Conditions: Irritable Bowel Syndrome
Keywords: Irritable Bowel Syndrome Irritable Bowel Syndrome with predominantly diarrhea (IBS-D) Irritable Bowel Syndrome with mixed episodes of diarrhea and constipation (IBS-M) Vibegron Beta-3 adrenergic receptor (β3-AR) Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 222
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of vibegron, a beta-3 adrenergic receptor (β3-AR) agonist, in the treatment of pain associated with irritable bowel syndrome (IBS) due to IBS with predominant diarrhea (IBS-D) or mixed episodes of diarrhea and constipation (IBS-M).

Detailed description:

Arms:
arm 1: Participants will receive vibegron 75 milligrams (mg) orally once daily for 12 weeks. arm 2: Participants will receive matching placebo orally once daily for 12 weeks.

Interventions: intervention 1: Vibegron intervention 2: Placebo
Intervention descriptions: intervention 1: oral administration intervention 2: oral administration

Protocol document:
Prot_000.pdf: 
Urovant Confidential 
Protocol UR0-901-2001 
CLINICAL PROTOCOL 
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Vibegron Administered Orally for 12 Weeks to Women 
with Irritable Bowel Syndrome 
Protocol Number: 
Version Number: 
Product: 
Development Phase: 
Sponsor: 
IND Number: 
Emergency Contact Telephone Number: 
Contact for Serious Adverse Events 
(SAEs): 
Approval Date: 
Sponsor Signatory: 
NCT Number: NCT02929329 
UR0 -901-2001 
4.0 (Amendment 3) 
Replaces Amendment 2 (Version 3.0; dated 
30 August 2019) 
Vibegron (UR0-901, RVT-901, MK-4618, 
KRP-114V) 
2 
Urovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Telephone +41 (42) 2155999 
United States Contact: 
Clinical Development 
5281 California A venue, Suite 100 
Irvine, CA, USA 92617 
Telephone: 
Email: 
140291 
Refer to separate Study Contacts Page 
19 November 2019 
This NCT number has been applied to the document for pmposes of posting on Clinicalti·ials.gov 
Version 4.0 
1 
19 November 2019 


Urovant Confidential 
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CONFIDENTIAL 
This document contains proprietary and confidential information of Urovant Sciences GmbH 
Acceptance of this document constitutes agreement by the recipient that no previously 
unpublished information contained herein will be published or disclosed without the prior written 
approval of Urovant Sciences GmbH with the exception that this document may be disclosed to 
study personnel under your supervision who need to know the contents for conducting the study 
and appropriate Institutional Review Boards (IRBs)/Ethics Committees (EC) under the condition 
that the personnel have agreed to keep this information confidential. The foregoing shall not 
apply to disclosure required by governmental regulations or laws, however, Urovant Sciences 
GmbH shall be promptly notified of any such disclosure. 


Urovant Confidential 
Protocol UR0-901-2001 
SPONSOR SIGNATURE PAGE 
Study Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Vibegron Administered Orally for 12 Weeks to Women with Irritable 
Bowel Syndrome 
Protocol Number: UR0-901-2001 
This protocol has been approved by a representative of Urovant Sciences GmbH. The following 
signature documents this approval. 
Date 
Version 4.0 
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INVESTIGATOR STATEMENT 
Study URO-901-2001: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Vibegron Administered Orally for 12 Weeks to Women 
with Irritable Bowel Syndrome 
• 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 (DD/MON/YYYY) 
 
Site Number 
 
 
 


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PROTOCOL AMENDMENT 3 - SUMMARY OF CHANGES 
This protocol was amended to include the following notable changes: 
• Justification for Dose (Section 4.3) 
o Added data from Phase 2 and 3 studies showing that doses up to 100 mg 
(including 75mg) of vibegron vs. placebo were safe and efficacious in patients 
with OAB up to 52 weeks. 
• Inclusion criteria (Section 5.1) and Section 10.2 
o Made fecal calprotectin testing optional per investigator’s discretion, reserving 
evaluation only in subjects with a strong suspicion for inflammatory bowel 
disease (IBD) (eg, IBD family history in a 1st degree relative, other genetic 
factors, etc) 
• Inclusion criteria (Section 5.1):  
o Removed C-reactive protein (CRP) testing as an eligibility requirement for all 
subjects 
o Updated diary completion for screening to “any 5 days out of 7 days at baseline 
prior to Day 1 Randomization” 
o Removed the IBS-D diarrhea criterion (Bristol Stool Scale Type 6 or 7) 
• Exclusion criteria (Section 5.2), Section 6.5.1, 10.7.2, and Schedule of Assessments 
o For subjects who had a positive urine drug screen at Visit 1 due to a prohibited 
concomitant medication, the urine drug screen must be repeated at Visit 2 to 
determine if sufficient washout of the prohibited concomitant medication has 
occurred and to confirm eligibility.  The urine drug screen does not need to be re-
tested at Visit 2 if the initial positive result at Visit 1 was due to a permitted 
concomitant medication based on the clinical judgment of the investigator.   
• Table 6-2 Medications Permitted at Stable Doses 
o Added class of medications:  Antispasmodics/Smooth muscle relaxants and 
Peppermint Oil 
• Subject Stratification 
o Increased cap on IBS-M subjects from n ≤ 40 (20%) to n ≤ 100 (50%) 
• Statistics Considerations (Section 9): 
o Removed the formal hypothesis testing.  The primary objective is to estimate the 
treatment effect of each group.  Nominal p-values will be provided for descriptive 
purposes 
o Updated the sample size section accordingly based on the requirement that 50% 
of the subjects be IBS-M 
o Added two additional analysis populations: Full analysis set (FAS):  FAS-D and 
FAS-M, which are each subsets of FAS. 
o Added that an interim analysis may be performed 
 


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PROTOCOL AMENDMENT 2 - SUMMARY OF CHANGES 
This protocol was amended to include the following notable changes: 
• Changed the timing of the Safety Follow-up telephone call from 21 days to 14 days after 
the last dose of study drug (with −7 day window), and clarified that the Safety Follow-up 
assessment applies only to randomized subjects (Sections 1.3, 8.4.3, 10.7.8 and elsewhere 
for consistency) 
• Clarified that the scheduled urine assessment at Visits 1, 3, 4, 5, 6, and 7 will be a urine 
dipstick, with urinalysis and culture/sensitivity testing performed if the urine dipstick 
results suggest a urinary tract infection; also clarified that a urine dipstick should be 
performed when a subject presents at an Unscheduled Visit with symptoms of urinary 
tract infection (with subsequent urinalysis and culture/sensitivity testing if warranted) 
(Sections 1.3 and 10.2) 
• Inclusion criteria (Section 5.1):  
− Clarified acceptable fecal calprotectin level (≤ 150 mcg/g) and acceptable 
C-reactive protein level (< 17 mg/L) in subjects with irritable bowel syndrome 
(IBS) 
• Exclusion criteria (Section 5.2): 
− Provided exclusionary timeframes for both uncomplicated and complicated prior 
appendectomy  
− Clarified that acute, symptomatic cholecystitis or symptomatic cholelithiasis 
within the past 6 months is exclusionary 
− Removed known or suspected human immunodeficiency virus or acquired 
immunodeficiency syndrome as an exclusion 
• Endpoints (Section 3):  
− Primary: Clarified the primary endpoint for consistency with Food and Drug 
Administration guidance for clinical evaluation of IBS treatments 
− Secondary 
 Clarified the Week 12 Global Improvement Scale (GIS) endpoint as the 
proportion of GIS responders  
 Added the endpoint of proportion of IBS subjects with predominantly 
diarrhea (IBS-D) who are abdominal pain intensity (API) weekly 
responders with ≥ 40% improvement 
 Added the endpoint of proportion of IBS-D subjects who are API weekly 
responders with ≥ 50% improvement  
− Exploratory 
 


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• Changed planned number of sites from approximately 30 to approximately 40 
(Section 4.1) 
• Concomitant medications (Section 6.5):  
− Removed nonsteroidal anti-inflammatory drugs and beta antagonists from the list 
of prohibited medications 
− Changed washout period for mu-opioid receptor agonists from 3 months to 
1 month 
− Clarified that systemic cannabidiol is prohibited 
− Added stable doses of antihypertensives to the list of permitted medications 
− Clarified that rescue medications should only be used beginning at Day 1 (Visit 3) 
− Added low-dose acetaminophen (500 mg three times daily or less) as a rescue 
medication for pain 
− Changed the dose of the rescue medication ibuprofen from 200 mg twice daily or 
less to 400 mg twice daily or less 
• Discontinuation of Study Drug (Section 7) 
− Clarified assessments and forms that should be completed for subjects who are 
screen failures or run-in failures 
− Removed Screen Failure and Run-in Failure as reasons for discontinuation of 
study drug for randomized subjects 
• Clarified that rescreening may occur beyond the 5-week Screening Period and that the 
Sponsor’s designated Medical Monitor, Sponsor, or its designee must be consulted and 
approve rescreens (Section 5.4 and elsewhere for consistency) 
• Statistical Methods (Section 9) 
− Clarified definition of Full Analysis Set to require at least 1 baseline diary 
assessment and at least 1 post-randomization diary entry instead of 1 evaluable 
change in abdominal pain response  
− Deleted process for imputation of missing Week 12 data because it is not 
applicable 
− Updated significance level for primary hypothesis to 0.10 for consistency with 
statistical methods  
− Added a Per-Protocol Set analysis 
• Clarified that abnormal screening laboratory values should not be documented as adverse 
events (Section 10.3) 
In addition, administrative updates (eg, footer dates, abbreviations), corrections of minor 
typographical errors, editorial changes, clarifications, and/or stylistic and formatting 
revisions have been made to improve clarity and consistency throughout the document.  


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PROTOCOL AMENDMENT 1 - SUMMARY OF CHANGES 
This protocol was amended to include the following notable changes: 
•  Specified eluxadoline as a prohibited medication, resulting in the following changes: 
− removed Inclusion Criterion #6 regarding the stability of eluxadoline dosage 
regimen for applicable subjects 
− removed “and currently receiving eluxadoline” from Exclusion Criterion #18 
− removed “current eluxadoline use (yes vs no)” as a stratification factor 
− added “Mu-opioid receptor agonist/eluxadoline” to Table 6-1 (Prohibited 
Medications)  
− removed “Mu-opioid receptor agonist/eluxadoline” from Table 6-2 (Medications 
Permitted at Stable Doses) 
• Added body temperature to list of vital sign assessments (Section 1.3, Section 8.3.2, and 
Section 10.7). 
• Clarified that subjects will be supplied with stool sample collection kits if they are unable 
to provide a stool sample during the Screening visit (Section 1.3 and Section 10.7.1). 
• 
• Added a Data Safety Monitoring Board (DSMB) to assess safety aspects of this study, 
with 3 planned DSMB data reviews after 25%, 50%, and 75% of randomized subjects 
have received study drug and completed study visits through Week 4 (Visit 5) 
(Section 4.1 and Section 9.6). 
• Changed maximum allowable enrollment for subjects with irritable bowel syndrome with 
mixed episodes of diarrhea and constipation (IBS-M) from 40% to 20% of the total study 
population (Section 4.1). 
• Reduced total target enrollment from 350 subjects to 200 subjects (and updated expected 
evaluable subjects from 140 subjects to 90 subjects per treatment group) (Section 4.1 and 
Section 9.2). 
• Reduced planned number of sites from 50 to approximately 30, and limited enrollment to 
sites in the United States (Section 4.1). 
• Added “completing patient registry verification” as part of the inclusion criterion for 
demonstrating that subject is capable of giving informed consent (Section 5.1). 
• Added “solitary rectal ulcer syndrome” to Exclusion Criterion #5 as an example of 
altered normal gastrointestinal anatomy (Section 5.2). 
• Added clinically significant electrocardiogram (ECG) abnormality as Exclusion Criterion 
#22 (and renumbered subsequent criteria) (Section 5.2). 


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• Added to list of prohibited drug classes and provided relevant examples (Section 6.5.1). 
• Added “Run-in failure” as a potential reason for termination of individual subjects 
(Section 7.1). 
• Added definition of treatment-emergent adverse event (TEAE) to the statistical methods 
(Section 9.4.3.1). 
• Clarified list of specific laboratory parameters to be tested (Section 10.2). 
•  Changed AE severity rating from a 3-point scale to a 5-point scale by adding Grade 
4/life-threatening and Grade 5/fatal severity grades (Section 10.3). 
In addition, administrative updates (eg, footer dates, abbreviations), corrections of minor 
typographical errors, editorial changes, and/or stylistic and formatting revisions have been made 
to improve clarity and consistency throughout the document. 


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Table of Contents 
Sponsor Signature Page .................................................................................................................3 
Investigator Statement ...................................................................................................................4 
Protocol Amendment 3 - Summary of Changes ..........................................................................5 
Protocol Amendment 2 - Summary of Changes ..........................................................................6 
Protocol Amendment 1 - Summary of Changes ..........................................................................8 
Table of Contents .........................................................................................................................10 
List of Tables ................................................................................................................................13 
1. 
Protocol Summary ........................................................................................................14 
1.1. 
Synopsis ..........................................................................................................................14 
1.2. 
Schema ............................................................................................................................16 
1.3. 
Schedule of Assessments ................................................................................................17 
2. 
Introduction ...................................................................................................................22 
2.1. 
Study Rationale ...............................................................................................................22 
2.2. 
Background .....................................................................................................................22 
2.2.1. 
Irritable Bowel Syndrome ...............................................................................................22 
2.2.2. 
Vibegron .........................................................................................................................23 
2.3. 
Benefit/Risk Assessment ................................................................................................24 
2.3.1. 
Potential Benefits ............................................................................................................24 
2.3.2. 
Potential Risks ................................................................................................................24 
3. 
Objectives and Endpoints ............................................................................................25 
4. 
Study Design ..................................................................................................................29 
4.1. 
Overall Design ................................................................................................................29 
4.1.1. 
Clinical Hypotheses ........................................................................................................29 
4.2. 
Scientific Rationale for Study Design ............................................................................29 
4.3. 
Justification for Dose ......................................................................................................30 
4.4. 
End of Study Definition ..................................................................................................30 
5. 
Study Population ...........................................................................................................31 
5.1. 
Inclusion Criteria ............................................................................................................31 
5.2. 
Exclusion Criteria ...........................................................................................................32 
5.3. 
Lifestyle Considerations .................................................................................................35 
5.4. 
Screen Failures ................................................................................................................35 
6. 
Study Drug ....................................................................................................................36 
6.1. 
Study Drugs Administered .............................................................................................36 
6.1.1. 
Run-in Medications and Administration .........................................................................36 
6.1.2. 
Treatment Period Medications and Administration ........................................................37 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................37 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................37 
6.4. 
Study Drug Compliance..................................................................................................38 
6.5. 
Concomitant Therapy .....................................................................................................38 
6.5.1. 
Prohibited Drugs and Washout Before the Study ...........................................................38 


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6.5.2. 
Permitted Drugs ..............................................................................................................39 
6.5.3. 
Rescue Medicine .............................................................................................................41 
6.6. 
Dose Modification ..........................................................................................................41 
6.7. 
Drug after the End of the Study ......................................................................................41 
7. 
Discontinuation of Study Drug and Subject 
Discontinuation/Withdrawal........................................................................................42 
7.1. 
Discontinuation of Study Drug .......................................................................................42 
7.2. 
Subject Discontinuation/Withdrawal from the Study .....................................................43 
7.3. 
Lost to Follow-up............................................................................................................43 
7.4. 
Early Study Termination .................................................................................................43 
8. 
Study Assessments and Procedures.............................................................................44 
8.1. 
Baseline Procedures ........................................................................................................44 
8.1.1. 
Informed Consent............................................................................................................44 
8.1.2. 
Assignment of Subject Number ......................................................................................44 
8.1.3. 
Screening.........................................................................................................................44 
8.1.4. 
Medical History ..............................................................................................................45 
8.1.5. 
Demographics .................................................................................................................45 
8.1.6. 
Prior and Concomitant Medications ...............................................................................45 
8.2. 
Efficacy Assessments .....................................................................................................45 
8.2.1. 
Symptom Diaries ............................................................................................................46 
8.2.2. 
Patient-reported Outcomes ..............................................................................................47 
8.3. 
Safety Assessments .........................................................................................................47 
8.3.1. 
Physical Examinations ....................................................................................................47 
8.3.2. 
Vital Signs .......................................................................................................................47 
8.3.3. 
Electrocardiograms .........................................................................................................48 
8.3.4. 
Clinical Safety Laboratory Assessments ........................................................................48 
8.4. 
Adverse Events and Serious Adverse Events .................................................................48 
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ................................................................................49 
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse 
Events ..............................................................................................................................49 
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................49 
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events ..................................50 
8.4.5. 
Pregnancy ........................................................................................................................50 
8.4.6. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events .............................................51 
8.4.7. 
Adverse Events of Special Interest .................................................................................51 
8.4.8. 
Medication Errors ...........................................................................................................54 
8.5. 
Treatment of Overdose ...................................................................................................54 
9. 
Statistical Considerations .............................................................................................55 
9.1. 
Statistical Hypotheses .....................................................................................................55 
9.2. 
Sample Size Determination ............................................................................................55 
9.3. 
Populations for Analyses ................................................................................................56 
9.4. 
Statistical Analyses .........................................................................................................56 
9.4.1. 
Demographic and Other Baseline Characteristics ..........................................................57 


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9.4.2. 
Efficacy Analyses ...........................................................................................................57 
9.4.3. 
Safety Analyses ...............................................................................................................58 
9.5. 
Interim Analyses .............................................................................................................59 
9.6. 
Data Safety Monitoring Board ........................................................................................60 
10. 
Supporting Documentation and Operational Considerations ..................................61 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................61 
10.1.1. Regulatory and Ethical Considerations ...........................................................................61 
10.1.2. Financial Disclosure ........................................................................................................61 
10.1.3. Informed Consent Process ..............................................................................................62 
10.1.4. Data Protection................................................................................................................62 
10.1.5. Committees Structure......................................................................................................62 
10.1.6. Posting Clinical Study Data ............................................................................................62 
10.1.7. Data Quality Assurance ..................................................................................................62 
10.1.8. Source Documents ..........................................................................................................64 
10.1.9. Study and Site Closure ....................................................................................................65 
10.1.10. Publication Policy ...........................................................................................................65 
10.1.11. Compliance with Protocol...............................................................................................65 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................66 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................68 
10.4. 
Appendix 4: Abbreviations .............................................................................................74 
10.5. 
Appendix 5: Study Tabular Summary ............................................................................76 
10.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................78 
10.6.1. Contraception Guidance ..................................................................................................78 
10.6.2. Pregnancy Testing and Reporting ...................................................................................79 
10.7. 
Appendix 7: Study Schedule Supplement ......................................................................81 
10.7.1. Screening, Visit 1 (between Day -42 and Day -15) ........................................................81 
10.7.2. Run-in, Visit 2 (Day -14) ................................................................................................81 
10.7.3. Baseline, Visit 3 (Day 1) .................................................................................................82 
10.7.4. Double-blind Treatment Period Week 2 (± 4 days), Visit 4 ...........................................82 
10.7.5. Double-blind Treatment Period Week 4 (± 4 days), Visit 5 ...........................................82 
10.7.6. Double-blind Treatment Period Week 8 (± 4 days), Visit 6 ...........................................83 
10.7.7. Double-blind Treatment Period Week 12 (± 4 days [Visit 7]), or 
Early Withdrawal ............................................................................................................83 
10.7.8. Safety Follow-up, Telephone Call; Week 14 (7 to 14 days after 
last dose of study drug; includes window of −7 days from Week 
14) ...................................................................................................................................83 
10.8. 
Appendix 8: Patient-Reported Outcomes Questionnaires ..............................................84 
10.8.1. Global Improvement Scale .............................................................................................84 
10.8.2. Irritable Bowel Syndrome - Quality of Life Measure (IBS – 
QoL) ................................................................................................................................85 
10.8.3. Work Productivity and Activity Impairment ..................................................................88 
10.8.4. Additional Questions on Abdominal Pain ......................................................................90 


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10.9. 
Appendix 9: 0- to 10-Point Numeric Rating Scale for Abdominal 
Pain .................................................................................................................................91 
10.10. 
Appendix 10: Bristol Stool Chart ...................................................................................92 
11. 
References ......................................................................................................................93 
 
List of Tables 
Table 6-1 
Prohibited Medications ..................................................................................... 39 
Table 6-2 
Medications Permitted at Stable Doses ............................................................. 40 
Table 10-1 
Clinical Laboratory Tests .................................................................................. 66 
  


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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of Vibegron Administered Orally for 12 Weeks to Women with Irritable 
Bowel Syndrome 
Protocol Number: URO-901-2001 
Brief Title: Double-blind, Placebo-controlled Study of Vibegron in Irritable Bowel Syndrome 
Study Rationale: 
Animal models have shown that beta-3 adrenergic receptor (β3-AR) activation protects against 
gastric ulcers, inhibits castor-oil induced diarrhea, and reduces observed pain behavior 
[Vasina, 2008; Cellek, 2007]. Clinical studies of solabegron, a β3-AR agonist, have shown 
improvement in pain among women with IBS, with no effect on gut motility in healthy subjects 
[Grudell, 2008; Kelleher, 2008]. Vibegron, a novel β3-AR agonist, is in clinical development for 
the treatment of overactive bladder. It has been studied in approximately 2300 subjects (1840 
with overactive bladder and 460 healthy subjects) and is currently being assessed in Phase 3 
studies. All clinical data available to date indicate that vibegron is well tolerated. 
Objectives and Endpoints (Primary and Secondary Only): 
The primary study objective is to compare the effect of vibegron vs placebo in subjects with 
abdominal pain due to irritable bowel syndrome (IBS) with predominantly diarrhea (IBS-D) on 
the abdominal pain intensity (API) weekly responder rate over 12 weeks. Secondary objectives 
are to:  
• Compare the effect of vibegron vs placebo in subjects with abdominal pain due to IBS-D 
or mixed episodes of diarrhea and constipation (IBS-M) on patient-reported outcomes 
• Compare the effect of vibegron vs placebo in subjects with abdominal pain due to IBS-D 
on the API weekly responder rate over 12 weeks based on different thresholds of 
improvement 
• Compare the effect of vibegron vs placebo in subjects with abdominal pain due to IBS-D 
or IBS-M on safety endpoints 
The primary endpoint is the proportion of API weekly responders over 12 weeks, with an API 
Weekly Responder defined as a subject who experiences a decrease in the weekly average of 
“worst abdominal pain in the past 24 hours” scores of at least 30% compared with the baseline 
weekly average. Secondary endpoints are the proportion of Global Improvement Scale 
responders at Week 12, the proportion of IBS-D subjects who are API weekly responders with at 
least 40% improvement over 12 weeks, the proportion of IBS-D subjects who are API 


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responders with at least 50% improvement over 12 weeks, adverse events (AEs), clinical 
laboratory values, and vital signs. 
Overall Study Design: 
This study is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study to evaluate the efficacy and safety of vibegron in women with irritable bowel 
syndrome with predominantly diarrhea (IBS-D) or mixed episodes of diarrhea and constipation 
(IBS-M). Subjects who meet all eligibility criteria will be randomized in a 1:1 ratio to receive 
either vibegron 75 mg or matched placebo. Randomization will be stratified by baseline 
abdominal pain intensity score (< 6 vs ≥ 6 on a 0- to 10-point numeric rating scale) and IBS 
subtype (IBS-D vs IBS-M). Enrollment for subjects with IBS-M will be capped at 50% of the 
total subject population (ie, up to 50% [n=100] of the study population can be subjects with IBS-
M). Stratification will be performed via central randomization across the study (not per site).  
The study consists of a Screening Period (1 to 5 weeks), a single-blind placebo Run-in Period 
(2 weeks), a randomized double-blind Treatment Period (12 weeks), and a Safety Follow-up 
telephone call (approximately 2 weeks).  
Number of Subjects: 
In total, approximately 200 subjects will be randomized in a 1:1 ratio (100 per treatment group). 
At most, 50% of randomized subjects (100 subjects total [50 per treatment arm]) will have IBS-
M; and at least 50% of randomized subjects (100 subjects total [50 per treatment arm]) will have 
IBS-D. Assuming a total of 10% of subjects will discontinue prior to Week 12 (for any reason), 
there will be a minimum of approximately 90 evaluable IBS-D subjects (45 per treatment group) 
at the end of Week 12. The sample size justification is provided in Section 9.2.  
Number of Sites:  
Approximately 40 sites in the United States. 
Study Drug Groups and Study Duration: 
Single-blind Run-in: 1 matched placebo tablet daily for 2 weeks 
Double-blind Treatment: 1 vibegron (75 mg) or matched placebo tablet daily for up to 12 weeks 
Data Safety Monitoring Committee: 
A Data Safety Monitoring Board (DSMB) will be retained to assess, on an ongoing basis, all 
safety aspects of this study, including serious AEs (SAEs), major adverse cardiac events 
(MACE), adverse events of special interest (AESIs), and all other AEs. The committee will meet 
to review the safety data at the following 3 times when the (1) first 25% of subjects enrolled 
complete the Week 4 visit (Visit 5); (2) first 50% of subjects enrolled complete the Week 4 visit 
(Visit 5); and (3) first 75% of subjects enrolled complete the Week 4 visit (Visit 5). This 


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committee will be an external independent DSMB that monitors the safety for UR0-901-2001. 
The detailed activities including meeting plans will be described and documented in the DSMB 
Chaiier. A sepai·ate statistical analysis plan will be prepai·ed for the DSMB. 
1.2. 
Schema 
Screening 
Day 
-42 
Visit 1 
WD = withdrawal 
Single-blind 
Run-in 
Day 
-14 
Visit2 
Day 
I 
Visit3 
Baseline 
Double-blind Treatment Period 
\I ibegron 7 5 mg daily 
Placebo daily 
Week 
Week 
Week 
2 
4 
8 
Visit4 
Visit5 
Visit 6 
Week 
12 
Visit 7/ 
Early 'WD 
End of 
Study 
Week 14 
Telephone 
Call 
Safety 
Follow-up 
The Week 14 Safety Follow-up telephone call should occur 7 to 14 days after the last dose of study dmg (includes 
window of- 7 days from Week 14) only for randomized subjects who complete Week 12 or withdraw from the 
study early. 
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1.3. 
Schedule of Assessments 
 
Screening 
Run-in 
Double-blind Treatment 
Safety 
Follow-up  
Notes 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Telephone 
Call 
Day/Week 
Day -42 
to -15 
Day -14 
Baseline 
Day 1 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 8 
(Day 57) 
Week 12 
or Early 
WD 
(Day 85) 
Week 14 
or  
14 days 
after last 
dose (at 
the latest) 
Visit Window 
 
± 4  
days 
 
± 4  
days 
± 4  
days 
± 4  
days 
± 4  
days 
−7 
days 
Safety Follow-up call will 
occur 7 to 14 days after the 
last dose of study drug 
(includes window of −7 
days) a 
Informed consent 
X 
 
 
 
 
 
 
 
 
Subject entry into IWRS and 
subject registry 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria review 
X 
X 
X 
 
 
 
 
 
Recheck clinical status 
before Run-in and 
randomization  
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history and surgical 
history  
X 
 
 
 
 
 
 
 
Includes current use of 
illicit drugs, alcohol and 
caffeine  
IBS history  
X 
 
 
 
 
 
 
 
Including previous 
treatments and diets 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
From informed consent to 
Safety Follow-up call 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Screening 
Run-in 
Double-blind Treatment 
Safety 
Follow-up  
Notes 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Telephone 
Call 
Day/Week 
Day -42 
to -15 
Day -14 
Baseline 
Day 1 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 8 
(Day 57) 
Week 12 
or Early 
WD 
(Day 85) 
Week 14 
or  
14 days 
after last 
dose (at 
the latest) 
Visit Window 
 
± 4  
days 
 
± 4  
days 
± 4  
days 
± 4  
days 
± 4  
days 
−7 
days 
Safety Follow-up call will 
occur 7 to 14 days after the 
last dose of study drug 
(includes window of −7 
days) a 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Body temperature, blood 
pressure (avg of 3 results) 
and pulse after sitting for 5 
min and before blood 
draw: Visits 1 to 7 
Weight: Visits 1, 3, and 7 
Height: Visit 1 
Brief physical examination 
X 
 
X 
 
 
 
X 
 
Heart, lungs, abdomen, 
external genitalia, perianal 
area, and others as needed 
Urine β-hCG pregnancy test 
X 
 
X 
 
 
 
X 
 
Women of child-bearing 
potential only; serum test 
required if urine test 
positive 
Urine drug screen 
X 
Xc 
 
 
 
 
 
 
Refer to exclusion criterion 
#29 and Section 6.5 for 
additional details on 
possible repeat testing at 
Visit 2 in the event of an 
initially positive result at 
Visit 1. 


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Screening 
Run-in 
Double-blind Treatment 
Safety 
Follow-up  
Notes 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Telephone 
Call 
Day/Week 
Day -42 
to -15 
Day -14 
Baseline 
Day 1 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 8 
(Day 57) 
Week 12 
or Early 
WD 
(Day 85) 
Week 14 
or  
14 days 
after last 
dose (at 
the latest) 
Visit Window 
 
± 4  
days 
 
± 4  
days 
± 4  
days 
± 4  
days 
± 4  
days 
−7 
days 
Safety Follow-up call will 
occur 7 to 14 days after the 
last dose of study drug 
(includes window of −7 
days) a 
Laboratory assessments 
(chemistry, hematology, urine 
dipstick) b 
X 
 
X 
X 
X 
X 
X 
 
Tests specified in 
Section 10.2 
Serum tissue 
transglutaminase antibody 
(IgA) 
X 
 
 
 
 
 
 
 
Screening only 
12-lead ECG 
X 
 
 
 
 
 
 
 
Screening only; supine 
Dispense/collect subject diary 
 
X 
Dispense 
 
 
 
 
X 
Collect 
 
Bowel Movement Diary 
will record bowel 
movement frequency and 
form, bowel urgency, and 
recurrent bowel 
movements; Pain Diary 
will record worst 
abdominal pain and use of 
rescue meds 
Dispense Run-in study drug 
 
X 
 
 
 
 
 
 
Daily dosing 
Administer witnessed dose of 
study drug 
 
X 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 


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Screening 
Run-in 
Double-blind Treatment 
Safety 
Follow-up  
Notes 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Telephone 
Call 
Day/Week 
Day -42 
to -15 
Day -14 
Baseline 
Day 1 
Week 2 
(Day 15) 
Week 4 
(Day 29) 
Week 8 
(Day 57) 
Week 12 
or Early 
WD 
(Day 85) 
Week 14 
or  
14 days 
after last 
dose (at 
the latest) 
Visit Window 
 
± 4  
days 
 
± 4  
days 
± 4  
days 
± 4  
days 
± 4  
days 
−7 
days 
Safety Follow-up call will 
occur 7 to 14 days after the 
last dose of study drug 
(includes window of −7 
days) a 
Dispense new bottle of 
double-blind study drug for 
daily dosing 
 
 
X 
 
X 
X 
 
 
At Visit 4 (Week 2), the 
Visit 3 (Baseline) bottle 
will checked for 
compliance and returned to 
subject  
GIS 
 
 
X 
X 
X 
X 
X 
 
Before vital signs and 
blood draw  
WPAI 
 
 
X 
 
 
X 
X 
 
Before vital signs and 
blood draw 
IBS-QoL 
 
 
X 
 
 
X 
X 
 
Before vital signs and 
blood draw 
Additional questions on 
abdominal pain (see 
Section 10.8.4) 
 
 
X 
X 
X 
X 
X 
 
Before vital signs and 
blood draw 
AE = adverse event; avg = average; ECG = electrocardiogram; GIS = Global Improvement Scale; IBS = irritable bowel syndrome; IBS-QoL = irritable bowel 
syndrome quality of life; IWRS = interactive web response system; min = minutes; SAE = serious adverse events; WD = withdrawal; WPAI = Work Productivity 
and Activity Impairment 
a Safety Follow-up telephone call will occur only for randomized subjects who complete Week 12 or withdraw from the study early. 
b A sample for urinalysis and urine culture/sensitivity testing will be sent to the laboratory if the urine dipstick performed at the site suggests a urinary tract 
infection (ie, positive for the presence of leukocytes, nitrites, or blood cells). In addition, subjects presenting with symptoms of a urinary tract infection at 
Unscheduled Visits will have a urine dipstick performed, with subsequent urinalysis and culture/sensitivity testing if dipstick suggests urinary tract infection.  


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c For subjects who had a positive urine drug screen at Visit 1 due to a prohibited concomitant medication, the urine drug screen must be repeated at Visit 2 to 
determine if sufficient washout of the prohibited concomitant medication has occurred and to confirm eligibility.  The urine drug screen does not need to be re-
tested at Visit 2 if the initial positive result at Visit 1 was due to a permitted concomitant medication based on the clinical judgment of the investigator.  


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2. 
Introduction 
2.1. 
Study Rationale 
This study will evaluate the efficacy and safety of vibegron, a beta-3 adrenergic receptor (β3-AR) 
agonist, in the treatment of pain associated with irritable bowel syndrome (IBS) that is associated 
with predominantly diarrhea (IBS-D) or has mixed episodes of diarrhea and constipation 
(IBS-M). The rationale for the study is based on both animal models of functional 
gastrointestinal disorders and Phase 1 and Phase 2 clinical studies of the β3-AR agonist 
solabegron. Animal models have shown that β3-AR activation can protect against gastric ulcers, 
inhibit castor-oil induced diarrhea, and reduce observed pain behavior [Vasina, 2008; 
Cellek, 2007]. The clinical studies of solabegron have shown improvement in pain among 
women with IBS, with no effect on gut motility in healthy subjects [Grudell, 2008; 
Kelleher, 2008]. Although this is the first study of vibegron in the setting of IBS, vibegron has 
been studied in the overactive bladder population (including a completed large Phase 2b 
dose-ranging study, 2 completed Phase 3 studies in Japan, and 2 ongoing global Phase 3 studies), 
and all clinical data available to date indicate that vibegron has been well tolerated.  
2.2. 
Background 
2.2.1. 
Irritable Bowel Syndrome 
Irritable bowel syndrome is a chronic, functional, bowel disorder associated with changes in the 
frequency or consistency of stool (ie, diarrhea, constipation, or a combination of both) as well as 
abdominal pain and distension [Sinagra, 2017]. The etiology of IBS is complex and affects 
bidirectional communication between the central and the enteric nervous system (ie, gut-brain 
axis). Altered colonic motility, defects in epithelial and secretory function, immune dysfunction, 
neurohormonal regulation, stress, and infection have been implicated in the pathogenesis of IBS 
[Occhipinti, 2012]. The Rome IV criteria classify IBS into 4 distinct subtypes based on 
predominant stool consistency: IBS with predominantly constipation (IBS-C), IBS with 
predominantly diarrhea (IBS-D), IBS with mixed episodes of diarrhea and constipation (IBS-M), 
and IBS with unknown subtype (IBS-U) [Lacy, 2017]. The definitions of diarrhea and 
constipation correlate with the Bristol Stool Form Scale, with Types 1 and 2 defined as 
constipation and Types 6 and 7 defined as diarrhea. The Rome IV IBS classification is based on 
the patient’s predominant bowel habit on days with abnormal bowel movement as follows:  
• IBS-C: ≥ 25% constipation (Bristol Type 1 or 2) and < 25% diarrhea (Bristol Type 6 
or 7).  
• IBS-D: ≥ 25% diarrhea (Bristol Type 6 or 7) and < 25% constipation (Bristol Type 1 or 2) 
• IBS-M: ≥ 25% constipation (Bristol Type 1 or 2) and ≥ 25% diarrhea (Bristol Type 6 
or 7) 
• IBS-U: unclassified (insufficient abnormality to meet other criteria)  


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The Rome IV diagnostic criteria must be met within the most recent 3 months, with symptom 
onset at least 6 months before diagnosis. 
Among functional gastrointestinal disorders, IBS is the most prevalent, affecting approximately 
11% of the world’s population (range: 1% to 45%, depending on country and criteria) 
[Lovell, 2012]. Epidemiology studies indicate that gender plays a role in the development of 
IBS, as women are at a higher risk for the condition than men; however, the predominance of 
women has been observed only in Western countries (approximately 2:1 to 5:1, depending on the 
care setting) possibly because of under diagnosis or differences in diet or infection risk factors 
[Sinagra, 2017]. IBS has a significant impact on quality of life and considerable economic 
burden to the health care system, with total cost (direct and indirect) estimates of $30 billion in 
the United States (US) [Lembo, 2007]. 
Abdominal pain is an important aspect and largely unmet medical need of IBS. Visceral 
structures are highly sensitive to distension, ischemia, and inflammation, and activation of 
nociceptors in response to tension or stretching can cause pain in patients with IBS. Colon 
spasms are common in patients with IBS and are associated with the symptoms of pain and 
bloating. Patients with IBS may also exhibit visceral hypersensitivity (ie, lowered pain threshold) 
[Melchior, 2018; Camilleri, 2008; Sabate, 2008]. IBS pain is often refractory to currently 
available therapeutic options (ie, diet, antispasmodics, antidepressants, laxatives, or 
antidiarrheals), creating a significant challenge for clinicians and patients trying to manage the 
disorder [Camilleri, 2017]. In addition, the side effects associated with pharmacotherapies, such 
as the anticholinergic effects of antispasmodics, may lead to lack of compliance or even 
discontinuation of treatment [Camilleri 2017; Saha 2014]. 
2.2.2. 
Vibegron 
Vibegron is a potent, highly selective, orally available, β3-AR agonist demonstrating > 9000-fold 
selectivity for activation of β3-AR over β2-AR and β1-AR in cell-based in vitro assays. 
Nonclinical and clinical studies suggest β3-AR activation is a novel target for treating pain and 
gastrointestinal motility in patients with IBS. β3-ARs are widely expressed and distributed on 
vascular and non-vascular smooth muscle and enteric neurons in the gastrointestinal tracts of 
many species, including humans [Cellek, 2007; De Ponti, 1996; Anthony, 1996; Krief, 1993]. 
Mechanistically, β3-AR agonists are hypothesized to reduce colon smooth muscle contractions, 
enteric neuron hyperactivity, and visceral pain by mediating a direct effect on smooth muscle 
and indirectly by promoting release of somatostatin within the intestine. In isolated circular 
muscle strips of human colon, activation of β3-AR induced smooth muscle relaxation 
[Cellek, 2007; De Ponti, 1999; Bardou, 1998; De Ponti, 1996], which was blocked using β3-AR 
antagonists [Schemann, 2010; De Ponti, 1999]. In addition, β3-AR agonists have been shown to 
reduce hyperexcitability of human enteric neurons and stimulate release of somatostatin 
[Schemann, 2010; Cellek, 2007], which inhibits submucosal neuronal excitability and pain in 
both animal models and humans [Prasoon, 2015; Shi, 2014; Mihara, 1987]. 


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Approximately 2300 subjects (including 1840 with overactive bladder and 460 healthy subjects) 
have received vibegron in 19 clinical studies. Data from these studies indicate that vibegron has 
been well tolerated when administered alone or in combination 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 an antimuscarinic 
comparator. Discontinuation rates due to AEs were low (less than 5%) in all clinical studies. A 
more detailed description of vibegron, including pharmacology, efficacy, and safety data in 
overactive bladder, is provided in the most recent version of the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Potential Benefits 
Vibegron’s novel mechanism of action has the potential to demonstrate significant therapeutic 
benefit in subjects with IBS pain. Early phase clinical studies of another β3-AR agonist, 
solabegron, showed improvement in the pain scores of women with IBS and no effect on gut 
motility in healthy subjects [Grudell, 2008; Kelleher, 2008]. 
2.3.2. 
Potential Risks 
To date, in subjects (male or female) with overactive bladder, no adverse reactions specific to 
vibegron have been identified. 
Based on aggregate preclinical, clinical pharmacology, and Phase 2 and 3 studies, AEs of special 
interest (AESIs) predefined for specific evaluations in vibegron clinical studies are as follows: 
• Potential major cardiovascular events 
• Hypertension 
• AEs suggestive of orthostatic hypotension 
• AEs suggestive of cystitis or urinary tract infection 
• Elevated AST or ALT lab value requiring that the study drug be temporarily withheld or 
permanently discontinued 
Prespecified definitions of AESIs are provided in Section 8.4.7. More detailed information about 
the known and expected benefits and risks and reasonably expected AEs of vibegron may be 
found in the most recent version of the Investigator’s Brochure. 


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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To compare the effect of vibegron 
vs placebo in subjects with 
abdominal pain due to IBS-D on 
the API weekly responder rate 
over 12 weeks  
• 
Proportion of IBS-D subjects who are API weekly responders 
over 12 weeks  
- An API Weekly Responder is defined as a subject who 
experiences a decrease in the weekly average of “worst 
abdominal pain in the past 24 hours” scores of at least 
30% compared with the baseline weekly average 
Secondary 
 
To compare the effect of vibegron 
vs placebo in subjects with 
abdominal pain due to IBS-D or 
IBS-M on patient-reported 
outcomes 
• 
Proportion of GIS responders at Week 12 for all IBS subjects, 
including IBS-D and IBS-M subjects  
To compare the effect of vibegron 
vs placebo in subjects with 
abdominal pain due to IBS-D on 
the API weekly responder rate 
over 12 weeks based on different 
thresholds of improvement 
 
• 
Proportion of IBS-D subjects who are API weekly responders 
over 12 weeks  
- An API Weekly Responder is defined as a subject who 
experiences a decrease in the weekly average of “worst 
abdominal pain in the past 24 hours” scores of at least 
40% compared with the baseline weekly average 
• 
Proportion of IBS-D subjects who are API weekly responders 
over 12 weeks  
- An API Weekly Responder is defined as a subject who 
experiences a decrease in the weekly average of “worst 
abdominal pain in the past 24 hours” scores of at least 
50% compared with the baseline weekly average 
To compare the effect of vibegron 
vs placebo in subjects with 
abdominal pain due to IBS-D or 
IBS-M on safety endpoints 
• 
AEs, clinical laboratory values, vital signs 


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Objectives 
Endpoints 
Other/Exploratory 
 


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Objectives 
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Objectives 
Endpoints 
AE(s) = adverse event(s); API = Abdominal Pain Intensity; GIS = Global Improvement Scale; IBS = irritable bowel 
syndrome; IBS-D = irritable bowel syndrome with predominantly diarrhea; IBS-M = irritable bowel syndrome with 
mixed episodes of diarrhea and constipation; PRO = patient-reported outcomes; IBS-QoL = irritable bowel 
syndrome Quality of Life; WPAI = Work Productivity and Activity Impairment 


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4. 
Study Design 
4.1. 
Overall Design 
This study is a Phase 2 randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study to evaluate the efficacy and safety of vibegron in women with IBS-D or IBS-M. Subjects 
who meet all eligibility criteria will be randomized in a 1:1 ratio to receive either vibegron 75 mg 
or matched placebo. Randomization will be stratified by baseline abdominal pain intensity score 
(< 6 vs ≥ 6 on a 0 to 10 numeric rating scale [NRS]) and IBS subtype (IBS-D vs IBS-M). 
Enrollment for subjects with IBS-M will be capped at 50% of the total subject population (ie, up 
to 50% of the study population will be subjects with IBS-M). Stratification will be performed via 
central randomization across the study (not per site). 
A Data Safety Monitoring Board (DSMB) will be retained to assess, on an ongoing basis, all 
safety aspects of this study, including SAEs, major adverse cardiac events (MACE), adverse 
events of special interest (AESIs), and all other AEs. The committee will meet to review the 
safety data at the following 3 times when the (1) first 25% of subjects enrolled complete the 
Week 4 visit (Visit 5); (2) first 50% of subjects enrolled complete the Week 4 visit (Visit 5); and 
(3) first 75% of subjects enrolled complete the Week 4 visit (Visit 5). 
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 Safety Follow-up telephone call 
(2 weeks). The Safety Follow-up telephone call will occur 14 days (with a window of −7 days) 
after the subject’s last dose of study drug (ie, at Week 14 for subjects who complete the 
Week 12 Visit, or 2 weeks after the last dose of study drug for randomized subjects who 
discontinue treatment early) (see Schedule of Assessments, Section 1.3). Additionally, 
Unscheduled Visits may be arranged for subjects with study-related safety concerns as needed. 
Approximately 200 subjects will be enrolled at approximately 40 sites in the US to achieve 
approximately 90 evaluable IBS-D subjects (45 per treatment group). Enrollment will be 
competitive. The sample size justification is provided in Section 9.2. 
4.1.1. 
Clinical Hypotheses 
The primary objective will be to estimate the treatment effect of vibegron relative to placebo 
with respect to improvement in IBS-related abdominal pain in IBS-D subjects.  There is no 
formal statistical hypothesis.  Nominal p-values from comparisons to placebo may be provided 
for descriptive purposes. 
4.2. 
Scientific Rationale for Study Design 
A single-blind, placebo Run-in Period will be used to assess placebo response and to ensure that 
subjects have adequate experience with dosing compliance and completing the diaries. The 
double-blind Treatment Period will include a placebo arm to accurately demonstrate and measure 


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the efficacy of vibegron. Subjects with IBS-D or IBS-M were chosen as the study population 
because the abdominal pain due to colonic contractions in these subjects is an unmet medical 
need that may be addressed by vibegron’s ability to relax smooth muscle contractions, as 
demonstrated in the overactive bladder population. The study population is limited to women 
because data from the Phase 2 clinical study of the β3-AR agonist solabegron have shown 
improvement in IBS pain among women [Kelleher, 2008]. 
4.3. 
Justification for Dose 
This study is a proof-of-concept study that will evaluate the effect of vibegron in subjects with 
IBS-D or IBS-M. The dose of vibegron for this study (75 mg once daily) is the same dose that 
was evaluated in the recent Phase 3 program for subjects with overactive bladder. The evidence 
to support this dose comes from the following data:  
• Several Phase 2 and Phase 3 clinical studies with vibegron at doses up to 100 mg 
(including 75 mg) have demonstrated that it is generally safe, well tolerated, and 
efficacious in subjects with overactive bladder over 52 weeks of treatment: 
o Vibegron 75 mg (2 Phase 3 studies): Studies 3003 and 3004 
o Vibegron 50 mg and 100 mg (2 Phase 3 studies and 1 Phase 2b study): Studies 
301, 302, and 008 
• Study 008 demonstrated dose-dependent significant efficacy over placebo across 
multiple clinical endpoints in overactive bladder, with the maximal effect generally 
estimated at doses between 50 and 100 mg 
• Compared with placebo, no clinically relevant differences in heart rate or blood pressure 
were observed for vibegron (50 and 100 mg once daily) in the overactive bladder 
population 
• Vibegron 75 mg administered once daily is expected to capture approximately 90% of 
the efficacy of 100 mg daily; the mean trough concentration for vibegron 75 mg at 
steady-state is 40 ng/mL, which is several fold above the β3 half-maximal effective 
concentration of 1.7 nM (0.76 ng/mL) 
The dose of vibegron used in this IBS study (75 mg once daily) is expected to have a similar 
safety profile to that observed with the same dose in the overactive bladder population. 
4.4. 
End of Study Definition 
The end of the study is defined as the date that the last subject completes both the Week 12 Visit 
and Week 14 Safety Follow-up Telephone Call Visit, discontinues from the study, or is lost to 
follow-up. 
A subject is considered to have completed the study if she completes 12 weeks of double-blind 
treatment at the Week 12 Visit. 


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5. 
Study Population 
The study is being conducted in women with IBS-D or IBS-M, which is representative of the 
subject population to which the results will be generalized. Specific inclusion and exclusion 
criteria are specified below. Prospective approval of protocol deviations to recruitment and 
enrollment criteria, also known as protocol waivers or exemptions, is not permitted. Subjects 
may be rescreened once to meet inclusion criteria (see Section 5.4). 
5.1. 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply at 
Visit 1 (Screening), unless otherwise noted: 
1. 
Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form, including agreeing to 
patient registry verification. 
2. 
Female, 18 to 70 years of age, inclusive 
3. 
Body weight ≥ 50 kg; body mass index < 45 
4. 
Diagnosis of IBS-D or IBS-M according to the Rome IV criteria: 
• Recurrent abdominal pain, on average at least 1 day per week in the last 3 months, 
associated with 2 or more of the following criteria: 
- 
Related to defecation  
- 
Associated with a change in frequency of stool  
- 
Associated with a change in form (appearance) of stool 
• Diagnostic criteria must be fulfilled for the last 3 months, with symptom onset at 
least 6 months before diagnosis.  
• Subtyping performed by the predominant stool pattern present in a subject:  
- 
IBS-D: loose, mushy, or watery stools (Bristol Type 6 or 7) for > 25% of 
bowel movements and hard or lumpy stools (Bristol Type 1 or 2) for < 25% 
of bowel movements 
- 
IBS-M: hard or lumpy stools (Bristol Type 1 or 2) for > 25% of bowel 
movements and loose, mushy, or watery stools (Bristol Type 6 or 7) for 
> 25% of bowel movements 
5. 
Has completed a colonoscopy according to the American Gastroenterological 
Association criteria (if necessary), with no clinically significant findings in the last 
5 years 
6. 
Willing and able, as assessed by the Investigator, to follow study instructions, including 
completing the subject diaries and quality of life questionnaires and attending all study 
visits 
7. 
Willing and able to maintain regular diet for the duration of the study 
8. 
Has no clinically significant findings on a physical examination or clinical laboratory 
tests that could interfere with study participation or confound study assessments, in the 


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opinion of the Investigator. Serum tissue transglutaminase antibody (IgA) must be 
negative.  Fecal calprotectin testing is optional and should only be considered if there is 
a strong suspicion that the subject has IBD (eg, family history in a 1st degree relative, 
other genetic factors, etc.) or other organic disease, according to the clinical judgement 
of the investigator.   
9. 
Women of childbearing potential must agree to use one of the contraception methods 
listed in Section 10.6.1 
10. Agrees not to participate in another clinical trial while participating in this study 
11. At Baseline (Visit 3), 
• Must continue to meet all inclusion criteria 
• During any 5 days in the 7 days immediately prior to Baseline (Visit 3), as 
reported in the subject’s daily pain diary: 
- Subject must have a weekly average of “worst abdominal pain in the past 
24 hours” score of ≥ 3.0 on a 0- to 10-point NRS (see Section 10.9 for NRS) 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply at Visit 1 (Screening), 
unless otherwise noted: 
1. 
Diagnosis of IBS-C or IBS-U per Rome IV criteria 
2. 
History of chronic idiopathic constipation or functional constipation 
3. 
Current or history (in the past year) of substance or alcohol abuse, alcoholism, alcohol 
addiction, or drinks > 3 alcoholic beverages per day (one drink defined as 12 ounces of 
beer, 5 ounces of wine, or 1.5 ounces of distilled spirits) 
4. 
History of clinically relevant liver disease or severe hepatic impairment (Child-Pugh 
Class C) 
5. 
Pre-existing condition that has altered normal gastrointestinal anatomy (eg, prior 
bariatric surgery or gastric banding, solitary rectal ulcer syndrome) 
6. 
History of or suspected mechanical gastrointestinal obstruction or current symptoms 
suggestive of gastrointestinal obstruction or infection 
7. 
Diverticulitis within prior 3 months 
8. 
Structural abnormality of the gastrointestinal tract or a disease or condition that can 
affect gastrointestinal motility 
9. 
History of a gastrointestinal motility disorder other than IBS (eg, gastroparesis, 
intestinal pseudo-obstruction, achalasia, Parkinson’s disease, multiple sclerosis, spinal 
cord injury) 
10. Severe constipation or sequelae from constipation 
11. Active duodenal or gastric ulcer 
12. History of solitary rectal ulcer syndrome 


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13. Prior history of a gastrointestinal malignancy, inflammatory bowel disease, celiac 
disease 
14. History of colitis (ischemic, lymphocytic, collagenous or radiation-induced) or hepatic 
and/or renal function that could interfere with the absorption, metabolism and/or 
excretion of the study drug (eg, carcinoid syndrome, amyloidosis) 
15. Uncomplicated appendectomy within the past 3 months; subjects who had an 
appendectomy that was associated with any related complications or sequelae are 
eligible if the procedure was performed at least 6 months prior and all 
complications/sequelae have resolved 
16. Planned gastrointestinal or abdominal surgery within the next 6 months 
17. Co-existing gastroesophageal reflux disease or functional dyspepsia with symptoms 
predominant to IBS symptoms 
18. Symptoms or diagnosis of a medical condition other than IBS that may contribute to 
abdominal pain (eg, interstitial cystitis; fibromyalgia currently being treated with 
pregabalin or gabapentin; and endometriosis with uncontrolled abdominal pain) 
19. History of pancreatitis, structural diseases of the pancreas (including known or 
suspected pancreatic duct obstruction), known or suspected biliary duct obstruction, or 
sphincter of Oddi disease or dysfunction; acute, symptomatic cholecystitis or 
symptomatic cholelithiasis within the last 6 months is also exclusionary 
20. Lactose intolerance not controlled by lactose-free diet 
21. History or evidence of symptomatic arrhythmia, angina/ischemia, coronary artery 
bypass grafting surgery, percutaneous transluminal coronary angioplasty, 
cerebrovascular accident, transient ischemic attack, or any clinically significant cardiac 
disease 
22. Clinically significant electrocardiogram (ECG) abnormality that, in the opinion of the 
Investigator, exposes the subject to risk by participating in the study. 
23. Uncontrolled hypertension (sitting systolic blood pressure ≥ 180 mmHg and/or sitting 
diastolic blood pressure ≥ 100 mmHg) or resting heart rate (by pulse) > 100 beats per 
minute 
24. Systolic blood pressure ≥ 160 mmHg but < 180 mmHg is excluded unless deemed by 
the Investigator as safe to proceed in this study and agreed to by the Sponsor’s 
designated Medical Monitor; must be on stable hypertension medication for at least 
3 months prior to entering Run-in (Visit 2) 
25. Concurrent malignancy or history of any malignancy (within the last 5 years), except 
non-metastatic basal or squamous cell carcinoma of the skin that has been treated 
successfully 
26. Uncontrolled diabetes mellitus defined by a hemoglobin A1C level > 8% 
27. Significant psychiatric or psychologic disorder that would preclude meaningful 
participation in the study (eg, bipolar disorders or schizophrenia; however, treated 


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depression on a stable regimen [eg SNRI, SSRI] is allowed) in the opinion of the 
Investigator 
28. Presence of any unexplained alarm symptoms (eg, anemia, gastrointestinal bleeding, 
unintentional weight loss, suspected malignancy) 
29. Use of any prohibited medications, such as eluxadoline, for which a subject cannot 
complete the appropriate washout period (see Section 6.5.1).  Positive urine drug screen 
at Visit 1 is exclusionary except for the following situations: 
• Subjects who have a positive urine drug screen at Visit 1 due to a prohibited 
concomitant medication that can be washed out, the urine drug screen must be 
repeated at Visit 2 to determine if sufficient washout of the prohibited 
concomitant medication has occurred and to confirm eligibility   
• If the initial positive result at Visit 1 was due to a permitted concomitant 
medication (see Section 6.5.2), based on the clinical judgment of the investigator, 
a subject is still eligible and the urine drug screen would not need to be re-tested 
at Visit 2  
30. Dose change for any medications requiring a stable dose (see Section 6.5.2) prior to the 
Screening Visit or plans to initiate or change the dosing of any of these medications 
during the study 
31. Currently participating in or has participated in a study with an investigational 
compound or device or procedure within 28 days prior to screening 
32. Currently participating in or has participated in a study with vibegron 
33. ALT or AST > 2.0 times 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) 
34. Lipase > 2 x ULN 
35. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 
36. Women who are pregnant, nursing, or planning a pregnancy during the study 
37. History of sensitivity to any of the study drugs, or components thereof, or a history of 
drug or other allergy that, in the opinion of the Investigator, contraindicates study 
participation 
38. At Baseline (Visit 3), noncompliant with dosing during the 2-week Run-in Period 
(taking < 80% or > 120% of study medication) 
39. Clinically significant medical or surgical history or any condition that could interfere 
with study participation or confound the assessments in the opinion of the study 
Investigator 


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5.3. 
Lifestyle Considerations 
Subjects are expected to maintain their pre-study diet for the duration of the study. Alcoholic 
drinks must be limited to ≤ 3 per day (one drink is defined as 12 ounces of beer, 5 ounces of 
wine, or 1.5 ounces of distilled spirits).  
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE) that occurred within the Screening Period. 
Individuals who do not meet the criteria for participation in the study (screen failures prior to 
initiation of run-in study medication) may be rescreened once upon consultation with, and 
approval by, the Sponsor’s designated Medical Monitor, Sponsor, or its designee. Subjects who 
initiate Run-in study drug dosing may not be rescreened. Rescreened subjects will be assigned a 
new subject number, and both subject numbers will be linked to the subject, and a new informed 
consent with the new subject number should be signed. Screening assessments specified in 
Section 1.3 should be repeated if subjects are rescreened. 


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6. 
Study Drug 
6.1. 
Study Drugs Administered 
 
Study Drug Name 
Vibegron 
Matched Placebo 
Dosage Formulation 
tablet 
tablet 
Identity of Formulation 
75 mg 
placebo 
Route of 
Administration  
oral 
oral 
Dosing Instructions 
once daily 
once daily 
Packaging and 
Labeling 
Study drug will be provided in 
HDPE bottles with child resistant 
caps. Each bottle will contain 32 
tablets and will be labeled as 
required per country requirement. 
Study drug will be provided in 
HDPE bottles with child resistant 
caps. Each bottle will contain 32 
tablets and will be labeled as 
required per country requirement. 
Manufacturer 
Patheon, Cincinnati, Ohio, US 
Patheon, Cincinnati, Ohio, US 
Number and Timing of 
Drugs 
Treatment Period: 1 tablet daily  
Run-in Period: 1 tablet daily 
Treatment Period: 1 tablet daily 
HDPE = high density polyethylene 
The study drug will be supplied in bottles each containing 32 tablets (4-week supply) and labeled 
with the protocol number, bottle number, lot number, expiration date, study drug name (vibegron 
75 mg or placebo tablets), number of tablets, directions for use, storage information, warning 
language (Keep Out of Reach of Children. For Clinical Trial Use Only. To be used by qualified 
Investigators only. Caution: New Drug—Limited by United States Law to Investigational Use.), 
and the US Sponsor name and address. Immediately before dispensing the study drug, the 
Investigator (or appropriately trained designee) will write the subject number, visit number. and 
the dispense date on the detachable panel of the label, which also includes the protocol number, 
bottle number and lot number. 
6.1.1. 
Run-in Medications and Administration 
During the single-blind Run-in Period, all subjects will take 1 tablet of study drug (ie, placebo) 
once daily for 2 weeks. All subjects will take their first dose of study drug at the study site as a 
witnessed dose. The date and time of the study drug dosing will be recorded. The Investigator 
will be aware that the study drug is placebo, but the subject will not know either the identity of 
the treatment or that entry into the double-blind Treatment Period is dependent on compliance 
with dosing in the Run-in Period. The matched placebo will be identical in appearance to the 
study drug administered during double-blind treatment.  


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6.1.2. 
Treatment Period Medications and Administration 
During the double-blind Treatment Period, subjects will take 1 tablet of study drug (vibegron or 
matched placebo) once daily for up to 12 weeks. The appearance of the vibegron and placebo 
tablets will be identical. All subjects will take their first dose of study drug at the study site as a 
witnessed dose. The date and time of the study drug dosing will be recorded. 
6.2. 
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 drug 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 subjects, 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. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Single-blind (Run-in only) and double-blind (Treatment Period) techniques will be used. 
Vibegron and its matched placebo will be packaged identically so that the treatment blind is 
maintained. The subject, Investigator, and Sponsor personnel or delegate(s) who are involved in 
the treatment or clinical evaluation of the subjects will be unaware of the treatment group 
assignments during the double-blind Treatment Period. Subjects will be centrally assigned to 
randomized study drug using an interactive web response system (IWRS) and the randomization 
schedule generated by the Sponsor or designee. Before the screening is initiated at each site, 
login information and directions for the IWRS will be provided. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a subject’s study drug 
assignment is warranted. Subject safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, the Investigator should 
make every effort to contact the Sponsor or designee prior to unblinding a subject’s study drug 
assignment unless this could delay emergency treatment of the subject. If a subject’s study drug 
assignment is unblinded, the Sponsor or designee must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
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At the end of the study, 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 subjects complete the study. 
6.4. 
Study Drug Compliance 
Study drug compliance will be closely monitored by counting the number of tablets dispensed 
and returned. Before dispensing new study drug at applicable visits, study site personnel will 
make every effort to collect all unused study drug and empty bottles. 
The study site will keep an accurate drug disposition record that specifies the amount of study 
drug administered to each subject and the date of administration. 
6.5. 
Concomitant Therapy 
The use of any concomitant medication, prescription or over-the-counter, is to be recorded on the 
subject’s electronic case report form (eCRF) at each visit, along with the reason the medication is 
taken, the dates of administration, and the dose. 
6.5.1. 
Prohibited Drugs and Washout Before the Study 
Table 6-1 provides a list of specific restrictions for concomitant therapy use during the study, 
with any necessary washout periods described (see Section 6.5.2 for permitted medications 
requiring a stable dose prior to study entry and Table 6-1 for the list of prohibited medications 
and washout periods). For subjects who had a positive urine drug screen at Visit 1 due to a 
prohibited concomitant medication, the urine drug screen must be repeated at Visit 2 to 
determine if sufficient washout of the prohibited concomitant medication has occurred and to 
confirm eligibility.  The urine drug screen does not need to be re-tested at Visit 2 if the initial 
positive result at Visit 1 was due to a permitted concomitant medication based on the clinical 
judgment of the Investigator.   
If there is a clinical indication for any therapy that is specifically prohibited during the study, 
discontinuation from study drug may be required. The Investigator should discuss any questions 
regarding this with the Sponsor’s designated Medical Monitor. The final decision on any 
supportive therapy rests with the Investigator and/or the subject's primary physician. However, 
the decision to continue the subject on study treatment requires the mutual agreement of the 
Investigator and the Sponsor’s designated Medical Monitor. 
Consult the Sponsor’s designated Medical Monitor if there is any uncertainty regarding subject 
use of a particular drug or drug class. 


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Table 6-1 
Prohibited Medications 
Class 
Examples 
Washout Period 
Mu-opioid receptor 
agonist 
eluxadoline 
1 month prior to Run-in 
(Visit 2) 
Opiates and narcotic 
pain-relievers 
morphine, codeine, paregoric, 
opium, propoxyphene, fentanyl, 
methadone 
14 days prior to Run-in (Visit 2) 
Beta agonists 
mirabegron, dobutamine, 
isoprenaline, albuterol (systemic 
only) 
14 days prior to Run-in (Visit 2) 
Musculoskeletal drugs 
baclofen, cyclobenzaprine, 
methocarbamol, metaxalone 
14 days prior to Run-in (Visit 2) 
Previous use of 
antibiotics to treat IBS 
rifaximin, neomycin 
90 days prior to Run-in (Visit 2) 
Antibioticsa 
amoxicillin, doxycycline, 
cephalexin, ciprofloxacin 
14 days prior to Run-in (Visit 2) 
Psychoactive drugs 
used to treat IBS 
cannabis products (including 
systemic cannabidiol [CBD]) 
14 days prior to Run-in (Visit 2) 
CNS stimulants 
cocaine, amphetamines 
14 days prior to Run-in (Visit 2) 
Barbiturates 
Phenobarbitalb, secobarbital  
14 days prior to Run-in (Visit 2) 
NMDA receptor 
agonist 
phencyclidine 
14 days prior to Run-in (Visit 2) 
CNS = central nervous system; IBS = irritable bowel syndrome; NMDA = N-methyl-D-aspartate 
a Antibiotics are permitted during the Treatment Period as needed. 
b Unless prescribed and at stable doses as anticonvulsant for documented epilepsy. 
6.5.2. 
Permitted Drugs 
Medications listed in Table 6-2 are permitted as long as the dose has been stable for the specified 
time period.  


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Table 6-2 
Medications Permitted at Stable Doses 
Class 
Examples 
Stable Dose Period 
Anticonvulsants for 
subjects with documented 
epilepsy 
Carbamazepine, gabapentin, 
pregabalin, topiramate 
6 months prior to Run-in 
(Visit 2) 
Antidepressants 
Tricyclic antidepressants, 
trazodone, SNRIs (eg, 
duloxetine), SSRIs 
3 months prior to Run-in 
(Visit 2) 
Antihypertensives 
Diuretics, ACE inhibitors, 
calcium channel blockers, 
angiotensin receptor blockers, 
beta blockers, alpha agonists 
3 months prior to Run-in 
(Visit 2) 
Injectable and standard 
therapy for acute, episodic 
or chronic migraine unless 
prohibited (Section 6.5.1) 
Botulinum toxin A injections, 
erenumab or other CGRP 
antagonists if approved, 
triptans 
1 month prior to Run-in 
(Visit 2) 
Antispasmodics/smooth 
muscle relaxants and 
peppermint oil 
Otilonium, pinaverium, 
hyoscyamine, dicyclomine, 
peppermint oil, 
butylscopolamine 
1 month prior to Run-in 
(Visit 2) 
ACE = angiotensin-converting enzyme; CGRP = calcitonin gene-related peptide; SNRI = serotonin-norepinephrine reuptake 
inhibitor; SSRI= Selective Serotonin reuptake inhibitor 
Medications for the treatment of allergies, chronic medical conditions, and acute migraines are 
permitted with the exception of prohibited pain medications (see Section 6.5.1). As needed, the 
use of benzodiazepines for anxiety is permitted.  
With the exception of the agents specified in Table 6-1 and the medications requiring stable 
doses prior to study entry (Table 6-2), any other concomitant medication deemed necessary for 
the welfare of the subject during the study may be given at the discretion of the Investigator. If 
the permissibility of a specific medication/drug is in question, please contact the Sponsor’s 
designated Medical Monitor. Any medication or vaccine (including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements) that the subject is receiving at the 
time of enrollment or receives during the study must be recorded in the eCRF. Allowed rescue 
medication for pain, constipation, and diarrhea are listed in Section 6.5.3. 


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6.5.3. 
Rescue Medicine 
Rescue medications should only be used starting at Day 1 (Visit 3) or after. The following rescue 
medications may be used:  
For pain 
• Equivalent of ibuprofen 400 mg twice daily or less  
• Low-dose acetaminophen 500 mg three times daily or less 
• Low-dose aspirin (≤ 325 mg daily) 
For constipation (not thought to affect IBS pain) 
• Polyethylene glycol 
• Bisacodyl (no more than one 5-mg dose weekly) 
For diarrhea (not thought to affect IBS pain) 
• Loperamide (up to 4 mg four times daily) 
Rescue medications will not be provided by the Sponsor. 
Use of rescue medication will be collected on the daily diary (ie, subjects will respond to 
prompts asking if any rescue medication was taken for abdominal pain or stool symptoms). 
During the subsequent subject visit, the details of the rescue medication will be collected for 
inclusion on the concomitant medication eCRF page, as needed. 
6.6. 
Dose Modification 
No dose modification of study drug is permitted. Study drug should be withheld for liver test 
abnormalities as described in Section 8.4.7.1. 
6.7. 
Drug after the End of the Study 
No further study drug will be administered to subjects who complete the study.  


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7. 
Discontinuation of Study Drug and Subject 
Discontinuation/Withdrawal 
A premature discontinuation will occur if a subject who signs the informed consent form (ICF) 
and is randomized ceases participation in the study, regardless of circumstances, before the 
completion of the protocol-defined study procedures. 
7.1. 
Discontinuation of Study Drug 
Subjects who discontinue study drug post-randomization will complete the Week 12/Early 
Withdrawal assessments specified in the Schedule of Assessments (Section 1.3). Reasons for 
discontinuation from double-blind study drug treatment and the study include the following: 
• Adverse event (AE) 
• Lack of efficacy 
• Noncompliance 
• Withdrawal of consent 
• Lost to follow-up 
• Physician decision 
• Protocol deviation 
• Pregnancy 
• Death 
• Other 
Discontinuation of study drug for abnormal liver function should be considered by the 
Investigator when a subject meets all of the conditions outlined in Section 8.4.7.2 for Hy’s law or 
if the Investigator believes that it is in the best interest of the subject (reason for discontinuation 
will be AE). Reporting and follow-up requirements for pregnancy are provided in Section 8.4.5 
and Section 10.6.2. 
For subjects who are not randomized into the 12-week double-blind treatment period and, 
therefore, are either screen failures or run-in failures, the End of Study eCRF should be 
completed (refer to eCRF completion guidelines for additional information). 
 
 


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7.2. 
Subject Discontinuation/Withdrawal from the Study 
• Subjects who discontinue post-randomization study drug will also withdraw from the study. 
• A subject may choose to withdraw from the study at any time at her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. 
• If a subject withdraws consent for disclosure of future information, the Sponsor or designee 
may retain and continue to use any data collected before such a withdrawal of consent. 
• If a subject withdraws from the study, she may request destruction of any blood or urine 
samples taken and not tested, and the Investigator must document this in the site study 
records. 
• Subjects who withdraw from the study will not be replaced (enrollment accounts for a 
predetermined dropout rate). 
• The Week 12/Early Withdrawal assessments will be completed, if possible, when a subject 
withdraws or is withdrawn from the study (see Schedule of Assessments in Section 1.3). 
7.3. 
Lost to Follow-up 
Should a subject fail to attend a required study visit, the site should attempt to contact the subject 
and reschedule the missed visit as soon as possible. The site should also counsel the subject on 
the importance of maintaining the assigned visit schedule and ascertain whether or not the 
subject wishes to and/or should continue in the study based on previous noncompliance. In cases 
where the subject 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 subject so that they can 
appropriately be withdrawn from the study with a primary reason of “Lost to Follow-up”, 
including at least three documented attempts to contact the subject (ie, phone, email, or certified 
letter). Efforts to establish the possible reason for discontinuation should be documented. 
7.4. 
Early Study Termination 
The Sponsor reserves the right to terminate the study at any time. 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 or other applicable regulatory 
requirements; procedure-related problems; or the number of discontinuations for administrative 
reasons is too high. 


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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the Schedule of Assessments (Section 1.3). 
A detailed listing of study assessments by visit is provided in Section 10.7. 
• Protocol waivers or exemptions are not allowed; however, subjects who fail to meet 
eligibility criteria may be rescreened once, as appropriate. Any notable protocol 
deviations should be noted and raised to the Sponsor’s or designee’s attention. 
• Immediate safety concerns should be discussed with the Sponsor’s designated Medical 
Monitor immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue study drug. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. 
• Note that patient-reported outcome (PRO) assessments will be completed prior to vital 
signs, and vital signs will be taken prior to blood draws. 
8.1. 
Baseline Procedures 
8.1.1. 
Informed Consent 
Documented consent must be obtained from each potential subject prior to participating in any 
study procedures according to the process described in Section 10.1.3. 
8.1.2. 
Assignment of Subject Number 
All subjects who sign the ICF will be assigned a unique subject number by IWRS. This number 
will be used to identify the subject throughout the study. Subjects who are rescreened will be 
assigned a new subject number. If a new number is assigned, the subject will be linked to both 
subject numbers. 
8.1.3. 
Screening 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Inclusion and exclusion criteria (Section 5.1 and Section 5.2) will be reviewed by the 
Investigator or qualified designee at Screening, the start of the Run-in Period, and the start of the 
double-blind Treatment Period. 
Subjects who fail to meet entry criteria may be rescreened once upon consultation with, and 
approval by, the Sponsor’s designated Medical Monitor, Sponsor, or designee (See Section 8.1.2 
regarding subject number). 


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The Screening Period may also be used for washout of prohibited medications (see 
Section 6.5.1). 
8.1.4. 
Medical History 
A medical history will be obtained by the Investigator or qualified designee. Medical history will 
include all chronic and ongoing conditions, regardless of year diagnosed; surgical history; 
substance abuse history; and IBS history (eg, Rome subtype, date of diagnosis, prior treatment). 
A history of previous diets for IBS and their perceived effectiveness will also be collected. All 
events occurring after the subject signs the ICF will be recorded as AEs. 
8.1.5. 
Demographics 
Demographic data collection will include sex, age, race, and ethnicity. 
8.1.6. 
Prior and Concomitant Medications 
Prior IBS medications and ongoing (concomitant) medications will be recorded beginning at the 
signing of the ICF and continuing until the Safety Follow-up call. 
8.2. 
Efficacy Assessments 
Efficacy assessments will be collected as outlined in the Schedule of Assessments (Section 1.3). 


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Assessment 
Timing 
Measurement 
Abdominal Pain 
Intensity (API) 
Daily during Run-in and 
double-blind Treatment Period 
• 
0- to 10-point numeric rating scale: 
- 0 = no pain 
- 10 = worst possible pain 
Subjects will record worst abdominal 
pain on evening Pain Diary in response 
to daily prompt 
PRO 
Questionnaires 
At Baseline and specified visits 
during double-blind Treatment 
Period before vital signs and blood 
draw 
• 
GIS 
• 
WPAI 
• 
IBS-QoL 
• 
Additional abdominal pain 
questions 
eCRF = electronic case report form; GIS = Global Improvement Scale; IBS-QoL = IBS quality of life assessment; 
PRO = patient-reported outcomes; WPAI = Work Productivity and Activity Impairment 
8.2.1. 
Symptom Diaries 
Subjects will complete 2 diaries daily, a Bowel Movement Diary and a Pain Diary. The Bowel 
Movement Diary will be event-driven (ie, subjects will record events as they occur) and will 
capture bowel movement frequency and form, bowel urgency, and recurrent bowel movements. 
The Pain Diary will prompt subjects each evening to answer a question regarding worst 
abdominal pain for the past 24 hours using the 0- to 10-point NRS to rate pain and to capture use 
of rescue medications. 
Subjects will receive the diaries and be trained on their use at the start of the Run-in Period 
(Visit 2). At subsequent visits, subjects will be re-instructed or retrained as needed. Subjects 


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must be able to complete the diaries to be eligible for the study. Further details on training and 
the use of the diaries are provided in a separate manual. 
8.2.2. 
Patient-reported Outcomes 
Subjects will complete questionnaires at the site at the start of each required study visit (before 
vital signs and blood draws) to assess subject-perceived symptom relief and health-related 
quality of life. The PRO questionnaires are provided in Section . 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the Schedule of Assessments 
(Section 1.3). Immediate safety concerns should be discussed with the Sponsor’s designated 
Medical Monitor immediately upon occurrence or awareness to determine if the subject should 
continue or discontinue study drug. 
8.3.1. 
Physical Examinations 
Brief physical examinations will include examination of the heart, lungs, abdomen, visual 
examination of the external genitalia and perianal area, and any other areas as needed. In 
addition, any organ system in which a previous abnormality was noted at Baseline or a subject 
has a complaint or AE will be examined. 
8.3.2. 
Vital Signs 
Vital signs, including blood pressure, pulse, body temperature, weight, and height, will be 
assessed at the timepoints specified in the Schedule of Assessments (Section 1.3) and 
Section 10.7 as follows: 
• Blood pressure and pulse will be measured after the subject has been resting in a seated 
position for 5 minutes, after PRO assessments and before any blood draws.  
• Blood pressure measurements will be taken on the same arm and by the same site staff 
throughout the study, if possible.  
• 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 measurements will be 
used for eligibility and safety assessments.  
• The same method for assessing temperature should be used at all visits for a particular 
subject. 
• Body weight will be measured with subjects in street clothing with jacket/coat and shoes 
removed, using the same scale throughout the study, if possible. 
• Standing height will be measured without shoes, at Screening only. 


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8.3.3. 
Electrocardiograms 
At Screening only, a 12-lead ECG will be performed in the supine position using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. ECGs will be read by trained personnel at the study site. 
8.3.4. 
Clinical Safety Laboratory Assessments 
All protocol-required laboratory assessments, as defined in Section 10.2 and including urine 
pregnancy test and drug screen, must be conducted in accordance with the laboratory manual and 
the Schedule of Assessments (Section 1.3). Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples. 
The clinical significance of test results will be evaluated as follows: 
• At Screening, the Investigator or physician sub-investigator will assess the clinical 
significance of any values outside the reference ranges provided by the laboratory, and 
subjects with abnormalities judged to be clinically significant will be excluded from the 
study. 
• The Investigator or physician sub-investigator must review the laboratory report, document 
this review, and record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the Investigator to be more severe than expected for 
the subject’s condition. 
• All laboratory tests with values considered clinically significant during participation in the 
study or within 14 days after the last dose of study drug should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Sponsor’s designated Medical Monitor. 
- If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor’s designated 
Medical Monitor notified. 
- If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in subject management or are considered 
clinically significant by the Investigator (eg, SAE or AE), then the results must be 
recorded in the eCRF. 
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Section 10.3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 


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The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the subject to discontinue the study drug or the study (see Section 7). 
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs and SAEs will be collected from the signing of the ICF through 14 days after the last 
dose of study drug. AEs will be collected at the timepoints specified in the Schedule of 
Assessments (Section 1.3), and as observed or reported spontaneously by study subjects. 
Medical occurrences that begin before the start of double-blind study drug, but after obtaining 
informed consent, will be recorded in the AE section of the eCRF. 
All SAEs (including serious AESIs) will be recorded and reported on the eCRF within 24 hours 
of the study site personnel’s knowledge of the event, as indicated in Section 8.4.4. Marking the 
event as “serious” will automatically send required notifications for Sponsor or designee review. 
The Investigator will also submit any updated SAE data within 24 hours of receipt of the 
information. Nonserious AESIs will be reported on the eCRF within 72 hours of the site’s 
knowledge of the information. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor or designee. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the Investigator is required to proactively follow each subject 
at subsequent visits/contacts. All AEs will be followed until the Week 14 Safety Follow-up 
telephone call (14 days [with a −7-day window] after the last dose of study drug). All SAEs will 
be followed until resolution, stabilization, the event is otherwise explained, or the subject is lost 
to follow-up (as defined in Section 7.3). If a subject dies during participation in the study or 


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within 14 days of the last dose of study drug, the Investigator will provide the Sponsor or 
designee with a copy of any postmortem findings including histopathology. 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
New or updated information will be recorded in the originally completed eCRF. As noted above, 
the Investigator will submit any updated SAE data within 24 hours of receipt of the information. 
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification of an SAE by the Investigator to the Sponsor or designee is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a study drug under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor or designee 
will review and then file it and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.4.5. 
Pregnancy 
If any subject becomes pregnant during the study (from signing the ICF through 14 days after the 
last dose of study drug), the site must discontinue the subject from study drug immediately and 
have the subject return for an Early Withdrawal Visit (Week 12 Visit assessments). The 
Investigator must inform the subject of the right to receive treatment information. If the subject 
chooses to receive unblinded treatment information, the individual blind should be broken and 
the treatment assignment provided to the subject (see Section 6.3 for unblinding information). 
The study team will remain blinded to the subject’s treatment assignment.  
In the case of a pregnant subject, if she agrees, the Investigator should notify the subject’s 
primary care physician of the pregnancy and provide details of the subject’s participation in the 
study and treatment (blinded or unblinded, as applicable). 


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A pregnancy is to be reported to the Sponsor’s designated Medical Monitor within 24 hours of 
awareness by the study site personnel using the contact information on the Study Contacts Page 
and the dedicated pregnancy reporting form. 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 or designee. 
If the pregnant subject experiences an SAE during pregnancy, or the outcome of the pregnancy 
meets the criteria for immediate classification as an SAE (ie, spontaneous abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, 
or congenital anomaly), the Investigator should follow the procedures for reporting SAEs (ie, 
report the event on the AE eCRF within 24 hours of the Investigator’s knowledge of the event). 
All neonatal deaths and congenital anomalies that occur within 30 days of birth (regardless of 
causality) should be reported as SAEs. In addition, any infant death or congenital anomaly 
occurring after study completion that the Investigator suspects is related to the in-utero exposure 
to the study drug should also be reported. Refer to Section 10.6.2 for additional information 
regarding collection of pregnancy data.  
8.4.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
No disease-related events or outcomes are excluded from AE reporting. Any worsening of 
diarrhea or constipation and any new onset of constipation should be collected as AEs. 
8.4.7. 
Adverse Events of Special Interest 
Selected nonserious and serious AEs will be reported as AESIs. The events must be reported on 
the AE eCRF within 24 hours of the study site personnel’s knowledge of the event. AESIs that 
also meet the definition of an SAE must be reported as described in Section 10.3. 
Adverse events of clinical interest for this study include: 
• Potential major cardiac and cerebrovascular events, including death (or any event with 
fatal outcome), myocardial infarction, cerebrovascular accident, hospitalization for 
unstable angina or chest pain, hospitalization for heart failure, and coronary 
revascularization/angioplasty/stent 
• Hypertension, defined as follows: 
- 


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- 
- 
• AEs consistent with orthostatic hypotension as confirmed by orthostatic vital signs 
• AEs suggestive of cystitis or urinary tract infection (UTI) 
- 
- 
- 
• Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value 
requiring that study drug be temporarily withheld or permanently discontinued (see 
Sections 8.4.7.1 and 8.4.7.2). To date, no concern regarding drug-induced liver toxicity 
has been identified; however, the Sponsor is monitoring laboratory data for a potential 
safety signal, consistent with Food and Drug Administration (FDA) guidance 
[FDA Guidance, 2009]. 
Serious AESIs and elevated liver enzymes or bilirubin requiring withholding of study drug must 
be reported within 24 hours of the study site personnel’s knowledge of the event by marking the 
appropriate box on the AE eCRF and assigning the most appropriate category. Additional 
information should be provided as directed in the eCRF Completion Guidelines. AESIs that also 
meet the definition of an SAE must be reported as an SAE, as described in Section 8.4.4. 
Nonserious AESIs should be reported within 72 hours of the site personnel’s knowledge, using 
the AE eCRF. 
8.4.7.1. 
Criteria for Temporary Withholding of Study Drug 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 
AESI -specific eCRFs/forms/worksheets provided for the study. 


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Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA Guidance, 2009]. 
If any of the following liver test abnormalities develop, study drug should be withheld 
immediately with appropriate clinical follow-up (including repeat laboratory tests, until a 
subject’s laboratory profile has returned to normal/baseline status), and the event reported as an 
SAE:  
• ALT or AST > 8 x upper limit of normal (ULN)  
• ALT or AST > 5 x ULN and persists for more than 2 weeks  
• 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’s designated Medical Monitor 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. 
8.4.7.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver 
Test Abnormalities 
Study drug should be discontinued permanently if all of the following 4 criteria are met (ie, 
potential severe drug-induced liver injury/Hy’s law case): 
• Total bilirubin increases to > 2 x ULN or INR > 1.5 and 
• AST or ALT increases to ≥ 3 x ULN and 
• Alkaline phosphatase value does not reach 2 x ULN and 
• 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 (eg, 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 


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- 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 drug should be withheld or permanently 
discontinued as appropriate for the safety of the subject, following consultation with the 
Sponsor’s designated Medical Monitor. 
8.4.8. 
Medication Errors 
Medication error refers to any unintended error in the dosing and/or administration of the study 
drug as per instructions in the protocol. Medication errors generally fall into 4 categories as 
follows: 
• Wrong study drug 
• Wrong dose (including dosing regimen, strength, form, concentration, amount) 
• Wrong route of administration 
• Wrong subject (ie, not administered to the intended subject) 
Medication errors include occurrences of overdose and underdose of the study drug. 
Overdose: Unintentional administration of a quantity of the study drug given per administration 
or per day that is above the maximum recommended dose according to the protocol. This also 
takes into account cumulative effects due to overdose (see Section 8.5 for treatment and 
reporting of overdose). For this study, any dose of vibegron or placebo > 2 tablets within a 
24-hour window is an overdose. There is no known antidote for an overdose. 
Underdose: No underdose is defined for this study. 
8.5. 
Treatment of Overdose 
In the event of an overdose (> 2 tablets of study drug within 24 hours), the Investigator or 
treating physician should: 
• Contact the Sponsor’s designated Medical Monitor immediately 
• Closely monitor the subject for any AEs, SAEs, and laboratory abnormalities 
• Report all overdose events within 24 hours of awareness by the study site, using the 
Overdose eCRF, whether or not the overdose is associated with an AE 
• Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor’s designated Medical Monitor based on the clinical evaluation of 
the subject. 


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9. 
Statistical Considerations 
This section contains a brief summary of the statistical analyses for this study; full details will be 
provided in the Statistical Analysis Plan (SAP). 
The randomized allocation schedule will be generated by the Sponsor or designee and 
implemented by the vendor of the study. Stratification will be performed across the study (not 
per site). The statistical analysis of the data obtained from this study will be the responsibility of 
the Sponsor or designee. At the end of the study, 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 SAP will be approved prior to data being unblinded. 
A subject is considered enrolled in the study at randomization.  
9.1. 
Statistical Hypotheses 
The primary objective will be to estimate the treatment effect of vibegron relative to placebo 
with respect to improvement in IBS-related abdominal pain in IBS-D subjects.  There is no 
formal statistical hypothesis.  Nominal p-values from comparisons to placebo may be provided 
for descriptive purposes.  An improvement in the primary endpoint is defined as a subject who 
experiences a decrease in the weekly average of “worst abdominal pain in the past 24 hours” 
scores of at least 30% compared with the baseline weekly average. 
9.2. 
Sample Size Determination 
In total, approximately 200 subjects will be randomized in a 1:1 ratio to receive 1 of the 
following study drugs: 
• Vibegron 75 mg (N = 100) 
• Placebo (N = 100) 
At most, 50% of randomized subjects (approximately 100 subjects total [50 per treatment arm]) 
will have IBS-M; and at least 50% of randomized subjects (approximately 100 subjects total [50 
per treatment arm]) will have IBS-D, and the IBS-D subgroup will be used for the primary 
endpoint analysis. 
Assuming a total of 10% of subjects will discontinue prior to Week 12 (for any reason), there 
will be a minimum of approximately 90 evaluable IBS-D subjects (45 in the vibegron arm and 45 
in the placebo arm) at the end of Week 12. The study has approximately 60% power to detect a 
between-group treatment difference of 20% in proportion of abdominal pain responders at a 
2 -sided test at the α = 0.10 level assuming a responder rate of 51% versus 31% for vibegron and 
placebo, respectively. The assumptions were based on results from a solabegron study female 
subgroup analysis [Kelleher, 2008]. 


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9.3. 
Populations for Analyses 
The analysis populations will consist of subjects as defined below: 
• The Screened Analysis Set includes all subjects who are screened for the study. This 
population is used primarily for subject accounting purposes and will generally not be used 
for summary or analysis. 
• The Randomized Set includes all subjects who are randomized to receive study drug 
regardless of whether they take a dose. 
• The Safety Analysis Set includes all subjects who receive at least one dose of study drug. 
Subjects will be classified according to the treatment they actually receive. 
• The Full Analysis Set (FAS) includes all randomized IBS-D and IBS-M subjects who took at 
least one dose of double-blind study drug and had a baseline diary assessment and at least 
1 post -randomization diary entry. Subjects will be analyzed according to randomized 
treatment, irrespective of whether or not they have prematurely discontinued, according to 
the Intent -to-Treat principle. The Full Analysis Set for IBS-D (FAS-D) and Full Analysis 
Set for IBS-M (FAS-M) are each a subset of FAS and consists of IBS-D and IBS-M subjects, 
respectively. The FAS-D will serve as the primary population for the primary analysis of 
efficacy data in this study. 
• The Per-Protocol Set for IBS-D excludes subjects from the FAS-D due to important 
deviations from the protocol that may substantially affect the result of the primary efficacy 
endpoint (ie, Major Protocol Deviations associated with efficacy). The Per -Protocol Set will 
serve as the supportive population for the analysis of efficacy data in this study.  Other Per-
Protocol Sets may be defined. 
9.4. 
Statistical Analyses 
Endpoints that will be evaluated for within- and/or between-treatment differences are provided 
below. The descriptions of the endpoints and timepoints at which they are measured are 
described in Section 3 and the Schedule of Assessments (Section 1.3). 
In general, continuous variables will be summarized by treatment to indicate the population 
sample size (N), number of subjects with available data (n), arithmetic mean, standard deviation 
(SD), median, first and third quartile, minimum and maximum values. Categorical variables will 
be summarized by N, n, number of subjects in each category and the percentage of subjects in 
each category. Unless otherwise noted, the denominator to determine the percentage of subjects 
in each category will be based on the number of subjects with available data. Tables 
summarizing demographics and other baseline characteristics will also include a column for all 
subjects combined. 


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9.4.1. 
Demographic and Other Baseline Characteristics 
All demographic data such as age, sex, race, ethnicity and baseline characteristic data will be 
summarized by treatment group for the Full Analysis Set. Subject disposition will be 
summarized using the Screened Analysis Set.  
Descriptions of medical history findings will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.1 (or later). Medical history may be summarized in the 
descending order of overall frequency, by System Organ Class (SOC) and Preferred Term (PT). 
Prior and concomitant medications will be coded using the latest version of World Health 
Organization Drug Dictionary. The number and percentage of subjects receiving prior or 
concomitant medications will be summarized by treatment group. 
9.4.2. 
Efficacy Analyses 
Statistical analysis of efficacy endpoints will be for descriptive purposes only.  Nominal p-values 
will be based on statistical tests will be 2-sided hypothesis tests performed at the 10% level of 
significance for main effects. All confidence intervals will be 2-sided 90% confidence intervals, 
unless stated otherwise. When summarizing diary data by visit, including weekly response 
endpoints, only the data from the 7 days prior to the subject’s clinic visit will be included. 
9.4.2.1. 
Primary Efficacy Analysis 
Response efficacy endpoints from Week 1 through Week 12 will be analyzed using the 
Cochran -Mantel-Haenszel risk difference estimate. The estimated difference in the proportion of 
responders and 90% confidence interval for the difference will be calculated using the 
Cochran -Mantel-Haenszel risk difference estimate stratified by baseline abdominal pain 
(< 6 vs ≥ 6) with weights proposed by Greenland and Robins.  
For the analysis of other continuous endpoints (eg, change from baseline at Week 12), a mixed 
model for repeated measures with restricted maximum likelihood estimation will be used by 
incorporating on treatment- values at all time points. The analysis model for the efficacy 
endpoint will include terms for treatment, visit, 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 for denominator degrees of freedom 
will be used with restricted (or residual) maximum likelihood to make statistical inference. 
Further details will be provided in the SAP. 
9.4.2.2. 
PRO Analyses 
Details of PRO analyses will be provided in the SAP. 


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9.4.2.3. 
Exploratory Efficacy Analyses 
Details of exploratory efficacy analyses will be provided in the SAP. 
9.4.2.4. 
Multiplicity Adjustment 
No formal multiplicity adjustment will be performed.  All efficacy analyses will be considered 
descriptive.  Ninety-percent confidence intervals will be provided for each treatment group and 
nominal p-values from comparisons to placebo may be provided for descriptive purposes.  The 
nominal p-values will be tested using a hierarchical testing strategy using 2-sided tests with 
significant level α = 0.10.  Nominal p-values will be provided for all secondary efficacy analyses 
as a measure of the strength of the association between the endpoint and the treatment effect 
rather than formal tests of hypotheses. 
9.4.3. 
Safety Analyses 
The safety analysis will be performed using the Safety Analysis Set and will be fully defined in 
the SAP. The safety parameters will include AEs and clinical laboratory and vital sign 
parameters. For each safety parameter of the clinical laboratory and vital sign parameters, the last 
non--missing safety assessment before the first dose of double-blind study drug will be used as 
the baseline for all analyses of that safety parameter. 
9.4.3.1. 
Adverse Events 
An AE will be considered a treatment-emergent AE (TEAE) if: 
• The AE began on or after the date of the first dose of study drug; or 
• The AE was present before the date of the first dose of study drug, but increased in 
severity or became serious on or after the date of the first dose of study drug 
An AE that occurs more than 14 days after the last dose of study drug will not be counted as a 
TEAE. 
An AE will be considered a treatment-emergent SAE (TESAE) if it is a TEAE that additionally 
meets any SAE criteria. 
AEs will be coded using MedDRA version 21.1 (or later). An overall summary table of AEs by 
treatment group will be presented with number and percentage of subjects. The incidence of all 
TEAEs by primary SOC and PT will be prepared for all TEAEs, serious TEAEs, 
treatment -related TEAEs, treatment-related serious TEAEs, TEAEs leading to discontinuation 
from study drug, AESIs, and all TEAEs by maximum intensity. All AEs will be listed, with a 
flag designating AEs that are treatment emergent. 


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9.4.3.2. 
Clinical Laboratory Assessments 
All continuous safety laboratory parameters will be summarized descriptively by absolute value 
at each visit by treatment group, together with the corresponding changes from baseline. Central 
laboratory reference ranges will be used to identify abnormalities with low, normal or high. 
9.4.3.3. 
Vital Signs 
Descriptive statistics of observed values and change from baseline for vital signs will be 
presented for each treatment group by visit. 
9.5. 
Interim Analyses 


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9.6. 
Data Safety Monitoring Board 
One external independent DSMB will be formed for the study URO-901-2001. The detailed 
activities including meeting and analysis plan will be described and documented in the DSMB 
Charter and the DSMB SAP, respectively. 
 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
- Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
- Applicable ICH/ISO Good Clinical Practice (GCP) guidelines 
- Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
• The Investigator will be responsible for the following: 
- Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
- Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 Code of Federal Regulations 
(CFR), ICH guidelines, the IRB/IEC, and European regulation 536/2014 for clinical 
studies (if applicable) 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor or designee with sufficient, accurate 
financial information as requested to allow the Sponsor or designee to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the subject 
and answer all questions regarding the study. 
• Subjects must be informed that their participation is voluntary. Subjects will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
• Subjects who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
• Subjects will be assigned a unique identifier. Any subject records or datasets that are 
transferred to the Sponsor or designee will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. If a subject is 
rescreened and assigned a new subject number, both subject numbers for that individual will 
be linked. 
• The subject must be informed that his/her personal study-related data will be used by the 
Sponsor or designee in accordance with local data protection law. The level of disclosure 
must also be explained to the subject.  
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor or 
designee, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
Not applicable. 
10.1.6. 
Posting Clinical Study Data 
Clinical study information will be posted on external registries and websites (eg, US National 
Institutes of Health’s website www.ClinicalTrials.gov). 
10.1.7. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on eCRFs unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. 


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• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 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. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Study Site 
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 (ie, US, 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. 
The study site and the record retainer should take measures in such a way that these records are 
not lost or abandoned during the designated period of preservation and that they are presented 
upon request. 
Institutional Review Board, Independent Ethics Committee, Research Ethics Board 
(IRB/IEC/REB) 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and any 
other relevant materials, including accompanying material to be provided to the subject (eg, 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the Investigator to an IRB/IEC/REB. Approval from the 
IRB/IEC/REB 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  


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• Date on which the committee met and granted the approval 
Any amendments to the protocol will require IRB/IEC/REB 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/IEC/REB’s 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC/REB 
• Notifying the IRB/IEC/REB of SAEs or other significant safety findings as required 
by procedures established by the IRB/IEC/REB. 
10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Current 
medical records must be available during the site monitor’s visit.  
• The required source documents are: 
• Subject identification (name, date of birth, sex) 
• Documentation that the subject meets eligibility criteria, (eg, 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 AEs and other safety parameters (start and end date, and causality and 
intensity as assigned by the Investigator) 
• Concomitant medication (including start and end date) 
• Date of study completion and reason for early discontinuation, if applicable 


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10.1.9. 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected, and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC/REB or local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further study drug development 
10.1.10. 
Publication Policy 
• The Sponsor has proprietary interest in this study. Authorship and manuscript composition 
will reflect joint cooperation between multiple Investigators and sites and Sponsor or 
designee personnel. Authorship will be established prior to the writing of the manuscript. As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with the Sponsor. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. 
10.1.11. 
Compliance with Protocol 
The Investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the Sponsor will make frequent contact with the Investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review subject and study 
drug accountability records for compliance with the protocol. Protocol deviations will be 
discussed with the Investigator upon identification. The use of the data collected for the subject 
will be discussed to determine if the data are to be included in the analysis. The Investigator will 
enter data that may be excluded from analysis as defined by the protocol deviation specifications. 
Significant protocol deviations will be reported to the IRB/IEC/REB according to the 
IRB/IEC/REB’s reporting requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10-1 will be performed by the laboratory chosen by the Sponsor or the 
Sponsor’s designee. Subjects do not need to fast prior to laboratory testing. Refer to the 
Laboratory Manual for information on where testing should be performed (site, local laboratory, 
central laboratory).  
A urine dipstick will be performed at the study site at scheduled visits as noted in the Schedule of 
Assessments (Section 1.3) and when a subject presents with symptoms of a urinary tract 
infection at Unscheduled Visits. If the urine dipstick is positive for leukocytes, nitrites, or blood 
cells, a urinalysis and culture/sensitivity testing will be performed.  
A urine pregnancy test will be performed at the site for all women of childbearing potential. If 
the urine pregnancy test is positive, a serum pregnancy test will be performed.  
Table 10-1 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urine Dipstick/ 
Urinalysisa 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-hCGb 
Hemoglobin 
Alkaline phosphatase 
Glucose 
Urine drug screen 
Platelet count 
ALT 
Protein 
Fecal calprotectinc,d 
WBC (total and 
differential) 
AST 
Specific gravity 
Serum tissue 
transglutaminase 
antibody (IgA)d 
RBC 
Bicarbonate 
Microscopic exam 
(RBCs, WBCs, 
epithelial cells and 
bacteria) 
Coagulation 
(INR/PT/APTT)g 
 
Calcium 
pH 
 
 
Chloride 
Color 
 
 
Creatininee 
Urine pregnancy test 
(β-hCG)b 
 
 
Follicle-stimulating 
hormone 
 
 


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Hematology 
Chemistry 
Urine Dipstick/ 
Urinalysisa 
Other 
 
Glucose (fasting or non-
fasting) 
 
 
 
Lipase 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Total bilirubin 
 
 
 
Direct bilirubinf 
 
 
 
Blood urea nitrogen 
 
 
 
Total cholesterol 
 
 
APTT = activated partial thromboplastin time; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
β-hCG = β−human chorionic gonadotropin; INR = international normalized ratio; PT = prothrombin time; RBC = 
red blood cell count; WBC = white blood cell count  
a A sample for urinalysis and urine culture/sensitivity testing will be sent to the laboratory only if the urine dipstick 
performed at the site tests positive for the presence of leukocytes, nitrites, or blood cells.  
b Urine β-hCG will be tested for women of childbearing potential only. If urine β-hCG is positive, a serum β-hCG 
must be performed.  
c Optional at Screening only.  
d  Performed at Screening only per inclusion criterion #8. 
e Estimated glomerular filtration rate will be calculated and reported by the central lab.  
f If total bilirubin is elevated above the upper limit of normal. 
g Only upon request from Principal Investigator (if ALT, AST and bilirubin are increased). 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of study diug, whether or not considered related to the study diug. 
An AE can therefore be any unfavorable and unintended sign (including an abnonnal 
laborato1y finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study diu g. 
AE of Special Interest 
An AES! (serious or nonserious) is one of scientific and medical concern specific to the 
Sponsor's study di11g or program, which wan ants ongoing monitoring and rapid 
communication by the Investigator to the Sponsor or designee. Such an event might 
wan ant further investigation in order to characterize and understand it. See Section 8.4.7 
for AESis defined for this study. 
Events Meeting the AE Definition 
• 
Any abnonnal laborato1y test results (hematology, clinical chemistiy, or urinalysis) or 
other safety assessments ( eg, ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease) 
• 
Exacerbation of a chronic or intennittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• 
New condition detected or diagnosed after study diug adininisu-ation even though it 
may have been present before the staii of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected diug-diug interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study di11g 
or a concomitant medication. For this study, repo1i all overdose events within 
24 hours of awareness by the study site, using the Overdose eCRF, whether or not the 
overdose is associated with an AE. 
• 
Lack of efficacy or failure of expected phaimacological action per se will not be 
repo1ied as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AEs or SAEs if they fulfill the definition of an AE 
or SAE. Any worsening of diaiThea or constipation and any new onset of constipation 
in IBS-D subjects should be collected as AEs. 
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Events NOT Meeting the AE Definition 
• 
Abnonnal screening laborato1y values, including fecal calprotectin, C-reactive 
protein, etc. 
• 
Any clinically significant abno1m al laborat01y findings or other abno1m al safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject's condition. Merely 
repeating an abno1m al test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnonnal test result that is dete1mined to be an enor does not 
require recording as an AE. 
• 
The disease/disorder being studied or expected signs, or symptoms ( clearly defined) 
of the disease/disorder being studied, unless more severe than expected for the 
subject's condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy) the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occunence did not occur (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 staii of the study that do not worsen. 
Definition of SAE 
SAEs must meet both the AE criteria described above and the seriousness criteria listed below. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 
The te1m life-threatening in the definition of serious refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically Inight have caused death, if it were more severe. 
C. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been admitted to the hospital or 
kept in the Emergency Room for ~ 24 hours for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occuned or was necessa1y, the AE should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
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d. Results in persistent disability/incapacity 
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 (eg, sprained ankle) which may interfere with or prevent activities of 
daily living but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE 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 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
Examples of such medically significant events include invasive or malignant cancers, 
intensive treatment with a drug in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
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Recordin2 and Follow-Up of AEs and SAEs 
AE and SAE Recording 
• 
When an AE or SAE occurs, it is the responsibility of the Investigator to review all 
documentation ( eg, hospital progress notes, laborato1y repo1is, and diagnostics 
repo1is) related to the event. 
• 
The Investigator will then record all relevant AE or SAE information in the eCRF 
page. 
• 
All SAEs (including serious AESis) 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 diug. 
-
The event te1m , sta1i date, severity, and initial causality assessment must be 
entered in the AE eCRF page and the event must be marked as "Serious". This 
will activate additional assessment fields including "action taken with study 
di11g", "seriousness criteria", and "brief description" which should be completed 
as soon as infonnation is available. Marking the event as "serious" will 
automatically send required notifications for Sponsor or designee review. 
-
The initial SAE repo1i should include: 
o The date of the repo1i 
o A description of the SAE ( event tenn, seriousness of the event, date of 
onset, intensity) 
o 
Causal relationship to the study diug 
-
A discharge summaiy should be provided for all hospitalizations. If the subject 
died, the repo1i should include the cause of death as the event te1m (with death as 
the outcome) and whether the event leading to death was related to study diug, as 
well as the autopsy findings, if available 
• 
Nonserious AESis should be repo1ied on the eCRF within 72 hours of knowledge of 
the infonnation. 
• 
It is not acceptable for the Investigator to send photocopies of the subject's medical 
records to the Sponsor or designee in lieu of completion of the AE or SAE eCRF. 
• 
There may be instances when copies of medical records for ce1iain cases are 
requested by the Sponsor or designee. In this case, all subject identifiers, with the 
exception of the subject number, will be redacted on the copies of the medical records 
before submission. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical info1mation. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
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Assessment of Intensity 
1/MILD 
2/MODERATE 
3/SEVEREOR 
MEDICALLY 
SIGNIFICANT 
4/LIFE-
THREATENING 
5/DEATH 
Asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated. 
Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
Not inunediately life-tlu·eatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care activities of daily living 
Life tlu·eatening consequences; urgent intervention indicated 
Death related to adverse event 
An event is defined as serious when it meets at least one of the predefined criteria as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study drng and each 
occmTence of each AE or SAE. 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be rnled out. 
The Investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drng administration will 
be considered and investigated. 
The Investigator will also consult the Investigator's Brochure and/or product information, 
for marketed products, in his/her assessment. 
For each AE or SAE, the Investigator !!!!!.U document in the medical notes that he/she has 
reviewed the AE or SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occmTed and the Investigator has minimal 
info1mation to include in the initial report. However, it is very important that the 
Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE to the Sponsor or designee. 
The Investigator may change his/her opinion of causality in light of follow-up 
info1mation and send an SAE follow-up repo1i with the updated causality assessment. 
The causality assessment is one of the criteria used when detennining regulato1y 
repo1i ing requirements. 
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Reportin2 of SAEs 
SAE Reporting 
All SAEs 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 drng. Marking the event as "Serious" will activate additional 
assessment fields. 
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10.4. 
Appendix 4: Abbreviations 
Abbreviation 
Definition 
β3-AR 
beta-3 adrenergic receptor 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
API 
abdominal pain intensity 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GIS 
Global Improvement Scale 
HRT 
hormonal replacement therapy 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
IBS-C 
irritable bowel syndrome with predominantly constipation 
IBS-D 
irritable bowel syndrome with predominantly diarrhea 
IBS-M 
irritable bowel syndrome with mixed episodes of diarrhea and constipation 
IBS-QoL 
irritable bowel syndrome quality of life 


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IBS-U 
irritable bowel syndrome with unknown subtype 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
MACE 
Major Adverse Cardiac Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
numeric rating scale 
OAB 
Overactive bladder 
PRO 
patient-reported outcomes 
PT 
preferred term 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
UTI 
urinary tract infection 
WPAI 
Work Productivity and Activity Impairment 


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10.5. 
Appendix 5: Study Tabular Summary 
 
Parameter 
Group 
Parameter 
Value 
Trial information 
Trial Title 
A Phase 2, Randomized, Double-
Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety 
of Vibegron Administered Orally 
for 12 Weeks to Women with 
Irritable Bowel Syndrome 
 
Clinical Study Sponsor 
Urovant Sciences GmbH 
 
Trial Phase Classification 
Phase 2 
 
Trial Indication 
IBS pain 
 
Trial Indication Type 
Treatment 
 
Trial Type 
Efficacy 
Safety 
 
Trial Length 
21 weeks 
 
Planned Country of Investigational Sites 
US  
 
Planned Number of Subjects 
Approximately 200 
 
FDA-Regulated Device Study 
No 
 
FDA-Regulated Drug Study 
Yes 
 
Pediatric Study 
No 
Subject 
information 
Diagnosis Group 
IBS-D, IBS-M 
 
Healthy Subject Indicator 
No 
 
Planned Minimum Age of Subjects 
18 
 
Planned Maximum Age of Subjects 
70 
 
Sex of Subjects 
Female 
 
Stable Disease Minimum Duration 
3 months 


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Parameter 
Group 
Parameter 
Value 
Treatments 
Investigational Therapy or Treatment 
Vibegron 
 
Drug Type 
Drug 
 
Pharmacological Class of Invest. Therapy 
Beta-3 adrenergic receptor agonist 
 
Dose per Administration 
75 mg vibegron (or placebo) 
 
Dose Units 
1 tablet 
 
Dosing Frequency 
Once daily 
 
Route of Administration 
Oral 
 
Current Therapy or Treatment 
Diet, antispasmodics, antidepressants, 
laxatives, antidiarrheals 
 
Added on to Existing Treatments 
Add on to stable doses of 
antidepressants, anticonvulsants (for 
epilepsy), diet 
 
Control Type 
Placebo 
 
Comparative Treatment Name 
-- 
Trial design 
Study Type 
Randomized, controlled, double-blind 
 
Drug Model 
Parallel 
 
Planned Number of Arms 
2 
 
Trial is Randomized 
Yes 
 
Randomization Quotient 
0.5 
 
Trial Blinding Schema 
Double blind 
 
Stratification Factor 
Baseline abdominal pain intensity 
(< 6 vs ≥ 6) and IBS subtype (IBS-D 
vs IBS-M)  
 
Adaptive Design 
No 
 
Study Stop Rules 
Unacceptable risk/benefit ratio; 
noncompliance with protocol, GCP, 
other regulatory requirements; 
procedure-related issues; unacceptable 
number of discontinuations for 
administrative reasons; Sponsor 
decision 
 
FDA = Food and Drug Administration; GCP = Good Clinical Practice; IBS = irritable bowel syndrome; IBS-
D = irritable bowel syndrome with predominantly diarrhea; IBS-M = irritable bowel syndrome with mixed episodes 
of diarrhea and constipation; US = United States 


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10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information  
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Women in the following categories are not considered women of 
childbearing potential:  
• Premenopausal woman with 1 of the following: 
- Documented hysterectomy 
- Documented bilateral salpingectomy 
- Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the subject’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal woman 
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
- Women on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.6.1. 
Contraception Guidance 
Women of childbearing potential must agree to use (or have their male partner use) a highly 
effective contraception method, 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. 
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)  


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• Bilateral tubal occlusion (including ligation and blockage methods such as Essure™ at 
least 6 months prior to the initial Screening Visit [subjects with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram])  
• Sexual partner(s) who was documented to be vasectomized at least 6 months prior to the 
Screening Visit 
• Sexual abstinence from heterosexual intercourse 
Subjects will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm when they sign an ICF that 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 subjects 
understand how to properly use these methods of contraception. 
10.6.2. 
Pregnancy Testing and Reporting 
10.6.2.1. Pregnancy Testing  
Women of childbearing potential should only be included after a confirmed menstrual period and 
a negative highly sensitive urine pregnancy test at Screening, Baseline (Visit 3, prior to dosing), 
and at Week 12 or Early Withdrawal. A serum β-human chorionic gonadotropin test must be 
performed if the urine test is positive.  
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected.  
10.6.2.2. Reporting Pregnancy  
The Investigator will collect pregnancy information on any subject who becomes pregnant while 
participating in this study. Information will be recorded on the dedicated pregnancy reporting 
form and submitted to the Sponsor or designee within 24 hours of learning of a subject’s 
pregnancy. The subject will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the subject and the neonate, and the 
information will be forwarded to the Sponsor or designee. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication will 
be reported as an AE or SAE. A spontaneous or elective abortion is always considered to be an 
SAE and will be reported as such. Any poststudy pregnancy-related SAE considered reasonably 
related to the study drug by the Investigator will be reported using the eCRF as described in 


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Section 10.3. While the Investigator is not obligated to actively seek this information in former 
study subjects, he or she may learn of an SAE through spontaneous reporting.  
Any subject who becomes pregnant while participating in the study will discontinue study drug 
and be withdrawn from the study. 
 


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10.7. 
Appendix 7: Study Schedule Supplement 
10.7.1. 
Screening, Visit 1 (between Day -42 and Day -15) 
• Obtain Informed Consent 
• Enter subject into IWRS and subject registry 
• Assess inclusion/exclusion criteria 
• Collect demographic data 
• Collect medical and surgical history data including use of illicit drugs, alcohol, and 
caffeine  
• Collect IBS history including previous treatments and diets 
• Collect concomitant medications 
• Begin recording AEs/SAEs after signing ICF 
• Record vital signs (blood pressure [average of 3 results]; record each reading in the 
source document), body temperature, pulse, weight, and height 
• Perform brief physical examination (heart, lungs, abdomen, external genitalia, perianal 
area, and any other areas as needed) 
• Perform urine pregnancy test on women of child-bearing potential; if positive, perform 
serum test 
• Perform urine drug screen 
• Perform laboratory assessments, including urine dipstick 
• Perform 12-lead ECG 
10.7.2. 
Run-in, Visit 2 (Day -14) 
• Assess inclusion/exclusion criteria 
• Review concomitant medications 
• Record blood pressure (average of 3 results; record each reading in the source document), 
body temperature, and pulse  
• Urine drug screen to be repeated for subjects who had a positive urine drug screen at 
Visit 1 if due to a prohibited concomitant medication. The urine drug screen does not 
need to be re-tested at Visit 2 if the initial positive result at Visit 1 was due to a permitted 
concomitant medication based on the clinical judgment of the investigator.   
• Dispense study drug for single-blind Run-in Period 
• Administer witnessed dose of study drug 
• Review AEs/SAEs 
• Dispense subject diary 


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10.7.3. 
Baseline, Visit 3 (Day 1) 
• Assess inclusion/exclusion criteria 
• Review concomitant medications  
• Administer questionnaires (GIS, WPAI, IBS-QoL, and additional abdominal pain 
questions) 
• Record blood pressure (average of 3 results; record each reading in the source document), 
body temperature, pulse, and weight 
• Perform brief physical examination (heart, lungs, abdomen, external genitalia, perianal 
area, and any other areas as needed) 
• Perform urine pregnancy test; if positive, perform serum test (subject may not begin 
double-blind treatment if serum pregnancy test is positive) 
• Perform laboratory assessments, including urine dipstick 
• Obtain subject randomization assignment 
• Dispense double-blind study drug 
• Administer witnessed dose of study drug  
• Review AEs/SAEs 
10.7.4. 
Double-blind Treatment Period Week 2 (± 4 days), Visit 4  
• Administer questionnaires (GIS and additional abdominal pain questions) 
• Review AEs/SAEs 
• Review concomitant medications, including use of rescue medication from diary 
• Record blood pressure (average of 3 results; record each reading in the source document), 
body temperature, and pulse 
• Perform laboratory assessments, including urine dipstick 
• Review remaining double-blind study drug from Baseline (Visit 3) for compliance and 
return to subject 
10.7.5. 
Double-blind Treatment Period Week 4 (± 4 days), Visit 5 
• Administer questionnaire (GIS and additional abdominal pain questions) 
• Review AEs/SAEs 
• Review concomitant medications, including use of rescue medication from diary 
• Record blood pressure (average of 3 results; record each reading in the source document), 
body temperature, and pulse 
• Perform laboratory assessments, including urine dipstick 
• Dispense double-blind study drug 


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10.7.6. 
Double-blind Treatment Period Week 8 (± 4 days), Visit 6 
• Administer questionnaires (GIS, WPAI, and IBS-QoL, and additional abdominal pain 
questions) 
• Review AEs/SAEs 
• Review concomitant medications, including use of rescue medication from diary 
• Record blood pressure (average of 3 results; record each reading in the source document), 
body temperature, and pulse 
• Perform laboratory assessments, including urine dipstick 
• Dispense double-blind study drug 
10.7.7. 
Double-blind Treatment Period Week 12 (± 4 days [Visit 7]), or Early 
Withdrawal 
• Administer questionnaires (GIS, WPAI, IBS-QoL, and additional abdominal pain 
questions)  
• Collect subject diary 
• Review AEs/SAEs 
• Review concomitant medications, including use of rescue medication from diary 
• Record blood pressure (average of 3 results; record each reading in the source document), 
body temperature, pulse, and weight 
• Perform brief physical examination (heart, lungs, abdomen, external genitalia, perianal 
area, and any other areas as needed) 
• Perform urine pregnancy test on women of child-bearing potential; if positive, perform 
serum pregnancy test 
• Perform laboratory assessments, including urine dipstick 
• Collect double-blind study drug 
10.7.8. 
Safety Follow-up, Telephone Call; Week 14 (7 to 14 days after last dose of study 
drug; includes window of −7 days from Week 14) 
• Contact subject to review AEs and concomitant medications; only for randomized 
subjects who complete Week 12 or withdraw from the study early. 


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10.8. 
Appendix 8: Patient-Reported Outcomes Questionnaires 
10.8.1. 
Global Improvement Scale 
Global improvement assessment asks subjects to evaluate their current IBS status by asking the 
following question: How would you rate your IBS signs or symptoms overall over the past 
7 days? 
1) significantly relieved  
2) moderately relieved 
3) slightly relieved 
4) unchanged 
5) slightly worse 
6) moderately worse 
7) significantly worse  
A responder is defined as a subject who answered that their symptoms were either moderately 
relieved or significantly relieved [Gordon, 2003; Lembo, 2001]. 
 


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10.8.2. 
Irritable Bowel Syndrome - Quality of Life Measure (IBS – QoL) 
1. I feel helpless because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
2. I am embarrassed by the smell caused by my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
3. I am bothered by how much time I spend on the toilet. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
4. I feel vulnerable to other illnesses because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
5. I feel fat because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
6. I feel like I’m losing control of my life because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
7. I feel like life is less enjoyable because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
8. I feel uncomfortable when I talk about my bowel problems.  
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
9. I feel depressed about my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
10. I feel isolated from others because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
11. I have to watch the amount of food that I eat because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
12. Because of my bowel problems, sexual activity is difficult for me. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
13. I feel angry that I have bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
14. I feel like I irritate others because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 


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15. I worry that my bowel problems will get worse. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
16. I feel irritable because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
17. I worry that people think I exaggerate my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
18. I feel I get less done because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
19. I have to avoid stressful situations because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
20. My bowel problems reduce my sexual desire. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
21. My bowel problems limit what I can wear. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
22. I have to avoid strenuous activity because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
23. I have to watch the kind of food I eat because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
24. Because of my bowel problems, I have difficulty being around people I do not know well. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
25. I feel sluggish because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
26. I feel unclean because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
27. Long trips are difficult for me because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
28. I feel frustrated that I cannot eat when I want because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
29. It is important to be near a toilet because of my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 


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30. My life revolves around my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
31. I worry about losing control of my bowels. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
32. I feel that I won’t be able to have a bowel movement. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
33. My bowel problems are affecting my closest relationships. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  A great deal 
 
34. I feel that no one understands my bowel problems. 
 Not at all 
 Slightly 
 Moderately  
 Quite a bit 
  Extremely 
 
\\Stan\cdpr\SEAQOL\Instrument Distribution\IBSQOL - Do NOT Distribute\Instrument FAQ Information\IBSQOL 
Info.doc 3/22/07 10:37 AM 


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10.8.3. 
Work Productivity and Activity Impairment 
Work Productivity and Activity Impairment Questionnaire: 
General Health V2.0 (WPAI:GH) 
The following questions ask about the effect of your PROBLEM on your ability to work and 
perform regular activities. Please fill in the blanks or circle a number, as indicated. 
1. Are you currently employed (working for pay)?  _____ NO ___ YES 
  If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
 
2. During the past seven days, how many hours did you miss from work because of problems 
associated with your PROBLEM? Include hours you missed on sick days, times you went in 
late, left early, etc., because of your PROBLEM. Do not include time you missed to 
participate in this study. 
 
_____ HOURS 
 
3. During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS (If “0”, skip to question 6.) 
 
5. During the past seven days, how much did your PROBLEM affect your productivity while 
you were working?  
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual. If PROBLEM affected your work only a little, choose a low number. Choose a high 
number if PROBLEM affected your work a great deal.  
Consider only how much PROBLEM affected  
productivity while you were working. 
PROBLEM had 
no effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
PROBLEM 
completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 


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6. During the past seven days, how much did your PROBLEM affect your ability to do your 
regular daily activities, other than work at a job?  
 
By regular activities, we mean the usual activities you do, such as work around the house, shopping, 
childcare, exercising, studying, etc. Think about times you were limited in the amount or kind of 
activities you could do and times you accomplished less than you would like. If PROBLEM affected 
your activities only a little, choose a low number. Choose a high number if PROBLEM affected your 
activities a great deal.  
 
Consider only how much PROBLEM affected your ability  
to do your regular daily activities, other than work at a job. 
PROBLEM had 
no effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
PROBLEM 
completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
  
CIRCLE A NUMBER 
 
 
WPAI:GH V2.0 (US English)  
[Reilly, 1993] 
 


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10.8.4. 
Additional Questions on Abdominal Pain 
1. Did you experience abdominal pain within 1 hour of eating? Yes/No 
2. Did you experience abdominal pain associated with a bowel movement? Yes/No 
 


Urovant Confidential 
Protocol UR0-901-2001 
10.9. 
Appendix 9: 0- to 10-Point Numeric Rating Scale for Abdominal 
Pain 
On a scale of Oto 10 where "O" is equal to no pain and "10" is worst possible pain, how would 
you rate your !BS-related abdominal pain at its worst in the past 24 hours? 
~I 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain 
NRS 
Worst 
possible pain 
Version 4.0 
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Urovant Confidential 
Protocol UR0-901-2001 
10.10. 
Appendix 10: Bristol Stool Chart 
Type I 
Type 2 
Type 3 
Type 4 
Type 5 
Ty pe 6 
Type 7 
[Lewis, 1997] 
Version 4.0 
Brist:ol St:ool Chart: 
e .• e • Separate hard lumps, like nuts 
• 
(hard to pass) 
Sausage-shaped but lumpy 
Like a sausage but w ith cracks on 
its surface 
Like a sausage or snake, smooth 
and soft: 
Soft blobs w itll clear-cut edges 
(passed easily ) 
Fluffy p ieces w ith ragged edges, a. 
mushy stool 
Watery, no solid pieces. 
Ent:irel y Liquid 
92 
19 November 2019 


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11. 
References 
Anthony A. Review article: β3-adrenoceptor agonists – future anti-inflammatory drugs for the 
gastrointestinal tract? Aliment Pharmacol Ther. 1996;10:859-63. 
Bardou M, Dousset B, Deneux-Tharaux C, Smadja C, Naline E, Chaput J-C, Naveau S, Manara 
L, Croci T, Advenier C. In vitro inhibition of human colonic motility with SR 59119A and 
SR59104A: evidence of a β3-adrenoceptor-mediated effect. Eur J Pharmacol. 1998;353:281-7. 
Camilleri M, Boeckxstaens G. Dietary and pharmacological treatment of abdominal pain in IBS. 
Gut. 2017;66:966–74. 
Camilleri M, Mckinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, 
Zinsmeister AR. Prospective study of motor, sensory, psychologic, and autonomic functions in 
patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2008;6:772–81. 
Cellek S, Thangiah R, Bassil AK, Campbell CA, Gray KM, Stretton JL, Lalude O, 
Vivekanandan S, Wheeldon A, Winchester WJ, Sanger GJ, Schemann M, Lee K. Demonstration 
of functional neuronal β3-adrenoceptors within the enteric nervous system. Gastroenterol. 
2007;133:175–83. 
De Ponti F, Modini C, Gibelli G, Crema F, Frigo G. Atypical beta-adrenoceptors mediating 
relaxation in the human colon: functional evidence for beta 3 rather than beta 4 adrenoceptors. 
Pharmacol Res. 1999;39:345-8. 
De Ponti F, Gibelli G, Croci T, Arcidiaco M, Crema F, Manara L. Functional evidence of 
atypical beta 3-adrenoceptors in the human colon using the beta 3-selective adrenoceptor 
antagonist, SR 59230A. Br J Pharmacol. 1996;117:1374–6. 
FDA Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. July 
2009. Available at: https://www.fda.gov/downloads/Drugs/…/Guidances/UCM174090.pdf. 
Accessed: 29 July 2018. 
Gordon S, Ameen V, Bagby B, Shahan B, Jhingran P, Carter E. Validation of irritable bowel 
syndrome global improvement scale: an integrated symptom end point for assessing treatment 
efficacy. Dig Disease Sci. 2003;48:1317-23. 
Grudell AB, Camilleri M, Jensen KL, Foxx-Orenstein AE, Burton DD, Ryks MD, Baxter KL, 
Cox DS, Dukes GE, Kelleher DL, Zinsmeister AR. Dose-response effect of a beta3-adrenergic 
receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels 
in health. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1114-9. 
Kelleher DL, Hicks KJ, Cox DS, Williamson RR, Alpers DH, and Dukes GE. Randomized 
double-blind, placebo (PLA)-controlled, crossover study to evaluate efficacy and safety of the 
beta 3-adrenergic receptor agonist solabegron in subjects with irritable bowel syndrome. 
Neurogastroenterol Motil. 2008;20(Suppl 1):131. 
Krief S, Lönnqvist F, Raimbault S, Baude B, Van Spronsen A, Arner P, Strosberg AD, Ricquier 
D, Emorine LJ. Tissue distribution of beta 3-adrenergic receptor mRNA in man. J Clin Invest. 
1993;91:344-9. 
Lacy BE, Patel NK. Rome Criteria and a Diagnostic Approach to Irritable Bowel Syndrome. 
J Clin Med. 2017;11 doi:10.3390/jcm6110099. 


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Lembo AJ. The clinical and economic burden of irritable bowel syndrome. Pract Gastroenterol. 
2007;September:3-9.  
Lembo T, Wright RA, Lotronex Investigator Team, Bagby B, Decker C, Gordon S, Jhingrin P, 
Carter E. Alosetron controls bowel urgency and provides global symptom improvement in 
women with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. 2001;96:2662-
70. 
Lewis SJ, Heaton KW. Stool Form Scale as a useful guide to intestinal transit time. Scand J 
Gastroent. 1997;32:920-4. DOI:10.3109/00365529709011203. 
Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-
analysis. Clin Gastroenterol Hepatol. 2012;10:712-21.  
Melchior C, Bril L, Leroi AM, Gourcerol G, Ducrotte P. Are characteristics of abdominal pain 
helpful to identify patients with visceral hypersensitivity in irritable bowel syndrome? Results of 
a prospective study. Neurogastroenterol Motility. 2018; 30:e13290. 
Mihara S, North RA, Surprenat A, Somatostatin increases an inwardly rectifying potassium 
conductance in guinea pig submucous plexus neurons. J Physiol. 1987;390:335-55. 
Occhipinti K, Smith JW. Irritable bowel syndrome: a review and update. Clin Colon Rectal Surg. 
2012; 25:46–52.  
Prasoon R, Kumar R, Gautam M, Sebastian EK, Reeta KH, Ray SB. Role of somatostatin and 
somatostatin receptor type 2 in postincisional nociception in rats. Neuropeptides. 2015; 49:47-54. 
Reilly MC, Zbrozek AS, Dukes E. The validity and reproducibility of a work productivity and 
activity impairment measure. PharmacoEconomics. 1993;4:353-65. 
Sabate JM, Veyrac M, Mion F, Siproudhis L, Ducrotte P, Zerbib F, Grimaud JC, Dapoigny M, 
Dyard F, Coffin B. Relationship between rectal sensitivity, symptoms intensity and quality of life 
in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2008;28:484-90.  
Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidence-based 
medicine. World J Gastroenterol. 2014;20:6759-73.  
Schemann M, Hafsi N, Michel K, Kober OI, Wollmann J, Li Q, Zeller F, Langer R, Lee K, 
Cellek S. The beta3-adrenoceptor agonist GW427353 (Solabegron) decreases excitability of 
human enteric neurons via release of somatostatin. Gastroenterol. 2010;138:266-74. 
Shi TS, Xiang Q, Zhang M, Barde S, Kai-Larsen Y, Fried K, Josephson A, Gluck L, Deyev SM, 
Zvyagin AV, Schulz S, Hokfelt T. Somatostatin and its 2A receptor in dorsal root ganglia and 
dorsal horn of mouse and human: expression, trafficking and possible role in pain. Molecular 
Pain. 2014;10:12. 
Sinagra E, Morreale GC, Mohammadia G, Fusco G, Guarnotta V, Tomasello G, Capello F, Rossi 
F, Amvrosiadis G, Raimondo D. New therapeutic perspectives in irritable bowel syndrome: 
Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond. 
World J Gastroenterol. 2017;23:6593-627. 
Vasina V, Abu-Gharbieh E, Barbara G, de Giorgio R, Colucci R, Blandizzi C, Bernardini N, 
Croci T, Del Tacca M, de Ponti F. The beta3-adrenoceptor agonist SR58611A ameliorates 
experimental colitis in rats. Neurogastroenterol Motil. 2008;20:1030-41.  

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Protocol Number: 
URO-901-2001 
Protocol Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Vibegron Administered Orally 
for 12 Weeks to Women with Irritable Bowel Syndrome 
Protocol Version and 
Date: 
Version 4.0 (Amendment 3); 19 Nov 2019 
Investigational 
Product: 
Vibegron (URO-901, RVT-901, MK-4618, KRP-114V) 
Indication 
Irritable Bowel Syndrome (IBS) 
Development Phase: 
Phase 2 
US IND Number: 
140291 
EudraCT Number: 
Not Applicable 
Sponsor: 
Urovant Sciences, GmbH  
Viadukststrasse 8  
4051 Basel Switzerland  
Telephone +41 (42) 2155999 
SAP Version 
Effective Date 
v2.0 
21Sep2020 
SAP Author 
 
, Biostatistics, Programming and Data Management, 
Urovant Sciences, Inc. 
NCT Number: NCT02929329
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov


Urovant Sciences 
Statistical Analysis Plan - UR0-901-2001 v2.0 
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Signing Reason: I approve this document 
Signing Time: 21 -Sep-2020 113:27 PDT 
10030D83BODB457682147A274A8713EO 
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Statistical Analysis Plan - UR0-901-2001 v2.0 
This document has been approved by 
11111111: 
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Signer Name: 
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Urovant Sciences 
Statistical Analysis Plan – URO-901-2001 v2.0 
21 Sep 2020 
4 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................ 4 
SAP VERSION HISTORY............................................................................................. 9 
1. 
INTRODUCTION ..................................................................................... 10 
1.1. 
Study Objectives and Endpoints ................................................................ 10 
1.1.1. 
Primary Efficacy Objectives ...................................................................... 10 
1.1.2. 
Secondary Efficacy Objectives .................................................................. 10 
1.1.3. 
Other Efficacy Objectives .......................................................................... 11 
1.2. 
Study Design .............................................................................................. 13 
1.2.1. 
Overall Study Design ................................................................................. 13 
1.2.2. 
Randomization and Blinding ..................................................................... 14 
1.2.3. 
Statistical Hypotheses ................................................................................ 14 
2. 
PLANNED ANALYSES ........................................................................... 15 
2.1. 
Interim Analysis......................................................................................... 15 
2.2. 
Final Analysis ............................................................................................ 16 
3. 
ANALYSIS POPULATION ..................................................................... 16 
3.1. 
Analysis Sets .............................................................................................. 16 
3.1.1. 
Screened Set............................................................................................... 16 
3.1.2. 
Placebo Run-in Set .................................................................................... 16 
3.1.3. 
Randomized Set ......................................................................................... 16 
3.1.4. 
Safety Analysis Set .................................................................................... 16 
3.1.5. 
Full Analysis Set ........................................................................................ 16 
3.1.6. 
Per-Protocol Set ......................................................................................... 17 
3.2. 
Violations and Deviation ........................................................................... 17 
3.2.1. 
Protocol Deviations ................................................................................... 17 
4. 
GENERAL STATISTICAL CONSIDERATIONS ................................... 18 
4.1. 
General Principles for Data Analysis ........................................................ 18 
4.1.1. 
Multicenter Study ...................................................................................... 18 
4.1.2. 
Testing Strategy and Multiplicity Adjustments ......................................... 18 
4.1.3. 
Examination of Subgroups ........................................................................ 18 
4.2. 
General Data Handling Conventions ......................................................... 18 


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4.2.1. 
Study Treatment Description ..................................................................... 18 
4.2.2. 
Reporting Conventions .............................................................................. 19 
4.2.3. 
Premature Withdrawal and Missing Data .................................................. 20 
4.2.4. 
Assessment Windows ................................................................................ 21 
4.2.4.1. 
Study Reporting Periods ............................................................................ 21 
4.2.4.2. 
Analysis Visiting Window ......................................................................... 22 
4.3. 
Data Definitions and Derivations .............................................................. 25 
4.3.1. 
Efficacy Endpoints..................................................................................... 25 
4.3.1.1. 
API Weekly Responder ............................................................................. 26 
4.3.1.2. 
GIS Responder ........................................................................................... 28 
4.3.1.3. 
Change from Baseline in API score ........................................................... 28 
4.3.1.4. 
 .................................................................................... 28 
4.3.1.5. 
 ................................ 29 
4.3.1.6. 
 ............ 29 
4.3.1.7. 
 ..................................................... 29 
4.3.1.8. 
 ................................................. 29 
4.3.1.9. 
 ............................................................................ 30 
4.3.1.10. 
 ................................................................. 31 
4.3.1.11. 
 ...................................................... 32 
4.3.2. 
Reporting Questionnaire Scoring .............................................................. 35 
4.3.2.1. 
.......................................................................................... 35 
4.3.2.2. 
 .................................. 35 
4.3.3. 
Study Day and Duration ............................................................................ 36 
4.3.4. 
Baseline and Change from Baseline .......................................................... 37 
5. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION .......................................................................................... 37 
5.1. 
Subject Disposition and Withdrawals ........................................................ 37 
5.2. 
Demographic and Baseline Characteristics ............................................... 38 
5.3. 
Other Baseline Characteristics ................................................................... 39 
5.4. 
Medical History and Concomitant Disease ............................................... 40 
5.5. 
Prior and Concomitant Medication ............................................................ 40 
5.5.1. 
Rescue Medication..................................................................................... 40 


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6. 
EFFICACY ANALYSIS ........................................................................... 41 
6.1. 
Primary Efficacy Analyses ........................................................................ 41 
6.1.1. 
Primary Analysis ....................................................................................... 41 
6.1.2. 
Sensitivity Analysis ................................................................................... 42 
6.1.3. 
Subgroup Analysis ..................................................................................... 43 
6.2. 
Secondary Efficacy Analyses .................................................................... 44 
6.3. 
Exploratory Efficacy Analysis ................................................................... 44 
7. 
SAFETY ANALYSIS ............................................................................... 48 
7.1. 
Extent of Exposure .................................................................................... 48 
7.2. 
Treatment Compliance ............................................................................... 49 
7.3. 
Adverse Events .......................................................................................... 49 
7.4. 
Laboratory Evaluations .............................................................................. 52 
7.5. 
Vital Signs ................................................................................................. 53 
7.6. 
ECG ........................................................................................................... 54 
7.7. 
Physical Examination ................................................................................ 54 
8. 
COVID-19 CONSIDERATIONS .............................................................. 54 
9. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ................... 55 
10. 
REFERENCES .......................................................................................... 55 
11. 
APPENDIX................................................................................................ 57 
11.1. 
Table of Contents for Data Display Specifications ................................... 57 
11.1.1. 
Output Tables............................................................................................. 57 
11.1.2. 
Output Figures ........................................................................................... 68 
11.1.3. 
Output Listings .......................................................................................... 69 
11.2. 
General Information Related to Data Presentation .................................... 72 
11.3. 
Summary of SAP Changes from v1.0 to v2.0 ........................................... 72 
 
 


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 LIST OF ABBREVIATIONS  
Abbreviation 
Term 
ADaM 
analysis data model 
AE 
adverse event 
AESI 
adverse events of special interest 
API 
Abdominal Pain Intensity 
BMI 
body mass index 
BP 
blood pressure 
CFB 
change from baseline 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
DBP 
diastolic blood pressure 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
GIS 
global improvement scale 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
IBS-D 
IBS that is associated with predominantly diarrhea 
IBS-M 
IBS that has mixed episodes of diarrhea and constipation 
 
 
IxRS 
interactive voice or web response system 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
NRS 
Numeric Rating Scale 
PT 
preferred term 
PRO 
patient reported outcome 
REML 
restricted (or residual) maximum likelihood 
SAE 
serious adverse event 
SAF 
safety set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SDTM 
study data tabulation model 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 


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Abbreviation 
Term 
WAP 
worst abdominal pain  
WHO 
World Health Organization  
 
 
ȕ3-AR 
beta-3 adrenergic receptor 


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SAP VERSION HISTORY 
Version 
Date 
Descrivtion of Chanf!es 
1.0 
25June 2020 
Orif(inal Document 
2.0 
See Aooendix 11.3 for a description of chanf!es 
9 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a description of the statistical methodology to be 
implemented for the analyses of data from Protocol Version 1.0, and to be included in the clinical 
study report. Any deviations from this analysis plan will be documented in the final clinical study 
report.  
Irritable bowel syndrome is a chronic, functional gastrointestinal disorder associated with 
abdominal pain and changes in the frequency or consistency of stool (i.e., diarrhea, 
constipation, or a combination of both). The Rome IV criteria classify IBS into 4 distinct 
subtypes based on predominant stool consistency: IBS with predominantly constipation (IBS-
C), IBS with predominantly diarrhea (IBS-D), IBS with mixed episodes of diarrhea and 
constipation (IBS-M), and IBS with undefined subtype (IBS-U). The definitions of diarrhea 
and constipation correlate with the Bristol Stool Form Scale, with Types 1 and 2 defined as 
constipation and Types 6 and 7 defined as diarrhea. The Rome IV IBS classification is based 
on the patient’s predominant bowel habit on days with abnormal bowel movement as follows: 
• IBS-C:  25 constipation (Bristol Type 1 or 2) and  25 diarrhea (Bristol Type 6or 7). 
• IBS-D:  25 diarrhea (Bristol Type 6 or 7) and  25 constipation (Bristol Type 1 or 2) 
• IBS-M:  25 constipation (Bristol Type 1 or 2) and  25 diarrhea (Bristol Type 6or 7) 
• IBS-U: unclassified (insufficient abnormality to meet other criteria) 
The Rome IV diagnostic criteria must be met within the most recent 3 months, with symptom 
onset at least 6 months before diagnosis. The primary population is IBS-D for this proof of 
concept study with a small group of subjects with IBS-M for exploratory evaluation. 
1.1. 
Study Objectives and Endpoints 
1.1.1. 
Primary Efficacy Objectives  
Primary Efficacy Objectives 
 Endpoints 
To compare the effect of vibegron vs 
placebo in subjects with abdominal 
pain due to IBS-D on the abdominal 
pain intensity (API) weekly 
responder rate over 12 weeks 
 
 Proportion of IBS-D subjects who are API weekly 
       responders with 30 improvement over 12 weeks 
x 
An API Weekly Responder is defined as a subject 
             who experiences a decrease in the weekly average  
             of “worst abdominal pain in the past 24 hours”     
             scores of at least 30 compared with the baseline     
             weekly average  
 
1.1.2. 
Secondary Efficacy Objectives  
Secondary Efficacy Objectives 
 Endpoints 
To compare the effect of vibegron vs 
placebo in subjects with abdominal 
pain due to IBS-D or IBS-M on 
patient-reported outcomes 
 Proportion of Global Improvement Scale (GIS) 
responders at Week 12 for all IBS subjects 
including IBS-D and IBS-M subjects.   
To compare the effect of vibegron vs 
 Proportion of IBS-D subjects who are API weekly 


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placebo in subjects with abdominal 
pain due to IBS-D on the abdominal 
pain intensity (API) weekly responder 
rate over 12 weeks based on different 
thresholds of improvement 
 
       responders with 40 improvement over 12 weeks 
x 
An API Weekly Responder is defined as a subject 
             who experiences a decrease in the weekly average  
             of “worst abdominal pain in the past 24 hours”     
             scores of at least 40 compared with the baseline
 
             weekly average  
 
 
 Proportion of IBS-D subjects who are API weekly 
       responders with 50 improvement over 12 weeks  
x 
An API Weekly Responder is defined as a subject 
             who experiences a decrease in the weekly average  
             of “worst abdominal pain in the past 24 hours”     
             scores of at least 50 compared with the baseline
 
             weekly average  
 
To compare the effect of vibegron vs 
placebo in subjects with abdominal 
pain due to IBS-D or IBS-M on 
safety endpoints 
 AEs, clinical laboratory values, vital signs 
1.1.3. 
Other Efficacy Objectives  
Other Efficacy Objectives 
 Endpoints 


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Other Efficacy Objectives 
 Endpoints 


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Other Efficacy Objectives 
 Endpoints 
1.2. 
Study Design 
1.2.1. 
Overall Study Design 
This study is a Phase 2 randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study to evaluate the efficacy and safety of vibegron in women with IBS-D or IBS-
M. Subjects who meet all eligibility criteria will be randomized in a 1:1 ratio to receive either 
vibegron 75 mg or matched placebo. Approximately 200 subjects will be enrolled at 
approximately 40 sites in the US to achieve approximately 180 evaluable subjects (90 per 
treatment group). 
The study consists of a Screening Period (1 to 5 weeks), a single-blind Placebo Run-in Period 
(2 weeks), a randomized, Double-blind Treatment Period (12 weeks), and a Safety Follow-up 
Period (2 weeks). Subjects will have a Safety Follow-up phone call approximately 14 days 
after the subject’s last dose of study drug (i.e., at Week 14 for subjects who complete the Week 
12 Visit, or approximately 2 weeks after the last dose of study drug for subjects who 
discontinue treatment early). The study schema is shown in Figure 1.  
 


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Figure 1:  Study Schema 
 
WD = withdrawal 
The Week 14 Safety Follow-up telephone call should occur 7 to 14 days after the last dose of study drug (includes 
window of – 7 days) only for randomized subjects who complete Week 12 or withdraw from the study early. 
Refer to Section 1.3 of the protocol for a detailed time and events schedule. 
1.2.2. 
Randomization and Blinding 
Randomization will occur centrally using an interactive voice or web response system (IxRS) 
using central, stratified block randomization. Randomization will be stratified based on the 
following stratification factors: 
x Baseline abdominal pain intensity score (6 vs  6) on a 0 to 10 numeric rating scale 
[NRS], and 
x IBS subtype (IBS-D vs IBS-M)  
For this study a double-blind/masking technique will be used: vibegron and its matching 
placebo will be packaged identically so that treatment blind/masking is maintained.  The 
subject, the Investigator, and Sponsor personnel or delegate(s) who are involved in the 
treatment or clinical evaluation of the subjects will not be aware of the treatment group 
assignments. 
1.2.3. 
Statistical Hypotheses  
The primary objective will be to estimate the treatment effect of vibegron relative to placebo 
with respect to improvement in IBS-related abdominal pain in IBS-D subjects. There is no 
formal statistical hypothesis. Nominal p-values from comparisons to placebo may be provided 


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for descriptive purposes. An improvement in the primary endpoint is defined as a subject who 
experiences a decrease in the weekly average of “worst abdominal pain in the past 24 hours” 
scores of at least 30 compared with the baseline weekly average. Sample Size Justification 
Approximately 200 subjects will be randomized in a 1:1 ratio to receive one of the following 
study treatments: 
x Vibegron 75 mg tablet (N = 100) 
x Matching placebo tablet (N = 100)  
At most, 50 of randomized subjects (approximately 100 subjects total [approximately 50 per 
treatment arm]) will have IBS-M; at least 50 of randomized subjects (approximately 100
subjects total [approximately 50 per treatment arm]) will have IBS-D, and the IBS-D subgroup 
will be used for the primary endpoint analysis. Assuming a total of 10 of subjects will
discontinue prior to Week 12 (for any reason), there will be a minimum of approximately 90 
evaluable IBS-D subjects (approximately 45 in the vibegron arm and approximately 45 in the 
placebo arm) at the end of Week 12. The study has approximately 60 power to detect a
between-group treatment difference of 20 in proportion of abdominal pain responders at a 2 -
sided test at the Į = 0.10 level assuming a responder rate of 51 versus 31 for vibegron and
placebo, respectively. The assumptions were based on results from a solabegron study female 
subgroup analysis [Kelleher, 2008]. 
2. 
PLANNED ANALYSES  
2.1. 
Interim Analysis  


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2.2. 
Final Analysis  
 will perform the production and quality control of all tables, figures 
and listings on behalf of Urovant Sciences, Inc. 
Statistical programming will start after data have been collected and are available in the 
database.  Blinded dry runs using dummy treatment code will be performed prior to database 
lock and unblinding to ensure programming displays and algorithms are developed as planned.   
3. 
ANALYSIS POPULATION  
3.1. 
Analysis Sets 
3.1.1. 
Screened Set 
The Screened Set consists of all subjects who are screened for the study. This population is 
used primarily for subject accounting purposes and will generally not be used for summary or 
analysis. 
3.1.2. 
Placebo Run-in Set 
The Placebo Run-in Set consists of all subjects who entered the single-blind placebo Run-in 
period of the study. Subjects will be considered Run-in failures if they enter the Run-in period 
but are not randomized to receive double-blind medication. 
3.1.3. 
Randomized Set 
The Randomized Set consists of all subjects who are randomized to receive any double-blind 
study medication regardless of whether they took a dose.  
3.1.4. 
Safety Analysis Set   
The Safety Analysis Set (SAF) consists of all subjects who receive at least one dose of double-
blind study medication. Subjects will be classified according to the treatment they actually 
received. 
3.1.5. 
Full Analysis Set  
The Full Analysis Set (FAS) consists of all randomized subjects who took at least one dose of 
double-blind study medication and had at least one evaluable  post-baseline weekly API score 
(i.e., where evaluable is considered minimum of  5 diary entries in a week).  Subjects will be 
analyzed according to their randomized treatment, irrespective of whether or not they have 
prematurely discontinued, according to the Intent-to-Treat principle. The Full Analysis Set for 
IBS-D (FAS-D) and Full Analysis Set for IBS-M (FAS-M) are each a subset of FAS and 
consists of IBS-D and IBS-M subjects, respectively, based on the randomization strata.   In 
general, the efficacy endpoints will be summarized using all three populations: FAS, FAS-D 


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and FAS-M.  However, the FAS-D will serve as the primary population for the primary 
analysis of efficacy data in this study. 
3.1.6. 
Per-Protocol Set 
The Per-Protocol Set for IBS-D (PPS-D) excludes subjects from the FAS-D due to important 
deviations from the protocol that may substantially affect the result of the primary efficacy 
endpoint. This Per -Protocol Set will serve as the supportive population for the analysis of 
efficacy data in this study. Other Per Protocol Sets may be defined. The final determination on 
major protocol deviations, and thereby the composition of the Per-Protocol Sets, will be made 
prior to the unblinding of the database and will be documented.  
3.2. 
Violations and Deviation  
Subjects who do not meet eligibility criteria but were still randomized will be analyzed 
according to the analysis sets described in Section 3.1. 
3.2.1. 
Protocol Deviations  
 
The final list of major protocol deviations will be finalized and documented prior to database 
lock except for the deviation category of wrong treatment which will be confirmed upon study 
unblinding. Only major (i.e., significant per the protocol deviation plan) protocol deviations 
will be summarized and listed in the Clinical Study Report (CSR). Major deviations will be 
those which are considered to potentially impact upon the interpretation of the primary efficacy 
endpoint in the study or may potentially impact the interpretation of safety. Major protocol 
deviations  may include, but are not limited to the following: 
x Randomized subjects who do not meet the inclusion criteria 
x Randomized subjects who meet any of the exclusion criteria 
x Subjects who received the wrong treatment  
x Concomitant use of prohibited medications 
x  Randomized subjects who met withdrawal criteria during the study but were not 
withdrawn 
x Subjects whose IP was interrupted 14 consecutive days or more during the double-blind 
treatment period OR had IP compliance less than 80 from Weeks 8-12 
x Subjects who were not compliant in study procedures (e.g., if 3 or more days of diary 
entry were missed between visits that were a 2-week period or if 6 or more days of 
diary entry missed between visits that were a 4-week period)  
 


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4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
General Principles for Data Analysis  
4.1.1. 
Multicenter Study  
In this study the stratified permuted block randomization is not done within centers.  The 
analyses will be conducted by pooling data from all study centers and will not include study 
center as a covariate in the statistical modeling. 
4.1.2. 
Testing Strategy and Multiplicity Adjustments  
No formal multiplicity adjustment will be performed. All efficacy analyses will be considered 
descriptive. Ninety-percent confidence intervals will be provided for each treatment group and 
nominal p-values from comparisons to placebo may be provided for descriptive purposes as a 
measure of the strength of the association between the endpoint and the treatment effect. 
4.1.3. 
Examination of Subgroups  
To determine whether the treatment effect is consistent across various subgroups, the primary 
efficacy endpoint will be summarized descriptively for each of the following subgroups: 
x Baseline abdominal pain intensity score (6 vs  6)  
x Age category (40, 40 to 65, 65 years) 
x Race (as CRF page) 
x Randomized prior to 31Dec2019 vs Randomized after 31Dec2019 
x Baseline Bristol Stool Scale ( 5.5 vs  5.5) 
Note, the protocol amendment in Nov2019 changed the fecal calprotectin testing to optional 
and that it should only be considered if there is a strong suspicion in the opinion of the 
investigator that the subject has inflammatory bowel disease (IBD) (e.g., family history in a 1st 
degree relative). In order to allow time operationally for sites to implement this a date of 
31Dec2019 was chosen as the cutoff.  
All efficacy data including eDiary and ePRO data will be summarized by IBS sub-type (IBS-D 
and IBS-M) and all IBS.  
4.2. 
General Data Handling Conventions 
4.2.1. 
Study Treatment Description 
Randomized treatment groups will be displayed as show in the following table: 
Data Displays for Reporting 


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Description 
Order in TLF 
Placebo 
1 
Vibegron 75mg  
2 
 Overall  
3 
4.2.2. 
Reporting Conventions 
General rules 
In general, all collected safety data and any derived efficacy parameters from daily evening 
pain diary and daily bowel movement diary and PRO data will be presented in subject data 
listings, for all enrolled subjects. Listings will be ordered by treatment subject number, and 
assessment week or event date. The treatment group presented in listings will be based on the 
planned assignment, unless otherwise noted. 
Summary tables will be provided for all randomized subjects. All demographic and baseline 
data will be presented by treatment arm and overall, unless otherwise specified. Efficacy, PRO 
and safety data will be presented by treatment arm only. In general, continuous variables will 
be summarized to include the population sample size (N), number of subjects with available 
data (n), arithmetic mean, SD, median, minimum, Q1, Q3 and maximum values. Categorical 
variables will be summarized by the population size (N), number of subjects with available 
data (n), number of subjects in each category, and the percentage of subjects in each category. 
Unless otherwise noted, the denominator to determine the percentage of subjects in each 
category will be based on the number of subjects with available data (n) in the analysis set of 
interest. Selective ordinal data may be summarized using both descriptive statistics and counts 
and percentages of subjects in each category, as appropriate.  
The data analyses will be conducted using the SAS® System (SAS Institute Inc., Cary, NC) 
version 9.4 or above. The 
’ standard operating procedures will be followed 
for the validation of all SAS programs and outputs. 
Formats 
Numeric data will be reported at the precision collected on the eCRF.  The reported precision 
from non eCRF sources may be adjusted to a clinically interpretable number or decimal places. 
Unscheduled Visits 
Unscheduled visits will be assigned to a study visit using the all-inclusive windows defined in 
Section 4.2.4. However, for by visit summaries, only the planned assessment time points will 
be summarized. Assessments at unscheduled visits will be included for “any time On-
treatment” timepoints and in data listings, as well as algorithms to determine the maximum. 


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4.2.3. 
Premature Withdrawal and Missing Data  
All data collected in the study database after the subject’s early withdrawal of study treatment 
should be included in summary and analysis. 
If any missing data are present in diary data for any reasons, no imputation will be applied to 
derive responder since the minimum compliance rules described in responder definition in 
Section 4.3.1 accounted for missing diary entries. No explicit missing data imputation will be 
performed for change from baseline since a mixed model for repeated measures (MMRM) will 
be applied to change from baseline analysis. Missing items from the subject reported outcomes 
(PROs) will be handled according to the respective measure instructions as described in Section 
4.3.2. 
 
In general, missing safety data will not be imputed and only observed values will be analyzed. 
Data of subjects who withdraw after the screening examination or are not treated will be only 
listed. 
 
If the relationship of an AE record (“Relationship to investigational product” on AE CRF) is 
missing this AE will be considered “Probably Related” to the study treatment. If the AE 
intensity is missing every effort should be made to acquire the information from the 
investigator. “Severe” will be assigned to a missing intensity for reporting purpose 
 
The general imputation rules of partial missing date for both AE and concomitant medication is 
detailed below: 
 
Dates missing only the day of the month within a year will adhere to the following 
conventions:  
x The missing day of onset date will be set to: 
 First day of the month that the event occurred, if the onset YYYY-MM is after the 
YYYY-MM of first double-blind treatment 
 The day of the first run-in treatment, if the onset YYYY-MM is the same as YYYY-
MM of the first run-in treatment, but different from YYYY-MM of the first double-
blind treatment 
 The day of the first double-blind study treatment, if the onset YYYY-MM is the same 
as YYYY- MM of the first double-blind treatment and the first single-blind treatment 
 The date of informed consent, if the onset YYYY-MM is before the YYYY-MM of 
the first single-blind treatment. 
 
x The missing day of end date will be set to: 
 The last day of the month of the occurrence. If the subject died in the same month, 
then set the imputed date as the death date. 
 
Dates missing both the day and month of the year will adhere to the following conventions: 


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x Missing day of onset date will be set to: 
 January 1 of the year of the onset, if the onset YYYY is after the YYYY of the first 
double-blind treatment 
 The date of the first run-in treatment, if the onset YYYY is the same as YYYY of the 
first run-in treatment, but different from YYYY of the first double-blind treatment 
 The date of the first double-blind treatment, if the onset YYYY is the same as YYYY 
of the first double-blind treatment 
 The date of informed consent, if the onset YYYY is before YYYY of the first run-in 
treatment 
 
x The missing date of end date will be set to: 
 December 31 of the year of occurrence. If the subject died in the same year, then set 
the imputed date as the death date. 
Missing items from the subject reported outcomes (PROs) will be handled according to the 
respective measure instructions as described in Section 4.3.2.  
4.2.4. 
Assessment Windows 
4.2.4.1. 
Study Reporting Periods 
Based on study design and variables under consideration, study time periods are defined as 
below. 
   Table 1:  
 Definition of Study Reporting Periods 
Analysis 
description 
Analyzing 
Study Period 
Start Date  
End Date 
General 
Screening  
Date of informed 
consent 
Date of first run-in dose 
 
Run-in  
Date of first run-in 
single-blind dose 
Date of last run-in single-
blind dose 
 
Blinded 
Treatment (Day 
1 – Week 12) 
Date of first double-
blind dose 
Date of last double-blind 
dose + 14 
 
Follow-up (up to 
Week 15) 
Date of last dose + 14 
days  
Date of last contact 
Adverse 
events  
Screening  
Start date  date of
informed consent 
End date  date of first
single-blind run-in dose 
 
Run-in  
Start date  date of first
single-blind run-in dose 
End data  date of last
single-blind run-in dose  
 
Blinded 
Treatment  
Start date  date of first
double-blind dose 
End data  date of last
double-blind dose + 14 days 
 
Follow-up  
Start date > date of last 
dose + 14 days 
Date of last contact 
 
Concomitant 
Medication 
Prior medication 
Start date > date of first  
double-blind dose 
 


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Analysis 
description 
Analyzing 
Study Period 
Start Date  
End Date 
 
Concomitant 
mediation 
Start date  date of first
double-blind dose, or  
End date  date of last
double-blind dose + 14 days 
 
 
Start date > date of first  
double-blind dose, but 
ongoing during double-
blind treatment period 
End date  date of last
double-blind dose + 14 days 
 
Post medication 
Start date > date of last 
double-blind dose +14 
days 
 
The date of last contact is the maximum date of study discontinuation, follow-up contact or 
the return of study medication. When lost to follow-up, the latest date of assessment/event 
in the database will be used as the last known date of the subject in study. 
4.2.4.2. 
Analysis Visiting Window  
 
Analysis windows will be used for eDiary, safety (vitals and labs) as well as quality of 
life endpoints. 
All measurements including the ones from the unscheduled visits that fall within the 
“Visit Window” will be used in the windowing algorithm to determine the analysis visit. 
Relative study day will be derived based on Section 4.3.3. Note that the date of the first 
double-blind dose is Day 1 and the day before the date of the double-blind first dose is 
Day -1.  Thus, there is no Day 0. 
For the safety assessments and quality of life endpoints, if there are multiple values for in 
one window, the visit closest to the nominal day will be selected for assessing endpoints 
at a particular visit and for by-visit displays. If the visits are equally distant from the 
nominal day, then the earlier visit will be selected. All values will be stored in analysis 
datasets.  
Check that all records slotted to a post-treatment visit are greater or equal to 15 days after the 
last dose date.  Any post-treatment visit occurring less than 15 days after the last dose date 
should be re-slotted to an on-treatment visit using the corresponding relative day windows 
constructed for that parameter. 
 
Table 1. For eDiary, the following analysis visit window slotting will be used to determine 
weekly assessments: 
 
Analysis window 
label 
Visit Window 
Screening  
                    NA 
Run-in  
NA 
           Baseline             
[-7, -1] 


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Analysis window 
label 
Visit Window 
Week 1 
[1, 7] 
Week 2 
[8, 14] 
Week 3 
[15, 21] 
Week 4 
[22, 28] 
Week 5 
[29, 35] 
Week 6 
[36, 42] 
Week 7 
[43, 49] 
Week 8 
[50, 56] 
Week 9 
[57, 63] 
Week 10 
[64, 70] 
Week 11 
[71, 77] 
Week 12 
[78, 84] 
 
 
Follow-Up for Early 
Withdrawals 
>Last dose date + 14 
Follow-Up for 
Completers 
 >Last dose date + 14 
Note: Only calculate the upper bound of last dose date + 14 if the 
relative study day of the last dose date is  71 days 
 
         Table 2: Analysis Visit Window Slotting for Safety Laboratory and Vitals  
Analysis window 
label 
Nominal visit 
Nominal 
day 
Visit Window 
Screening  
Visit 1 
NA 
                    NA 
Run-in  
Visit 2 
NA 
NA 
           Baseline1           
Visit 3 
1 
NA 
Week 2 
Visit 4 
15 
[2, 22] 
Week 4 
Visit 5 
29 
[23, 42] 
Week 8 
Visit 6 
57 
[43, 70] 
Week 12 
Visit 7 
85 
[71,last dose date + 14, ] 
Follow-Up for Early 
Withdrawals 
NA 
NA 
>Last dose date + 14 
Follow-Up for 
Completers 
NA 
NA 
 >Last dose date + 14 
1 See section 4.3.4 for definition of baseline 
Note: Only calculate the upper bound of last dose date + 14 if the relative study day 
of the last dose date is   71 days 
Table 3: Analysis Visit Window Slotting for ePRO assessments GIS and Additional Pain 
questions 


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Analysis window 
label 
Nominal visit 
Nominal 
day 
Visit Window 
Screening  
Visit 1 
NA 
                    NA 
Run-in  
Visit 2 
NA 
NA 
           Baseline1           
Visit 3 
1 
NA 
Week 2 
Visit 4 
15 
[2, 22] 
Week 4 
Visit 5 
29 
[23, 42] 
Week 8 
Visit 6 
57 
[43, 70] 
Week 12 
Visit 7 
85 
[71, last dose date + 14] 
Follow-Up for Early 
Withdrawals 
NA 
NA 
>Last dose date + 14 
Follow-Up for 
Completers 
NA 
NA 
 >Last dose date + 14 
           1 See section 4.3.4 for definition of baseline 
           Note: Only calculate the upper bound of last dose date + 14 if the relative study day of the 
last dose date is  71 days 
 
Table 5: Analysis Visit Window Slotting for Weekly Pain and Bowel Movement Diary 
 
Analysis window 
label 
Visit Window 
Screening  
                    NA 
Run-in  
NA 
           Baseline             
[-7, 1] 
Week 1 
[1, 7] 
Week 2 
[8, 14] 
Week 3 
[15, 21] 
Week 4 
[22, 28] 
Week 5 
[29, 35] 
Week 6 
[36, 42] 
Week 7 
[43, 49] 


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Analysis window 
Visit Window 
label 
Week8 
rso. 561 
Week9 
f 57, 631 
Week 10 
f 64, 701 
Week 11 
f71, 771 
Week 12 
f78, 841 
4.3. 
Data Definitions and Derivations 
4.3.1. 
Efficacy Endpoints 
Efficacy Assessments will be collected as outlined in Table 6 below. Refer to protocol section 
1.3 (Schedule of Assessments) for the details on the day of visit and timing of measurement. 
Table 6: 
Assessment 
Abdominal Pain 
Intensity 
Efficacy Assessments 
Form 
Daily Evening Pain Diaiy 
(eDiaiy) 
PRO Questionnaires 
• Global Improvement Scale 
Additional 
abdominal pain 
questions 
(GIS) 
Daily Evening Pain Diaiy 
(eDiaiy) 
25 
Measurement and Timing 
Subjects will record daily worst abdominal 
pain over the past 24-hours with 0- to 10-point 
NRS (0 = no pain, 10 = worst possible pain) 
during both Run-in and Double-blind Pe1iod 
Day 1, Weeks 2, 4, 8, 12 
• Abdominal pain within 1 hour of eating 
• Abdominal pain associated with a bowel 
movement 


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Assessment 
Form  
Measurement and Timing 
There are responders and efficacy endpoints that require further details to clearly define the 
endpoints without ambiguity. The endpoints and their definitions are described in detail below.  
4.3.1.1. 
API Weekly Responder  
 
To derive API Weekly Responder during various week intervals, the initial two steps should be 
followed to derive (1) Weekly average worst abdominal pain (WAP) score; (2) Weekly 
Responder status by week 
 
Step 1: 
 
x Weekly average is defined as the sum of WAP scores on the NRS (0-10) in the 7 days 
immediately prior to baseline visit (Day 1) or each of post-baseline Weeks (Week 1-Week 
12), divided by the number of days with non-missing pain diary entries during the 7 days. 
Weekly average will be set missing if there are more than 2 missed diary days over the past 
7 days.  
x API Weekly Responder with  30 improvement at each week (i.e., Week 1, Week 2, 
Week 3, …, Week 12) is defined as a subject who experiences a decrease in the weekly 
average of WAP score of at least 30 compared with the baseline weekly average. To
qualify as a responder for the specific week, a subject must have at least 5 days of non-
missing pain diary entries during the week (i.e.,  5 of 7 days).  A Subject will be assigned 
as non-responder for the specific week if the weekly average is missing.  
Similarly, the API Weekly Responder will be further derived based on more stringent measures 
of weekly reduction as below: 
x API Weekly Responder with  40 improvement at each week (i.e., Week 1, Week 2, 
Week 3, …, Week 12) is defined as a subject who experiences a decrease in the weekly 


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average of WAP score of at least 40 compared with the baseline weekly average. To 
qualify as a responder for the specific week, a subject must have at least of 5 days of non-
missing pain diary entries during the week (i.e.,  5 of 7 days).  
x API Weekly Responder with  50 improvement at each week (i.e., Week 1, Week 2, 
Week 3, …, Week 12) is defined as a subject who experiences a decrease in the weekly 
average of WAP score of at least 50 compared with the baseline weekly average. To
qualify as a responder for the specific week, a subject must have at least of 5 days of non-
missing pain diary entries during the week (i.e.,  5 of 7 days).  
 
Step 2: 
Then API Weekly Responder will be derived during different treatment intervals using primary 
criteria as an example below:  
 
API Weekly responder with  30 improvement over 12 weeks (i.e., from randomization 
through to Week 12) - primary efficacy endpoint 
 
x To qualify as an overall API Weekly Responder from randomization through to Week 12 
(Weeks 1-12), a subject must satisfy the following criteria: 
x Must meet the API Weekly Response criteria  30 improvement on  50 of weeks,
i.e., success on 6 or more weeks during the past 12 weeks 
x Must have had  60 diary days over the past 12 weeks  
 
API Weekly responder from randomization through to Week 2 (Weeks 1-2) 
 
x To qualify as an API Weekly Responder from randomization through to Week 2, a subject 
must satisfy the following criteria: 
x Must meet the API Weekly Response criteria on more than 50 of weeks, i.e., success on
1 or 2 weeks during past 2 weeks 
x Must have had  10 diary days over the past 2 weeks 
 
API Weekly Responder from randomization through to Week 4 (Weeks 1-4) 
x To qualify as an API Weekly Responder over 4-week interval, a subject must satisfy the 
following criteria: 
x Must meet the API Weekly Response criteria on more than 50 of weeks, i.e., success on
2 or more weeks during past 4 weeks 
x Must have had  20 diary days over the past 4 weeks 
 
API Weekly Responder from randomization through to Week 8 (Weeks 1-8) 


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x To qualify as an API Weekly Responder over 8-week interval, a subject must satisfy the 
following criteria: 
x Must meet the API Weekly Response criteria on more than 50 of weeks, i.e., success
on 4 or more weeks during past 8 weeks 
x Must have had  40 diary days over the past 8 weeks 
The secondary efficacy endpoints of Weekly API Responder with either  40 or  50
improvement will be classified using the same rules above. 
4.3.1.2. 
GIS Responder 
GIS responder at Week 12 is the secondary efficacy endpoint. It is defined as a subject who 
selected either 1) (significantly relieved) or 2) (moderately relieved) on the GIS questionnaire 
at Week 12. A subject with a missing response will be considered as non-responder in the 
specific visit. GIS responder will be derived at Day 1, Week 2, Week 4, Week 8, and Week 12 
for all IBS subjects.  
4.3.1.3. 
Change from Baseline in API score 
All endpoints will be derived at Baseline, Weeks 2, 4, 8 and 12. 
x Weekly average of WAP score:  
Derivation is defined as described in the first step in Section 4.3.1.1. 
x Weekly average number of pain-free days  
Weekly average number of pain-free days is defined as the sum of all pain-free days in the 
past 7 days immediately prior to baseline visit (Day 1) or each of post-baseline Weeks 
(Weeks 2, 4, 8, 12), divided by the number of  days with non-missing pain diary entries and 
then multiply 7. Weekly average will be set missing if more than 2 missed diary days over 
the past 7 days.   
x Change from baseline in abdominal pain within 1 hour of eating  
Change from baseline will be summarized categorically as “Improved (Yes to No)” vs “Not 
Improved”, where “Not Improved” is further categorized as “No Change”, “Worsened (No 
to Yes)”, or “Missing Post-baseline Assessment”.  
x Change from baseline in abdominal pain associated with a bowel movement:  
Change from baseline will be summarized categorically as “Improved (Yes to No)” vs “Not 
Improved”, where “Not Improved” is further categorized as “No Change”, “Worsened (No 
to Yes)”, or “Missing Post-baseline Assessment”. 


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4.3.2. 
Reporting Questionnaire Scoring 


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4.3.3. 
Study Day and Duration  
Study day is relative to the start date of the double-blind treatment. This is used to describe the 
relative time of an event or assessment happened during the study. The first day of the study is 
defined as the day a subject first receives either vibegron or placebo in the double-blind 
treatment period. This is expected to be the same day as the randomization as Day 1.  There is 
no study Day 0 is defined in the study.  
x For an event or assessment that occurred on or after the first dose of double-blind 
treatment date: 
:   
Study day = Date of event or examination – date of first double-blind study treatment + 1 
x For an event or assessment that occurred prior to the first dose of double-blind 
treatment date:   
Study day = Date of event or examination – date of first double-blind study 
treatment 
Similarly, a duration between any two dates (such as AE duration) expressed in days will be 
calculated using the following conventions: 
x Duration = Later date – earlier date + 1, if the earlier date is on or after the date of first 
dose of double-blind treatment 
x Duration = Later date – earlier date, if the earlier date is prior to the date of first dose 
of double-blind treatment 


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4.3.4. 
Baseline and Change from Baseline 
In general, the last recorded value on or prior to the date of double-blind treatment start will 
serve as the baseline measurement for efficacy endpoints while the last recorded value prior to 
first dose of double-blind treatment will serve as the baseline measurement for safety 
endpoints. The mean of the multiple values will be used as baseline for the following 
situations: 
x If multiple measurements are scheduled on the same baseline day (i.e., blood pressure) 
x If multiple measurements are collected on the same baseline day without the time or 
“repeat” status to differentiate the records 
Change from baseline will be calculated as the post-baseline value minus the baseline value. 
Percentage change from baseline will be calculated as the change from baseline divided by the   
baseline value, multiplied by 100. If either the baseline or post-baseline value is missing, then 
change from baseline and percentage change from baseline will be set to missing. 
5. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS 
AND MEDICATION 
5.1. 
Subject Disposition and Withdrawals 
Subject disposition will be summarized by treatment group for the Screened, Run-in and 
Randomized Sets separately. The summary table will present the frequency and percentage of 
subjects in each of the analysis sets and those who discontinued the study prematurely along 
with the primary reasons for discontinuation.  
For the summary under the Randomized Set, the following additional categories will be 
presented as well; randomized, received treatment with study drug, did not receive treatment 
with study drug, completed treatment with study drug, discontinued treatment with study drug 
(and reason), and withdrawn from study (and reason). 
The frequency and percentage of subjects with at least one major Protocol Deviation (PD), 
major PD by classification and reasons/category for PD will be summarized by treatment arm 
and by FAS-D, FAS-M and FAS. Inclusion in each of the analysis sets (SAF, FAS, FAS-D, 
etc.), and any reasons for exclusion will be summarized by treatment arm for the Randomized 
Set.  
Screen Failure, Run-in and Double-Blind Period disposition, with reasons for discontinuation 
of study will also be listed, including the date of discontinuation and date of last contact.  The 
date of last contact is the maximum date of study discontinuation, follow-up or the return of 
study medication. When lost to follow-up, the latest date of assessment/event in the database 
will be used as the last known date of the subject in study. 


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Eligibility criteria, screening and run-in failures (including date and primary reason for failure), 
and informed consent (protocol version, informed consent version date and date signed) will be 
listed for all subjects screened. 
A summary of randomized subjects by country, investigator name and site identification will 
be provided. 
Randomization details will also be listed, including the date of randomization, randomization 
number and randomization strata.  A listing will also be provided for the subjects who had 
misclassification of the stratification factors (i.e., randomization stratification does not match 
actual stratification values). The actual stratification is based on medical history lower level 
terms of "Irritable bowel syndrome" which indicates the subjects has a history of IBS-M and 
the term of "Diarrhea predominant irritable bowel syndrome" which indicates the subject has a 
history of IBS-D.  If more than one term is available, the term ongoing just prior to 
randomization should be used. In the rare event that no medical history term is able to be 
mapped to either IBS-D or IBS-M then the actual stratification will be assigned the value of the 
randomization strata. 
5.2. 
Demographic and Baseline Characteristics 
All demographic and baseline characteristic data will be summarized by treatment group using 
descriptive statistics for all IBS subjects, IBS-D and IBS-M based on the FAS. In addition, the 
summary will be prepared for PPS-D. 
The summary table will include age, age category ((40, 40 to 65, 65 years), sex, child 
bearing potential (Yes/No), ethnicity, race, baseline abdominal pain intensity score (6 vs  6),
baseline IBS subtype (IBS-D vs. IBS-M) (only for all IBS subjects), previous IBS diet 
(Yes/No), category of previous IBS diet if Yes, baseline hypertension category ( Hypertension 
vs. normotensive), pre-existing hypertension (Yes/No), weight, height and BMI.  
Baseline Hypertension will be defined as baseline systolic blood pressure (SBP) 140 mmHg 
or baseline diastolic blood pressure (DBP) 90 mmHg, regardless of medical history. 
Pre-existing hypertension will be defined as having a medical history of hypertension or 
baseline hypertension (baseline SBP 140 mmHg or baseline DBP 90 mmHg). The following 
list of preferred terms will be used to search for medical history of hypertension:  
 
x 
Accelerated hypertension 
x 
Diastolic hypertension 
x 
Essential hypertension 
x 
Hypertension 
x 
Hypertensive crisis 
x 
Hypertensive emergency 
x 
Hypertensive heart disease 
x 
Malignant hypertension 
x 
Malignant hypertensive heart disease 


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x 
Secondary hypertension 
x 
Supine hypertension 
x 
Systolic hypertension 
 
Age (years), height (cm), weight (kg), and BMI captured at Screening will be summarized as a 
continuous variable. 
All demographic data will be listed. 
5.3. 
Other Baseline Characteristics 
The data from the Daily Evening Pain Diary and Bowel Movement diary during run-in period 
(reviewed at Visit 3 Baseline visit) prior to first double-blind dose will be used as baseline for 
each subject. This includes endpoints: 
 
x Weekly average of worst daily pain score,  
x Weekly average number of pain-free days  
x Daily average bowel urgency episodes,  
x Weekly average number of days with bowel urgency,  
x Abdominal pain within 1 hour of eating (Yes vs No),  
x Abdominal pain associated with a bowel movement, (Yes vs No)  
x Weekly average number of days with recurrent bowel movement,  
x Daily average number of bowel movements,  
x Weekly average number of days with diarrhea (Bristol Type 6 or 7), 
x Weekly number of days with diarrhea (Bristol 
Type 6 or 7)  
x Weekly average number of days with at least 1 stool with Bristol Type 3, 4, or 5 
consistency  
x Weekly average number of stools with Bristol Type 3, 4, or 5 consistency 
 
In addition, the following parameters will be presented in the baseline table  
 
x Daily average stool consistency  
x Daily average number of diarrhea bowel movement 
x Daily average number of stools with Bristol Type 3, 4, 5 consistency  
x Weekly average number of days with constipation (Bristol Type 1 or 2) 
x Daily average number of stools with constipation (Bristol Type 1 or 2) 
x Weekly average number of stools with constipation (Bristol Type 1 or 2) 
 
These will be summarized by IBS subtype (IBS-D, IBS-M) and for all IBS subjects, and 
treatment group using descriptive statistics for continuous data for all subjects in each analysis 
set.  


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5.4. 
Medical History and Concomitant Disease 
Descriptions of medical history findings will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 23.0 or higher. 
A disease or illness reported as medical history without a start date will be included in medical 
history without a date assigned. Medical history will be sorted by descending overall 
frequency, by system organ class (SOC) and preferred term (PT) in the summary table. 
Medical history data listings will be sorted by treatment, subject number, start date, SOC and 
PT. 
5.5. 
Prior and Concomitant Medication  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug B3-March Format, 2020 version or later. These medications will be further classified as 
follows.  
x 
Prior medication: are defined as those medications taken prior to the first dose of double-
blind treatment.  
x Non-IBS prior medication 
x IBS prior medication  
x 
Concomitant medication: are defined as those taken on or after the first dose of double-
blind medication but prior to the last dose of double-blind medication + 14 days.  If 
medications started prior to double-blind medication and were ongoing during the Double-
Blind Period, those medication will be considered as concomitant medication as well.  See 
Table 1.  
x 
Post medication:  medication taken after last dose of double-blind medication + 14 days 
Except for Prior IBS medication, the number and percentage of subjects taking prior non-IBS 
medications and non-rescue concomitant medications will be summarized overall by ATC 
(Anatomical Therapeutical Chemical) Levels 2 and 4 for all subjects in the SAF. Prior IBS 
medications and rescue concomitant medications will be summarized by ATC Levels 2, 4 and 
Preferred Term in the SAF. Prior medications, IBS rescue concomitant and non-rescue 
concomitant medications will be listed for all subjects in the SAF. Post medication if any will 
be listed only.  
 
5.5.1. 
Rescue Medication 
Use of rescue medication will be collected on the daily diary (i.e., subjects will respond to 
prompts asking if any rescue medication was taken for abdominal pain or stool or pain/stool 
symptoms). The proportion of subjects who used rescue medication and the reason for the 
medication will be summarized by treatment groups. This data will be summarized for the 
efficacy populations. 


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Note, protocol Amendment 3 clarified that rescue medications should only be used beginning 
at Day 1 (Visit 3). 
6. 
EFFICACY ANALYSIS 
In general, the FAS will be used for all analyses of efficacy endpoints unless stated otherwise. 
6.1. 
Primary Efficacy Analyses  
6.1.1. 
Primary Analysis  
The primary efficacy endpoint of proportion of IBS-D subjects who are API weekly responders 
with 30 improvement from Week 1 through Week 12 is defined in the Section 4.3.1.   
The number and percentage of responders and non-responders will be tabulated by treatment 
and visit. The treatment comparison will use a Cochran-Mantel-Haenszel (CMH) common risk 
difference estimate stratified by baseline abdominal pain ( 6 vs. 6) strata per randomization 
stratification [11] with weights proposed by Greenland and Robins [6], which is calculated as 
follows: 
 
ߜመெுൌ
σ
௪೔ήఋ෡೔
ೠ
೔సభ
σ
௪೔
ೠ
೔సభ
ǡ  
ߜመ௜ൌݔ௜
݊௜
െ ݕ௜
݉௜
݅ǡ ݅ൌͳǡ ڮ ǡ ݑ 
ݓ௜ൌ
௡೔ή௠೔
௡೔ା௠೔݅ǡ ݅ൌͳǡ ڮ ǡ ݑ  
ݔ௜ଵǡ ݅ൌͳǡ ڮ ǡ ݑ 
ݕ௜ଶǡ ݅ൌͳǡ ڮ ǡ ݑ 
݊௜ଵǡ ݅ൌͳǡ ڮ ǡ ݑ 
݉௜ଶǡ ݅ൌͳǡ ڮ ǡ ݑ 
The estimated variance of ߜመெு is calculated as: 
ݒܽݎ
ෞ൫ߜመெு൯ൌ
σ
ܮ௜
௨
௜ୀଵ
ሺσ
ݓ௜
௨
௜ୀଵ
ሻଶ 
ܮ௜ൌݔ௜ሺ݊௜െݔ௜ሻ݉௜
ଷ൅ݕ௜ሺ݉௜െݕ௜ሻ݊௜
ଷ
݊௜ή ݉௜ή ሺ݊௜൅݉௜ሻଶ
ǡ ݅ൌͳǡ ڮ ǡ ݑ 
Assuming a normal distribution of ߜመெு , an approximate 90 CI is given as follows, where ݖ଴Ǥଽହ 
is the 95 quantile of the standard normal distribution: 


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ܥܫൌቈߜመெுേݖ଴Ǥଽହή ටݒܽݎ
ෞ൫ߜመெு൯቉ 
Also, the approximate p-value can be calculated using the following: 
 െ ൌʹ ή 
ۏ
ێ
ێ
ۍ
ܼ൐ተተ
ߜመெு
ටݒܽݎ
ෞ൫ߜመெு൯
ተተ
ے
ۑ
ۑ
ې
ǡ ܼ̱ܰሺͲǡ ͳሻ 
If there is a stratum for a treatment group that has 0 s 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 and 
Robins.   
The estimated common risk difference, and associated p-value and 2-sided 90 confidence
interval will be tabulated. The stratified strata is based on the baseline abdominal pain score 
which is the average from 7 days immediately prior to the baseline visit.  If more than 10
mis-classification of the stratification factors (randomization stratification vs. actual 
stratification values) happens a sensitivity analysis will be carried out to repeat the primary 
analysis where the actual stratification will be used in the model (See Section 6.1.2).  
The number and percentage of responders with 30 improvement over Weeks 1-2, Weeks 1-
4, Weeks 1-8 and Weeks 1-12 will be summarized by treatment. The proportion of subjects 
who meet the Weekly responder criteria at each week will be plotted by treatment.  
To assess the impact of missing data, a categorical summary of missing pain and bowel 
movement diary day entries, summarized by week, will be provided with the categories of  
none, 1-2, > 2 days, >3.  The denominator used for the percentages will be the number of 
subjects who completed diaries for the given week. 
6.1.2. 
Sensitivity Analysis  
The following sensitivity analyses will be performed: 
6.1.2.1 API weekly responder 30 improvement from Week 1 through Week 12 using 
PPS-D 
The treatment comparison of proportion of IBS-D subjects who are API weekly responders 
with 30 improvement from Week 1 through Week 12 will be performed using CMH 
described in the primary analysis based on the PPS.  
6.1.2.2 API weekly responder 30 improvement from Week 1 through Week 12 using 
Logistic Regression 
In addition, Logistic regression will be used as a sensitivity analysis to analyze the API weekly 
responder with 30 improvement over Weeks 1-12 based on the FAS but will be considered 


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exploratory. Responder proportion over Weeks 1-12 will be modeled using treatment and baseline 
abdominal pain ( 6 vs. 6) strata per randomization stratification fixed effects. A summary 
table will present the estimated incidence for each treatment along with the odds ratio, and 
associated corresponding 90 CI and p-value for the treatment comparison. Wald statistics and 
Wald confidence limits from SAS PROC LOGISTIC will be used for the test and the construction 
of 90 CI.  
An example of the SAS code for the base procedure is given below if responder is assigned to 
1 and no-responder is assigned to 0. 
6.1.2.3 API weekly responder accounting for the use of rescue medication  
Additionally, a sensitivity analysis of the primary analysis will be performed to assess the 
impact of subjects receiving rescue medications for pain where subject’s diary will be 
considered non-evaluable on the days that they received rescue medications.  This analysis 
approach will also be performed in FAS-D to assess the treatment comparison of API weekly 
responders 40 and 50 improvement, respectively. 
6.1.2.4 API weekly responder based on actual randomization 
The stratified strata is based on the baseline abdominal pain score which is the average from 7 
days immediately prior to the baseline visit.  If more than 10 mis-classification of the 
stratification factors (randomization stratification vs. actual stratification values) happens a 
sensitivity analysis of the primary analysis will be carried out to repeat the primary analysis 
where the actual stratification will be used in the model.  
 
6.1.3. 
Subgroup Analysis 
The CMH estimate of treatment difference for API weekly responder with 30 improvement 
over Weeks 1-12 with will be prepared for each of stratified strata (abdominal pain intensity 
score 6 vs  6) based on the FAS.   
In addition, the proportion of responder will be summarized by the following three subgroups. 
x Age category (40, 40 to 65, 65 years) 
x Race (as recorded in CRF) 
x Subjects randomized prior to 31Dec2019 vs Subjects randomized after 31Dec2019 
x Baseline Bristol Stool Scale ( 5.5 vs  5.5) 


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6.2. 
Secondary Efficacy Analyses  
The secondary efficacy endpoint GIS responder at Week 12 is defined in Section 4.3.1.  The 
proportion of responders will be analyzed similarly as described for primary endpoints using 
CMH for IBS-D and IBS_M subjects. When all subjects are included for the analysis, 
additional IBS subtype (IBS-D vs. IBSM will be used for stratification as well.  The number 
and percentage of responder and non-responder for IBS-D, IBS-M and all IBS subjects will be 
tabulated by treatment and visit. GIS response data will be listed.  
The secondary efficacy endpoints of proportion of IBS-D subjects who are API weekly 
responders with 40 improvement and API weekly responders with 50 improvement from 
Week 1 through Week 12 are defined in the Section 4.3.1.  The similar statistical analyses 
described in primary efficacy endpoint will be performed for these API weekly responders 
including subgroup analysis. 
The secondary efficacy analyses will be primarily based on the FAS, unless stated otherwise.  
6.3. 
Exploratory Efficacy Analysis 


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7. 
SAFETY ANALYSIS 
The SAF will be used for all safety analyses. Safety will be assessed on the basis of extent of 
exposure and compliance, AE reports, clinical laboratory data, ECGs, physical examinations, 
and vital signs. 
No inferential statistical testing is planned on the safety data, all data will be descriptively 
summarized by treatment and visit.  
7.1. 
Extent of Exposure 
The duration of exposure during the double-blind treatment period will be expressed as the 
time in days from the first dose as recorded on the Study Drug Administration CRF page at 
Visit 3 through to last treatment day (inclusive) as recorded on the End of Treatment CRF 


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page, excluding any days where it is recorded that an interruptions has occurred on the AE 
CRF page and as indicated on the COVID19 CRF page.  
Interruption in days = date started – date stopped + 1  
This is given by the following formula: 
ܦݑݎܽݐ݅݋݊ (݀ܽݕݏ) = ݀ܽݐ݁ ݈ܽݏݐ ݀݋ݑܾ݈݁ ܾ݈݅݊݀ ݀݋ݏ݁ í ݀ܽݐ݁ ݂݅ݎݏݐ ݀݋ݑܾ݈݁ ܾ݈݅݊݀ ݀݋ݏ݁ –     
                                interruption days + 1 
Duration of exposure will be summarized by treatment group for the SAF using summary 
statistics for continuous variables. The proportion of subjects with Dose Interruptions  2
weeks (14 consecutive days) will be summarized by treatment group, if applicable.   
A listing will present the treatment start and end date together with the date of interruption, and 
the overall days of exposure. 
7.2. 
Treatment Compliance 
Study treatment compliance () will be calculated as the actual number of doses divided by 
the expected number of doses, multiplied by 100 and summarized by treatment group for 
double-blind treatment period 
These numbers will be determined by the number of tablets dispensed and returned unused by 
the subject. Where no treatment bottle is returned, and thus the actual number of doses is 
unknown, it will be assumed that the subject took all medication available in the bottle. The 
overall compliance will be calculated for double-blind treatment period, respectively.  
ܱݒ݁ݎ݈݈ܽܥ݋݉݌݈݅ܽ݊ܿ݁ሺΨሻൌ
ܰݑܾ݉݁ݎ݋݂ݐ݋ݐ݈ܽݐܾ݈ܽ݁ݐݏݐܽ݇݁݊
ܶܽݎ݃݁ݐ݊ݑܾ݉݁ݎ݋݂ݐ݋ݐ݈ܽݐܾ݈ܽ݁ݐݏ݀݅ݏ݌݁݊ݏ݁݀ ൈͳͲͲΨ 
The number of tablets taken is obtained by: (no. dispensed – no. returned). The target number of 
tablets to be taken is calculated as: (last dose date – first dose date – drug interruption in days + 
1). Partial dates will be imputed if the day of the month is missing as described in section 4.2.3.  
However, if month and/or year are missing for the date of last dose then date of last dose will be 
assigned the study discontinuation date. Treatment Compliance will be summarized by treatment 
group and overall for the SAF population. Additionally, the number and percentage of subjects 
within each treatment with compliance in the following categories will be provided: 80, 80 – 
120, and >120.  A listing will present compliance data, including bottle number of tablets 
dispensed, returned, and dispensed and returned dates and overall compliance.  
7.3. 
Adverse Events 
AEs will be coded using MedDRA version 23.0. or later. 


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All reported AEs (whether treatment emergent or not) will be included in by-subject AE 
listings. Sorting will be by treatment subject, date of event, SOC, PT and then verbatim 
description. 
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 14 days after the last dose of study 
treatment. Partial AE start dates will be imputed as detailed in Section 4.2.2 
Summary tables will be based on TEAEs. The incidence of TEAEs will be presented using 
counts and percentages of subjects 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 subjects overall. If a subject has multiple occurrences (start and 
stop) of an event associated with a specific SOC or PT within a SOC, a subject 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 subjects, and number of events for the following categories: 
x At least one TEAE; 
x At least one Treatment-Related TEAE; 
x At least one Grade  3 TEAE (Mild = Grade 1, Moderate = Grade 2, Severe = 
Grade 3,      
     Life-Threatening = Grade 4, Death = Grade 5) 
x At least one Grade  3 Treatment-Related TEAE; 
x At least one Serious TEAE; 
x At least one Serious Treatment-Related TEAE; 
x At least one TEAE leading to Discontinuation from Study Medication; 
x At least one TEAE of Special Interest; 
x At least one Treatment-Related TEAE of Special Interest 
Except for all TEAEs which will be summarized by SOC and PT, the incidence of all other 
TEAEs by PT will be presented for the following  
x All TEAEs by SOC and PT;  
x Treatment-related TEAEs (i.e., possibly or probably related); 
x All TEAEs by PT, and maximum severity (where the maximum intensity per 
subject will be counted at each level of summarization);  
x TEAES with Grade  3; 


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x Treatment-related TEAES with Grade  3; 
x Serious TEAEs; 
x Treatment-related serious TEAEs; 
x Fatal TEAE; 
x TEAEs leading to discontinuation from study treatment; 
x TEAE of Special Interest; 
x Treatment-related TEAE of Special Interest; 
x Non-fatal serious TEAE; 
x Hypertension TEAEs by Pre-existing Hypertension (Yes vs No) and Baseline 
Hypertension (Yes vs. No). Hypertension TEAEs will be selected using the same 
list of preferred terms as specified in Section 5.2. 
x All TEAEs by PT occurring in at least 2 of subjects in the vibegron arm and
greater than the placebo arm will be created and sorted by descending frequency in 
the vibegron arm. 
x Gastrointestinal/IBS-related TEAEs by PT will be prepared and sorted by 
descending frequency in the vibegron arm. The final list of GI/IBS-related PT will 
be finalized and documented prior to database lock.  
Adverse events of special interest for this study include:  
x Adverse events suggestive of cystitis or urinary tract infection (UTI)  
x Potential major cardiac and cerebrovascular events, including all cause death,         
      myocardial infarction, cerebrovascular accident, hospitalization for unstable angina or    
      chest pain, hospitalization for heart failure and coronary    
      revascularization/angioplasty/stent  
x Hypertension 
x AEs consistent with orthostatic hypotension as confirmed by orthostatic vital signs 
x Elevated serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT)  
      lab value requiring that study drug be temporarily withheld or permanently   
     discontinued  
Overall AE listing will include the treatment arm, start and stop dates/times of the AE, first 
dose and last dose dates/times of double-blind treatment and days on study relative to the day 
of first dose and last dose of double-blind study treatment. In addition, the listing will indicate 
if the AE is treatment emergent (Yes vs No), an AE is of Special Interest (Yes vs No) and 
include the onset period (See Section 4.2.4.1 for the definition of the periods).  


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A Treatment related AE is defined as an AE for which the investigator classifies the AE as 
being “Probably Related” or “Possibly Related” to study treatment on Adverse Event CRF. 
Missing relationship and severity (intensity) will be imputed per Section 4.2.2. 
The following additional listings will be provided: 
x Listing of deaths 
x Listing of Serious TEAEs 
x Listing of treatment-emergent AESIs 
x Listing of TEAEs leading to withdrawal or Interruption of study treatment 
7.4. 
Laboratory Evaluations 
The Clinical Laboratory Tests are the following: 
Hematology 
Chemistry 
Urine Dipstick/ 
Urinalysisa 
Other 
Hematocrit 
Hemoglobin 
Platelet count 
WBC (total and 
differential) 
RBC 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bicarbonate 
Calcium 
Chloride 
Creatininee 
FSH 
Glucose 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubinf 
Blood urea nitrogen 
Total cholesterol 
Blood 
Glucose 
Protein 
Specific gravity 
Microscopic exam 
pH 
Color 
Urine pregnancy test 
(B-hCG)b 
Serum ȕ-hCGb 
Urine Drug screen 
Fecal calprotectinc,d 
Serum tissue 
transglutaminase 
antibody (IgA)d 
Coagulation 
(INR/PT/APTT)g 
APTT = activated partial thromboplastin time; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; 
ȕ-hCG = ȕíhuman chorionic gonadotropin; INR = international normalized ratio; PT = prothrombin time; RBC = 
red blood cell count; WBC = white blood cell count 
a A sample for urinalysis and urine culture/sensitivity testing will be sent to the laboratory only if the urine 
dipstick performed at the site tests positive for the presence of leukocytes, nitrites, or blood cells. 
b Urine ȕ-hCG will be tested for women of childbearing potential only. If urine ȕ-hCG is positive, a serum ȕ-hCG 
must be performed. 
c Optional at Screening only. 
d Performed at Screening only per inclusion criterion #8. 
e Estimated glomerular filtration rate will be calculated and reported by the central lab. 
f If total bilirubin is elevated above the upper limit of normal. 
g Only upon request from Principal Investigator (if ALT, AST and bilirubin are increased). 
 


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All continuous laboratory parameters will be summarized descriptively by absolute value at 
each visit by treatment group, together with the corresponding changes from baseline. All 
parameters will be summarized in SI units.   For continuous laboratory parameters with values 
that have a qualifier of “” , ” >”, “”, or “”  than a limit of quantification will be set to the 
quantification value (e.g. 0.03 will be set to 0.03).  
The number and percentage of subjects with laboratory measurements outside of the central 
laboratory normal range will also be summarized by treatment group and visit. Shift tables 
from baseline to maximum post-baseline value, to minimum post-baseline value, last post-
baseline value, and at each post-baseline visit will be provided for hematology and chemistry 
parameters to display low, normal, high, and missing values by treatment group in a 3-by-3 
contingency table. Denominators for percentages will be the number of subjects with non-
missing data at the specific assessment and baseline. 
Maximum post-baseline total bilirubin will be presented (2 and 2 x ULN) and plotted
against maximum post-baseline ALT (3, 3 - 5, 5-10, and 10 x ULN), expressed as
multiples of ULN. This will be repeated to show maximum post-baseline total bilirubin against 
maximum post-baseline AST. 
Data for subjects, who may potentially meet Hy’s law, with ALT or AST 3 x ULN, and
bilirubin 2 x ULN will be presented, which will include all visits for this subset of subjects. A
line plot of liver biochemistry test results (including ALP, ALT, AST, total bilirubin, and 
GGT) over time will also be presented for this subset of subjects. 
Urinalysis was performed at the central laboratory and the urine cultures were analyzed by 
local laboratories.  A sample for the urinalysis and urine culture were assessed only if the urine 
dipstick performed at the site tests positive for the presence of leukocytes, nitrites, or blood 
cells. Urinalysis data will be summarized for each visit for both categorical and numeric 
results. 
Any data outside the central laboratory normal reference ranges will be explicitly noted on the 
listings that are produced.  
7.5. 
Vital Signs 
Vital sign data including blood pressure, pulse rate and body temperature will be collected at 
all study visits except for the safety telephone follow-up visit. Body weight will be measured at 
Screening, baseline visit and Week 12 and Height will be measured at Screening only. Blood 
pressure and pulse will be measured in triplicate at each visit. The average of triplicates will be 
used for summary.  
For all parameters, absolute values and change from baseline will be presented for scheduled 
visits using descriptive statistics for continuous variables. In addition, the maximum post-
baseline, change from baseline to the maximum post-baseline, and change from baseline to the 
end of treatment will be summarized for each of the vital signs. 


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To further investigate changes in SBP/DBP/pulse rate from baseline, the following tables will 
be prepared:  
x Counts and percent of subjects in each group with at least a 5/10/15 CFB at 3 
consecutive post-baseline visits and at Week 12 will be produced for all subjects, by 
pre-existing hypertension category (Yes/No) and by baseline hypertension category 
(Yes/No).  If the percentage of subjects in a subgroup is less than 25 of the total
population, the subgroup in question will be not included in summary 
x CFB in Maximum post-baseline (including 95 CI of Mean) 
A by-subject listing, sorted by subject identifier, will be presented including all vital sign 
results (scheduled or unscheduled). 
7.6. 
ECG 
12-Lead ECG data will be collected at the screening visit only. All data collected will be listed. 
7.7. 
Physical Examination 
Brief physical examination data will be collected at Screening, Baseline, Week 12. Shift tables 
(normal, abnormal, not done) of baseline versus the last observation post-baseline [normal, 
abnormal (same as baseline), abnormal (new or aggravated), not done] may be generated, 
presenting the assessment for each component of the physical examination separately. Listing 
of abnormal results will be produced.  
8. 
COVID-19 CONSIDERATIONS 
This study was conducted during the COVID-19 global pandemic.  During the time period of 
the pandemic, it is anticipated that changes in study visit schedules, missed visits, or subject 
discontinuations may lead to missing information (e.g., for protocol-specified procedures). In 
accordance with the FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency, it is important to capture specific information in the case 
report form that explains the basis of the missing data, including the relationship to COVID-19 for 
missing protocol-specified information (e.g., from missed study visits or study discontinuations due 
to COVID-19).  
 
The proportion of subjects with COVID-19 impact on visits will be summarized by treatment 
group overall and by visit for the FAS, FAS-D and FAS-M populations.  The type of impact 
(e.g., visit cancelled, visit postponed, etc.) and the reason (e.g. subject acquired COVID-19, 
Subject unable to travel due to COVID-19, investigative site closure due to COVID-19, etc.) 
will also be summarized. A listing based on all subjects who had COVID-19 information 
collected will be generated which will document the visit impacted, type of impact, reason, 
date of contact of any telephone visits (if applicable), and if any doses were missed due to IP 


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unavailability. Protocol deviations associated with COVID-19, identified with a “#COVID” in 
the protocol description,  will also be included in the listing.   
9. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
In Section 1.1.3, the other efficacy endpoint of the “Change from baseline to Weeks 2, 4, 8, 
and 12 in average weekly number of days of abdominal pain within 1 hour of eating for all IBS 
subjects including IBS-D and IBS-M subjects” was changed to  “Change from baseline to 
weeks 2,4,8, and 12 in pain within 1 hour of eating for all IBS subjects including IBS-D and 
IBS-M subjects” since the data was collected as Yes or No to the following question, “In the 
past 7 days, did you experience abdominal pain within 1 hour of eating”.  The data will be 
summarized by visit as the proportion of subjects who improved vs not improved (no change, 
worsened, or missing post-baseline assessment). 
 
Similarly, in Section 1.1.3, the “Change from baseline to weeks 2, 4, 8 and 12 in the weekly 
number of days with pain associated with a bowel movement” was changed to “Change from 
baseline to weeks 2, 4, 8 and 12 in pain associated with a bowel movement”. 
 
The following additional exploratory analyses will be conducted (See Section 4.3.1.11): 
10. 
REFERENCES 
[1] Kelleher DL, Hicks KJ, Cox DS, Williamson RR, Alpers DH, and Dukes GE. Randomized 
     double-blind, placebo (PLA)-controlled, crossover study to evaluate efficacy and safety of    
     the beta 3-adrenergic receptor agonist solabegron in subjects with irritable bowel syndrome. 
     Neurogastroenterol Motil. 2008;20(Suppl 1):131.   
[2] D. L. Patrick, D. A. Drossman, I. O. Frederick, J. DiCesare, and K. L. Puder, “Quality of 
life in persons with irritable bowel syndrome: development and validation of a new 
measure,” Dig. Dis. Sci., vol. 43, no. 2, pp. 400–411, Feb. 1998. 
[3] “Information Sheet on the Irritable Bowel Syndrome-Quality of Life Measure (IBS-
QOL).” [Online]. Available: http://depts.washington.edu/seaqol/docs/IBS-QOL_Info.pdf. 
[4] “WPAI:SHP V2.0.” [Online]. Available: http://www.reillyassociates.net/WPAI_SHP.html. 
[5] “WPAI Scoring.” [Online]. Available: 
http://www.reillyassociates.net/WPAI_Scoring.html. 
[6] S. Greenland and J. M. Robins, “Estimation of a Common Effect Parameter from Sparse 
Follow-Up Data,” Biometrics, vol. 41, no. 1, p. 55, Mar. 1985. 
[7] D. B. Rubin, Multiple imputation for nonresponse in surveys. New York: Wiley, 1987. 


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[8] “Guideline on adjustment for baseline covariates in clinical trials.” EMA, 26-Feb-2015. 
[9] "Guidance for Industry for Irritable Bowel Syndrome - Clinical Evaluation of Drugs for      
       Treatment." FDA, May-2012 
[10] Patrick DL, Drossman DA, Frederick IO, et al. Quality of life in persons with irritable     
       bowel syndrome: Development of a new measure. Dig Dis Sci 1998;43:400–11 
[11] Chunlei Ke, Jianming Wang, Charlie Zhang, Qi Jiang & Steven Snapinn 
      (2017): On Errors in Stratified Randomization, Statistics in Biopharmaceutical Research,    
       DOI:10.1080/19466315.2016.1270229  


 
 
11. 
APPENDIX 
11.1. 
Table of Contents for Data Display Specifications 
11.1.1. 
Output Tables 
Table 8: 
List of Output Tables  
Title 
Analysis Set 
 
Programming Note 
Deliverable 
 
Study Population  
14.1.1.1 
Subject Enrollment -All Subjects 
Screened  
Include screening and run-in. The 
percentages within the run-in 
should be based on the number of 
subjects who entered the run-in. 
EOS 
14.1.1.2.1 
Subjects by Population and Subject Disposition  
Randomized 
 
TL, EOS 
14.1.1.2.2-
14.1.1.2.4 
Subjects by Population and Subject Disposition 
FAS-D/FAS-
M/FAS 
 
TL. EOS 
14.1.1.3 
Subject Randomization by US Investigator 
Randomized 
 
EOS 
14.1.2.1.1-
14.1.2.1.3 
 Major Protocol Deviations  
FAS-D/FAS-
M/FAS 
 
EOS 
14.1.2.2.1-
14.1.2.2.3 
Reasons for Exclusion from Analysis  
FAS-D/FAS-
M/FAS 
 
EOS 
14.1.3.1 
Demographics and Baseline Characteristics  
FAS 
Race presented in descending 
frequency 
TL, EOS 
14.1.3.2 
Demographics and Baseline Characteristics – IBS-D Subjects 
FAS-D 
Race presented in descending 
frequency 
TL, EOS 
14.1.3.3 
Demographics and Baseline Characteristics – IBS-M Subjects 
FAS-M 
Race presented in descending 
frequency 
TL, EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.1.3.4 
Demographics and Baseline Characteristics – IBS-D Subjects 
PPS-D 
Race presented in descending 
frequency 
EOS 
14.1.3.5 
IBS Baseline Characteristics  
FAS 
 
TL, EOS 
14.1.3.6 
IBS Baseline Characteristics – IBS-D Subjects 
FAS-D 
 
TL, EOS 
14.1.3.7 
IBS Baseline Characteristics – IBS-M Subjects 
FAS-M 
 
TL, EOS 
14.1.3.8 
Demographics and Baseline Characteristics  
Randomized 
 
EOS 
14.1.4.1 
Medical History 
FAS 
 
EOS 
14.1.4.2 
Medical History 
SAF 
 
EOS 
14.1.5.1 
Prior Non-IBS Medication  
FAS 
ATC Level 2 and 4 
EOS 
14.1.5.2 
Prior IBS Medication  
FAS 
ATC Levels 2, 4 and PT  
EOS 
14.1.5.3 
Non-Rescue Concomitant Medication  
FAS 
ATC Level 2 and 4 
EOS 
14.1.5.4 
Rescue Concomitant Medication  
FAS 
ATC Levels 2, 4 and PT 
EOS 
14.1.5.5 
Additional Rescue Medication Data in Double-Blinded 
Treatment Period 
FAS 
Additional questions in CM form 
under ATC Levels 2 
 EOS 
14.1.5.6 
Prior IBS Medication  
SAF 
 
EOS 
14.1.5.7 
Non-Rescue Concomitant Medication  
SAF 
 
 EOS 
14.1.6.1-
14.1.6.3 
COVID-19 Impact 
FAS-D/FAS-
M/FAS 
 
EOS 
Efficacy Endpoints  
 
 
 
14.2.1.1 
API Weekly Responder Primary Analysis (CMH): 30
Improvement) – IBS-D Subjects 
FAS-D 
Include all intervals but over 
Weeks 1-12 in the front  
TL, EOS 
14.2.1.2 
API Weekly Responder Primary Analysis (CMH): 30
Improvement) – IBS-D Subjects 
PPS-D 
Include all intervals but over 
Weeks 1-12 in the front  
EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.2.1.3.1 
API Weekly Responder over Weeks 1-12: 30 Improvement
Sensitivity Analysis (Logistic Regression) – IBS-D Subjects 
FAS-D 
 
 EOS 
14.2.1.3.2 
FAS-D 
Include all intervals but over 
Weeks 1-12 in the front; The 
subject is considered a non-
responder for the days receiving 
pain medication 
EOS 
14.2.1.4 
API Weekly Responder Analysis (CMH): 40 Improvement– 
IBS-D Subjects 
FAS-D 
Include all intervals but over 
Weeks 1-12 in the front  
TL, EOS 
14.2.1.5 
FAS-D 
Include all intervals but over 
Weeks 1-12 in the front; The 
subject is considered a non-
responder for the days receiving 
pain medication 
EOS 
14.2.1.6 
API Weekly Responder Analysis (CMH): 50 Improvement– 
IBS-D Subjects 
FAS-D 
Include all intervals but over 
Weeks 1-12 in the front  
TL, EOS 
14.2.1.7 
FAS-D 
Include all intervals but over 
Weeks 1-12 in the front; The 
subject is considered a non-
responder for the days receiving 
pain medication 
EOS 
14.2.1.8 
API Weekly Responder Analysis (CMH):  30 Improvement
-IBS-M Subjects 
FAS-M 
 
TL, EOS 
14.2.1.9 – 
14.2.1.10 
FAS-M 
 
EOS 
14.2.1.11 
API Weekly Responder Analysis (CMH):  30 Improvement 
-IBS All Subjects 
FAS 
 
TL, EOS 
14.2.1.12 – 
14.2.1.13 
API Weekly Responder Analysis (CMH):  40/50
Improvement -IBS All Subjects 
FAS 
 
EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.2.1.14 – 
14.2.1.16 
 API Weekly Responder over Weeks 1-12 Subgroup Analysis 
by API Strata (CMH):  30/40/50 Improvement – IBS-D 
Subjects 
FAS-D 
Percentages are based on the n 
within each subgroup 
EOS 
14.2.1.17 
API Weekly Responder  30/40/50 Improvement over
Weeks 1-12 by Subgroup 
FAS 
Descriptive summary. Subgroups 
are listed under SAP subgroup 
section; include three thresholds  
EOS 
14.2.2.1  
Global Improvement Scale Responder Analysis (CMH) – IBS-
D Subjects 
FAS-D 
Include all Weeks but Week 12 in 
the front. Include a footnote, “A 
responder is defined as a subject 
who answered that their symptoms 
were either moderately relieved or 
significantly relieved." 
TL, EOS 
14.2.2.3 
Global Improvement Scale Responder Analysis (CMH) – IBS-
M Subjects 
FAS-M 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.2.4 
Global Improvement Scale Responder Analysis (CMH) –All 
Subjects 
FAS 
Include all Weeks but Week 12 in 
the front 
 EOS 
14.2.2.5 
Shift Table of Global Improvement Scale from Baseline   - 
IBS-D Subjects 
FAS-D 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.2.6 
Shift Table of Global Improvement Scale from Baseline – IBS-
M Subjects 
FAS-M 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.2.7 
Shift Table of Global Improvement Scale from Baseline – IBS-
M Subjects 
FAS 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.3.1 – 
14.2.3.3 
Change from Baseline in Weekly Average Worst Abdominal 
Pain Score (MMRM) – IBS-D/IBS-M/All Subjects 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
TL, EOS 
14.2.3.4 
Change from Baseline in Weekly Average Worst Abdominal 
Pain Score 
FAS 
Place IBS-D, IBS-M and All IBS 
on the column and treatment arm 
underneath IBS columns 
EOS 
14.2.4.1 – 
14.2.4.3 
Change from Baseline in Weekly Average of Number of Pain 
Free Day (MMRM) – IBS-D/IBS-M/All Subjects 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.2.4.4 
Change from Baseline in Weekly Average of Number of Pain 
Free Day 
 
Table 14.2.3.4 
 EOS 
14.2.5.1 – 
14.2.5.3 
Change from Baseline in Abdominal Pain Within 1 Hour of 
Eating  – IBS-D/IBS-M/All Subjects 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.5.4 
Change from Baseline in Abdominal Pain Within 1 Hour of 
Eating  
FAS 
Table 14.2.3.4 but showing 
proportion of subjects Improved vs 
Not Improved (No Change, 
Worsened, Missing Post-baseline 
Assessment) 
EOS 
14.2.6.1 – 
14.2.6.3 
Change from Baseline in Abdominal Pain Associated with a 
Bowel Movement – IBS-D/IBS-M/All Subjects 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
 EOS 
14.2.6.4 
Change from Baseline in Abdominal Pain Associated with a 
Bowel Movement 
FAS 
Table 14.2.3.4 but showing 
proportion of subjects Improved vs 
Not Improved (No Change, 
Worsened, Missing Post-baseline 
Assessment) 
EOS 
14.2.7.1 – 
14.2.7.3 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.7.4 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
 EOS 
14.2.8.1 – 
14.2.8.3 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
 EOS 
14.2.8.4 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
EOS 
14.2.9.1 – 
14.2.9.3 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.9.4 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
 EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.2.10.1 – 
14.2.10.3 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
 EOS 
14.2.10.4 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
EOS 
14.2.11.1 – 
14.2.11.3 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.11.4 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
 EOS 
14.2.12.1  
FAS-D 
Include all intervals but Week 1-12 
in the front 
 EOS 
14.2.14.1  
FAS-D 
Include all Weeks but Week 12 in 
the front 
 EOS 
14.2.14.2 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
 EOS 
14.2.15.1  
FAS-D 
Include all Weeks but Week 12 in 
the front 
EOS 
14.2.15.2 
FAS 
Table 14.2.3.4 
EOS 
14.2.16.1  
FAS-D 
Include all Weeks but Week 12 in 
the front 
 EOS 
14.2.16.2 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
 EOS 
14.2.17.1.1 
– 
14.2.17.3.1 
FAS-D/FAS-
M/FAS 
Include all intervals, but over 
Weeks 1-12 in the front 
EOS 
14.2.17.1.2-
14.2.17.3.2 
FAS-D/FAS-
M/FAS 
Include all intervals, but over 
Weeks 1-12 in the front 
EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.2.18.1 – 
14.2.18.3 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
Include all 4 domains 
EOS 
14.2.18.4 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
 EOS 
14.2.19.1 – 
14.2.19.3 
FAS-D/FAS-
M/FAS 
Include all Weeks but Week 12 in 
the front 
 EOS 
14.2.19.4 – 
14.2.19.6 
FAS-D/FAS-
M/FAS 
Include 8 domains; Include all 
Weeks but Week 12 in the front 
EOS 
14.2.19.7 – 
14.2.19 .9      
FAS-D/FAS-
M/FAS 
Include Week 12 first 
EOS 
14.2.19.10 
FAS 
Table 14.2.3.4; Include all Weeks 
but Week 12 in the front 
immediately following Baseline 
 EOS 
14.2.19.11 
FAS 
Similar to Table 14.2.3.4 but 
showing proportion of subjects 
who responded 
EOS 
14.2.20.1-
14.2.20.3 
FAS-D/FAS-
M/FAS 
 
TL, EOS 
14.2.20.4-
14.2.20.6 
FAS-D/FAS-
M/FAS 
 
 EOS 
14.2.20.7-
14.2.20.9 
FAS-D/FAS-
M/FAS 
 
EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.2.21.1-
14.2.21.3 
FAS-D/FAS-
M/FAS 
 
TL, EOS 
14.2.21.4-
14.2.21.6 
FAS-D/FAS-
M/FAS 
 
EOS 
14.2.21.7-
14.2.21.9 
FAS-D/FAS-
M/FAS 
 
EOS 
14.2.22.1-
14.2.22.3 
FAS-D/FAS-
M/FAS 
 
TL, EOS 
14.2.22.4-
14.2.22.6 
FAS-D/FAS-
M/FAS 
 
EOS 
14.2.22.7-
14.2.22.9 
FAS-D/FAS-
M/FAS 
 
EOS 
14.2.23.1-
14.2.23.3 
Missing Diary Days 
FAS-D/FAS-
M/FAS 
 
TL, EOS 
Safety Endpoints 
14.3.1.1 
 Treatment Exposure 
SAF 
 
EOS 
14.3.1.2 
 Treatment Compliance 
SAF 
 
 EOS 
14.3.1.3 
Treatment Exposure 
All Subjects 
To capture the subject with a 
dosing error during run-in 
 
Adverse Events 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.3.2.1 
 Overall Treatment-Emergent Adverse Events 
SAF 
Include the AESI categories as 
subcategories 
TL, EOS 
14.3.2.2 
Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
SAF 
 
EOS 
14.3.2.3 
Treatment-related TEAEs by Preferred Term 
SAF 
 
EOS 
14.3.2.4 
Treatment-Emergent Adverse Events by Preferred Term and 
Maximum Intensity 
SAF 
 
EOS 
14.3.2.5 
Treatment-Emergent Adverse Events Occurring in  2
Subjects of Vibegron Arm and Greater Than the Placebo by 
Preferred Term 
SAF 
 
EOS 
14.3.2.6 
Treatment-Emergent Adverse Events with Grade  3 by
Preferred Term 
SAF 
 
TL, EOS 
14.3.2.7 
Treatment-related TEAEs with Grade  3 by Preferred Term  
SAF 
 
EOS 
14.3.2.8 
Serious TEAEs by Preferred Term 
SAF 
 
EOS 
14.3.2.9 
Treatment-related Serious TEAEs by Preferred Term 
SAF 
 
EOS 
14.3.2.10 
 Fatal TEAEs by Preferred Term 
SAF 
 
EOS 
14.3.2.11 
 TEAEs Leading to Treatment Discontinuation by Preferred 
Term  
SAF 
 
TL, EOS 
14.3.2.12 
TEAEs of Special Interest by Preferred Term 
SAF 
 
EOS 
14.3.2.13 
Treatment-related TEAEs of Special Interest by Preferred 
Term 
SAF 
 
TL, EOS 
14.3.2.14 
Non-Fatal Serious TEAEs by Preferred Term 
SAF 
 
EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
14.3.2.15 
Hypertension TEAEs by Preferred Term and Pre-existing 
Hypertension  
SAF 
Search for the following terms 
hypertension PTs: 
Accelerated hypertension, 
Diastolic hypertension, Essential 
hypertension, Hypertension, 
Hypertensive crisis, Hypertensive 
emergency, Hypertensive heart 
disease, Malignant hypertension, 
Malignant hypertensive heart 
disease, Secondary hypertension, 
Supine hypertension, Systolic 
hypertension 
EOS 
14.3.2.16 
Hypertension TEAEs by Preferred Term and Baseline 
Hypertension Status 
SAF 
Search for the following terms 
hypertension PTs: 
Accelerated hypertension, 
Diastolic hypertension, Essential 
hypertension, Hypertension, 
Hypertensive crisis, Hypertensive 
emergency, Hypertensive heart 
disease, Malignant hypertension, 
Malignant hypertensive heart 
disease, Secondary hypertension, 
Supine hypertension, Systolic 
hypertension 
EOS 
14.3.2.17 
GI/IBS-related TEAEs by Preferred Term 
SAF 
 
EOS 
14.3.2.18 
List of Deaths 
SAF 
 
EOS 
14.3.2.19 
Listing of Treatment Emergent Serious TEAEs 
SAF 
 
EOS 
14.3.2.20 
Listing TEAEs Leading to Withdrawal or Interruption of Study 
Treatment 
SAF 
 
EOS 
14.3.2.21 
Listing of TEAEs of Special Interest 
SAF 
 
EOS 


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Title 
Analysis Set 
 
Programming Note 
Deliverable 
Laboratory data 
14.3.3.1 
Hematology Laboratory Parameters 
SAF 
Include observed and CFB; include 
conventional units as well for 
hematocrit 
EOS 
14.3.3.2 
Abnormal Classification of Hematology Laboratory Parameters 
SAF 
 
EOS 
14.3.3.3 
Shift Table of L/N/H Classification for Hematology Laboratory 
Parameters from Baseline  
SAF 
Include max/min post-dose, by 
visit, last-post dose  
EOS 
14.3.3.4 
Clinical Chemistry Laboratory Parameters 
SAF 
Include observed and CFB 
EOS 
14.3.3.5 
Abnormal Classification of Clinical Chemistry Laboratory 
Parameters 
SAF 
 
EOS 
14.3.3.6 
Shift Table of L/N/H Classification for Clinical Chemistry 
Laboratory Parameters from Baseline  
SAF 
 
EOS 
14.3.3.7 
Maximum Post-baseline ALT and AST vs. Maximum Post-
baseline Bilirubin 
SAF 
 
EOS 
14.3.3.8 
Listing of Subjects Potentially Met Hy’s Law 
SAF 
 
EOS 
 
 
 
 
 
Other Safety 
14.3.4.1 
Vital Sign Parameters 
SAF 
Include all observed and CFB 
EOS 
14.3.4.2 
Vital Sign Parameter Change from Baseline Shifts at 3 
Consecutive Visits 
SAF 
SBP, DBP and PR 
EOS 
14.3.4.3 
Vital Sign Parameter Change from Baseline Shifts at Week 12 
SAF 
 
EOS 
14.3.4.4 
Vital Sign Parameter Maximum Post-Baseline Change from 
Baseline  
SAF 
 
EOS 
14.3.5.1 
Physical Examination Shift from Baseline 
SAF 
 
EOS 
[1] TL= Topline Results (priority delivery after DBL); EOS= End of Study 


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11.1.2. 
Output Figures 
Table 9: 
List of Output Figures  
 
Title 
Population 
 
Programming Note 
Deliverable 
Study Population 
 
 
 
 
 
 
 
14.1.1 
Kaplan Meier Plot of Time to Study Discontinuation 
SAF 
 
EOS 
Efficacy Endpoints 
 
 
 
14.2.1.1 
Forest Plot of Risk Difference Estimates and 90 CI API 
Weekly Responder Analysis over Weeks 1-12 
FAS 
Include all thresholds. Under each 
threshold, list IBS-D, IBS-M and 
All IBS in order 
TL, EOS 
14.2.1.2 
Line Plot of Proportion Subjects Who Met Weekly Responder 
with 30 improvement by Week – IBS-D Subjects 
FAS 
Include all individual weeks.  
EOS 
14.2.1.3 
Line Plot of Proportion Subjects Who Met Weekly Responder 
40 improvement by Week – IBS-D Subjects 
FAS 
Include all individual weeks.  
EOS 
14.2.1.4 
Line Plot of Proportion Subjects Who Met Weekly Responder 
50 improvement by Week – IBS-D Subjects 
FAS 
Include all individual weeks.  
EOS 
14.2.1.5 
Line Plots of LSMEAN (SE) of Change from Baseline in 
Weekly Average Worst Abdominal Pain Score from MMRM – 
IBS-D Subjects 
FAS 
Include Weeks 2, 4, 8 and 12 
EOS 
14.2.1.6 
Line Plots of LSMEAN (SE) of Change from Baseline in 
Weekly Average Worst Abdominal Pain Score from MMRM – 
IBS-M Subjects 
FAS-M 
Include Weeks 2, 4, 8 and 12 
EOS 
14.2.1.7 
Line Plots of LSMEAN (SE) of Change from Baseline in 
Weekly Average Worst Abdominal Pain Score from MMRM – 
FAS Subjects 
FAS 
Include Weeks 2, 4, 8 and 12 
EOS 


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Title 
Population 
 
Programming Note 
Deliverable 
14.2.1.8 
FAS 
Include all thresholds. Under each 
threshold, list IBS-D, IBS-M and 
All IBS in order 
EOS 
14.2.1.9 
Forest Plot of Risk Difference Estimates and 90 CI API 
Weekly Responder AND  50 Increase from Baseline in 
Average Number of Days/Week with BSS Type 6 or 7 over 
Weeks 1-12 
FAS 
Include all thresholds. Under each 
threshold, list IBS-D, IBS-M and 
All IBS in order 
EOS 
14.2.1.10 
FAS 
Include all thresholds. Under each 
threshold, list IBS-D, IBS-M and 
All IBS in order 
EOS 
Safety Endpoints 
 
 
 
14.3.3.1 
Scatter Plot of Maximum Post-Baseline ALT  versus 
Maximum Total Bilirubin Expressed as Multiples of ULN 
SAF 
 
EOS 
14.3.3.2 
Scatter Plot of Maximum Post-Baseline AST  versus Maximum 
Total Bilirubin Expressed as Multiples of ULN 
SAF 
 
EOS 
14.3.3.3 
Line Plot of Liver Chemistry Test Results over Time for 
Subjects with Elevated ALT or AST, and Elevated Total 
Bilirubin at Any Time 
SAF 
Only produce for subjects who 
potentially met Hy’s law 
EOS 
 
11.1.3. 
Output Listings 
Table 8: 
List of Output Listings  
Title 
Population 
        Programming Note 
Deliverable 
Disposition and Demographics 
 
 
 
16.2.1.1 
Subject Disposition for Screen Failures 
Screened 
 
EOS 


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Title 
Population 
        Programming Note 
Deliverable 
16.2.1.2 
Run-In Treatment Administration  
Placebo Run-
In Set 
 
EOS 
16.2.1.3 
Subject Disposition 
Randomized 
 
EOS 
16.2.1.4 
Subjects who did not Satisfy Inclusion/Exclusion Criteria  
Screened 
 
EOS 
16.2.1.5 
Subject Randomization Details 
Randomized 
 
EOS 
16.2.1.6 
Major Protocol Deviations 
Randomized 
 
EOS 
16.2.1.7 
Subject Demographic and Baseline Characteristics 
Randomized 
 
EOS 
16.2.1.8 
Medical History  
Randomized 
 
EOS 
16.2.1.9 
Prior and Concomitant Medications 
Randomized 
 
EOS 
16.2.1.10 
Prior Irritable Bowel Syndrome (IBS) Medications 
Randomized 
 
EOS 
16.2.1.11 
Additional Rescue Concomitant Medication information 
Randomized 
 
EOS 
16.2.1.12 
Subjects with Misclassification of Stratification Factors 
Randomized 
 
EOS 
16.2.1.13 
COVID-19 Impact 
All Subject 
include treatment IBS subtype 
and all the information 
collected on COVID-19 eCRF 
EOS 
Efficacy 
 
 
EOS 
16.2.2.1 
Weekly API Responder  
FAS 
Sort by Treatment, IBS 
Subtype, Subject ID, Baseline 
API Strata, Week 
TL 
16.2.2.2 
Global Improvement Scale Responder Classification 
FAS 
 
EOS 
16.2.2.3 
Derived Parameters from Bowel Movement Diary 
FAS 
Sort by Treatment, IBS 
Subtype, Subject ID, Baseline 
API Strata 
EOS 
16.2.2.4 
Additional Abdominal Pain Questionnaires 
FAS 
 
EOS 
16.2.2.5 
Additional IBS-related Baseline Data 
 
 
 
16.2.2.6 
FAS 
 
EOS 


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Title 
Population 
        Programming Note 
Deliverable 
16.2.2.7 
FAS 
 
EOS 
16.2.2.8 
Missing Diary Days 
FAS 
 
TL 
16.2.2.9 
Cumulative Weekly API Responder 
FAS 
Sort by Treatment, IBS 
Subtype, Subject ID, Baseline 
API Strata 
TL 
16.2.2.10 
FAS 
Sort by Treatment, IBS 
Subtype, Subject ID, Baseline 
API Strata 
TL 
16.2.2.11 
FAS 
Sort by Treatment, IBS 
Subtype, Subject ID, Baseline 
API Strata 
TL 
16.2.2.12 
Cumulative Daily API Responder  
FAS 
Sort by Treatment, IBS 
Subtype, Subject ID, Baseline 
API Strata 
TL 
16.2.2.13 
FAS 
Sort by Treatment, IBS 
Subtype, Subject ID, Baseline 
API Strata 
TL 
Safety  
 
 
 
16.2.3.1.1 
Treatment Exposure and Compliance 
SAF 
 
EOS 
16.2.3.1.2 
Subjects with Compliance > 120 who Were Not Lost to
Follow-Up 
SAF 
To identify any subject with >> 
120 compliance who was not
lost of follow-up 
EOS 
16.2.3.2.1 
Adverse Events 
SAF 
 
EOS 
16.2.3.2.2 
TEAE Serious Adverse Events 
SAF 
Use the vertical format 
EOS 
16.2.3.2.3 
TEAEs of Special Interest  
SAF 
Use the vertical format 
 
16.2.3.3 
Hematology Laboratory Results 
SAF 
 
EOS 
16.2.3.4 
Clinical Chemistry Laboratory Results 
SAF 
 
EOS 
16.2.3.5 
Urinalysis Laboratory Results 
SAF 
 
EOS 


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Title 
Population 
        Programming Note 
Deliverable 
16.2.3.6 
Vital Sign Results 
SAF 
 
EOS 
16.2.3.7 
ECG Results 
SAF 
 
EOS 
16.2.3.8 
Physical Examination 
SAF 
 
EOS 
16.2.3.9 
Other Laboratory Results 
SAF 
 
EOS 
11.2. 
General Information Related to Data Presentation 
The general formats and layouts of tables, listings, and figures (TLFs) are provided in a separate “programming consideration” 
document. Actual formats and layouts may be altered slightly to accommodate actual data or statistics. Minor format changes will 
not require updates to the statistical analysis plan (SAP).  
The TLF numbering and general content follow the ICH E3 guidelines. 
11.3. 
Summary of SAP Changes from v1.0 to v2.0 
 
 
Section 
Change 
#1 
3.1.5 
 
3.1.6 
 
3.2.1 
Modified definition of FAS to be at least one evaluable  post-
baseline weekly API score (i.e.,  where evaluable is considered 
minimum of  4 diary entries in a week).   
Removed an example from the paragraph regarding PPS 
 
Clarified that “significant” and “major” protocol deviations are the 
synonymous. 


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Section 
Change 
#2 
4.1.3 
 
4.3.18 
 
 
 
4.3.4 
Added a subgroup of Baseline Bristol Stool Scale ( 5.5 vs 
5.5) 
Updated baseline definition to be the last recorded value on or 
prior to the date of double-blind treatment start (note date of 
randomization) 
#3 
5.4 
5.5 
Changed the medDRA version to “23.0” or higher  
Added “or later” after “World Health Organization (WHO) 
Drug B3-March Format, 2020 version” in case the dictionary 
version is changed before data base lock 
#4 
7.4 
Clarified to set the value to the limit of quantification only for  
continuous laboratory parameters with values that have a 
qualifier of “” , ” >”, “”, or “”. 
#5 
8 
Added the protocol deviations associated with COVID to the 
listing 


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Section 
Change 
#6 
11.1 
Updated the topline tables 
Added a shift table for GIS 
Added the daily composite responder analysis for IBS-M and 
IBS, respectively 
Removed the Summary of Urinalysis.  The data will be listed 
since it is only available for subjects who had a positive 
dipstick 
Other minor update