term of OAB 
Type.   
 Males with BPH vs. Males without BPH 
o This category will only be used for descriptive statistics.   
 Prior Anticholinergic Use in the Last 12 Months  (Yes vs No) 
o This category will only be used for descriptive statistics. 
 Prior Beta-3 Agonist Use within the Last 12 Months (Yes vs No), 
o This category will only be used for descriptive statistics.   
 OAB Type (OAB Wet vs. OAB Dry)  
o The analysis model for CFB in micturition will include terms for treatment, 
visit, OAB Type (Wet vs Dry), Sex (Female vs Male), Region (US vs Non-
US), baseline score, interaction of OAB Type by treatment, and interaction 
of visit by treatment.  
o The analysis model for CFB in UUI endpoint will not be applicable for this 
subgroup analysis. 
 OAB-d Type (OAB Wet vs. OAB Dry)  
o The analysis model for CFB in micturition will include terms for treatment, 
visit, OAB-d Type (Wet vs Dry), Sex (Female vs Male), Region (US vs 
Non-US), baseline score, interaction of OAB-d Type by treatment, and 
interaction of visit by treatment.  
o The analysis model for CFB in UUI endpoint will not be applicable for this 
subgroup analysis. 
A forest plot will be provided to present the results from subgroup analyses. Side-by-side 
95% confidence intervals will be plotted for each comparison to control within each 
subgroup, where the 95% confidence intervals are taken from the analysis table described 
above.  The confidence intervals are stacked vertically on the page, with a reference line at 
zero for mean. All the subgroups should be plotted on a single figure (using multiple 
pages, if necessary).   
49


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


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 51 of 88 
Where aval is the value at Week 12 and base is the baseline value.  The achievement of at 
least a 75% reduction in UUI episodes (and similarly, a 100% reduction in UUI episodes) 
is a binary variable of 0 (endpoint is not attained) or 1 (endpoint is attained). The 
difference in proportion responding between vibegron and placebo, and tolterodine and 
placebo along with the associated 95% confidence interval and p-value, will be calculated 
using the Cochran-Mantel-Haenszel risk difference estimate stratified by Sex (Female vs 
Male)., with weights proposed by Greenland and Robins, which is calculated as follows: 
𝛿̂𝑀𝐻= ∑
𝑤𝑖∙𝛿̂𝑖
𝑢
𝑖=1
∑
𝑤𝑖
𝑢
𝑖=1
 , where 
𝛿̂𝑖= 𝑥𝑖
𝑛𝑖
 − 𝑦𝑖
𝑚𝑖
  denotes the risk difference in stratum 𝑖, 𝑖= 1, ⋯, 𝑢 
𝑤𝑖= 𝑛𝑖∙𝑚𝑖
𝑛𝑖+ 𝑚𝑖
  denotes the weight of stratum 𝑖, 𝑖= 1, ⋯, 𝑢 
𝑥𝑖 denotes the number of patients with event in treatment1in stratum i, 𝑖= 1, ⋯, 𝑢 
𝑦𝑖 denotes the number of patients with event in treatment2in stratum i, 𝑖= 1, ⋯, 𝑢 
𝑛𝑖 denotes the number of patients on treatment1in stratum i, 𝑖= 1, ⋯, 𝑢 
𝑚𝑖 denotes the number of patients on  treatment2in stratum i, 𝑖= 1, ⋯, 𝑢 
The estimated variance of 𝛿̂𝑀𝐻 is calculated as: 
𝑣𝑎𝑟
̂ (𝛿̂𝑀𝐻) =
∑
𝐿𝑖
𝑢
𝑖=1
(∑
𝑤𝑖
𝑢
𝑖=1
)2 
where 𝐿𝑖= 𝑥𝑖(𝑛𝑖−𝑥𝑖) 𝑚𝑖
3 + 𝑦𝑖(𝑚𝑖−𝑦𝑖) 𝑛𝑖
3
𝑛𝑖∙𝑚𝑖∙(𝑛𝑖+ 𝑚𝑖)2
 , 𝑖= 1, ⋯, 𝑢 
Assuming a normal distribution of 𝛿̂𝑀𝐻 , an approximate 95% CI is given as follows, 
where 𝑧0.975 is the 97.5% quantile of the standard normal distribution: 
𝐶𝐼= [𝛿̂𝑀𝐻 ± 𝑧0.975 ∙√𝑣𝑎𝑟
̂ (𝛿̂𝑀𝐻)] 
Also, the approximate p-value can be calculated using the following: 
51


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 52 of 88 
pvalue =  2 ∙Pr
[
 
 
 
𝑍> ||
𝛿̂𝑀𝐻
√𝑣𝑎𝑟
̂ (𝛿̂𝑀𝐻)
|| 
]
 
 
 
 , where 𝑍 ~ 𝑁(0, 1) 
If there is a stratum for a treatment group that has 0 patients in it, the 0 count will be 
replaced by 0.5 in order to prevent dividing by 0 in the above equations, as suggested in 
Greenland & Robins.   
The primary inference will be drawn from the treatment difference between vibegron and 
placebo at Week 12. The table output will show the number and percent of patients 
attaining the endpoint for all treatment arms, the CMH estimated risk difference between 
vibegron and placebo, and tolterodine and placebo with 95% CI and p-value using the 
above formula at Week 12. The table output will also include this summary at Weeks 2, 4, 
and 8.  
To further characterize meaningful change from baseline at Week 12 in urgency episodes 
as defined by various anchor levels of PGI-Severity, PGI-Control, and PGI-Frequency. 
Cumulative function (CDF) plots and kernel density plots of percent change from baseline 
at Week 12 in average daily urgency episodes will be categorized by the following anchor 
levels. The anchor levels of PGI-Severity, PGI-Control, and PGI-Frequency are shifts from 
baseline to Week 12, separately. The number of patients and mean percent CFB at Week 
12 in average daily urgency episodes will be presented on the plots.  
 ≥2 categories worse 
 One-category worse 
 No change  
 One-category improvement 
 Two-categories improvement  
 ≥3 categories improvement 
To further evaluate clinical meaningful improvement in the PGI-Control and PGI-
Frequency items, the described CDF and kernel density plots will be provided for the 
subset of patients with severe symptoms at baseline (e.g., patients with “no control” over 
OAB symptoms’ in PGI-Control; patients experiencing OAB symptoms “very often” in 
PGI-Frequency).  These are further described in the Exploratory Efficacy Endpoints 
section. 
52


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


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1
 
 
Page 54 of 88 
populations, and there is strong evidence to support the measure’s content validity in both 
target patient populations. In addition, the OAB-q has been shown to have excellent 
measurement properties, including validity and reliability. See Appendix 2 for a complete 
list of questions. 
The first 8 questions of the OAB-q LF ask patients much they are bothered by their bladder 
symptoms during the last week.  Each question has a response ranging from “Not at all” 
which is scored as a 1 to “A very great deal” which is scored as a 6. These questions make 
up the symptom bother scale. 
Questions 9 through 33 ask patients how much their symptoms have affected their life over 
the last week.  Each question has a response ranging from “None of the time” which is 
scored as a 1 to “All of the time” which is scored as a 6.  There are 4 subscales and one 
total score derived from these questions as follows: 
To transform the raw scores to a unified score ranging from 0 to 100, the following 
algorithms are used.   
For the Symptom Bother Score, the transformed score is: 
𝑠𝑐𝑜𝑟𝑒= 
(𝑎𝑐𝑡𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒−𝑙𝑜𝑤𝑒𝑠𝑡 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 )
𝑟𝑎𝑛𝑔𝑒
=
(𝑎𝑐𝑡𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒−8)
40
 x 100 
For Symptom Bother, higher scores correspond to the symptoms having a larger bother 
and lower scores represent a lower amount of bother due to symptoms. 
54


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Statistical Analysis Plan 
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Page 59 of 88 
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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 60 of 88 
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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 64 of 88 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
patient, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
An AE will be considered treatment emergent (TEAE) if it begins or worsens in severity 
after the first dose of the double-blind Study Treatment through 28 days after the last dose 
of Study Treatment, or the date of initiation of another investigational agent or surgical 
intervention or rollover to the extension study, whichever occurs first. Partial AE start 
dates will be imputed as detailed in Section 6.4. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is another medically important condition 
In addition, any illnesses reported before starting active treatment or AE meeting the 
criteria of seriousness (as defined above) and considered to be possibly related (according 
to the Investigator) to any study-specific procedure (e.g., laboratory testing procedure, liver 
biopsy) must be reported as an SAE. 
Summary tables will be based on treatment emergent adverse events (TEAEs). The 
incidence of TEAEs will be presented using counts and percentages of patients with 
TEAEs and tabulated by SOC and PT. SOC will be sorted in descending frequency and PT 
within SOC will be sorted by descending frequency based on the incidence across patients 
overall. If a patient has multiple occurrences (start and stop) of an event associated with a 
specific SOC or PT within a SOC, a patient will only be counted once in the incidence 
count for the SOC or PT within SOC respectively. 
An overall summary table of AEs by treatment group will be presented detailing the 
number and percentage of patients, and number of events for the following categories: 
 At least one TEAE; 
 At least one Treatment-Related TEAE; 
 At least one Grade ≥ 3 TEAE; 
 At least one Grade ≥ 3 Treatment-Related TEAE; 
 At least one Serious TEAE; 
 At least one Serious Treatment-Related TEAE; 
 At least one TEAE leading to Discontinuation from Study Medication; 
64


Statistical Analysis Plan 
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Version 3.1 
 
 
 
Page 65 of 88 
 At least one TEAE of Clinical Interest; 
 At least one Treatment-Related TEAE of Clinical Interest 
 
The incidence of all TEAEs by SOC and PT will be presented for the following: 
 All TEAEs; 
 Treatment-Related TEAEs; 
 TEAES with Grade ≥ 3; 
 Serious TEAEs; 
 Serious TEAEs with Grade ≥ 3; 
 Treatment Related Serious TEAEs; 
 TEAEs leading to Discontinuation from Study Treatment; 
 Non-Serious TEAEs  ≥ 5% Threshold 
 Non-fatal TEAEs 
 Hypertension TEAEs by Pre-existing Hypertension (Yes vs No) and Baseline 
Hypertension (Yes vs. No). Hypertension TEAEs will be selected as any TEAE with 
Preferred Term of Hypertension. 
Treatment listings will include the treatment arm, start and stop dates/times of the AE, and 
days on study relative to the day of first dose of study treatment.   
A Treatment related AE is defined as an AE for which the investigator classifies the AE as 
being related to study treatment.  To be conservative, the summary table will include 
events where the relationship to study treatment is missing. Missing severity for TEAEs 
will be counted as ‘Severe’. 
For the Non-Serious TEAEs ≥ 5% Threshold, it will include adverse events if the event 
occurs at an incidence of greater than or equal to 5% in any treatment arm. No rounding is 
allowed. If an adverse event occurs at an incidence of 4.8%, for example, the incidence 
will not be rounded up to 5% for the purposes of this table. 
Treatment Emergent Adverse Events of Clinical Interest (AECI) and Treatment-Related 
TEAEs of Clinical Interest will also be summarized by SOC and PT.  Adverse Events of 
Clinical Interest for this study include: 
 Potential Major Adverse Cardiac and Cerebrovascular Events (MACCE), which 
will be adjudicated by an independent external expert clinical adjudication 
committee (CAC) into the following categories according to the definitions in the 
CAC Charter:  
o Death or any event with fatal outcome  
o Myocardial infarction / Heart Attack  
o Cerebrovascular Accident / Stroke  
65


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 66 of 88 
o Hospitalization for Unstable Angina / Chest Pain  
o Hospitalization for Heart Failure  
o Coronary revascularization / Angioplasty / Stent  
 Hypertension: An adverse event of hypertension should be reported and will be an 
AECI as follows:  
o For patients without hypertension (average SBP <140 mmHg, DBP <90 
mmHg) at baseline, at two consecutive visits, the average of three systolic 
blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 
mmHg (or both); at 2 consecutive visits in patients who were not hypertensive 
at baseline; or,  
o For patients with hypertension at baseline, an increase compared to baseline at 
2 consecutive visits in the average of three SBP by ≥20 mmHg OR DBP by ≥10 
mmHg;  
o Initiation of, or increase in dose of, medication for treatment of hypertension in 
any patient.  
 Adverse events consistent with orthostatic hypotension as confirmed by orthostatic 
vital signs.  
 Adverse events suggestive of cystitis or urinary tract infection.  
 Elevated AST or ALT lab value requiring that study drug be temporarily withheld or 
permanently discontinued (see Section 8.6.1 and Section 8.6.2).  
The following additional listings will be provided: 
 Listing of deaths 
 Listing of Serious TEAEs 
 Listing of non-treatment-emergent SAEs 
 Listing of TEAEs leading to withdrawal or temporary withdrawal of study treatment 
 Listing of all AEs with a flag for TEAEs and onset (Prior = prior to first dose of single-
blind medication, Run-in = on or after first dose of single-blind medication but prior to 
first dose of double-blind medication, or Treatment = on or after first dose of double-
blind medication.) 
A summary of all TEAEs by maximum intensity (mild, moderate, severe, life-threatening, 
death), SOC, and PT will be presented, where the maximum intensity per patient will be 
counted at each level of summarization. In addition, a summary of all TEAEs by 
relationship to study treatment (related, not related), SOC and PT will be presented, where 
all relationships to study treatment per patient will be counted at each level of 
summarization.  A summary of all TEAEs by PT occurring in at least 2% of patients in the 
66


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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
  
 
Page 70 of 88 
10. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
The following changes to the analyses specified in the Protocol are enacted. Where 
specified, the section relates to the section of the SAP. 
70


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 71 of 88 
11. 
REFERENCE LIST 
1. Coyne KS, Gelhorn H, Thompson C, Kopp ZS, Guan Z.The psychometric validation of 
a 1-week recall period for the OAB-q. Int Urogynecol J. 2011;22(12):1555-1563. 
2. Matza LS, Thompson C L, Krasnow J, Brewster-Jordan J, Zyczynski T, Coyne K S. 
Test-retest reliability of four questionnaires for patients with overactive bladder: The 
overactive bladder questionnaire (OAB-q), patient perception of bladder condition 
(PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire 
(POSQ). Neurourol. Urodyn. 2005; 24(3): 215–225.  
3. REILLY 
ASSOCIATES. 
(2017). 
WPAI 
Scoring. 
Available: 
http://www.reillyassociates.net/WPAI_Scoring.html . Last accessed 08/28/2017. 
4. EuroQol. (2017). EQ-5D Instruments | About EQ-5D. Available: https://euroqol.org/. 
Last accessed 08/28/2017. 
5. Coyne KS, Thompson CL, Lai JS, Sexton C. An Overactive Bladder Symptom and 
Health-Related Quality of Life Short-Form: Validation of the OAB-q SF. 
Neurourology and Urodynamics 34:255–263 (2015) 
 
71


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Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
Page 75 of 88 
 If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 patient 
represented in 1 or more groups should be included. 
 An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more patients.  
 Unless otherwise specified, the estimated mean and median for a set of values should 
be printed out to 1 more significant digit than the original values, and standard 
deviations should be printed out to 2 more significant digits than the original values. 
The minimum and maximum should report the same significant digits as the original 
values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
 X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 
decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-value 
should be less than 0.0001 then present as <0.0001. If the p-value is returned as >0.999 
then present as >0.999 
 Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0.  A common convention is to display as '<0.1', or 
as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of patients in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should not 
be displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
75


Statistical Analysis Plan 
Urovant Protocol #3003 
Version 3.1 
 
 
 
 
Page 76 of 88 
 Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence over all treatment groups in 
decreasing order, assuming all terms are coded. Within the body system, drug class and 
SOC, medical history (by preferred term), drugs (by ATC1 code), and adverse events 
(by preferred term) should be displayed in decreasing order. If incidence for more than 
1 term is identical, they should then be sorted alphabetically. Missing descriptive 
statistics or p-values which cannot be estimated should be reported as “-”. 
 The percentage of patients is normally calculated as a proportion of the number of 
patients assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
patients exposed. Describe details of this in footnotes or programming notes. 
 For categorical summaries (number and percentage of patients) where a patient can be 
included in more than one category, describe in a footnote or programming note if the 
patient should be included in the summary statistics for all relevant categories or just 1 
category and the criteria for selecting the criteria. 
 Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
12.2.5.3. 
Listing Conventions 
 Listings will be sorted for presentation in order of treatment groups as above, patient 
number, visit/collection day, and visit/collection time. 
 Missing data should be represented on patient listings as either a hyphen (“-”) with a 
corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
 Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). 
Missing portions of dates should be represented on patient listings as dashes (--
JUL2000). Dates that are missing because they are not applicable for the patient are 
output as “N/A”, unless otherwise specified. 
 All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
 Units will be included where available 
76


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13. 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary tables, 
data listings, figures or statistical analyses. 
 provide 
an overview of the development of such SAS programs. 
 describes the quality control procedures that are performed for 
all SAS programs and output. Quality control is defined here as the operational techniques 
and activities undertaken to verify that the SAS programs produce the output by checking 
for their logic, efficiency and commenting and by review of the produced output. 
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14. 
APPENDICES 
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Appendix 2: OAB-q-1 wk English-US-original 
 
 
 
 
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Appendix 3: Global Impression Items 
Patient Global Impression of Severity (PGI-Severity) 
1.  Over the past week, how would you rate your overactive bladder symptoms? 
 None 
 Mild  
 Moderate 
 Severe 
Patient Global Impression of Control (PGI-Control) 
2.  Over the past week, how much control did you have over your overactive bladder 
symptoms? 
 Complete control 
 A lot of control 
 Some control 
 Only a little control 
 No control 
Patient Global Impression of Symptom Frequency (PGI-Frequency) 
3.  Over the past week, how often did you have overactive bladder symptoms? 
 Never  
 Rarely  
 Sometimes 
 Often 
 Very often 
 
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Patient Global Impression of Urgency-Related Leakage (PGI-Leakage)  
4.   Over the past week, how often did you have accidental urine leakage? 
 Never  
 Rarely  
 Sometimes 
 Often 
 Very often 
Patient Global Impression of Change (PGI-Change) 
5.  Overall, compared to the start of the study, how would you rate your overactive bladder 
symptoms over the past week? 
 Much better 
 Moderately better 
 A little better 
 No change 
 A little worse 
 Moderately worse 
 Much worse 
 
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Appendix 4: Cover Note for Listings 
For the following listings, the given questions are represented by numbers within the 
listing.  The relevant mapping is shown below.  
Listing 16.2.6.4 
OAB-q LF Questions 
During the past week, how bothered were you by… 
1. Frequent urination during the daytime 
2. An uncomfortable urge to urinate? 
3. A sudden Urge to Urinate with little or no warning 
4. Accidental loss of small amounts of urine? 
5. Nighttime urination? 
6. Waking up at night because you had to urinate? 
7. An uncontrollable urge to urinate? 
8. Urine loss associated with a strong desire to urinate? 
        
During the past week how often have your bladder symptoms… 
9. Made you carefully plan your commute? 
10. Caused you to feel drowsy or sleepy during the day? 
11. Caused you to plan “escape routes” to restrooms in public places? 
12. Caused you distress? 
13. Frustrated you? 
14. Made you feel like there is something wrong with you? 
15. Interfered with your ability to get a good night’s rest? 
16. Caused you to decrease your physical activities (exercising, sports, etc.)? 
17. Prevented you from feeling rested upon waking in the morning? 
18. Frustrated your family and friends? 
19. Caused you anxiety or worry? 
20. Caused you to stay home more often than you would prefer? 
21. Caused you to adjust your travel plans so that you are always near a restroom? 
22. Made you avoid activities away from restrooms (i.e., walks, running, hiking)? 
23. Made you frustrated or annoyed about the amount of time you spend in the restroom? 
24. Awakened you during sleep? 
25. Made you worry about odor or hygiene? 
26. Made you uncomfortable while traveling with others because of needing to stop for a restroom? 
27. Affected your relationships with family and friends? 
28. Caused you to decrease participating in social gatherings, such as parties or visits with family or 
friends? 
29. Caused you embarrassment? 
30. Interfered with getting the amount of sleep you needed? 
31. Caused you to have problems with your partner or spouse? 
32. Caused you to plan activities more carefully? 
33. Caused you to locate the closest restroom as soon as you arrive at a place you have never been? 
 
 
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Listing 16.2.6.4 
EQ-5D Answers 
 
Mobility 
1. I have no problems walking about 
2. I have some problems walking about 
3. I am confined to bed 
 
Self-Care 
4. I have problems with self-care 
5. I have some problems with washing or dressing myself 
6. I am unable to wash or dress myself 
 
Usual Activities 
1. I have no problems with performing my usual activities 
2. I have some problems with performing my usual activities 
3. I am unable to perform my usual activities 
 
Pain/ Discomfort 
1. I have no pain or discomfort 
2. I have moderate pain or discomfort 
3. I have extreme pain or discomfort 
 
Anxiety/ depression 
1. I am not anxious or depressed 
2. I am moderately anxious or depressed 
3. I am extremely anxious or depressed 
 
 
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