Clinical trial NCT04562090
Conditions: Urge Incontinence Overactive Bladder (OAB)
Keywords: mirabegron
Sponsor: Astellas Pharma China, Inc.
Start date: 2021-01-06; Completion date: 2022-03-30
Enrollment: 249 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy of mirabegron for the treatment of overactive bladder (OAB) in Chinese participants. This study also evaluated the safety of mirabegron for the treatment of OAB in Chinese participants, evaluated other efficacy variables of mirabegron for the treatment of OAB and explored different mirabegron starting doses.

Detailed description:
The study followed an open-label, randomized, 12-week, prospective, interventional post-authorization design for the treatment of OAB in 249 Chinese participants. Each eligible participant took part in a 12-week treatment period. Treatments were administered once daily orally after a meal during a 12-week, open-label treatment period. Study visits took place at weeks 4, 8 and 12. For the 25 mg mirabegron group, a dose escalation to 50 mg was permitted on visit 3 and visit 4 at the investigators' discretion. 15 study sites across China enrolled participants.

Arms: arm 1: Participants received single oral dose of Mirabegron 25 milligrams (mg) tablet once daily, at the same time after a meal for a duration of 12 weeks. Dose escalation to 50 mg was permitted at Visit 3 (Week 4) or Visit 4 (Week 8) at the discretion of investigator. arm 2: Participants received single oral dose of Mirabegron 50 mg tablet once daily, at the same time after a meal for a duration of 12 weeks.
Interventions: intervention 1: mirabegron
Intervention descriptions: intervention 1: Mirabegron was administered as single oral dose of 25 mg or 50 mg sustained-release tablet

Protocol documents:
Prot_000.pdf: 
Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 1 of 68 
Version 2.0 
A Phase 4, Open-label, Randomized, Prospective, Interventional 
Post-authorization Efficacy and Safety Study of Mirabegron 
50 mg and 25 mg for the Treatment of Overactive Bladder in 
Chinese Subjects 
Open-label Phase 4 Study with Mirabegron 50 mg and 25 mg in Chinese Subjects with 
Overactive Bladder 
 
ISN/Protocol 178-MA-2295 
Version 2.0 
 22Mar2021 
 
 
 
Sponsor: 
Astellas Pharma China, Inc. 
No 3 Jia 6 Road 10 
Shenyang Economic and Technological Development Zone, 
Shenyang 110027 China 
 
 
 
 
 
 
 
 
 
 
The information contained in this document is supplied as a background for clinical investigations.  This document contains 
confidential information, which is the intellectual property of Astellas.  By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research subject; and (4) where disclosure of such information is made to a member of the investigator’s team 
who agrees to hold this information in confidence. 
 


Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
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Version 2.0 
Table of Contents 
SIGNATURES ································································································ 7 
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ······································ 9 
1 
PROTOCOL SUMMARY ······································································· 10 
1.1 
Synopsis ························································································ 10 
1.2 
Study Schema ·················································································· 12 
1.3 
Schedule of Assessments ····································································· 13 
2 
INTRODUCTION ················································································· 15 
2.1 
Study Rationale ················································································ 15 
2.2 
Background ···················································································· 15 
2.3 
Risk/Benefit Assessment ····································································· 17 
2.3.1 
Risk Assessment ········································································· 17 
2.3.2 
Benefit Assessment ····································································· 18 
2.3.3 
Overall Risk-Benefit Conclusion ······················································ 18 
3 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ········································· 18 
4 
STUDY DESIGN AND DOSE RATIONALE ················································ 19 
4.1 
Overall Study Design ········································································· 19 
4.2 
Scientific Rationale for Study Design ······················································ 20 
4.3 
Dose Rationale ················································································ 20 
4.4 
End of Study Definition ······································································ 21 
5 
STUDY POPULATION ·········································································· 21 
5.1 
Inclusion Criteria ·············································································· 21 
5.2 
Exclusion Criteria ············································································· 22 
5.3 
Lifestyle Considerations ······································································ 24 
5.4 
Screen Failures ················································································ 24 
5.4.1 
Rescreening ·············································································· 24 
6 
INVESTIGATIONAL PRODUCT(S) ························································· 24 
6.1 
Investigational Product(s) Administered ··················································· 24 
6.2 
Preparation/Handling/Storage/Accountability ············································· 25 
6.2.1 
Packaging and Labeling ································································ 25 
6.2.2 
Handling, Storage and Accountability ················································ 25 
6.3 
Randomization and Blinding ································································ 26 


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6.3.1 
Blinding Method ········································································· 26 
6.3.2 
Assignment and Allocation····························································· 26 
6.3.2.1 
Subject Number ···································································· 26 
6.3.2.2 
Randomization Number ··························································· 26 
6.3.2.3 
Subject Replacement ······························································ 26 
6.4 
Investigational Product Compliance ························································ 26 
6.5 
Dose Modification ············································································ 26 
6.6 
Continued Access to Investigational Product After the End of the Study ·············· 26 
6.7 
Treatment of Overdose ······································································· 27 
6.8 
Concomitant Therapy ········································································· 27 
7 
STUDY PROCEDURES AND ASSESSMENTS ············································ 27 
7.1 
Efficacy Assessments ········································································· 28 
7.1.1 
Bladder e-Diary ·········································································· 28 
7.2 
Safety Assessments ··········································································· 28 
7.2.1 
Laboratory Assessments ································································ 28 
7.2.2 
Vital Signs ················································································ 29 
7.2.3 
Physical Examination ··································································· 29 
7.2.4 
Electrocardiogram ······································································· 29 
7.2.5 
Post Void Residual Volume Assessments ············································ 30 
7.2.6 
Overactive Bladder Symptom Score ·················································· 30 
7.2.7 
Order of Assessments ··································································· 30 
7.3 
Adverse Events and Other Safety Aspects ················································· 30 
7.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information····························································· 31 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ··············· 31 
7.3.3 
Follow-up of Adverse Events and Serious Adverse Events ························ 32 
7.3.4 
Regulatory Reporting Requirements for Serious Adverse Events ················· 32 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ·········································· 32 
7.3.6 
Adverse Events of Special Interest ···················································· 33 
7.3.7 
Special Situations ········································································ 33 
7.4 
Pharmacokinetics ·············································································· 33 
7.5 
Pharmacodynamics ··········································································· 33 
7.6 
Electronic Clinical Outcome Assessment ·················································· 34 


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7.7 
Other Assessments ············································································ 34 
7.8 
Total Amount of Blood ······································································· 34 
8 
SUBJECT DISCONTINUATION ······························································ 35 
8.1 
Discontinuation of Individual Subject(s) from Study Treatment ························ 35 
8.2 
Discontinuation of Individual Subject(s) from Study ····································· 35 
8.3 
Lost to Follow-up ············································································· 36 
9 
STATISTICAL CONSIDERATIONS ························································· 36 
9.1 
Statistical Hypotheses ········································································ 36 
9.2 
Sample Size Determination ·································································· 36 
9.3 
Populations for Analyses ····································································· 37 
9.4 
Statistical Analyses ··········································································· 37 
9.4.1 
General Considerations ································································· 37 
9.4.2 
Analysis of Efficacy ····································································· 37 
9.4.2.1 
Analysis of Primary Endpoint ···················································· 37 
9.4.2.2 
Sensitivity Analysis ······························································· 38 
9.4.2.3 
Analysis of Secondary Endpoints ················································ 38 
9.4.2.4 
Analysis of Exploratory Endpoints ·············································· 38 
9.4.3 
Analysis of Safety ······································································· 38 
9.4.3.1 
Adverse Events····································································· 38 
9.4.3.2 
Laboratory Assessments ·························································· 39 
9.4.3.3 
Vital Signs ·········································································· 39 
9.4.3.4 
Physical Examination ····························································· 39 
9.4.3.5 
Routine 12-lead Electrocardiogram ············································· 39 
9.4.3.6 
Post Void Residual Volume ······················································ 39 
9.4.4 
Analysis of Pharmacokinetics ·························································· 39 
9.4.5 
Analysis of Pharmacodynamics | Immunogenicity ·································· 39 
9.4.6 
Other Analyses ··········································································· 39 
9.5 
Interim Analysis ··············································································· 39 
9.6 
Additional Conventions ······································································ 40 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ············································································· 40 
10.1 
Appendix 1: Ethical, Regulatory and Study Oversight Considerations ················· 40 
10.1.1 
Regulatory and Ethical Considerations ··············································· 40 


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10.1.2 
Financial Disclosure ···································································· 40 
10.1.3 
Informed Consent of Subjects ························································· 41 
10.1.3.1 
Informed Consent Process ························································ 41 
10.1.3.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ····························· 41 
10.1.4 
Data Protection ·········································································· 41 
10.1.5 
Committee(s) Structure ································································· 42 
10.1.6 
Dissemination of Clinical Study Data················································· 42 
10.1.7 
Data Quality Assurance ································································· 42 
10.1.8 
Source Documents ······································································ 43 
10.1.9 
Study and Site Start and Closure ······················································ 44 
10.1.10 
Arrangement for Use of Information and Publication of the Study ··············· 44 
10.1.11 
Quality Assurance ······································································· 45 
10.2 
Appendix 2: Contraception Requirements ················································· 46 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ······················································ 48 
10.3.1 
Definition of Adverse Events ·························································· 48 
10.3.1.1 
Abnormal Laboratory Findings ·················································· 49 
10.3.1.2 
Potential Cases of Drug-induced Liver Injury ·································· 49 
10.3.2 
Definition of Serious Adverse Events················································· 49 
10.3.3 
Assessment of Causality ································································ 50 
10.3.4 
Assessment of Severity ································································· 52 
10.3.5 
Recording and Follow-Up of AEs and/or SAEs ····································· 52 
10.3.6 
Reporting Procedures for Serious Adverse Events ·································· 52 
10.3.7 
Reporting Procedures for Special Situations ········································· 54 
10.3.7.1 
Contraceptive Guidance and Collection of Pregnancy Information ········· 54 
10.3.7.2 
Medication Error, Overdose and “Off-label Use” ····························· 55 
10.3.7.3 
Misuse/Abuse ······································································ 55 
10.3.7.4 
Occupational Exposure ··························································· 55 
10.3.7.5 
Suspected Drug-drug Interaction ················································ 55 
10.3.8 
Supply of New Information Affecting the Conduct of the Study ·················· 55 
10.3.9 
Urgent Safety Measures ································································ 56 
10.3.10 
Reporting Urgent Safety Measures ···················································· 56 
10.4 
Appendix 4: Liver Safety Monitoring and Assessment ··································· 56 
10.5 
Appendix 5: List of Excluded Concomitant Medications ································ 59 


Sponsor: ACN 
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10.6 
Appendix 6: Clinical Laboratory Assessments ············································ 60 
10.7 
Appendix 7: Overactive Bladder Symptom Score Questionnaire ······················· 61 
10.8 
List of Abbreviations and Definition of Key Study Terms ······························· 62 
11 
REFERENCES ···················································································· 66 
12 
SPONSOR SIGNATURE ········································································ 68 
 
List of In-text Tables 
Table 1 
Schedule of Assessments ····································································· 13 
Table 2  
Study Objectives and Endpoints ····························································· 18 
Table 3 
Investigational Product(s) ···································································· 24 
Table 4 
Blood Volume ················································································· 35 
Table 5 
Quality Tolerance Limits ····································································· 45 
Table 7 
Moderate and Severe Liver Abnormalities ················································· 57 
Table 8 
Clinical Laboratory Tests ···································································· 61 
 
List of In-text Figures 
Figure 1 
Study Schema ·················································································· 12 
 


Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
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SIGNATURES 
1. SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in 
[Section 12 Sponsor Signature]. 
 


Sponsor: ACN 
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2.   INVESTIGATOR’S SIGNATURE 
A Phase 4, Open-label, Randomized, Prospective, Interventional Post-authorization 
Efficacy and Safety Study of Mirabegron 50 mg and 25 mg for the Treatment of 
Overactive Bladder in Chinese Subjects 
ISN/Protocol 178-MA-2295, version 2.0 
22Mar2021  
I have read all pages of this protocol for which Astellas is the sponsor.  I agree to conduct 
the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein.  I confirm that I will conduct the study in accordance with International Council 
for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulations.  I will also 
ensure that sub-investigator(s) and other relevant members of my personnel have access to 
copies of this protocol and the ICH GCP guidelines to enable them to work in accordance 
with the provisions of these documents. 
Principal Investigator: 
Signature: 
 
 
 
 
Date (DD-MMM-YYYY) 
Printed Name:  
  
 
Address of 
trial site: 
 
 
 
 
 
 
 
 
 


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CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL 
 
24-hour Contact for 
Serious Adverse Events 
 
See [Section 10.3.6 
Reporting Procedures for 
Serious Adverse Events] 
Please fax or email the serious adverse events/special 
situations worksheet to: 
Astellas Pharma Global Development Inc. 
Global Pharmacovigilance 
 
Fax number: +1-888-396-3750  
Email: safety-us@astellas.com 
Medical Monitors 
 
 
 
 
 
 
 
PPD


Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title of Study: 
A Phase 4, Open-label, Randomized, Prospective, Interventional Post-authorization Efficacy and 
Safety Study of Mirabegron 50 mg and 25 mg for the Treatment of Overactive Bladder in Chinese 
Subjects 
Planned Study Period/Duration: 
From approximately Q2/2020 to Q1/2023  
Planned Total Number of Study Sites and Location(s): 
Approximately 10-15 study sites in China 
Study Objectives, Endpoints and Estimands: 
Objectives and Endpoints: 
The primary and secondary objectives and endpoints for this study are listed in the table below. 
Objectives 
Endpoints 
Primary 
● 
To evaluate the efficacy of mirabegron 50 mg 
for the treatment of OAB in Chinese subjects 
● 
Change from baseline to the end of 12-week 
treatment period in mean number of 
micturition/24 hours 
 
Secondary 
● 
To evaluate the safety of mirabegron for the 
treatment of OAB in Chinese subjects 
● 
Incidence and severity of AEs. 
● 
Clinical laboratory tests (hematology, 
biochemistry and urinalysis) 
● 
Vital signs (blood pressure and pulse) 
● 
Routine 12-lead ECG 
● 
Post Void Residual (PVR) 
 
● 
To evaluate other efficacy variables of 
mirabegron 50 mg for the treatment of OAB 
● 
Change from baseline to the end of 12-week 
treatment period in mean number of grade 3 or 
4 (PPIUS) urgency episodes, incontinence 
episodes, urge incontinence episodes/24 hours 
and OABSS  
● 
All efficacy variables change from baseline to 
weeks 4 and 8 
 
● 
To explore mirabegron starting dose of 25 mg 
 
● 
Change from baseline to weeks 4, 8, and 12 in 
mean number of micturition/24 hours, mean 
number of grade 3 or 4 (PPIUS) urgency 
episodes, incontinence episodes, urge 
incontinence episodes/24 hours and OABSS 
 


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AE: adverse event; NA: not applicable; OAB: overactive bladder; PPIUS: patient perception of intensity of 
urgency scale; OABSS: OAB Symptom Score. 
Estimands 
The estimand of most clinical importance for this study is defined by the following 4 attributes: 
● 
Target population: all subjects who took at least 1 dose of the study drug, and in whom a non-
missing measurement for mean number of micturition per 24 hours at baseline and after 
administration of the study drug is available 
● 
Outcome measurement: mean number of micturition per 24 hours prior to switching (if 
switching occurs) 
● 
Intercurrent events: 
○ 
Dose escalation 
● 
Population-based summary: change from baseline to week 12/end of treatment (EoT) in 
micturition frequency per day within dose groups 
For this study, the treatment estimand is considered appropriate because of the fact that the 
response of subjects prior to switching is of primary interest. i.e., the estimate for 50 mg of 
mirabegron should be estimated from subjects who were randomized to 50 mg and the estimate for 
25 mg should be estimated from subjects who were randomized to 25 mg while they were treated 
with 25 mg. 
Study Population: 
Male and female adult Chinese subjects (≥ 18 years of age) with overactive bladder (OAB; as 
defined according to the International Continence Society [ICS]). 
Number of Subjects: 
A total of 249 male and female Chinese subjects with OAB will be randomized into 2:1 ratio 
within 2 dose groups (50 mg of mirabegron and 25 mg of mirabegron). 
Study Design Overview: 
The study follows an open-label, randomized, 12-week, prospective, interventional post-
authorization design for the treatment of OAB in approximately 249 Chinese subjects.  Each 
subject will participate in one 12-week treatment period. 
This study is designed to support the Imported Drug License (IDL) renewal and mirabegron safety 
surveillance in China. The data-cut with summaries and the planned primary analysis for the end of 
this study will be used for IDL renewal. Subjects fulfilling the screening inclusion/exclusion 
criteria will be randomized in 2:1 ratio to 50 mg mirabegron and 25 mg mirabegron using a 
computer-generated randomization to reduce selection bias. Treatments will be administered once 
daily orally recommended at the same time after meal during a 12-week, open-label treatment 
period.  Study visits will take place at weeks 4, 8 and 12.  For 25 mg mirabegron group, a dose 
escalation to 50 mg is permitted on visit 3 and visit 4 according to investigators' discretion. 
Treatment Groups and Duration: 
Arm/IP Name 
Mirabegron (BETMIGA®) 
Use 
Test product 
Dose 
25 and 50 mg 
Frequency/Duration 
Once daily doses for 12 weeks 
Route 
Oral 
IP: investigational product 
The anticipated duration of the study for each subject, including screening and follow up, is 
approximately 16 weeks. 
 


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1.2 
Study Schema 
Figure 1 
Study Schema 
 
QD: once daily. 
†The investigators may want to assess if 25 mg dose is effective for this group. Subject to their discretions, a dose escalation to 50 mg is permitted on visit 3/week 4 or visit 4/week 8. 
‡Telephone contact or site visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with 
key entry criteria 
Obtain informed 
consent screening 
procedures 
Randomization 
Screening Period 
Mirabegron 
50 mg QD 
Mirabegron 
25 mg QD† 
Treatment Period (12w) 
Follow-up visit‡ 
2:1 
Follow-up Period (2w) 


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1.3 
Schedule of Assessments 
Table 1 
Schedule of Assessments 
Assessments 
Screening Period 
Treatment Period 
Follow up period 
Visit 1 
Visit 2 
(Baseline) 
Visit 3 
Visit 4 
Visit 5 
(EoT)9 
Visit 6 (T/V1) or at 
Discontinuation of the Post 
treatment 
(End of Study)11,12 
Week 
-1 to -2 
0 
4 
8 
12 
14 
Visit Window (Days) 
0 
±2 
±3 
±3 
±3 
±3 
Visit Number 
1 
2 
3 
4 
5 
6 
Obtaining Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
Dispense/Collect IP 
 
X 
X 
X 
X 
 
Administration of IP2 
 
X 
 
 
Issue Bladder e-diary 
X3 
X 
X 
X 
 
 
Retrieval of the Bladder e-diary 
 
X 
X 
X 
X 
 
OABSS4 
 
X 
X 
X 
X 
 
Vital Signs5,9 
X 
X 
X 
X 
X 
 
Clinical Laboratory tests6,9 
X 
 
 
 
X 
 
Pregnancy Test7 
X 
 
 
 
X 
 
Routine 12-lead ECG8,9 
X 
 
 
 
X 
 
PVR10 
X 
 
 
 
X 
 
Previous and Concomitant Medication 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
AE: adverse event; CRF: case report form; ECG: electrocardiogram; eCRF: electronic case report form; e-diary: electronic diary; EoT: end of treatment; IP: investigational product; 
PVR: post void residual; OAB: overactive bladder; OABSS: OAB Symptom Score. 
Footnotes continued on next page 


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1. 
T/V = Telephone contact or site visit. 
2. 
Daily IP administration will start on day 1 (i.e., the day on visit 2/week 0 [baseline]). For 25 mg mirabegron group, a dose escalation to 50 mg is allowable on visit 3 and visit 4 
by investigator’s discretion.  
3. 
For the screening visit (visit 1/week -1 to -2 [screening]), all subjects will start with the completion of a 3-day bladder e-diary which includes collection of micturition volume 
over 2 days.  
4. 
The OABSS questionnaire will be completed on visit 2/week 0 (baseline), visit 3/week 4, visit 4/week 8 and visit 5/week 12 (EoT). 
5. 
Blood pressure, pulse measurements and body temperature will be measured in single measurements.  Subject to be in the sitting position (when possible, otherwise supine, but 
always in the same position for each procedure).  Subject should have been calm and without distress for at least 5 minutes.  Preferably, the right arm should be used to measure 
vital signs.  Body temperature will be measured with an ear thermometer.  These measurements will be used to assess eligibility. 
6. 
Hematology, biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 1/week -1 to -2 (screening) and visit 5/week 12 (EoT). Refer to Table 8 for the list of 
clinical laboratory tests. 
7. 
Urine pregnancy tests will be performed only in female subjects of childbearing potential at visit 1/week -1 to -2 (screening) and visit 5/week 12 (EoT) except for cases in which 
the possibility of pregnancy was clearly ruled out by hysterectomy, bilateral oophorectomy or the passage of 2 or more years after last menstruation. 
8. 
Routine 12-lead ECGs will be taken after the subject has been resting in the supine position for at least 5 minutes. Routine 12-lead ECGs will be taken as single measurements. 
9. 
The following sequence will be in effect when more than 1 assessment is required at a time point: routine 12-lead ECG, vital signs, and sampling for clinical laboratories. 
10. PVR volume will be assessed using ultrasonography at visit 1/week -1 to -2 (screening) and visit 5/week 12 (EoT).   
11. Subjects who withdraw early from the study after having received IP should complete both the EoT and end of study visits. 
12. The end of study visit (visit 6/week 14 [end of study]) should take place at least 14 days after the EoT visit (visit 5/week 12 [EoT]). 


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2 
INTRODUCTION 
The generic name of the investigational product (IP) is mirabegron sustained-release tablets 
(also called mirabegron oral controlled absorption system [OCAS] tablets internally) and the 
trade name is BETMIGA®. 
Mirabegron is a selective agonist for human beta 3-adrenoceptor (beta 3-AR).  It is an 
approved chemical entity and first-in-class compound with a distinct mechanism of action 
compared to the current standard of care (primarily antimuscarinics). 
Mirabegron is indicated for the symptomatic treatment of urgency, increased micturition 
frequency and/or urgency incontinence as may occur in adult patients with overactive bladder 
(OAB) syndrome. 
In the mirabegron approval letter, China National Medical Products Administration (NMPA) 
requested further investigation into the usage (before/after meal) and dosage (including 
initiation dose) of mirabegron in Chinese patients and data should be submitted when the 
Imported Drug License (IDL) is renewed. 
2.1 
Study Rationale 
In mirabegron approval letter, the NMPA has asked further data on the use of mirabegron in 
Chinese patients. The data ought to comprise mirabegron usage with two different starting 
doses available in China, 25mg and 50mg, as a prerequisite submission for the upcoming 
mirabegron IDL renewal.  
 
This study will be an open-label, randomized, prospective, interventional post-authorized, 
oral dose once daily during 12-week period in male and female Chinese subjects with OAB.  
It is intended to determine the efficacy and safety of mirabegron with starting doses 50 mg 
and 25 mg for the treatment of OAB in Chinese subjects. 
2.2 
Background 
OAB is a syndrome characterized by symptoms of urinary urgency with or without urge 
incontinence, often accompanied by frequency and nocturia in the absence of pathologic or 
metabolic factors that would explain these symptoms, according to the 2002 International 
Continence Society (ICS) definition [Neurourology and Urodynamics, 2019; Abrams et al, 
2002, Charlson et al, 1987]. 
Several publications have studied the prevalence of OAB in developed countries.  An overall 
OAB prevalence of 11.8% was observed in a population-based, cross-sectional survey of 
adults ≥ 18 years of age in Canada, Germany, Italy, Sweden and the UK (the European 
Prospective Investigation into Cancer and Nutrition [EPIC] study).  The prevalent rates of 
OAB were similar in men and women (10.8% versus 12.8%, respectively) and increased in 
individuals with age of > 40 years (13.1% in men and 14.6% in women, respectively) 
[Osman & Chapple, 2013; Irwin et al, 2006; Abrams et al, 2002].  A population-based survey 
of adults ≥ 18 years of age in the US (the National Overactive Bladder Evaluation [NOBLE] 


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study) reported an overall OAB prevalence of 16.5% with a similar distribution between the 
2 sexes (16.0% in men and 16.9% in women). 
The knowledge of the epidemiology of OAB is limited in Asia.  A questionnaire-based 
survey conducted in randomly selected women 18 to ≥ 70 years of age, who were treated at 
the outpatient clinics for nonurologic or nongynecologic problems under the supervision of 
medically trained personnel in 11 Asian countries (China, Hong Kong, India, Indonesia, 
Malaysia, Pakistan, Philippines, Singapore, South Korea, Taiwan and Thailand), reported an 
overall OAB prevalence of 53.1%, with only 21.1% wanting treatment [Lapitan & Chye, 
2001].  In the same 11 Asian countries, a prevalence of 29.9% was reported in a 
self-administered questionnaire survey completed by a randomly chosen sample of male 
patients (18 to ≥ 70 years of age) visiting clinics other than urology clinics [Moorthy et al, 
2004].  An internet-based self-administered survey conducted among men and women at 
least 40 years of age in China, Taiwan and South Korea reported an OAB prevalence of 
20.8% (19.5% in men and 22.1% in women) and increased significantly with age, from 
10.8% in those 40 to 44 years of age to 27.9% in those > 60 years of age (p = 0.001) [Chuang 
et al, 2019].  An overall OAB prevalence of 26.5% in adults 30 years of age and older (18.0% 
in men and 28.7% in women) was reported in another population-based, cross-sectional 
questionnaire survey conducted in South China [Chen and Li, 2016]. 
Many studies have shown significantly greater symptom bother, worse health-related quality 
of life (HRQoL), higher rates of depression and decreased enjoyment of sexual activity in 
OAB patients [Chen & Li, 2016; Osman & Chapple, 2013; Coyne et al, 2008; Stewart et al, 
2003].  In addition, the economic burden of OAB is substantial. 
The management of OAB is multimodal, including lifestyle modifications, behavioral 
therapies and pharmacological therapeutic strategies.  Antimuscarinics, which exert their 
effect through the blockade of postjunctional muscarinic receptors, are currently the mainstay 
of pharmacological treatment of OAB and they represent the most commonly prescribed 
drugs.  Meta-analyses of several randomized controlled trials (RCTs) have shown that 
antimuscarinics (including propiverine, fesoterodine, tolterodine, oxybutynin, solifenacin, 
trospium and darifenacin) are efficacious, safe and well-tolerated therapies that improve 
HRQoL [Chapple et al, 2008; Novara et al, 2008].  However, the lack of persistence with 
antimuscarinics is a well-known challenge in OAB treatment, which may occur due to the 
side-effects such as dry mouth, conspiration, blurred vision and urinary retention or the lack 
of perceived efficacy [Andersson, 2013].  A systematic literature review indicated high rates 
of discontinuation from 12-week RCTs, ranging from 4% to 31% in treatment groups and 5% 
to 20% in placebo groups, respectively.  Findings from medical claims data also suggested 
that over half of the patients never refilled their initial prescription and that adherence levels 
were low, with mean/median medication possession ratio (MPR) values ranging from 0.30 to 
0.83 [Sexton et al, 2011]. 
Mirabegron, a first in class beta-3-adrenergic receptor agonist, has been approved for OAB 
treatment in the US, Europe, Canada, Japan, Australia, Hong Kong, Korea, China and 
Taiwan.  A review of 6 RCTs of mirabegron concluded that mirabegron had clinically 


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significant efficacy and tolerability in treating OAB symptoms.  The tolerability profile of 
mirabegron provided the potential for improving patient adherence with OAB treatment, as 
dry mouth was often the reason for antimuscarinics treatment discontinuation [Chapple et al, 
2014]. 
2.3 
Risk/Benefit Assessment 
2.3.1 
Risk Assessment 
Preclinical and clinical safety data, including adverse events (AEs) of interest, support the 
safety of 50 mg mirabegron in the treatment of patients with OAB. 
The global OAB 12-week phase 2/3 studies (178-CL-046, 178-CL-047 and 178-CL-074) 
included 4414 patients treated with mirabegron, 2142 patients treated with placebo and 
958 patients treated with tolterodine. 
One or more serious adverse events (SAEs) were reported by 1.7% of mirabegron patients, 
1.8% of placebo patients and 1.7% of tolterodine patients, with no apparent mirabegron dose 
response.  The most common SAEs in the total mirabegron group were atrial fibrillation 
(mirabegron: 0.1%; placebo: < 0.1%; tolterodine: 0%), chest pain (mirabegron: 0.1%; 
placebo: 0.1%; tolterodine: 0%) and pneumonia (mirabegron: 0.1%; placebo: < 0.1%; 
tolterodine: 0%).  The most common treatment-emergent adverse events (TEAEs) (by 
preferred term) reported in the total mirabegron group were nasopharyngitis 
(mirabegron: 6.7%; placebo: 6.6%; tolterodine: 5.9%), hypertension (mirabegron: 5.0%; 
placebo: 5.0%; tolterodine: 4.5%) and blood glucose increased (mirabegron: 4.7%; 
placebo: 5.4%; tolterodine: 7.6%). 
Study 178-CL-090 included 366 patients treated with mirabegron, 371 patients treated with 
tolterodine and 366 patients treated with placebo.  One or more SAEs were reported by 
1.4% of mirabegron patients, 1.6% of tolterodine patients and 1.9% of placebo patients.  All 
SAEs were unique to a single patient in each treatment group.  All SAEs were considered by 
the investigator to be not related to the IP except for headache and vomiting, which occurred 
in 1 patient in the tolterodine sustained release 4 mg group. 
In the 1-year long term study, Study 178-CL-049, 1632 patients treated with mirabegron and 
812 patients treated with tolterodine were included.  The most common SAEs in the total 
mirabegron group were osteoarthritis (mirabegron: 0.2%; tolterodine: 0.1%) and 
cerebrovascular accident (mirabegron: 0.2%; tolterodine: 0.1%).  The most common TEAEs 
(by preferred term) reported in the total mirabegron group were hypertension 
(mirabegron: 9.5%; tolterodine: 9.6%), urinary tract infection (UTI) (mirabegron: 5.7%; 
tolterodine: 6.4%) and nasopharyngitis (mirabegron: 4.1%; tolterodine: 3.1%). 
AEs of interest have been thoroughly evaluated in all completed studies and do not represent 
product-related safety concerns.  Potential risks included QT prolongation with 
supratherapeutic doses or in high-risk populations, increased heart rate with supratherapeutic 
doses, increased blood pressure with supratherapeutic doses, nonimmediate cutaneous 
hypersensitivity reactions and exposure in utero.  The potential risks of QT prolongation, 


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increased heart rate or increased blood pressure are greater with increasing exposure at 
supratherapeutic doses and can be mitigated with optimal dose selection. 
Detailed reference safety information (RSI) can be found in the Investigator’s Brochure. 
2.3.2 
Benefit Assessment 
Although OAB is not a life-threatening disease, it has profound psychological and social 
influences on patients, their families and their caregivers, and may lead to a decline in quality 
of life. 
Mirabegron is a highly selective β3-AR agonist that activates β3-ARs in the detrusor muscle 
of the bladder, resulting in muscle relaxation and an increase in bladder capacity, thereby 
improving OAB symptoms of urinary urgency, frequency and urge urinary incontinence.  
Mirabegron has a more favorable safety profile than antimuscarinic agents, which are often 
associated with dry mouth, constipation and blurred vision. 
Medical evaluations/assessments associated with study procedures include; completion of 
electronic diary (e-diary), clinical laboratory tests, vital signs, physical examination, 
electrocardiogram (ECG), post void residual (PVR) volume assessments, and OAB Symptom 
Score (OABSS). 
2.3.3 
Overall Risk-Benefit Conclusion 
Subjects participating in this study might benefit from administration of mirabegron.  In 
addition, subjects might experience AEs related to mirabegron or procedural complications 
(e.g., blood draws, slight skin irritation from the adhesive on the ECG electrodes). 
Overall, the risk associated with the participation of OAB patients in this study is considered 
acceptable. 
3 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Objectives and Endpoints: 
The primary and secondary objectives and endpoints for this study are listed in the table 
below. 
Table 2  
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
● 
To evaluate the efficacy of mirabegron 50 mg 
for the treatment of OAB in Chinese subjects 
● 
Change from baseline to the end of 12-week 
treatment period in mean number of 
micturition/24 hours 
Secondary 
● 
To evaluate the safety of mirabegron for the 
treatment of OAB in Chinese subjects 
● 
Incidence and severity of AEs. 
● 
Clinical laboratory tests (hematology, 
biochemistry and urinalysis) 
● 
Vital signs (blood pressure and pulse) 
● 
Routine 12-lead ECG 


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Objectives 
Endpoints 
● 
Post Void Residual (PVR) 
 
● 
To evaluate other efficacy variables of 
mirabegron 50 mg for the treatment of OAB 
● 
Change from baseline to the end of 12-week 
treatment period in mean number of grade 3 or 
4 (PPIUS) urgency episodes, incontinence 
episodes, urge incontinence episodes/24 hours 
and OABSS  
● 
All efficacy variables change from baseline to 
weeks 4 and 8 
 
● 
To explore mirabegron starting dose of 25 mg 
● 
Change from baseline to weeks 4, 8, and 12 in 
mean number of micturition/24 hours, mean 
number of grade 3 or 4 (PPIUS) urgency 
episodes, incontinence episodes, urge 
incontinence episodes/24 hours and OABSS 
 
AE: adverse event; NA: Not applicable; OAB: overactive bladder; PPIUS: patient perception of intensity of 
urgency scale; OABSS: OAB Symptom Score. 
Estimands 
The estimand of most clinical importance for this study is defined by the following 
4 attributes: 
● 
Target population: all subjects who took at least 1 dose of the study drug, and in whom a 
non-missing measurement for mean number of micturitions per 24 hours at baseline and 
after administration of the study drug is available 
● 
Outcome measurement: mean number of micturitions per 24 hours prior to switching (if 
switching occurs) 
● 
Intercurrent events: 
o 
Dose escalation 
● 
Population-based summary: change from baseline to week 12/end of treatment (EoT) in 
micturition frequency per day within dose groups 
For this study, the treatment estimand is considered appropriate because of the fact that the 
response of subjects prior to switching is of primary interest i.e., the estimate for 50 mg of 
mirabegron should be estimated from subjects who were randomized to 50 mg and the 
estimate for 25 mg should be estimated from subjects who were randomized to 25 mg while 
they were treated with 25 mg. 
4 
STUDY DESIGN AND DOSE RATIONALE 
4.1 
Overall Study Design 
The study follows an open-label, randomized, 12-week, prospective, interventional post-
authorization design for the treatment of OAB in approximately 249 Chinese subjects.  Each 
subject will participate in one 12-week treatment period. 
Planned total number of study sites include approximately 10-15 study sites across China. 


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This study is designed to support the IDL renewal and mirabegron safety surveillance in 
China.  Subjects fulfilling the screening inclusion/exclusion criteria will be randomized in 
2:1 ratio to 50 mg mirabegron and 25 mg mirabegron using a computer-generated 
randomization to reduce selection bias. 
Treatments will be administered once daily orally recommended at the same time after meal 
during a 12-week, open-label treatment period.  Study visits will take place at weeks 4, 
8 and 12.  For 25 mg mirabegron group, a dose escalation to 50 mg is permitted on visit 3 and 
visit 4 according to investigators' discretion. 
4.2 
Scientific Rationale for Study Design 
An open-label design will be applied considering the primary objective is to assess the 
efficacy of mirabegron in Chinese population, measured with the mean number of 
micturition/24 hours.  Subjects will be randomized to treatment to reduce selection bias.  The 
ratio of 2:1 was determined based on the optimal dose of 50 mg rather than 25 mg.  A 
follow-up of 12-week was chosen as previously documented in several Phase III clinical 
studies. 
4.3 
Dose Rationale 
In mirabegron approval letter, NMPA has asked further investigation on the usage and 
dosage of (including the initiation dose) mirabegron in Chinese subjects and data should be 
submitted upon IDL renewal. 
In accordance with Decree No. 81 of the Ministry of Health Provisions for Adverse Drug 
Reaction Reporting and Monitoring (July 2011) and draft guidance issues in 2013, drug 
manufacturers shall conduct regular safety surveillance for produced drugs and perform 
intensive monitoring over drugs during the new drug observation period as well as drugs 
imported for the first time within 5 years.  Mirabegron sustained release tablets 50 mg and 
25 mg are applicable for implementing the intensive monitoring. 
In accordance with the NMPA’s request, to continue the study on the posology of Chinese 
subjects, including the initial dose and taking drug after the meal and submit the study results 
upon renewal, both 25 and 50 mg doses of mirabegron will be investigated. 
Mirabegron label in China recommended the use of 25mg in liver and renal impairment 
patients. However there is a risk that there will be absent or too few subjects in 25mg arm to 
make meaningful conclusions should the label is followed. Therefore the study recruits the 
same inclusion criteria to be randomized in both arms. 
The 50mg group serves as the primary efficacy and safety assessment whilst the 25mg group 
is an exploratory starting dose observation in Chinese subjects. The investigators in 25mg 
group may want to assess in the next follow-ups if a dose escalation to 50mg is required at 
their own discretion. The study does not allow dose reduction from 50mg to 25mg as the 
former is considered a safe and effective recommended dose. 


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4.4 
End of Study Definition 
The end of the study is defined as the last visit or scheduled procedure shown in the Schedule 
of Assessments [Table 1] for the last subject in the study. 
5 
STUDY POPULATION 
The study population will consist of Chinese male and female subjects with OAB (≥ 18 years 
of age).  Eligible subjects must be able to provide written informed consent and meet all the 
inclusion criteria and none of the exclusion criteria. 
All screening assessments must be completed and reviewed to confirm the potential subject 
meets all eligibility criteria.  Prospective approval of protocol deviations to eligibility criteria 
(also known as protocol waivers or exemptions) is not permitted. 
5.1 
Inclusion Criteria 
Subject is eligible for participation in the study if all of the following apply: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations must be obtained from 
the subject prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable). 
2. Subject is considered an adult (≥ 18 years of age) according to local regulation at the time 
of signing the informed consent form (ICF). 
3. Subject should exhibit symptoms of OAB for at least 12 weeks before initiation of the 
screening period. 
4. Subject should have an average of ≥ 8 micturitions/24 hours. 
5. Subject should have an average of ≥ 1 episode of grade 3 or 4 (PPIUS) urgency or 
urgency incontinence/24 hours, during a 3-day micturition diary period. 
6. Female subject is not pregnant (see [Section 10.2 Appendix 2: Contraception 
Requirements]) and at least one of the following conditions apply: 
a. Not a woman of childbearing potential (WOCBP) (see [Section 10.2 Appendix 2: 
Contraception Requirements]) 
b. WOCBP who agrees to follow the contraceptive guidance (see 
[Section 10.2 Appendix 2: Contraception Requirements]) from the time of informed 
consent through at least 30 days after final IP administration. 
7. Female subject must agree not to breastfeed starting at screening and throughout the study 
period and for 30 days after final IP administration. 
8. Female subject must not donate ova starting at first dose of IP and throughout the study 
period and for 30 days after final IP administration. 
9. Male subject with female partner(s) of childbearing potential (including breastfeeding 
partner) must agree to use contraception (see [Section 10.2 Appendix 2 Contraception 
Requirements]) throughout the treatment period and 30 days after final IP administration. 
10. Male subject must not donate sperm during the treatment period and for 30 days after 
final IP administration. 


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11. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for 
the duration of the pregnancy throughout the study period and for 30 days after final IP 
administration. 
12. Subject agrees not to participate in another interventional study while participating in the 
present study, defined as 28 days prior screening until completion of the last study visit. 
5.2 
Exclusion Criteria 
Subject will be excluded from participation in the study if any of the following apply: 
Exclusion at Visit 1/Week -1 to -2 (Screening) 
1. Subject has stress urinary incontinence as a predominant symptom. 
2. Subject has an average total daily urine volume > 3000 mL (as recorded in a 3-day 
voiding diary period). 
3. Subject has indwelling catheter or practices intermittent self-catheterization. 
4. Subject has neurogenic detrusor overactivity or indicated pathology other than OAB. 
5. Subject has monosymptomatic enuresis. 
6. Subject has PVR volume of ≥ 100 mL or a clinically significant lower urinary tract 
obstructive disease, except if successfully treated. 
7. Subject has anatomical anomalies (surgically treated or untreated) that affect lower 
urinary tract function. 
8. Subject with hematuria on dipstick test.  In the case of hematuria on dipstick test in a 
female during menstruation, the test can be repeated before randomization (after the end 
of menstruation). 
9. Subject has lower urinary tract stones or clinically significant kidney stones requiring 
treatment.  
10. Subject has interstitial cystitis. 
11. Subject has suffered from chronic UTI or has had more than 3 UTIs in the 2 months 
prior to visit 1/week -1 to -2 (screening). 
12. Subject has uncontrolled hypertension (sitting systolic blood pressure 
[SBP] ≥ 180 mmHg or diastolic blood pressure [DBP] ≥ 110 mmHg). 
13. Subject has pulse rate ≥ 110 beats per minute (bpm) or < 50 bpm. 
14. Subject has corrected QT interval by Fredericia (QTcF) > 440 msec on screening ECG or 
a risk of QT prolongation (e.g., hypokalemia, long QT syndrome [LQTS] or family 
history of LQTS or exercise-induced syncope). 
15. Subject’s aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is 
≥ 2 × upper limit of normal (ULN) or total bilirubin (TBL) is ≥ 1.5 × ULN according to 
age and sex (subjects with Gilbert’s syndrome are excepted from the bilirubin threshold). 
16. Subject has moderate or severe renal impairment. 
17. Subject has a symptomatic (symptoms can include pain, fever, hematuria, new onset 
foul-smelling urine) UTI.  Note: if the UTI is treated successfully (clinical recovery: 
confirmed by dipstick test and repeated dipstick test after 14 days [both should be 
negative]), the subject can be rescreened. 


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18. Subject has a history or presence of any malignancy (previous or current diagnosis of 
bladder or prostate cancer). 
19. Subject uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates 
with a narrow therapeutic index or sensitive P-glycoprotein (P-gp) substrates after the 
start of washout. 
20. Subject is using or has used prohibited prior and/or concomitant medication(s) 
[Section 10.5 Appendix 5 List of Excluded Concomitant Medications]. In case α1-AR 
antagonists, 5α-reductase inhibitors (5-ARIs) and Phosphodiesterase type 5 inhibitors 
(PED-Is) are used for Benign Prostatic Hyperplasia(BPH), Subject can be included in the 
study. 
21. Subject has known or suspected hypersensitivity to mirabegron or any components of the 
formulations used. 
22. Subjects previously treated for OAB including medication and nondrug treatment. If the 
treatment stopped for 2 weeks or more prior to the screening visit, Subjects can be 
included in the study. 
23. Subject has participated in another clinical study (and/or subject has received any 
investigational therapy within 30 days (or 5 half-lives of the drug, or the limit set by 
national law, whichever is longer) prior to visit 1/week -1 to -2 (screening). 
24. Subject has constipation as defined by the Rome IV criteria that cannot be successfully 
treated prior to study entry. 
25. Female subject who has been pregnant within 6 months prior to screening or 
breastfeeding within 3 months prior to screening. 
26. Subject has a positive serology test for hepatitis A virus (HAV) antibodies 
(immunoglobulin M [IgM]), hepatitis B core (HBc) antibodies, hepatitis B surface 
antigen (HBsAg), hepatitis C virus (HCV) antibodies, antibodies to human 
immunodeficiency virus (HIV) or syphilis at screening. 
27. Subject is an employee of Astellas, the study-related contract research organizations 
(CROs) or the clinical unit. 
28. Subject has any condition, which in the opinion of the investigator, makes the subject 
unsuitable for study participation. 
Additional Exclusion at Visit 2/Week 0 (Baseline) 
29. Subject has stress urinary incontinence as a predominant symptom. 
30. Subject has an average total daily urine volume > 3000 mL (as recorded in a 3-day 
voiding diary period). 
31. Subject has monosymptomatic enuresis confirmed by the bladder e-diary. 
32. Subject suffers from a symptomatic (symptoms can include pain, fever, hematuria, new 
onset foul-smelling urine) UTI.  Note: if a symptomatic UTI is present, all 
visit 2/week 0 (baseline) assessments must be postponed until the UTI is successfully 
treated (clinical recovery: confirmed by dipstick test and repeated dipstick test after 
14 days [both should be negative]).  The postponed visit 2/week 0 (baseline) should be 
within 14 days of the intended visit 2/week 0 (baseline). 


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33. Subject with hematuria on dipstick test.  In the case of hematuria on dipstick test in a 
female during menstruation, the test can be repeated before randomization (after the end 
of menstruation). 
34. Subject has uncontrolled hypertension (sitting SBP ≥ 180 mmHg or DBP ≥ 110 mmHg). 
35. Any reason, in the opinion of the investigator, that makes the subject unsuitable for study 
participation. 
5.3 
Lifestyle Considerations 
Restrictions for foods and drinks are not applicable.  On visit days dosing should occur in the 
clinic and breakfast should be eaten at the clinic within 1 hour before dosing. 
Concomitant medications such as α1-AR antagonists, medication for diabetes insipidus 
(desmopressin, vasopressin), antidepressants (Selective Serotonin Reuptake Inhibitors 
[SSRIs] or tricyclic antidepressants), 5α-reductase inhibitors, capsaicin or resiniferatoxin 
injections into bladder, botulinum toxin injections to bladder muscles, strong cytochrome 
P450, family 3, subfamily A (CYP3A) inhibitors, antimuscarinics medications for OAB, and 
those metabolized by CYP2D6 should be restricted during the study except α1-AR 
antagonists, 5α-reductase inhibitors (5-ARIs) and Phosphodiesterase type 5 inhibitors (PED-
Is) use for Benign Prostatic Hyperplasia(BPH) 
5.4 
Screen Failures 
A screen failure is defined as a potential subject who signed the ICF but did not meet one or 
more criteria required for participation in the study and was not enrolled. 
For screen failures, the demographic data, date of signing the ICF, inclusion and exclusion 
criteria, AEs up to the time of screen failure and reason for screen failure will be collected in 
the electronic case report form (eCRF). 
5.4.1 
Rescreening 
Rescreening is allowed only in situations in which a subject underwent the screening 
procedures and due to logistical circumstances, the allocated time window for these tests has 
expired and the subject is documented as a screen failure.  In order to rescreen, a new ICF 
must be signed and a new subject screening number assigned.  Rescreening is only allowed 
once for an individual subject. 
6 
INVESTIGATIONAL PRODUCT(S) 
6.1 
Investigational Product(s) Administered 
Table 3 
Investigational Product(s) 
Name 
Mirabegron (BETMIGA®) 
Use 
Test product 
Dosage Form 
Sustained-release tablet 
Physical Description 
25 mg: oval, brown, film-coated tablet 
50 mg: oval, yellow, film-coated tablet 
Unit Dose Strength 
25 and 50 mg 


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Packaging and Labeling 
10 tablets per PTP sheet, 1 sheet per carton 
Route of Administration 
Oral 
Administration  
 
IMP will be administered orally, once daily in the morning around 
the same time of day and around time of food intake (i.e., within 
1 hour after breakfast).  Tablets will be administered with a sip of 
water (tablet should be taken as a whole and should not be chewed, 
divided or crushed). 
IMP or Non-IMP 
IMP 
Sourcing 
Provided locally by study site 
IMP: investigational medicinal product; PTP: Press Through Package. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Packaging and Labeling 
All IP used in this study will be prepared, packaged and labeled under the responsibility of 
qualified personnel at Astellas Pharma China, Inc. (ACN) or sponsor’s designee in 
accordance with ACN or sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) guidelines and applicable local laws/regulations. 
Refer to the product label and package insert for detailed information regarding packaging 
and labeling of the IP. 
6.2.2 
Handling, Storage and Accountability 
● The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and 
resolved before use of the IP. 
● Only subjects consented in the study may receive IP and only authorized study site 
personnel may supply or administer IP.  Only IP with appropriate expiry/retest date may 
be dispensed. 
● All IP must be stored in a secure, environmentally controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions and access must be 
limited to the investigator and authorized study site personnel. 
● The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records). 
● After final reconciliation is confirmed, further guidance and instructions on final 
disposition of used and unused IP will be provided. 
The site must return all IP (including unused or returned by subject) to the sponsor or 
designee at the end of study or upon expiration.  If due to institutional policy or local law, 
unused, expired or returned IP cannot be returned to the sponsor or designee the IP may be 
destroyed according to local law. 


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6.3 
Randomization and Blinding 
6.3.1 
Blinding Method 
This section is not applicable as this is an open-label study. 
6.3.2 
Assignment and Allocation 
6.3.2.1 Subject Number 
Subjects will be assigned a subject number at study entry (i.e., signing the ICF).  The subject 
numbers will be sequential and rising. 
The subject number will comprise of a 5 digit clinical unit number and 5 digit screening 
number. 
6.3.2.2 Randomization Number 
Subjects will be randomized in a 2:1 ratio to 50 mg mirabegron and 25 mg mirabegron using 
a computer-generated randomization Interactive Web Response System (IWRS).  All 
consented subjects who meet the eligibility criteria will be randomized through IWRS.  This 
service is set up prior to the study to allow the sites real-time allocation of the treatment to 
the next eligible subject based on the specifications and algorithm provided in the 
Randomization Specification Document. 
At visit 2/week 0 (baseline), subjects will be assigned a randomization number in accordance 
with the randomization code generated by the sponsor’s designee. 
6.3.2.3 Subject Replacement 
An enrolled subject who withdraws or discontinues before dosing or before randomization 
will be considered a screen failure.  Randomized subjects who withdraw or discontinue will 
not be replaced. 
6.4 
Investigational Product Compliance 
Subject compliance with IP will be assessed at each visit.  Compliance will be assessed by 
counting returned tablets.  Deviations from the prescribed dose regimen will be recorded. 
If compliance is less than 80%, the investigator or designee is to counsel the subject and 
ensure steps are taken to improve compliance. 
6.5 
Dose Modification 
For 25 mg mirabegron group, a dose escalation to 50 mg is permitted on visit 3 and visit 4, 
according to investigators' discretion. 
6.6 
Continued Access to Investigational Product After the End of the 
Study 
Mirabegron has been approved and commercially available in China. 


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6.7 
Treatment of Overdose 
Mirabegron administered at single doses up to 400 mg or at multiple doses up to 300 mg 
daily for 10 days cause overdose.  Treatment for overdose should be symptomatic and 
supportive.  In the event of overdose, pulse rate, blood pressure and ECG monitoring are 
recommended. 
6.8 
Concomitant Therapy 
Subjects are not allowed to use ongoing treatment with any of the following prohibited 
medications after the start of the washout: 
Any medication, other than the IP, used for the treatment of OAB 
● 
Any drugs that are sensitive CYP3A inhibitors, CYP2D6 substrates with a narrow 
therapeutic index or sensitive P-gp substrates. 
● 
Intradetrusor botulinum toxin injections; except if given > 9 months prior screening and 
symptoms reappeared comparable to those before botulinum toxin injections. 
● 
Drugs such as α1-AR antagonists, medication for diabetes insipidus (desmopressin, 
vasopressin), antidepressants ([SSRIs] or tricyclic antidepressants), 5α-reductase 
inhibitors, capsaicin or resiniferatoxin injections into bladder. 
● 
Nonmedication therapies like chiropractic, physical therapy will also be collected on the 
nonmedication therapy eCRF. 
Subjects are allowed to continue ongoing treatment of α1-AR antagonists, 5α-reductase 
inhibitors (5-ARIs) and Phosphodiesterase type 5 inhibitors (PED-Is) in case of use for 
Benign Prostatic Hyperplasia (BPH). 
Please refer to [Section 10.5 Appendix 5 List of Excluded Concomitant Medications] for 
drug classes or specific medications that are prohibited during participation in the study. 
7 
STUDY PROCEDURES AND ASSESSMENTS 
● 
Study procedures and their timing are summarized in the Schedule of Assessments 
[Table 1].  Adherence to the study design requirements, including those specified in the 
Schedule of Assessments, is essential and required for study conduct.  Prospective 
protocol waivers or exemptions are not allowed. 
● 
Any change, divergence or departure from the study design or procedures identified in 
the protocol is considered a protocol deviation.  All deviations from the protocol are to 
be recorded. 
● 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
treatment. 
● 
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. 


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● 
Procedures conducted as part of the subject’s routine clinical management (e.g., imaging, 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the Schedule of Assessments [Table 1]. 
7.1 
Efficacy Assessments 
7.1.1 
Bladder e-Diary  
The bladder diary is part of the subject’s e-diary which is used to collect micturition 
frequency, incontinence episodes as well as volume measurements.  After a successful 
visit 1 /week -1 to -2 [screening]), all subjects will start with the completion of a 3-day 
bladder e-diary recording micturition frequency and incontinence episodes as well as 
collection of micturition volume over 2 days.  The bladder e-diary should be completed over 
3 consecutive days, at minimum 3 days, but not more than 7 days, prior to visit 2/week 0 
(baseline). 
Upon successful completion of the 3-day bladder e-diary, subject should return for visit 
2/week 0 as soon as possible, and no more than 7 days after the start of the diary completion. 
The completed e-diary data should be reviewed by the investigator, discussed and confirmed 
with the subject at the start of visit 2/week 0. Upon confirmation of eligibility criteria, the 
subject shall proceed to randomization. If the investigator is under the impression that the 
subject is not able to perform all the required assessments and to complete all required forms 
with credible data, this subject should not be considered for randomization.  
After successful randomization, subsequent bladder e-diaries will be completed by the 
subject over 3 consecutive days in the week prior to visit 3/week 4, visit 4/week 8 and 
visit 5/week 12.  Completion of the 3-day bladder diaries should start at minimum, 3 days 
(but not more than 7 days) prior to the indicated visit. 
7.2 
Safety Assessments 
Study procedures and their timing are summarized in the Schedule of Assessments [Table 1].  
Protocol waivers or exemptions are not allowed. 
7.2.1 
Laboratory Assessments 
Clinical laboratory tests will be performed at a local laboratory. 
Blood samples will be collected via a peripherally placed intravenous cannula or by direct 
venipuncture in a suitable forearm vein. 
Blood samples for hematology and biochemistry and urine samples for urinalysis will be 
collected as indicated in the Schedule of Assessments [Table 1].  The clinical laboratory tests 
to be performed in the study are listed in [Section 10.6 Appendix 6 Laboratory Assessments]. 
A blood sample will be collected for serology tests (HAV antibodies [IgM], HBc antibodies, 
HBsAg, HCV antibodies, syphilis and antibodies to HIV) at screening only. 


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Urine pregnancy tests (female subjects only) will be performed according to the clinical site’s 
preferred method.  Pregnancy tests will be performed as indicated in the Schedule of 
Assessments [Table 1]. 
If any of the clinical laboratory tests results be outside the normal range at any scheduled 
time point during the study, the investigator may decide to repeat the test(s) on new samples.  
The clinical relevance of the abnormal results will be documented.  Clinically relevant 
changes will be recorded as AEs (see [Section 7.3 Adverse Events and Other Safety 
Aspects]). 
7.2.2 
Vital Signs 
Blood pressure (SBP and DBP), pulse measurements, and body temperature will be taken as 
indicated in the Schedule of Assessments [Table 1].  Single measurements of blood pressure 
and pulse will be measured in the sitting position (when possible, otherwise supine, but 
always in the same position).  Subject should have been calm and without distress for at least 
5 minutes.  Preferably, the right arm should be used to measure vital signs.  Body 
temperature will be measured with an ear thermometer.  These measurements will be used to 
assess eligibility. 
7.2.3 
Physical Examination 
Physical examination will be performed as indicated in the Schedule of Assessments 
[Table 1] and whenever there is a medical indication. 
The investigator should perform physical examinations in accordance with routine 
procedures.  Any abnormal finding observed at screening must be assessed and documented 
as not clinically significant if a subject is to be enrolled in the study.  After IP administration, 
new clinically significant findings or a worsening of an ongoing clinically significant 
abnormal condition will be recorded as an AE (see [Section 7.3 Adverse Events and Other 
Safety Aspects]). 
7.2.4 
Electrocardiogram 
Routine 12-lead ECGs will be taken as indicated in the Schedule of Assessments [Table 1].  
Routine 12-lead ECGs will be taken after the subject has been resting in the supine position 
for at least 5 minutes.  Routine 12-lead ECGs will be taken as single measurements. 
The investigator will review, sign and date the ECG after recording to ensure subject safety.  
The time of the ECG, the interval measurements, as well as an overall conclusion, will be 
documented.  This overall conclusion will be recorded as normal, abnormal not clinically 
significant, or abnormal clinically significant.  If the overall conclusion is abnormal, the 
details must be recorded. 
Per time point, the ECG will be stored electronically and reviewed in a timely manner by the 
investigator.  The electronic data file with all generated ECG variables and electronic files 
with the digitized tracings will be transferred to the sponsor at the end of the study. 


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7.2.5 
Post Void Residual Volume Assessments 
PVR volume will be assessed by ultrasonography at visit 1/week -1 to -2 (screening) and 
visit 5/week 12 (EoT).  The same method should be used for the same subject through the 
screening and the treatment period.  The bladder should only be emptied when it was initially 
filled with preferably > 50% of the bladder capacity.  Every attempt should be made to 
measure PVR volume within a minute of voiding.  A PVR volume of < 100 mL is sufficient 
and the assessment does not have to be repeated.  If the PVR volume is ≥ 100 mL, the PVR 
volume assessment should be repeated (filled with preferably > 50% of the bladder capacity).  
If the subject is unable to complete a second measurement, it is up to the investigator to judge 
whether it can be skipped (and write the reason in the eCRF).  The lowest PVR volume result 
measured should be used to evaluate the exclusion criterion.  In case the lowest PVR volume 
measured is ≥ 100 mL at visit 1/week -1 to -2 (screening), the subject should be excluded 
from the study. 
7.2.6 
Overactive Bladder Symptom Score 
The OABSS, an assessment tool which has been found to be reliable and valid and highly 
responsive to treatment related fluctuations in OAB will be performed at 
visit 2/week 0 (baseline), visit 3/week 4, visit 4/week 8 and visit 5/week 12 (EoT) 
[Urology; 2006].  Repeating the test after treatment interval is an effective way to assess the 
efficacy of a mirabegron treatment on OAB symptoms.  The OABSS questionnaire is 
designed to quantify OAB symptoms experienced in the previous week as a single score, and 
contains questions that address 4 symptoms of overactive bladder: 
● 
Daytime frequency, 
● 
Nighttime frequency, 
● 
Urgency, 
● 
Urge incontinence. 
The OABSS has a maximum score of 15 with more weight assigned to urgency and urgency 
incontinence than on frequency, (see [Section 10.7 Appendix 7 Overactive Bladder Symptom 
Score questionnaire]). 
Questionnaires to be completed by the subject in the local language and provided via the 
e-diary.  Results will be directly entered in the e-diary by the subject. 
7.2.7 
Order of Assessments 
The following sequence order will be in effect when more than 1 assessment is required at a 
time point: routine 12-lead ECG, vital signs, and samples for safety laboratories. 
7.3 
Adverse Events and Other Safety Aspects 
The definitions of an AE or SAE can be found in [Sections 10.3.1 Definition of Adverse 
Events and 10.3.2 Definition of Serious Adverse Events], respectively. 
AEs will be reported by the subject. 


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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 IP, or that caused the 
subject to discontinue the IP and/or study [Section 10.3 Appendix 3 Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting]. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in 
[Section 10.3 Appendix 3 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting]. 
7.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All SAEs will be collected from the signing of the ICF until 30 days after the final IP 
administration or when the subject is determined to be a screen failure and reported in the 
eCRF. 
All AEs will be collected from the signing of the ICF until 30 days after the final IP 
administration or when the subject is determined to be a screen failure and reported in the 
eCRF. 
If the severity of an SAE/AE changes, the event should be relisted in the eCRF with the new 
severity and new onset date. 
If the severity decreases, the SAE/AE should be relisted in the eCRF with the new severity 
and new onset date.  The exception is ongoing pre-dose events that continue post-dose and 
improve post-dose.  Such events should not be re-listed. 
If the severity of an SAE reduces, the details of the AE should be provided on the SAE 
worksheet for the medical assessor to be able to assess the course of the event. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in [Section 10.3 Appendix 3 Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting].  
The investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE 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 IP or study participation, the investigator must promptly 
notify the sponsor. 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 


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7.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All SAEs and AEs of special interest (AESI) (as defined in 
[Section 7.3.6 Adverse Events of Special Interest]) will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up (as defined 
in [Section 8.3 Lost to Follow-up]).  Further information on follow-up procedures is provided 
in [Section 10.3 Appendix 3 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting]. 
If after the protocol-defined AE collection period (see [Section 7.3.1 Time Period for 
Collecting Adverse Event and Serious Adverse Event Information]), an AE progresses to an 
SAE, or the investigator learns of any (S)AE (serious adverse event or adverse event) 
including death, where he/she considers there is reasonable possibility it is related to the IP or 
study participation, the investigator must promptly notify the sponsor. 
7.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
● 
Prompt notification by the investigator to the sponsor of a SAE within 24 hours is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study IP 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 IP under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC and investigators. 
● 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
● 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Under this protocol, the following event(s) will not be considered as an (S)AE: 
Disease progression: events including defined study endpoints that are clearly consistent with 
the expected pattern of progression of the underlying disease are not to be recorded as 
(S)AEs.  These data will be captured as efficacy assessment data as outlined in 
[Section 7.1 Efficacy Assessments].  If there is any uncertainty as to whether an event is due 
to anticipated disease progression and/or if there is evidence suggesting a causal relationship 
between the IP and the event, it should be reported as an (S)AE.  All deaths up to 30 days 
after the final administration of IP must be reported as an SAE, even if attributed to disease 
progression. 


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7.3.6 
Adverse Events of Special Interest 
AEs (serious or nonserious) of special interest are to be collected via the SAE worksheet and 
reported within 24 hours as described in [Section 10.3.6 Reporting Procedures for Serious 
Adverse Events]. 
AESI are AEs the sponsor may wish to carefully monitor.  These AEs may be serious or 
non-serious and should be reported on the eCRF and the SAE worksheet.  These AEs are not 
considered SAEs unless they meet the definition of an SAE.  AESI in this study will include: 
● 
Increased heart rate and tachycardia 
● 
Increased blood pressure 
● 
Hypersensitivity reactions 
● 
Urinary retention 
● 
QT prolongation 
7.3.7 
Special Situations 
Certain special situations observed in association with the IP, such as incorrect administration 
(e.g., wrong dose of IP or background therapy) are reported as protocol deviations and/or 
may require special reporting, as described below.  These special situations are not 
considered AEs, but do require to be communicated to Astellas as per the timelines defined 
below. 
If a special situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the special situation and captured as an AE in the eCRF.  If the AE meets the 
definition of an SAE, the SAE is to be reported as described in [Section 10.3.6 Reporting 
Procedures for Serious Adverse Events] and the details of the associated special situation are 
to be included in the clinical description on the special situation worksheet or pregnancy 
reporting form. 
The special situations are: 
● 
Pregnancy 
● 
Lactation 
● 
Medication error, overdose and off-label use 
● 
Misuse/abuse 
● 
Occupational exposure 
● 
Suspected drug-drug interaction 
Instructions and procedures for reporting special situations are provided in 
[Section 10.3.7 Reporting Procedures for Special Situations]. 
7.4 
Pharmacokinetics 
Not applicable. 
7.5 
Pharmacodynamics 
Not applicable. 


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7.6 
Electronic Clinical Outcome Assessment 
For this study, it has been decided that there are justifiable scientific reasons (i.e., recall bias) 
to limit subject reported changes to changes reported by the subject to the site within 
1 business day of its entry, as changes outside of this window could potentially impact the 
data integrity of the study.  The data under this rule should be: all subject, primary and 
secondary endpoints data.  However, the site/investigator can remove/inactivate any data that 
they determine to be in error at any time with recording the reason for the 
removal/inactivation. The inactivated data will be accessed and reviewed by study monitors.  
Subject bladder diaries, questionnaires and other data completed by the subject will be 
entered on an electronic device (e-diary).  The information on the electronic device will be 
automatically uploaded to a central website.  The investigator or site designee should review 
the diaries and questionnaire data on the website for correct completion before each planned 
visit of the subject (on site visit for all except end of study which can be either site visit or 
telephone contact) and discuss the results or retrain the subject if applicable.  In case 
clinically relevant adverse changes are noticed during review of the e-diary, these will be 
recorded as an AE [Section 10.3 Appendix 3 Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting]. 
The bladder e-diary, questionnaire results and other data collected in the e-diary will be 
transferred electronically to sponsor or designee at predefined intervals during the study.  The 
vendor will provide sponsor or designee with a complete and clean copy of the data. 
For this study the following information will be collected and entered by the subject in the 
e-diary (see [Section 7.2.6 Overactive Bladder Symptom Score for detailed information per 
visit): 
● 
Bladder e-diary 
● 
OABSS 
The investigator must guide the subject to ensure that on the evening before and during the 
2-day period of micturition volume collection, the subject’s fluid intake should be regulated 
(as per investigator guidance) to an appropriate level considering, e.g., age, sex and subject’s 
condition into account.  The intake must remain as consistent as possible on these volume 
collecting days prior to visit 2/week 0 (baseline). 
7.7 
Other Assessments 
Not applicable. 
7.8 
Total Amount of Blood 
The total amount of blood for each subject will vary depending on the course of their disease, 
duration on treatment and local laboratory requirements.  At any time during the study, if any 
laboratory abnormalities are found for a subject, additional blood may be drawn for safety 
monitoring. 


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Table 4 
Blood Volume 
Sample Type 
Number of Samples Sample Volume (mL) Total Volume (mL) 
Clinical Laboratory Tests 
2 
8-10 (+5†) 
25 
Total 
25 
†Includes serology test at screening. 
Additional blood may be drawn for safety reasons.  The maximum amount of blood drawn 
during the study will not exceed 50 mL. 
8 
SUBJECT DISCONTINUATION 
Refer to [Section 10.1.9 Study and Site Start and Closure] regarding discontinuation of study 
sites or of the study as a whole. 
8.1 
Discontinuation of Individual Subject(s) from Study Treatment 
A discontinuation from treatment is defined as a subject who enrolled in the study and for 
whom study treatment is permanently discontinued for any reason. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice.  The 
investigator is also free to discontinue the subject from study treatment or to terminate a 
subject’s involvement in the study at any time if the subject’s clinical condition warrants it. 
The reason for discontinuation from study treatment must be documented in the subject’s 
medical records. 
A subject must discontinue study treatment for any of the following reasons: 
● 
Subject requests to stop treatment 
● 
Any clinical AEs, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued treatment is not in the best interest of the subject 
● 
If signs or symptoms of hypersensitivity to mirabegron are observed (e.g., anaphylactic 
reaction, erythema multiforme or exfoliative dermatitis) 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or international normalized ratio (INR) 
> 1.5 (if INR testing is applicable/evaluated) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
If a subject discontinues treatment prematurely, the subject will be encouraged to complete 
all scheduled visits to record all available information. 
8.2 
Discontinuation of Individual Subject(s) from Study 
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specific follow-up procedures as outlined in Schedule of 
Assessments [Table 1].  The only exception to this is when the subject specifically withdraws 


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consent for any further contact with him/her or persons previously authorized by the subject 
to provide this information. 
8.3 
Lost to Follow-up 
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data and 
retrieve IP.  These contact attempts should be documented in the subject’s medical record. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The hypothesis for comparisons is given as follows: 
H0: The adjusted mean change from baseline at week 12 in mean number of micturitions per 
24 hours in the 50 mg group is not different from zero. 
H1: The adjusted mean change from baseline at week 12 in mean number of micturitions per 
24 hours in the 50 mg group is not equal zero. 
9.2 
Sample Size Determination 
The sample size for this study is based upon change from baseline for mean number of 
micturitions/24 hours within a single treatment arm.  Change from baseline will be tested to 
determine if the change is different from zero i.e., a change in mean number of 
micturitions/24 hours.  When the sample size is 125, a single group t-test with a 5% 
two-sided significance level will have 80% power to detect a change of 0.9 micturitions with 
a SD of 3.562 [Neurourology and Urodynamics, 2015].  Assuming 25% of the subjects will 
drop out, about 166 subjects will be enrolled to yield 125 evaluable subjects in 50 mg group. 
 
 


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9.3 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Enrolled 
All subjects who sign the ICF. 
Randomized 
All subjects who are randomized.  Subjects will be analyzed according to 
the study treatment to which they are randomized. 
Full Analysis Set 
The FAS will consist of all subjects who are randomized and receive at 
least 1 dose of IP and have at least 1 post baseline measurement for mean 
number of micturitions per 24 hours.  The FAS will be analyzed by 
treatment arm as randomized (i.e., treatment arm based on randomization 
assignment).  This will be the primary analysis set for efficacy analyses. 
Safety Analysis Set 
The SAF will consist of all subjects who took at least 1 dose of IP.  The 
safety set will be analyzed by treatment arm as treated (i.e., based on the 
treatment the subject actually received rather than the treatment to which 
the subject was randomized). 
FAS: Full Analysis Set; ICF: informed consent form; IP: investigational product; SAF: Safety Analysis Set. 
9.4 
Statistical Analyses 
A statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced.  Changes from the planned 
analyses in the final SAP that impact the statistical analyses will be justified in the clinical 
study report (CSR). 
9.4.1 
General Considerations 
In general, data will be summarized with descriptive statistics for continuous endpoints, and 
frequency and percentage for categorical endpoints, unless otherwise specified.  Percentages 
by categories will be based on the number of subjects with no missing data (i.e., will add up 
to 100%). 
Baseline will be defined as the last non-missing observation prior to first administration of 
IP, unless otherwise specified. 
9.4.2 
Analysis of Efficacy 
Efficacy analysis will be conducted on the full analysis set (FAS).  The interpretation of 
results from statistical tests will be based on the FAS. 
9.4.2.1 Analysis of Primary Endpoint 
9.4.2.1.1 
Primary Analysis 
The primary efficacy endpoint change from baseline in mean micturitions per 24 hours will 
be analyzed using a Mixed Models Repeated Measures (MMRM).  The MMRM model will 
include visit (the repeated term), treatment group (25 mg or 50 mg), pooled site, sex, and the 
interaction term between treatment and visit as fixed effects and baseline measurement (mean 
number of micturitions per 24 hours) as covariate.  If necessary, pooled centers will be 
generated and documented prior to database lock.  If the inclusion of pooled centers creates 
modeling problems, then dropping that factor will be considered.  Subject will be identified 
as subject in the repeated statement.  By treatment least squares (LS) means (± standard error 


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[SE]) along with 2-sided 95% CIs will be presented for changes at weeks 4, 8 and 12 (the 
primary endpoint). Consistent with the estimand described in section 3, data from subjects 
who switch from 25 to 50 mg mirabegron will be summarized only after switching, not 
included in MMRM model.  Data from those subjects prior to switching would still be 
included in the MMRM model. 
9.4.2.2 Sensitivity Analysis 
Any additional sensitivity analyses, if applicable, will be described in the SAP. 
9.4.2.2.1 
Subgroup Analysis 
The same analysis (MMRM) as for the primary endpoint will be applied to change from 
baseline for the following subgroups: 
● 
Prior OAB treatment 
9.4.2.3 Analysis of Secondary Endpoints 
The same analysis (MMRM, with corresponding baseline measurement for the endpoint as 
the covariate) as for the primary endpoint will be applied to change from baseline (weeks 4, 8 
and 12) for: 
● 
Mean number of grade 3 or 4 (PPIUS) urgency episodes per 24 hours 
● 
Mean number of daytime incontinence episodes per 24 hours 
● 
Mean number of nighttime incontinence episodes per 24 hours 
● 
Mean number of urge incontinence episodes per 24 hours 
● 
OABSS, the sum score of four symptoms (daytime frequency, nighttime frequency, 
urgency, and urgency incontinence) 
9.4.2.4 Analysis of Exploratory Endpoints 
Not applicable. 
9.4.3 
Analysis of Safety 
Safety analysis will be conducted on the safety analysis set (SAF).  Safety endpoints will be 
summarized using descriptive statistics. 
9.4.3.1 Adverse Events 
AEs will be coded using MedDRA.  A TEAE is defined as an AE observed after starting 
administration of the IP and 30 days after the final administration of IP.  An IP-related TEAE 
is defined as any TEAE with a causal relationship assessed as “yes” by the investigator. 
The number and percentage of subjects with TEAEs, drug-related TEAEs, serious TEAEs, 
drug-related serious TEAEs, TEAEs leading to leading to withdrawal of treatment and 
drug-related TEAEs leading to leading to withdrawal of treatment as well as TEAEs of 
special interest [Section 7.3.6 Adverse Events of Special Interest] will be summarized by 
SOC, preferred term and treatment group.  The number and percentage of TEAEs by severity 
will also be summarized.  The worst severity will be summarized if the same AE is recorded 
more than once for a subject. 


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AE data will be listed. 
9.4.3.2 Laboratory Assessments 
For quantitative clinical laboratory measurements (hematology, biochemistry and urinalysis), 
descriptive statistics will be used to summarize results and change from baseline by treatment 
group and visit. 
Shifts relative to normal ranges from baseline to each visit during the treatment period in 
clinical laboratory tests will be tabulated. 
Laboratory data will be listed. 
The laboratory parameters that will be assessed during the conduct of the study are listed in 
[Section 10.6 Appendix 6 Laboratory Assessments]. 
9.4.3.3 Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects in the SAF by treatment group and visit. 
Vital signs data will be listed. 
9.4.3.4 Physical Examination 
Abnormal findings/conditions identified during the physical examinations will be listed as 
part of the medical history for the screening visit, or as AEs at later visits. 
9.4.3.5 Routine 12-lead Electrocardiogram 
The routine 12-lead ECG results will be summarized by treatment group and visit. 
9.4.3.6 Post Void Residual Volume 
The PVR volume data and change from baseline data will be summarized by treatment group 
and visit. 
9.4.4 
Analysis of Pharmacokinetics 
Not applicable. 
9.4.5 
Analysis of Pharmacodynamics | Immunogenicity 
Not applicable. 
9.4.6 
Other Analyses 
Additional data driven exploratory analyses may be performed as appropriate. 
9.5 
Interim Analysis 
There is no planned interim analysis but a data cut with summaries and the planned primary 
analysis for the end of the study may be generated at a specific timepoint during the study for 
regulatory reporting purposes.  No decisions regarding conduct of the study (i.e., stopping) 
will be based on these results. 


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9.6 
Additional Conventions 
If the start and stop dates of AEs and concomitant medications are incomplete, imputed dates 
will be used to determine whether an AE is/is not treatment emergent or to allocate a 
concomitant medication to the study period it was taken. 
See the SAP for details of the definition for analysis windows to be used for analyses by 
visit/timepoint. 
Study sites that do not enroll sufficient subjects to allow estimation of a study site effect will 
be pooled for analyses by study site (pooled site).  The pooling decisions will be made and 
documented prior to study hardlock. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Ethical, Regulatory 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: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
● 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., 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: 
o 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 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2 Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 


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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. 
10.1.3 Informed Consent of Subjects 
10.1.3.1 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 reconsented 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. 
10.1.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
● 
The investigator or his/her representative will immediately inform the subject verbally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue participating in the study 
(e.g., report of serious adverse drug reaction).  The communication must be documented 
in the subject’s medical records and whether the subject is willing to remain in the study 
or not must be confirmed and documented. 
● 
The investigator must update the subject’s ICF and submit it for approval to the 
IRB/IEC.  The investigator or his/her representative must obtain written informed 
consent from the subject on all updated ICFs throughout their participation in the study.  
The investigator or his/her designee must reconsent subjects with the updated ICF even 
if relevant information was provided verbally.  The investigator or his/her representative 
who obtained the written informed consent and the subject should sign and date the ICF.  
A copy of the signed ICF will be given to the subject and the original will be placed in 
the subject’s medical record.  An entry must be made in the subject’s records 
documenting the reconsent process. 
10.1.4 Data Protection 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the subject provides written 
consent or approval.  Additional medical information may be given only after approval of the 
subject to the investigator or to other appropriate medical personnel responsible for the 
subject’s well-being. 


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The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the study without justifiable reasons. 
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to a subject’s privacy due to direct access to source 
documents, or from other sources, they may not disclose the content to third parties. 
The sponsor affirms the subject’s right to protection against invasion of privacy.  Only a 
subject identification number will identify subject data retrieved by the sponsor.  However, 
the sponsor requires the investigator to permit the sponsor, sponsor’s representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study. 
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and privacy laws in the US.  If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then the sponsor shall serve as the controller of 
such data, as defined by the European Union (EU) Data Protection Directive (DPD), and 
investigator and/or third party shall act only under the instructions of the sponsor in regard to 
personal data.  If the sponsor is not based in the EEA, the sponsor must appoint a third party 
to act as its local data protection representative or arrange for a co-controller established in 
the EU for data protection purposes in order to comply with the DPD. 
10.1.5 Committee(s) Structure 
An independent Data and Safety Monitoring Board (DSMB) can be implemented to act in an 
advisory capacity to the sponsor to monitor subject safety and data quality once it is required. 
A separate charter will describe the responsibilities, remit and timing of DSMB meetings. 
10.1.6 Dissemination of Clinical Study Data 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final CSR that 
forms part of a marketing authorization application, be signed by the representative for the 
coordinating investigator(s) or the principal investigator(s).  The representative for the 
coordinating investigator(s) or the principal investigator(s) will have the responsibility to 
review the final study results to confirm to the best of his/her knowledge it accurately 
describes the conduct and results of the study.  The representative for the coordinating 
investigator(s) or the principal investigator(s) will be selected from the participating 
investigators by the sponsor prior to database lock. 
10.1.7 Data Quality Assurance 
● 
All subject data relating to the study will be recorded on the eCRF unless transmitted to 
the sponsor or designee electronically in an external data file (e.g., local laboratory data).  
The investigator is responsible for verifying that data entries on the eCRF are accurate 
and correct by physically or electronically signing the eCRF. 


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● 
Guidance on completion of CRFs will be provided in a separate eCRF Completion 
Guideline. 
● 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
● 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
● 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
● 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., CROs). 
● 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator according to ICH or applicable local regulatory 
requirements, whichever is longer, after study completion.  No records may be destroyed 
during the retention period without the written approval of the sponsor.  No records may 
be transferred to another location or party without written notification to the sponsor. 
10.1.8 Source Documents 
1. Source data must be available at the study site to document the existence of the subjects 
and to substantiate the integrity of study data collected.  Source data must include the 
original documents relating to the study, as well as the medical treatment and medical 
history of the subject. 
2. The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
3. The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are handwritten on 
paper or entered electronically.  If source data are created (first entered), modified, 
maintained, achieved, retrieved or transmitted electronically via computerized systems 
(and/or other kind of electronic devices) as part of regulated study activities, such 
systems must be compliant with all applicable laws and regulations governing use of 
electronic records and/or electronic signatures.  Such systems may include, but are not 
limited to, electronic medical/health records, protocol-related assessments, AE tracking, 
electronic clinical outcome assessment (eCOA) and/or drug accountability. 
4. Paper records from electronic systems used in place of electronic format must be 
certified copies.  A certified copy must be an exact copy and must have all the same 
attributes and information as the original.  Certified copies must include signature and 
date of the individual completing the certification.  Certified copies must be a complete 
and chronological set of study records (including notes, attachments, and audit trail 
information, if applicable).  All printed records must be kept in the subject file and be 
available for archiving. 


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5. 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. 
10.1.9 Study and Site Start and Closure 
The study start date is the date the first subject signs the ICF for the study. 
The sponsor or 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: 
For study termination: 
● 
Discontinuation of further study test product development 
For site termination: 
● 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
● 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the investigator 
● 
Total number of subjects included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor or designee shall promptly 
inform the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements.  The Investigator shall promptly inform the subject 
and should assure appropriate subject therapy and/or follow-up. 
10.1.10 Arrangement for Use of Information and Publication of the Study 
Information concerning the test product, patent applications, processes, unpublished scientific 
data, the Investigator’s Brochure and other pertinent information is confidential and remains 
the property of the sponsor.  Details should be disclosed only to the persons involved in the 
approval or conduct of the study.  The investigator may use this information for the purpose 
of the study only.  It is understood by the investigator that the sponsor will use the 
information obtained during the study in connection with the development of the product and 
therefore may disclose it as required to other clinical investigators or to regulatory agencies.  
In order to allow for the use of the information derived from this study, the investigator 


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understands that he/she has an obligation to provide the sponsor with all data obtained during 
the study. 
Publication of the study results is discussed in the study agreement. 
10.1.11 Quality Assurance 
The sponsor is implementing and maintaining quality assurance (QA) and quality control 
(QC) systems with written SOPs to ensure that studies are conducted and data are generated, 
documented, recorded, and reported in compliance with the protocol, GCP and applicable 
regulatory requirement(s).  Where applicable, the QA and QC systems and written SOPs of 
the CRO will be applied. 
The sponsor or sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities.  The audit may include on-site review of regulatory documents, CRFs and source 
documents.  Direct access to these documents will be required by the auditors. 
To support quality around subject safety and reliability of study results, quality tolerance 
limits (QTLs) are defined and monitored.  QTLs represent the acceptable variation of study 
data, taking into consideration the current state of medical and statistical knowledge about the 
variables to be analyzed, as well as the statistical design of the study.  It is a level, point, or 
value associated with a parameter that should trigger an evaluation if a deviation is detected 
to determine if there is a possible systematic issue (i.e., a trend has occurred).  The QTLs 
defined for this study are provided below. 
Table 5 
Quality Tolerance Limits 
QTL #: Name and Parameter 
Definition 
Parameter Justification 
QTL1: Eligibility: % randomized 
subjects not meeting key criteria. 
% of randomized subjects who do 
not meet critical inclusion/ 
exclusion criteria, measured 
through protocol deviations, 
which lead to per-protocol 
population exclusion. 
A high percentage of eligibility 
violations can have a negative 
impact on interpretation of the 
endpoint data and overall study 
data validity, particularly the 
inclusion criteria that rely upon 
ongoing, consistent compliance 
from subjects for self-
administered pain assessments and 
electronic subject-reported 
outcome data collection. 
QTL2: Protocol Compliance: 
> 5% of subjects with major 
protocol deviations. 
% of subjects with protocol 
deviations, as measured via 
ongoing study monitoring, that 
leads to a lack of reliability 
around pharmacokinetic and 
AE/tolerability data. 
Assurance and impact on safety 
and overall data reliability. 
AE: adverse event; QTL: quality tolerance limit. 
QTL Management Activities: 
For control of risks associated with QTLs refer to Study Monitoring Plan. 


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10.2 
Appendix 2: Contraception Requirements 
WOCBP who are eligible for participation in the study, including those who choose complete 
abstinence, must have pregnancy tests as specified in the Schedule of Assessments [Table 1].  
Pregnancy test results must confirm that the subject is not pregnant. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS 
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile. 
Females in the following categories are not considered WOCBP 
● 
Premenarchal 
● 
Premenopausal with one of the following (i.e., permanently sterile): 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
● 
Postmenopausal 
A postmenopausal state is defined as at least 12 months after last menstrual bleeding without 
an alternative medical cause. 
In case the last menstrual bleeding cannot be clearly determined, confirmation with more 
than one follicle-stimulating hormone (FSH) measurement of at least > 40 IU/L (or higher 
per local institutional guidelines) is required. 
Females on hormone replacement therapy (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 by repeated FSH 
measurements before study enrollment. 
Documentation of any of these categories can come from the study site personnel’s review of 
the female subject’s medical records, medical examination or medical history interview. 
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILDBEARING 
POTENTIAL 
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use one of the highly effective methods of contraception listed below from the time 
of signing the ICF and until the end of relevant systemic exposure, defined as 30 days after 
the final IP administration a. 
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b: 
● 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 


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o Oral 
o Intravaginal 
o Transdermal 
● 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral 
o Injectable 
o Implantable 
● 
Other combined (estrogen- and progesterone-containing) methods 
o Vaginal ring 
o Injectable 
o Implantable 
o Intrauterine hormone-releasing system or intrauterine device 
● 
Bilateral tubal occlusion 
● 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed.  If not, an additional highly effective method of contraception should be used. 
● 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the test 
product.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the subject.  It is not 
necessary to use any other method of contraception when complete abstinence is elected. 
a Local laws and regulations may require use of alternative and/or additional contraception 
methods. 
b Typical use failure rates may differ from those when used consistently and correctly.  Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
subjects participating in clinical studies. 
CONTRACEPTION GUIDANCE FOR MALE SUBJECTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL. 
Male subjects with female partners of childbearing potential are eligible for participation in 
the study if they agree to the following during treatment and until the end of relevant 
systemic exposure defined as 30 days after final drug administration.a 
● 
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator 
● 
Use a condom 
● 
Female partners of male subjects who have not undergone a vasectomy with the absence 
of sperm confirmed or a bilateral orchiectomy should consider use of effective methods 
of contraception 


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a Local laws and regulations may require use of alternative and/or additional contraception 
methods. 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
10.3.1 Definition of Adverse Events 
AE Definition: 
An AE is any untoward medical occurrence in a patient or clinical study subject, temporally 
associated with the use of study IP whether or not considered related to the study IP. 
“Adverse event” means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study IP.  This includes events related to the comparator and events related to the 
(study) procedures. 
Events Meeting the AE Definition 
● 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease) 
● 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
● 
New conditions detected or diagnosed after study IP administration even though it may 
have been present before the start of the study 
Events NOT Meeting the AE Definition 
● 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition 
● 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition 
● 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE 
● 
Situations in which an untoward medical occurrence 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 start of the study that do not worsen 


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10.3.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (hematology, clinical chemistry, or urinalysis) or other 
safety assessment (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, that is considered to be clinically significant in the medical and 
scientific judgment of the investigator and not related to underlying disease, is to be reported 
as an (S)AE. 
Any clinically significant abnormal laboratory finding or other abnormal safety assessment, 
which is associated with the underlying disease, does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE.  Any abnormal test result that is determined to be 
an error does not require reporting as an AE. 
10.3.1.2 Potential Cases of Drug-induced Liver Injury 
Refer to [Section 10.4 Appendix 4: Liver Safety Monitoring and Assessment] for detailed 
instructions on drug induced liver injury.  Abnormal values in AST and/or ALT concurrent or 
with abnormal elevations in TBL that meet the criteria outlined in [Section 10.4 Appendix 4: 
Liver Safety Monitoring and Assessment], in the absence of other causes of liver injury, are 
considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and are 
always to be considered important medical events and reported per [Section 10.3.6 Reporting 
Procedures for Serious Adverse Events]. 
10.3.2 Definition of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that, at any dose: 
● 
Results in death 
● 
Is life-threatening 
The term “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 might have caused death, if it were more severe. 
● 
Requires inpatient hospitalization or prolongation of existing hospitalization 
o 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or 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” occurred or was 
necessary, the AE should be considered serious. 
o 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
● 
Results in persistent or significant disability/incapacity 
o 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 


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o 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
● 
Is a congenital anomaly/birth defect 
● 
Other situations: 
o 
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. 
o 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
If an event is not an AE per definition in [Section 10.3.1 Definition of Adverse Events], then 
it cannot be an SAE even if serious conditions are met (e.g., hospitalization for 
signs/symptoms of the disease under study, death due to progression of disease). 
10.3.3 Assessment of Causality 
● 
The investigator is obligated to assess the relationship between study IP and each 
occurrence of each AE/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 ruled 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 IP 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/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
● 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor.  However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the sponsor. 
● 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
● 
The causality assessment is one of the criteria used when determining regulatory 
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Following a review of the relevant data, the causal relationship between the IP and each 
(S)AE will be assessed by answering “yes” or “no” to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the IP?” 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the IP (rather than a relationship cannot be ruled out) 
or if there is evidence to reasonably deny a causal relationship: 
● 
Has the subject been administered IP? 
● 
Plausibility (i.e., could the event have been caused by the suspect IP?  Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and study data, etc.) 
● 
Dechallenge/dose reduction/rechallenge: 
o Dechallenge: did the (S)AE resolve or improve after only stopping the dose of the 
suspect drug without any treatment? 
o Dose reduction: did the (S)AE resolve or improve after reducing the dose of the 
suspect drug? 
o Rechallenge: did the (S)AE reoccur if the suspected drug was reintroduced after 
having been stopped? 
● 
Laboratory or other test results: a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the IP (e.g., based on values pre-, during and 
post-treatment) 
● 
Available alternative explanations independent of IP exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc., and strength of the 
alternative explanation 
● 
Temporal relationship between exposure to the IP and (S)AE onset and/or resolution.  
Did the (S)AE occur in a reasonable temporal relationship to the administration of the 
IP? 
● 
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible will 
be provided. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor.  While it is very important that the 
investigator always assesses causality for every event before the initial transmission of the 
SAE data to the sponsor, the initial report should be submitted without delay (i.e., within 
24 hours of awareness).  With limited or insufficient information about the event to make an 
informed medical judgment and in absence of any indication or evidence to establish a causal 
relationship, a causality assessment of “no” is to be considered.  In such instance, the 
investigator is expected to obtain additional information regarding the event as soon as 
possible and to re-evaluate the causality upon receipt of additional information.  The 
medically qualified investigator may revise his/her assessment of causality in light of new 


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information regarding the SAE and shall send an SAE follow-up report and update the eCRF 
with the new information and updated causality assessment. 
10.3.4 Assessment of Severity 
The investigator will use the following definitions to rate the severity of each AE: 
● Mild:  
No disruption of normal daily activities 
● Moderate: Affect normal daily activities 
● Severe:  
Inability to perform daily activities 
10.3.5 Recording and Follow-Up of AEs and/or SAEs 
AE and SAE Recording 
● 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
● 
The investigator will then record all relevant AE/SAE information in the eCRF. 
● 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the sponsor in lieu of completion of the eCRF. 
● 
There may be instances when copies of medical records for certain cases are requested 
by the sponsor.  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 to the 
sponsor. 
● 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Follow-Up of AEs and SAEs 
● 
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 
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. 
● 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post mortem findings 
including histopathology. 
● 
New or updated information will be recorded in the originally completed eCRF. 
● 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
10.3.6 Reporting Procedures for Serious Adverse Events 
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by fax or email immediately 
(within 24 hours of awareness). 


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The investigator must complete and submit the reports as required by local regulation, 
containing all necessary information, to the competent authority. 
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
delegation of authority log).  Signature confirms accuracy and completeness of the SAE data, 
as well as the investigator causality assessment including the explanation for the causality 
assessment. 
For contact details, see [Contact Details of Sponsor’s Key Personnel].  Fax or email the 
SAE/special situations/product defect worksheet to: 
Astellas Pharma Global Development Inc. 
Global Pharmacovigilance 
Fax number: +1-888-396-3750  
Email: safety-us@astellas.com (copy ACN_PV@astellas.com) 
 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor/study physician or their designee [Contact Details of Sponsor’s 
Key Personnel]. 
Follow-up information for the event should be sent promptly (as soon as available but no 
longer than within 7 days of the initial notification). 
Full details of the SAE should be recorded on the medical records, SAE/special situation 
worksheet and in the eCRF. 
The following minimum information is required: 
● 
International study number/study number 
● 
Subject number, sex and age 
● 
Date of report 
● 
Description of the SAE (event and seriousness criteria) 
● 
Causal relationship to the IP (including reason) 
● 
Drug provided (if any) 
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality, and 
expectedness of the events (e.g., SUSAR reporting) according to current local/regional 
regulatory requirements.  The sponsor or sponsor’s designee will submit expedited safety 
reports to competent authorities and concerned ethics committee per current local regulations 
and will inform the investigators of such regulatory reports as required.  Investigators must 
submit safety reports as required by their IRB/IEC within timelines set by regional 
regulations (e.g., EMA, FDA) where required.  Documentation of the submission to and 
receipt by the IRB/IEC of expedited safety reports should be retained by the study site.  In the 
US, FDA expedited Investigational New Drug (IND) reporting guidelines will be followed. 
The sponsor will notify all investigators responsible for ongoing clinical studies with the test 
product of all SUSARs, which require submission per local requirements IRB/IEC. 


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The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor. 
The investigator may contact the sponsor’s medical monitor/study physician for any other 
problem related to the rights, safety or well-being of the subject. 
10.3.7 Reporting Procedures for Special Situations 
10.3.7.1 Contraceptive Guidance and Collection of Pregnancy Information 
If a female subject becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 10.3.6 Reporting Procedures for Serious Adverse 
Events] using the SAE worksheet as a special situation and in the eCRF. 
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing and report the information to the sponsor according to the 
timelines in [Section 10.3.6 Reporting Procedures for Serious Adverse Events] using the 
special situation worksheet or pregnancy form. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data, etc., should be included in this 
information. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
subject as an AE in the eCRF or SAE per [Section 10.3.6 Reporting Procedures for Serious 
Adverse Events].  Subject pregnancy outcomes listed below are to be reported as SAEs: 
● 
Spontaneous abortion/miscarriage, abortion and missed abortion 
● 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the IP 
● 
If an infant dies more than 1 month after the birth, it is to be reported if a relationship 
between the death and intrauterine exposure to the IP is judged as “possible” by the 
investigator 
● 
Congenital anomaly (including anomaly in miscarried fetus) 
● 
Benign hydatidiform mole 
● 
Blighted ovum 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination or other 
means as appropriate.  (S)AEs experienced by the newborn/infant should be reported via the 
pregnancy reporting form.  Generally, follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. 


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10.3.7.2 Medication Error, Overdose and “Off-label Use” 
If a medication error (defined as an unintended failure in the treatment process that leads to, 
or has the potential to lead to, harm to the subject), overdose or “off-label use” (i.e., use 
outside of the target disease defined in the protocol) is suspected, refer to 
[Section 6.7 Treatment of Overdose].  Any associated (S)AEs are to be reported in the eCRF.  
If the AE meets the definition of an SAE, the SAE is also to be reported as described in 
[Section 10.3.6 Reporting Procedures for Serious Adverse Events] together with the details of 
the medication error, overdose and/or “off-label use.” 
10.3.7.3 Misuse/Abuse 
Definition of misuse: situations where the IP is/are intentionally and inappropriately used not 
in accordance with the intended use as defined in the protocol. 
Definition of abuse: persistent or sporadic, intentional excessive use of medicinal products 
which is accompanied by harmful physical or psychological effects. 
If misuse or abuse of the IP is suspected, the investigator must forward the special situation 
worksheet to the sponsor by fax or email immediately (within 24 hours of awareness).  Any 
associated (S)AEs are to be reported in the eCRF.  If the AE meets the definition of an SAE, 
the SAE is also to be reported as described in [Section 10.3.6 Reporting Procedures for 
Serious Adverse Events] together with details of the misuse or abuse of the IP. 
10.3.7.4 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the subject) to the IP occurs, the investigator must forward 
the special situation worksheet to the sponsor by fax or email immediately (within 24 hours 
of awareness).  Any associated (S)AEs occurring to the individual associated with or 
resulting from the special situation are to be reported on the special situations worksheet. 
10.3.7.5 Suspected Drug-drug Interaction 
If a drug-drug interaction associated with the IP is suspected, the investigator must forward 
the special situation worksheet to the sponsor by fax or email immediately (within 24 hours 
of awareness).  Any associated (S)AEs are to be reported in the eCRF.  If the AE meets the 
definition of an SAE, the SAE is also to be reported as described in [Section 10.3.6 Reporting 
Procedures for Serious Adverse Events] together with details of the suspected drug-drug 
interaction. 
10.3.8 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that is necessary for conducting the study 
properly, the sponsor will inform all investigators involved in the study as well as the 
appropriate regulatory authorities.  Investigators should inform the IRB/IEC of such 
information when needed. 
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the study. 


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10.3.9 Urgent Safety Measures 
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities, IRB/IEC, where applicable, in order to protect 
subjects from any immediate hazard to their health and/or safety.  Either the investigator or 
the sponsor can initiate a USM.  The cause of a USM can be safety-, product- or 
procedure-related. 
10.3.10 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the study physician (within 
24 hours of awareness).  Full details of the potential USM are to be recorded in the subject’s 
medical records.  The sponsor may request additional information related to the event to 
support their evaluation. 
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure the 
safety and welfare of the subjects.  These actions may include but are not limited to a change 
in study procedures or study treatment, halting further enrollment in the study, or stopping 
the study in its entirety.  The sponsor or sponsor’s designee will notify the relevant competent 
authorities and concerned ethics committee within the timelines required per current local 
regulations, and will inform the investigators, as required.  When required, investigators must 
notify their IRB/IEC within timelines set by regional regulations. 
10.4 
Appendix 4: Liver Safety Monitoring and Assessment 
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver 
injury during the course of the study.  It should be noted that this section does not specify the 
end-of-study analyses of liver enzymes.  The end-of-study liver enzymes analyses will be 
described in the SAP.  Any subject enrolled in a study with active drug therapy and reveals 
an increase of serum aminotransferases (AT) to > 3 × ULN or bilirubin > 2 × ULN should 
undergo detailed testing for liver enzymes (including at least alkaline phosphatase [ALP], 
ALT, AST and TBL).  Testing should be repeated within 72 hours of notification of the test 
results.  For studies for which a local laboratory is used, alerts will be generated by the local 
laboratory regarding moderate and severe liver abnormality to inform the investigator and 
study team.  Subjects should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN is as 
shown below. 


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Table 6 
Moderate and Severe Liver Abnormalities 
 
ALT or AST 
 
TBL 
Moderate 
> 3 × ULN 
or 
> 2 × ULN 
Severe 
> 3 × ULN 
and† 
> 2 × ULN 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; ULN: upper limit of 
normal 
†Samples taken simultaneously or within maximum 24 hours. 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and† TBL > 2 × ULN or INR > 1.5 (if INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN and† (TBL > 2 × ULN in subjects with liver metastases) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
†Samples taken simultaneously or within a maximum of 24 hours. 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and clinical laboratory tests.  The study site personnel are to complete 
the liver abnormality case report form (LA-CRF).  Subjects with confirmed abnormal liver 
function testing should be followed as described below. 
Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly, 
and then weekly or less if abnormalities stabilize or the IP has been discontinued and the 
subject is asymptomatic. 
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE.  The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to IP are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new-onset diseases are to be recorded as “AEs” within the eCRF.  Illnesses and 
conditions such as hypotensive events and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted.  Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic and/or diabetic subjects and may be associated with 


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fluctuating AT levels.  The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function. 
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets.  Medications are to be entered in the eCRF.  Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the subject’s history, other testing may be appropriate including:  
o 
Acute viral hepatitis (A, B, C, D, E or other infectious agents) 
o 
Ultrasound or other imaging to assess biliary tract disease 
o 
Other clinical laboratory tests, including INR and direct bilirubin 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Treatment Discontinuation 
In the absence of an explanation for increased liver function tests, such as viral hepatitis, 
preexisting or acute liver disease, or exposure to other agents associated with liver injury, the 
subject may be discontinued from study treatment.  The investigator may determine that it is 
not in the subject’s best interest to continue study treatment.  Discontinuation of study 
treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and† TBL > 2 × ULN or INR > 1.5) (if INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN and† (TBL > 2 × ULN in subjects with liver metastases) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
†Samples taken simultaneously or within a maximum of 24 hours. 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued. 
Hy’s Law definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant). 
The 2 “requirements” for Hy’s Law are: 
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in AT elevations > 3 × ULN (“2 × ULN elevations are too common in treated 
and untreated subjects to be discriminating”). 


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2. Cases of increased total bilirubin (at least 2 × ULN) with concurrent AT elevations at 
least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
ALP) or Gilbert’s syndrome [Temple, 2006]. 
FDA Guidance for Industry titled, “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control 
drug or placebo. 
2. Among subjects showing such AT elevations, often with ATs much greater than 
3 × ULN, one or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 
10.5 
Appendix 5: List of Excluded Concomitant Medications 
Any medication used for the management of OAB (including tricyclic antidepressants, 1st 
generation H1-antagonists and α1-AR antagonists) and any drugs that are sensitive 
CYP2D6 substrates with a narrow therapeutic index and sensitive P-gp substrates.  Use of 
these medications is not permitted during the study phase.  This list is not exhaustive.  In case 
of doubt, the investigator should contact the local study monitor.  
Subjects are allowed to continue ongoing treatment of α1-AR antagonists, 5α-reductase 
inhibitors (5-ARIs) and Phosphodiesterase type 5 inhibitors (PED-Is) in case of use for 
Benign Prostatic Hyperplasia (BPH). 




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Table 7 
Clinical Laboratory Tests 
Panel/Assessments 
Parameters to be Analyzed 
Hematology 
Hematocrit 
Hemoglobin 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Platelets 
Red blood cell count 
White blood cell count 
White blood cell count differential 
Biochemistry 
Albumin 
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Corrected serum calcium 
Creatinine 
Creatinine kinase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Total bilirubin (total and direct) 
Total protein 
Urinalysis 
Leukocyte esterase 
Nitrites 
pH 
Protein 
Red blood cells 
Human chorionic gonadotropin (female subjects only) 
Serology (Plasma/serum) 
HAV antibodies (IgM) 
HBsAg 
HBc antibodies 
HCV antibodies 
HIV antibodies  
Syphilis 
HAV: hepatitis A virus; HBc: hepatitis B core; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; 
HIV: human immunodeficiency virus; IgM: immunoglobulin M 
10.7 
Appendix 7: Overactive Bladder Symptom Score Questionnaire 
OABSS questionnaire (Please circle the score that best applies to your urinary condition 
during the past week in response to each question). 
Question 
Score 
Frequency 


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How many times do you typically urinate from waking in the 
morning until sleeping at night 
0 
7 or less 
1 
8 to 14 
2 
15 or more 
How many times do you typically wake up to urinate from 
sleeping at night until waking in the morning? 
0 
0 
1 
1 
2 
2 
3 
3 or more 
How often do you have a sudden desire to urinate, which is 
difficult to control? 
0 
Not at all 
1 
Less than once a week 
2 
Once a week or more 
3 
About once a day 
4 
2 to 4 times a day 
5 
5 times a day or more 
How often do you accidentally urinate because you can’t 
control the sudden desire to urinate? 
0 
Not at all 
1 
Less than once a week 
2 
Once a week or more 
3 
About once a day 
4 
2 to 4 times a day 
5 
5 times a day or more 
10.8 
List of Abbreviations and Definition of Key Study Terms 
List of Abbreviations 
 
Abbreviations 
Description of abbreviations 
ACN 
Astellas Pharma China, Inc. 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AR 
adrenoceptor 
AST 
aspartate aminotransferase 
AT 
aminotransferases 
BPH 
Benign Prostatic Hyperplasia 
CIOMS 
Council for International Organizations of Medical Sciences 
CSR 
clinical study report 
CYP3A 
cytochrome P450, family 3, subfamily 
CYP2D6 
cytochrome P450 2D6 
DBP 
diastolic blood pressure 
DPD 
Data Protection Directive 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
eCRF 
electronic case report form 
e-diary 
electronic diary 
EEA 
European Economic Area 
EoT 
end of treatment 


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Abbreviations 
Description of abbreviations 
EPIC 
European Prospective Investigation into Cancer and Nutrition 
EU 
European Union 
5-ARIs 
5α-reductase inhibitors 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
HAV 
hepatitis A virus 
HBc 
hepatitis B core 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICS 
International Continence Society 
IDL 
Imported Drug License 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LA-CRF 
liver abnormality case report form 
LS 
least squares 
LQTS 
long QT syndrome 
MMRM 
Mixed Models Repeated Measures 
MPR 
medication possession ratio 
NMPA 
National Medical Products Administration 
NOBLE 
National Overactive Bladder Evaluation 
OAB 
overactive bladder 
OABSS 
OAB Symptom Score 
OCAS 
oral controlled absorption system 
PED-Is 
Phosphodiesterase type 5 inhibitors 
P-gp 
P-glycoprotein 
PPIUS 
Patient perception of intensity of urgency scale 
PVR 
post-void residual 
QA 
quality assurance 
QC 
quality control 


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Abbreviations 
Description of abbreviations 
QTcF 
corrected QT interval by Fredericia 
QTLs 
quality tolerance limits 
RCTs 
randomized controlled trials 
RSI 
reference safety information 
(S)AE 
serious adverse event or adverse event 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SE 
standard error 
SOP 
standard operating procedure 
SSRIs 
Selective Serotonin Reuptake Inhibitors 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
TBL 
total bilirubin 
ULN 
upper limit of normal 
USM 
urgent safety measure 
UTI 
urinary tract infection 
WOCBP 
woman of childbearing potential 


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Definition of Key Study Terms 
Terms 
Definition of Terms 
Baseline 
The last non-missing observation prior to first administration of IP, unless 
otherwise specified. 
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a study. 
Note: not all endpoints are themselves assessments since certain endpoints 
might apply to populations or emerge from analysis of results.  That is, 
endpoints might be facts about assessments (e.g., prolongation of survival). 
Enroll 
To register or enter a subject into a study.  Note: once a subject has received 
the IP or placebo, the protocol applies to the subject. 
Investigational 
Product 
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study 
(e.g., health-related quality of life, efficacy, safety and pharmacoeconomics). 
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test product or comparative drug (sometimes without 
randomization) is given to a subject and continues until the last assessment 
after completing administration of the test product or comparative drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol.  Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Randomization 
The process of assigning subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias. 
NOTE: unequal randomization is used to allocate subjects into groups at a 
differential rate; for example, 3 subjects may be assigned to a treatment 
group for every 1 assigned to the control group. 
Screen failure 
Potential subject who signed the ICF, but did not meet one or more criteria 
required for participation in the study and was not randomized. 
Screening 
A process of active consideration of potential subjects for randomization in a 
study. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent form until just before the test product 
or comparative drug (sometimes without randomization) is given to a 
subject. 
Study period 
Period of time from the first study site initiation date to the last study site 
completing the study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 


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11 
REFERENCES 
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al.  The standardisation of 
terminology of lower urinary tract function: report from the Standardisation Sub-committee of 
the International Continence Society.  Neurourol Urodyn.  2002;21(2):167-78. 
Andersson KE.  New developments in the management of overactive bladder: focus on mirabegron 
and onabotulinumtoxinA.  Ther Clin Risk Manag.  2013;9:161-70. 
Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D.  The effects of 
antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-
analysis.  Eur Urol.  2008;54(3):543-62. 
Chapple CR, Cardozo L, Nitti VW, Siddiqui E, Michel MC.  Mirabegron in overactive bladder: a 
review of efficacy, safety, and tolerability.  Neurourol Urodyn.  2014;33:17-30. 
Charlson ME, Pompei P, Ales KL, Mackenzie CR.  A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation.  J Chronic Dis.  
1987;40(5):373-83. 
Chen D, Li Y.  The impact of overactive bladder on quality of life in south of China.  J Sci Appl: 
Biomed.  2016;4(2):19-23. 
Chuang YC, Liu SP, Lee KS, Liao L, Wang J, Yoo TK, et al.  Prevalence of overactive bladder in 
China, Taiwan and South Korea: Results from a cross-sectional, population-based study.  Low 
Urin Tract Symptoms.  2019;11(1):48-55. 
Coyne KS, Elinoff V, Gordon DA, Deng DY, Brodsky M, Glasser DB, et al.  Relationships between 
improvements in symptoms and patient assessments of bladder condition, symptom bother and 
health-related quality of life in patients with overactive bladder treated with tolterodine.  Int J 
Clin Pract.  2008;62(6):925-31. 
Investigator’s Brochure, Mirabegron Adult Monotherapy, Astellas. 
Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, et al.  Population-based survey of 
urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five 
countries: results of the EPIC study.  Eur Urol.  2006;50(6):1306-14. 
Lapitan MC, Chye PL.  The epidemiology of overactive bladder among females in Asia: a 
questionnaire survey.  Int Urogynecol J Pelvic Floor Dysfunct.  2001;12(4):226-31. 
Moorthy P, Lapitan MC, Quek PL, Lim PH.  Prevalence of overactive bladder in Asian men: an 
epidemiological survey.  BJU Int.  2004;93(4):528-31. 
Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V et al.  A systematic review and meta-
analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder.  Eur 
Urol.  2008;54(4):740-63. 
Neurourology and Urodynamics.  2015;34:685–92. 
Neurourology and Urodynamics.  2019;38(2):433-77.  doi: 10.1002/nau.23897. 


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Osman NI, Chapple CR.  Overactive bladder syndrome: Current pathophysiological concepts and 
therapeutic approaches.  Arab J Urol.  2013;11(4):313-18. 
Package Insert of Mirabegron Sustained-release Tablets, 2017. 
Sexton CC, Notte SM, Maroulis C, Dmochowski RR, Cardozo L, Subramanian D, et al.  Persistence 
and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a 
systematic review of the literature.  Int J Clin Pract.  2011;65(5):567-85. 
Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, et al.  Prevalence and 
burden of overactive bladder in the United States.  World J Urol.  2003;20(6):327-36. 
Temple R.  Hy’s law: predicting serious hepatotoxicity.  Pharmacoepidemiol Drug 
Saf.  2006;15:241-3. 
Urology.  2006;68(2):318-23.  doi: 10.1016/j.urology.2006.02.042. 


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 (Electronic signatures are attached at the end of the document). 
 
 
Signature: ______________________ 
 
 
 
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Signature: ______________________ 
 
  
 
 
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Date (DD Mmm YYYY) 
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Final Version 3.0 dated 19-May-2022 
 
 
A Phase 4, Open-label, Randomized, Prospective, Interventional Post-authorization Efficacy 
and Safety Study of Mirabegron 50 mg and 25 mg for the Treatment of Overactive Bladder in 
Chinese Subjects 
 
Open-label Phase 4 Study with Mirabegron 50 mg and 25 mg in Chinese Subjects with 
Overactive Bladder 
 
 
 
ISN: 178-MA-2295 
 
 
 
 
 
Astellas Pharma China, Inc. 
 
No 3 Jia 6 Road 10 
Shenyang Economic and Technological DeYes.velopment Zone, 
Shenyang 110027 China 
 
 
 
This document contains confidential information which is the intellectual property of Astellas. By accepting or reviewing 
this document, you agree to hold this information in confidence and not copy or disclose it to others or use it for 
unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) where 
disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of such information 
is made to a member of the investigator’s team who agrees to hold this information in confidence. 


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Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 5 
1 
INTRODUCTION ································
································
··················
 8 
2 
STUDY OBJECTIVE(S) AND DESIGN ································
·······················
 8 
2.1 
Study Objectives ································
································
···············
 8 
2.1.1 
Estimand ································
································
···················
 9 
2.2 
Study Design ································
································
····················
 9 
2.3 
Randomization ································
································
·················
 11 
3 
SAMPLE SIZE································
································
·····················
 11 
4 
ANALYSIS SETS ································
································
·················
 11 
4.1 
All Enrolled Set ································
································
···············
 12 
4.2 
All Randomized Set ································
································
···········
 12 
4.3 
Full Analysis Set ································
································
··············
 12 
4.4 
Safety Analysis Set ································
································
···········
 12 
5 
EFFICACY ENDPOINTS ································
································
·······  12 
5.1 
Primary Efficacy Endpoint ································
································
···  16 
5.2 
Secondary Efficacy Endpoints ································
·······························
 17 
5.2.1 
Mean Number of Micturitions per 24 hours (Week 4 and Week 8) ···············
 17 
5.2.2 
Mean Number of Urgency Episodes per 24 hours ································
···  17 
5.2.3 
Mean Number of Daytime and Nighttime Incontinence Episodes per 24 
hours ································
································
······················
 18 
5.2.4 
Mean Number of Urge Incontinence Episodes per 24 hour ························
 18 
5.2.5 
Overactive Bladder Symptom Score (OABSS) ································
······  19 
5.2.6 
Efficacy Endpoints for the Mirabegron 25 mg Starting Dose ······················
 19 
5.3 
Exploratory Endpoints ································
································
········  19 
5.4 
Safety Endpoints ································
································
··············
 20 
5.4.1 
Adverse Events ································
································
··········
 20 
5.4.2 
Vital Signs ································
································
················
 21 
5.4.3 
Clinical Laboratory Variables ································
··························
 21 
5.4.4 
Physical Examination ································
································
···  22 
5.4.5 
12 Lead ECGs ································
································
···········
 23 
5.4.6 
Post Void Residual Volume ································
····························
 23 
5.5 
Other Endpoints ································
································
···············
 23 
5.5.1 
Exposure to Study Drug ································
································
 23 
5.5.2 
Compliance to Study Drug ································
·····························
 24 
6 
STATISTICAL METHODOLOGY ································
···························
 25 
6.1 
General Considerations ································
································
·······  25 


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6.2 
Study Population ································
································
··············
 26 
6.2.1 
Disposition of Subjects ································
································
· 26 
6.2.2 
Protocol Deviations ································
································
·····  26 
6.2.3 
Demographic and Other Baseline Characteristics ································
···  27 
6.2.4 
Previous and Concomitant Medications ································
··············
 27 
6.3 
Study Drug Exposure and Compliance ································
·····················
 27 
6.3.1 
Exposure ································
································
··················
 28 
6.3.2 
Treatment Compliance ································
································
··  28 
6.4 
Analysis of Efficacy ································
································
··········
 29 
6.4.1 
Analysis of Primary Efficacy Endpoint ································
···············
 29 
6.4.2 
Analysis of Secondary Efficacy Endpoints ································
···········
 30 
6.5 
Analysis of Safety ································
································
·············
 31 
6.5.1 
Adverse Events ································
································
··········
 32 
6.5.2 
Clinical Laboratory Evaluation ································
························
 33 
6.5.3 
Vital Signs ································
································
················
 35 
6.5.4 
Electrocardiograms ································
································
······  35 
6.5.5 
Pregnancies ································
································
···············
 36 
6.5.6 
Other Safety-Related Assessments ································
····················
 36 
6.6 
Analysis of Pharmacokinetics ································
·······························
 37 
6.7 
Analysis of Pharmacodynamics ································
·····························
 37 
6.8 
Other Analyses ································
································
················
 37 
6.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 37 
6.10 
Additional Conventions ································
································
······  37 
6.10.1 
Analysis Windows ································
································
······  37 
6.10.2 
Imputation Rules for Incomplete Dates ································
···············
 38 
6.10.3 
Outliers ································
································
···················
 40 
7 
REVISION AND RATIONALE ································
································
 41 
7.1 
List of Changes in SAP Version 2.0 from Version 1.0 ································
···  41 
7.2 
List of Changes in SAP Version 3.0 from Version 2.0 ································
···  42 
8 
REFERENCES ································
································
····················
 43 
9 
APPENDICES ································
································
·····················
 44 
9.1 
Pooling of Sites Algorithm ································
································
···  44 
9.2 
List of Excluded Concomitant Medications································
················
 45 
9.3 
AEs of Interest not covered by Standard MedDRA SMQs v23.0 ·······················
 46 
9.4 
Key Contributors ································
································
··············
 47 
9.5 
Author and Approver Signatures ································
····························
 48 
 


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List of In-text Tables 
Table 1 
3-Day Diary Definitions and Calculations ································
·················
 14 
Table 2 
Daytime and Nighttime ································
································
·······  16 
Table 3 
Standardized MedDRA Queries and PTs ································
··················
 21 
Table 4 
Laboratory Assessments ································
································
······  22 
Table 5 
Visit Windows for Efficacy and Safety Parameters ································
·······  37 
 
List of In-text Figures 
Figure 1 
Study Schema ································
································
··················
 10 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations  
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
APGD 
Astellas Pharma Global Development 
ASCM 
Analysis Set Classification Meeting  
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Intervals 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
GCMSL 
Global Clinical Modeling & Simulation Lead 
GD 
Global Development 
H 
High 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
Investigational Product 
IWRS 
Interactive Web Response System 
L 
Low 
LS 
Least Squares 
LLN  
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Models Repeated Measures 
ms 
Millisecond 
N 
Normal 
OAB 
Overactive Bladder 
OABSS 
OAB Symptom Score 


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Abbreviations 
Description of abbreviations 
PD 
Pharmacodynamic 
PD1-x 
Protocol Deviation 1-x 
PPIUS 
Patient Perception of Intensity of Urgency Scale 
PT 
Preferred Term 
PVR 
Post Void Residual 
QTc 
Corrected Q-T Interval 
QTcF 
QT interval corrected by Fridericia's formula 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS  
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
UTI 
Urinary Tract Infection 
WHO-DG 
World Health Organization Drug Global 
 


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List of Key Terms 
Terms 
Definition of terms 
Baseline  
The last non-missing observation prior to first administration of IP, unless 
otherwise specified. 
Discontinuation 
The act of concluding participation in a trial by an enrolled subject, prior to 
completion of all protocol required elements.   
Note: subject discontinuation does not necessarily imply exclusion of subject 
data from analysis that was collected prior to discontinuation. 
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a study. 
Note: not all endpoints are themselves assessments since certain endpoints 
might apply to populations or emerge from analysis of results. That is, 
endpoints might be facts about assessments (e.g., prolongation of survival). 
Enroll 
To register or enter a subject into a study. Note: once a subject has received 
the IP or placebo, the protocol applies to the subject. 
EoT result 
End of treatment result is based on the last available result which is obtained 
earlier or on the same date as the treatment stop date. 
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test product or comparative drug (sometimes without 
randomization) is given to a subject and continues until the last assessment 
after completing administration of the test product or comparative drug. 
Postinvestigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Randomization 
The process of assigning subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias. 
NOTE: unequal randomization is used to allocate subjects into groups at a 
differential rate; for example, 3 subjects may be assigned to a treatment group 
for every 1 assigned to the control group. 
Screening 
A process of active consideration of potential subjects for a trial. 
Screening period 
Period of time before entering the investigational period, usually from the 
time the subject signed informed consent until just before the first dose of the 
study drug is given to a subject.   
Screening failure 
Potential subject who signed the ICF, but did not meet one or more criteria 
required for participation in the study and was not randomized. 
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Subject 
An individual in the population of interest who participates in a clinical trial 
as recipient of the investigational product. 
Treatment 
emergent adverse 
event 
An adverse event observed after starting administration of the study drug. 
 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes procedures for 
executing the statistical analysis to fulfil the objectives of the study.  
The final SAP will be approved prior to database hard lock.  If needed, revisions to the 
approved SAP may be made prior to database hard lock.  Revisions will be version 
controlled. 
Changes from the planned analyses in the final SAP that impact the statistical analyses will 
be documented in the Clinical Study Report (CSR).  
2 
STUDY OBJECTIVE(S) AND DESIGN 
2.1 
Study Objectives 
Objectives 
Endpoints 
Primary 
● 
To evaluate the efficacy of 
mirabegron 50 mg for the 
treatment of OAB in 
Chinese subjects 
● 
Change from baseline to the end of the 12-week treatment period in 
mean number of micturitions per 24 hours 
Secondary 
● 
To evaluate the safety of 
mirabegron for the 
treatment of OAB in 
Chinese subjects 
● 
Incidence and severity of AEs 
● 
Clinical laboratory tests (hematology, biochemistry and urinalysis) 
● 
Vital signs (blood pressure and pulse) 
● 
Routine 12-lead ECG 
● 
Post Void Residual (PVR) 
● To evaluate other efficacy 
variables of mirabegron 
50 mg for the treatment of 
OAB 
● 
Change from baseline to the end of the 12-week treatment period: 
○ 
Mean number of grade 3 or 4 (PPIUS) urgency episodes per 
24 hours 
○ 
Mean number of daytime incontinence episodes per 24 hours 
○ 
Mean number of nighttime incontinence episodes per 24 hours 
○ 
Mean number of urge incontinence episodes per 24 hours 
○ 
OAB Symptom Score (OABSS) 
● 
Change from baseline to Weeks 4 and 8: 
○ 
Mean number of micturitions per 24 hours 
○ 
Mean number of grade 3 or 4 (PPIUS) urgency episodes per 
24 hours 
○ 
Mean number of daytime incontinence episodes per 24 hours 
○ 
Mean number of nighttime incontinence episodes per 24 hours 
○ 
Mean number of urge incontinence episodes per 24 hours 
○ 
OAB Symptom Score (OABSS) 
Table continued on next page 


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Objectives 
Endpoints 
● 
To explore mirabegron 
starting dose of 25 mg 
● 
Change from baseline to weeks 4, 8, and 12 in: 
○ 
Mean number of micturitions per 24 hours 
○ 
Mean number of grade 3 or 4 (PPIUS) urgency episodes per 
24 hours 
○ 
Mean number of daytime incontinence episodes per 24 hours 
○ 
Mean number of nighttime incontinence episodes per 24 hours 
○ 
Mean number of grade 3 or 4 (PPIUS) urge incontinence episodes 
per 24 hours 
○ 
OAB Symptom Score (OABSS) 
AE: adverse event; OAB: overactive bladder; PPIUS: patient perception of intensity of  urgency scale; 
OABSS: OAB Symptom Score  
2.1.1 
Estimand 
The estimand of most clinical importance for this study is defined by the following four 
attributes: 
● Target population: all subjects who took at least 1 dose of the study drug, and in whom a 
nonmissing measurement for mean number of micturition per 24 hours at baseline and 
after administration of the study drug is available. 
● Outcome measurement: micturition frequency per 24 hours prior to switching (if 
switching occurs). 
● Intercurrent events: 
○ 
Dose escalation. 
● Population-based summary: change from baseline to week 12/end of treatment (EoT) in 
micturition frequency per day within dose groups. 
For this study, the treatment estimand is considered appropriate because of the fact that the 
response of subjects prior to switching is of primary interest. i.e., the estimate for 50 mg of 
mirabegron should be estimated from subjects who were randomized to 50 mg and the 
estimate for 25 mg should be estimated from subjects who were randomized to 25 mg while 
they were treated with 25 mg.  
2.2 
Study Design 
The study follows an open-label, randomized, 12-week, prospective, interventional 
postauthorization design for the treatment of OAB in approximately 249 Chinese subjects.  
Each subject will participate in one 12-week treatment period.  
This study is designed to support the Imported Drug License (IDL) renewal and mirabegron 
safety surveillance in China.  The data-cut with summaries and the planned primary analysis 
for the end of this study will be used for IDL renewal.  Subjects fulfilling the screening 
inclusion/exclusion criteria will be randomized in 2:1 ratio to 50 mg mirabegron and 25 mg 
mirabegron using a computer-generated randomization to reduce selection bias.  Treatments 
will be administered once daily orally after meal during a 12-week, open-label treatment 
period.  Study visits will take place at weeks 4, 8 and 12.  For 25 mg mirabegron group, a 
dose escalation to 50 mg is permitted on visit 3 and visit 4 according to investigators' 
discretion. 


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Planned total number of study sites include approximately 10 study sites across China. 
Figure 1 presents the study schema. 
Figure 1 
Study Schema 
 
a The investigators may want to assess if 25 mg dose is effective for this group. Subject to their discretions, a 
dose escalation to 50 mg is permitted on visit 3/week 4 or visit 4/week 8. 
b Telephone contact or site visit. 
The study consists of 3 periods with a total duration of 16 weeks.  
● 
Screening period (2 weeks): 
o This period starts with visit 1/week -2 (screening) and ends with visit 2/week 0 
(baseline). 
o After a successful visit 1 /week -1 to -2 (screening), all subjects will start with the 
completion of a 3-day bladder e-diary recording micturition frequency and 
incontinence episodes as well as collection of micturition volume over 2 days. The 
bladder e-diary should be completed over 3 consecutive days, at minimum 3 days, but 
not more than 7 days, prior to visit 2/week 0 (baseline).  
● 
Open-label, placebo-controlled period (12 weeks): 
o This period starts with the day after visit 2/week 0 (baseline) and ends with visit 
5/week 12 (EoT). 
o At visit 2/week 0 (baseline) inclusion and exclusion criteria will be evaluated.  
Subjects still fulfill the inclusion/exclusion criteria will enter the study.  These 
subjects will be randomized to receive 50 mg or 25 mg of mirabegron using a 2:1 
ratio.  Daily IP administration will start on day 1 (i.e., the day on visit 2/week 0 
[baseline]).  IP will be dispensed and collected on visit 2/week 0 (baseline), 
visit 3/week 4, visit 4/week 8 and visit 5/week 12 (only collected). 
o For 25 mg mirabegron group, a dose escalation to 50 mg is allowed on visit 3/week 4 
and visit 4/week 8 by investigator’s discretion. 
o Subjects will start with the subsequent 3-day bladder e-diaries minimally 3 days prior 
to the indicated visit. 
● 
Follow-up period (2 weeks): 
o This period starts the day after visit 5/week 12 (EoT) and ends with visit 6/week 14 
(end of study [EoS]).  The follow-up period is applicable to all subjects who have 
been randomized and received IP. 
o At visit 5/week 12 (EoT), IP administration will be stopped and a safety observation 
period of 2 weeks will start. 
An independent DSMB can be implemented.  A separate charter will describe the 
responsibilities of the DSMB. 
Randomization 
Mirabegron 
50 mg QD 
Mirabegron 
25 mg QD a 
Follow-Up 
Visits b 
Subjects with 
key entry criteria 
Obtain informed 
consent screening 
procedures 
2:1 


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A data cut with summaries and the planned primary analysis for the end of the study may be 
performed after 50% of subjects planned to be randomized have had their visit 5/week 
12/EoT assessment, for regulatory reporting purposes.  No decisions regarding conduct of the 
study (i.e., stopping) will be based on these results. 
Details of the schedule of clinical assessments are available in the protocol.  
2.3 
Randomization 
Subjects will be randomized in a 2:1 ratio to 50 mg mirabegron and 25 mg mirabegron using 
a computer-generated randomization Interactive Web Response System (IWRS).  All 
consented subjects who meet the eligibility criteria will be randomized through IWRS.  This 
service is set up prior to the study to allow the sites real-time allocation of the treatment to 
the next eligible subject based on the specifications and algorithm provided in the 
Randomization Specification Document.  At visit 2/week 0 (baseline), subjects will be 
assigned a randomization number in accordance with the randomization code generated by 
the sponsor’s designee. 
Subjects will be assigned a subject number at study entry (i.e., signing the Informed Consent 
Form (ICF)).  The subject numbers will be sequential and rising.  The subject number will 
comprise of a 5-digit clinical unit number and 5 digit screening number. 
Subjects will be randomized to receive IP according to the randomization schedule obtained 
via the IWRS system.  The study site personnel will dispense the treatment according to the 
IWRS system’s assignment.  Specific procedures for randomization through the IWRS 
system are contained in the study procedures manual. 
An enrolled subject who withdraws or discontinues before dosing or before randomization 
will be considered a screen failure.  Randomized subjects who withdraw or discontinue will 
not be replaced.  
3 
SAMPLE SIZE  
The sample size for this study is based upon change from baseline for mean number of 
micturitions/24 hours within a single treatment arm.  Change from baseline will be tested to 
determine if the change is different from zero i.e., a change in mean number of 
micturitions/24 hours.  When the sample size is 125, a single group t-test with a 5% two-
sided significance level will have 80% power to detect a change of 0.9 micturitions with a SD 
of 3.562 [Neurourology and Urodynamics, 2015].  Assuming 25% of the subjects will drop 
out, about 166 subjects will be enrolled to yield 125 evaluable subjects in 50 mg group. 
4 
ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
The determination of whether subjects are included or excluded from the safety and efficacy 
analysis sets will be made prior to database hard-lock for the primary report.  


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4.1 
All Enrolled Set 
The All Enrolled Set consists of all subjects who sign the ICF. 
The All Enrolled Set will be used to summarize disposition of subjects who were screened. 
4.2 
All Randomized Set 
The All Randomized Set consists of all randomized subjects, i.e. all those subjects with a 
randomization number. 
The All Randomized Set will be used to summarize disposition of subjects who were 
randomized to treatment. 
4.3 
Full Analysis Set 
The Full Analysis Set (FAS) consists of subjects who are randomized and receive at least 
1 dose of IP and have at least 1 post baseline measurement for mean number of micturitions 
per 24 hours.  The FAS will be analyzed by treatment arm as randomized (i.e., treatment arm 
based on randomization assignment). 
The FAS will be used for summaries of demographic and baseline characteristics and will be 
the primary analysis set for efficacy analyses.   
4.4 
Safety Analysis Set 
The Safety Analysis Set (SAF) will consist of all subjects who took at least 1 dose of IP.  The 
safety set will be analyzed by treatment arm as treated (i.e., based on the treatment the 
subject actually received rather than the treatment to which the subject was randomized). 
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety- and tolerability-related variables. 
5 
EFFICACY ENDPOINTS  
Efficacy data will be summarized by treatment group (25 mg and 50 mg) and visit, unless 
otherwise specified. 
Data for the efficacy endpoints will be recorded on an e-diary. 
The bladder diary is part of the subject’s e-diary which is used to collect micturition 
frequency, urgency and incontinence episodes as well as volume measurements.  In the 3-day 
bladder e-diary micturition frequency, urgency and incontinence episodes will be recorded as 
well as collection of micturition volume over 2 days.  Diaries will be completed at home by 
the subject in the week prior to visit 2/week 0 (baseline), visit 3/week 4, visit 4/week 8 and 
visit 5/week 12 for three consecutive days.  Completion of 3-day bladder diaries should start 
minimally 3 days (but not more than 7 days) prior to the visit.  
The following information will be recorded by the patient in the bladder diary:  
● 
Time to awake,  
● 
Time to bed,  
● 
Time of episode, 


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● 
Type of episode (micturition and/or incontinence), 
● 
Urgency severity, 
● 
Volume of micturition (mL) [collected prior to Visit 1 only]. 
The information from the diaries will be used to evaluate the efficacy of treatment or 
inclusion and/or exclusion from the study (e.g., subjects who have an average total daily 
urine volume > 3000 mL recorded in a 3-day diary at Visit 1; subjects who have an average 
of < 8 micturitions/24 hours; or subjects who have an average of <1 episode of grade 3 or 4 
(PPIUS) urgency and <1 urgency incontinence/24 hours, during a 3-day micturition diary 
period).  Therefore, patients will receive full instructions and training on how to complete the 
diary at Screening (Visit  1) and will be counseled on the importance of completing the 
diaries prior to the next visit.  The diaries and questionnaires will be reviewed during each 
visit after Screening (Visit 1) by the investigator or designee to ensure accuracy of 
completion. 
Voiding episodes will be recorded in one of three ways: “micturition”, “incontinence”, or 
“micturition and incontinence” in the electronic diary. Micturitions will be counted for 
“urination” episodes in which the patient fully voids in the toilet.  “Incontinence” will be 
counted for episodes in which the full void was incontinent and the patient did not make it to 
the toilet to finish urinating.  If a patient experienced incontinence and then passed urine into 
the toilet this should be recorded as “micturition and incontinence”.  
Definitions of efficacy variables based on the 3-day micturition diary are presented in 
Table 1.  


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Table 1 
3-Day Diary Definitions and Calculations 
Measurement 
Definition 
Calculation 
Micturition 
Any voluntary micturition 
(excluding incontinence only 
episodes). 
A micturition episode is counted as micturition 
regardless of whether volume voided was 
recorded or not. A micturition recorded before 
midnight of the first day or after midnight on the 
3rd day of the 3-day micturition diary period will 
not be counted. A micturition will also be 
counted if the patient assessed an episode as both 
micturition and incontinence. 
Valid Diary Day 
A diary day in which at least 
one voluntary micturition 
episode occurs. A diary day 
with episodes of incontinence 
only is not considered a valid 
diary day. 
A diary day is considered valid if at least one 
micturition was recorded on this calendar day. 
Days of visits to the clinic will not be counted as 
valid diary days. 
Number of Valid Diary 
Days 
Number of valid diary days 
per each 3-day micturition 
diary period. 
Count of the valid diary days during the 3-day 
micturition diary period. Days of visits to the 
clinic will not be counted as valid diary days. 
Valid Diary  
A valid diary is a diary with 
at least 2 valid diary days 
within the analysis visit 
window (i.e., minimally 
3 days but not more than 7 
days prior to the indicated 
visit). If more than 3 valid 
diary days are recorded, then 
the last 3 days will be used in 
the calculations.  
Not applicable. 
Incontinence Episode 
The complaint of any 
involuntary leakage of urine. 
An incontinence episode is counted if it was 
recorded in the diary on a valid diary day. An 
incontinence will also be counted if the patient 
assessed an episode as both micturition and 
incontinence. 
Number of Incontinence 
Episodes 
Number of times a patient 
records an incontinence 
episode during the 3-day 
micturition diary period. 
Total number of incontinence episodes recorded 
during the 3-day micturition diary period. 
Table continued on next page 


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Measurement 
Definition 
Calculation 
Severity of Urinary 
Urgency (based on 
PPIUS) 
Each micturition and/or 
incontinence episode is 
graded using the following 
5-point scale based on 
PPIUS: 
0 = No urgency, I felt no 
need to empty my bladder, 
but did so for other reasons. 
1 = Mild urgency, I could 
postpone voiding as long as 
necessary, without fear of 
wetting myself 
2 = Moderate urgency, I 
could postpone voiding for a 
short while, without fear of 
wetting myself 
3 = Severe urgency, I could 
not postpone voiding, but had 
to rush to the toilet in order 
not to wet myself 
4 = Urge incontinence, I 
leaked before arriving to the 
toilet. 
Not Applicable 
Urge Incontinence 
Episode 
The involuntary leakage of 
urine accompanied by or 
immediately preceded by 
urgency. 
One urge incontinence episode is counted for 
each record of the diary in which the following 
occurs:  
- incontinence episode is recorded AND 
- severity of urinary urgency recorded is 3 or 4 
NOTE: Only urge incontinence episodes 
recorded on a valid diary day will be counted. 
Number of Urge 
Incontinence Episodes 
Number of times a patient 
records an urge incontinence 
episode during the 3-day 
micturition diary period. 
Number of urge incontinence episodes recorded 
on valid diary days of the 3-day micturition diary 
period. 
Urgency Episodes 
(severity of 3 or 4) 
The complaint of a sudden, 
compelling desire to pass 
urine, which is difficult to 
defer. 
One urgency episode is counted for each record 
of the diary in which the following occurs:  
- micturition or incontinence episode is recorded 
AND 
- severity of urinary urgency recorded is 3 or 4 
NOTE: Only urgency episodes recorded on a 
valid diary day will be counted. If an episode 
was recorded as both a micturition and an 
incontinence episode with a urinary urgency of 3 
or 4, it will be counted as one urgency episode. 
 
In the event that in the 3-day Diary there are two entries with the same collection date and 
time but with different times of entry on the device, the last entry (time) will be used for 
analysis, regardless of episode characteristics. 


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For number of incontinence episodes, diary data will be classified as either “daytime” or 
“nighttime”, where “daytime” is considered to mean “between waking up in the morning and 
going to sleep later the same day or next day” and “nighttime” means “between going to 
sleep on a day and waking up on the same or next day.  These times are entered on this diary 
by the subject.  
For classifying daytime and nighttime data see Table 2. 
Table 2 
Daytime and Nighttime  
Day 
Time Period 
Daytime/Nighttime 
Classification 
Day -3,  
Diary Day 1 
Midnight (00:00) to reported wake time 
Nighttime 
Reported wake time to reported sleep time 
Daytime 
Reported sleep time to midnight (23:59) 
Nighttime 
Day -2,  
Diary Day 2 
Midnight (00:00) to reported wake time 
Nighttime 
Reported wake time to reported sleep time 
Daytime 
Reported sleep time to midnight (23:59) 
Nighttime 
Day -1*, 
Diary Day 3 
Midnight (00:00) to reported wake time 
Nighttime 
Reported wake time to reported sleep time 
Daytime 
Reported sleep time to midnight (23:59) 
Nighttime 
*Note: Day -1 is the last valid diary day prior to the visit to the clinic 
The procedure for calculating the efficacy endpoints is described below: 
Step 1: Take the last valid diary day closest to the visit to the clinic. 
Step 2: Take the two prior consecutive diary days (this makes the 3 consecutive diary days 
that will be used for the calculations). 
Step 3: Count the number of valid diary days within these 3 consecutive days. 
Step 4: If the number of valid diary days ≥ 2 then go to Step 5, else result of endpoint is 
missing. 
Step 5: Calculate the result for the endpoint as described in Sections 5.1 and 5.2. 
Baseline for bladder data will be defined as the last non-missing observation prior to first 
administration of IP, unless otherwise specified.  
5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to week 12 in mean number of 
micturitions per 24 hours. 
Number of micturitions per 24 hours will be derived from the Bladder Diary: responses “Pee 
in toilet” and “Pee in toilet and Leakage”. 
The mean number of micturitions is equal to the total number of micturitions recorded on 
valid diary days during the 3-day micturition diary period divided by the number of valid 
diary days during the 3-day micturition diary period. 


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For each subject, the mean number of micturitions at Visit x (x=2, 3, 4 and 5), using all 
available number of micturitions per 24 hours for the valid days in the diary, will be 
calculated as: 
Sum of the number of micturitions (per 24 hrs) over the valid diary days prior to Visit x
Number of valid diary days
 
Note: Incontinence only episodes will be excluded. 
A micturition will also be counted if the subject assessed an episode as both micturition and 
incontinence (leakage). 
If data of more than 3 days prior to a visit are available, only the last 3 days prior to the visit 
will be used for the analysis. 
Subjects without baseline or any post-baseline value will not be included in the change from 
baseline calculation although they will be included in the summary for either baseline or any 
post-baseline visit whichever timepoint the data is available. 
Change from baseline to visit 5/week 12 is defined as:  
Result at visit 5/week 12  –  Result at baseline (visit 2/week 0). 
5.2 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints, as derived from the e-diary, are the change from 
baseline to weeks 4, 8 and 12 in: 
● 
Mean number of micturitions per 24 hours (only week 4 and week 8) 
● 
Mean number of urgency episodes per 24 hours 
● 
Mean number of daytime incontinence episodes per 24 hours 
● 
Mean number of nighttime incontinence episodes per 24 hours 
● 
Mean number of urge incontinence episodes per 24 hours 
● 
OABSS, the sum score of four symptoms (daytime frequency, nighttime frequency, 
urgency, and urge incontinence) 
5.2.1 
Mean Number of Micturitions per 24 hours (Week 4 and Week 8) 
Derivation of the endpoint is the same described in Section 5.1.  
Change from baseline to visit 3/week 4 is defined as:  
Result at visit 3/week 4  –  Result at baseline (visit 2/week 0). 
Change from baseline to visit 4/week 8 is defined as:  
Result at visit 4/week 8  –  Result at baseline (visit 2/week 0). 
5.2.2 
Mean Number of Urgency Episodes per 24 hours 
Mean number of urgency episodes per 24 hours (see definition in Table 1) is derived from 
“PPIUS-Urgency of the Micturition” from Bladder Diary. 


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Scoring PPIUS scale: 
● 
Grade 0: No urgency – I felt no need to empty my bladder, but did so for other reasons 
● 
Grade 1: Mild urgency – I could postpone voiding as long as necessary, without fear of 
wetting myself 
● 
Grade 2: Moderate urgency – I could postpone voiding for a short while, without fear of 
wetting myself 
● 
Grade 3: Severe urgency – I could not postpone voiding, but had to rush to the toilet in 
order not to wet myself 
● 
Grade 4: Urge incontinence – I leaked before reaching the toilet 
Let N34 equal the number of times that a subject recorded a grade 3 or 4 urgency episode on a 
diary day.  If there are no valid diary days, then N34 is missing, while if there are no grade 3 
or 4 urgency episodes on a valid diary day, then N34 equals 0. 
For each subject, the mean number of grade 3 or 4 urgency episodes per 24 hours, at Visit x 
(x=2, 3, 4 and 5), is the mean of N34 over the valid diary days of the Episodic Diary. 
Sum of the number of grade 3 −4 urgency episodes (per 24 hrs) over the valid diary days prior to Visit x
Number of valid diary days
 
 
5.2.3 
Mean Number of Daytime and Nighttime Incontinence Episodes per 24 hours 
Number of Incontinence Episodes per 24 hours will be derived from “Number of 
Incontinence Episodes During the Day” and “Number of Incontinence Episodes During the 
Night” collected in the Bladder Diary: responses “Pee in toilet and Leakage” and “Leakage”. 
The number of incontinence episodes during the day includes the episodes from the time 
when subject wakes up until the time the subject sleeps. The number of incontinence 
episodes during the night includes the episodes from the time the subject sleeps till the next 
morning wake up time, see Table 2. 
For each subject, the mean number of incontinence episodes per day/night (during the 
day/night) at Visit x (x=2, 3, 4 and 5) will be calculated using all available number of 
incontinence episodes for the valid diary days in the Diary for daytime and for nighttime:  
Mean Number  of Daytime Incontinence Episodes at Visit x = 
              Total number of ”Daytime Leakage Counts"  over the Valid Diary Days prior to Visit x
Number of Valid Diary Days
 
 
Mean Number  of Nighttime Incontinence Episodes at Visit x = 
                Total number of ”Nighttime Leakage Counts"  over the Valid Diary Days prior to Visit x
Number of Valid Diary Days
 
 
5.2.4 
Mean Number of Urge Incontinence Episodes per 24 hour 
Number of urge incontinence episodes per 24 hours will be derived from the Bladder Diary: 
responses “Pee in toilet and Leakage”, “Leakage” and a PPIUS score of 3 or 4. 


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For each subject, the mean number of urge incontinence episodes at Visit x (x=2, 3, 4 and 5), 
using all available incontinence periods and PPIUS scores for the valid days in the diary, will 
be calculated as: 
Sum of the number of urge ncontinence episodes (per 24 hrs) over the valid diary days prior to Visit x
Number of valid diary days
 
 
5.2.5 
Overactive Bladder Symptom Score (OABSS) 
Baseline for OABSS is defined as the day the subject visits the clinic for visit 2. 
The OABSS questionnaire is designed to quantify OAB symptoms as a single score, and 
contains questions that address 4 symptoms of overactive bladder: 
● 
Daytime frequency, 
● 
Nighttime frequency, 
● 
Urgency, 
● 
Urge incontinence. 
The OABSS is composed of 4 questions (one per each symptom) and has a minimum score 
of 0 and a maximum score of 15. If a subject experiences a more urgent episode the 
corresponding urgency score is higher and, consequently, the total score will be higher (see 
[Section 10.7 Appendix 7 Overactive Bladder Symptom Score questionnaire in the 
protocol]).  If one or more of the 4 questions are not answered in the eDiary then the OABSS 
will be set to missing. 
Questionnaires to be completed by the subject at the site in the local language and provided 
via the e-diary.  In case the subject forgets to bring the device, then a back-up device will be 
used.  Results will be directly entered in the e-diary by the subject. 
5.2.6 
Efficacy Endpoints for the Mirabegron 25 mg Starting Dose 
The following efficacy endpoints for the Mirabegron 25 mg starting dose will be evaluated 
with descriptive statistics: 
● 
Change from baseline to weeks 4, 8, and 12 in mean number of micturition/24 hours; 
● 
Change from baseline to weeks 4, 8, and 12 in mean number of grade 3 or 4 (PPIUS) 
urgency episodes; 
● 
Change from baseline to weeks 4, 8, and 12 in mean number of incontinence 
episodes; 
● 
Change from baseline to weeks 4, 8, and 12 in urge incontinence episodes/24 hours; 
● 
Change from baseline to weeks 4, 8, and 12 in OABSS. 
5.3 
Exploratory Endpoints 
There are no exploratory endpoints. 


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5.4 
Safety Endpoints 
Safety data will be summarized for both treatment groups (‘Mirabegron 50 mg’ and 
‘Mirabegron 25 mg’) and visit, unless otherwise specified. Safety data will be assessed by 
evaluation of the following variables: 
● 
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and 
relationship to study drug). 
● 
Clinical laboratory variables (hematology, biochemistry including liver enzymes and 
total bilirubin, and urinalysis) 
● 
Vital signs (systolic and diastolic blood pressure, pulse rate and body temperature) 
● 
12-lead electrocardiogram (ECG) 
● 
Post Void Residual Volume (PVR) 
The following sequence order will be in effect when more than 1 assessment is required at a 
time point: routine 12-lead ECG, vital signs, and samples for safety laboratories. 
5.4.1 
Adverse Events 
AEs will be coded using MedDRA.  A TEAE is defined as an AE observed after starting 
administration of the IP until 30 days after the final administration of IP.  If the adverse event 
occurs on Day 1 and the onset check box on the (AE) eCRF is marked “Onset after first dose 
of study drug” or the onset check box is left blank, then the adverse event will be considered 
treatment emergent.  If the adverse event occurs on Day 1 and the onset check box is marked 
“Onset before first dose of study drug”, then the adverse event will not be considered 
treatment emergent.  If a subject experiences an event both during the pre-investigational 
period and during the investigational period, the event will be considered as TEAE only if it 
has worsened in severity (i.e., it is reported with a new start date). 
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.  
AEs may be upgraded by the sponsor according to the Important Medical Event process. 
A drug-related TEAE is defined as any TEAE with at least a possible relationship to study 
treatment as assessed by the investigator or with a missing assessment of the causal 
relationship. 
Common TEAEs are defined as preferred terms (PTs) that have been reported by at least 5% 
of the subjects, in any treatment group.  
When an AE start or stop date is missing, the date will be imputed using the rules in 
Section 6.10.2.2. 
Adverse Events of Special Interest  
Adverse Events of Special Interest include: 
● 
Increased heart rate and tachycardia 
● 
Increased blood pressure 


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● 
Hypersensitivity reactions 
● 
Urinary retention 
● 
QT prolongation 
AEs of interest will be identified using all Preferred Terms (PT) from Standardized MedDRA 
queries (SMQ), version 23.0 or higher, see Table 3, or sponsor-defined list of search terms, 
see Appendix 9.3 AEs of Interest not covered by Standard MedDRA SMQs v23.0. 
Table 3 
Standardized MedDRA Queries and PTs 
CV - Increased blood pressure 
Hypertension SMQ – Narrow search 
CV - Increased heart rate and tachycardia  
Arrhythmia supraventricular (PT) 
Atrial tachycardia (PT) 
Heart rate abnormal (PT) 
Heart rate increased (PT) 
Rebound tachycardia (PT) 
Sinus tachycardia (PT) 
Supraventricular tachyarrhythmia (PT) 
Supraventricular tachycardia (PT) 
Tachyarrhythmia (PT) 
Tachycardia (PT) 
Tachycardia paroxysmal (PT) 
Ventricular tachyarrhythmia (PT) 
Ventricular tachycardia (PT) 
Maximum heart rate increased (PT) 
Hypersensitivity reactions  
Hypersensitivity SMQ – Narrow search 
CV - QT prolongation  
Torsade de pointes/QT prolongation SMQ – Broad search 
 
5.4.2 
Vital Signs 
Single blood pressure, pulse and body temperature measurements will be performed at 
visit 1/screening, visit 2/baseline, visit 3/week 4, visit 4/week 8, visit 5/week 12 (EoT).   
Measurements will be per standard clinic practices.  Single measurements of blood pressure, 
pulse, and body temperature will be measured in the sitting position (when possible, otherwise 
supine, but always in the same position). 
Body temperature will be measured with an ear thermometer. 
5.4.3 
Clinical Laboratory Variables 
Hematology, biochemistry and urinalysis assessments will be taken at visit 1/week -2 
(screening), and visit 5/week 12 (EoT). 
All clinical laboratory assessments will be performed at a local laboratory.  Urine pregnancy 
tests (female subjects of childbearing potential only) will be performed according to the 
clinical site’s preferred method at visit 1/week -2 (screening) and visit 5/week 12 (EoT) 
except for cases in which the possibility of pregnancy was clearly ruled out by hysterectomy, 
bilateral oophorectomy or the passage of 2 or more years after last menstruation. 
A blood sample will be collected for serology tests (HAV antibodies [IgM], HBc antibodies, 
HBsAg, HCV antibodies, syphilis and antibodies to HIV types 1 and 2) at screening only. 


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Additional hematology, biochemistry and urinalysis (UA dipstick) tests may be performed at 
visit 1/week -2 (screening) and visit 5/week 12 (EoT).  If any of the clinical laboratory tests 
results are outside the normal range at any scheduled time point during the study, the 
investigator may decide to repeat the test(s) on new samples.  The clinical relevance of the 
abnormal results will be documented.  Clinically relevant changes will be recorded as AEs 
(see Section 7.3 of protocol). 
The laboratory parameters that will be assessed during the conduct of the study are listed in 
Table 4. 
Table 4 
Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Serology* 
Hematocrit 
Hemoglobin 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin 
Mean corpuscular 
hemoglobin concentration 
Platelets 
Red blood cell count 
White blood cell count 
White blood cell count 
differential 
Albumin 
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Corrected serum calcium 
Creatinine 
Creatinine kinase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Total bilirubin (total and 
direct) 
Total protein 
Leukocyte esterase 
Nitrites 
pH 
Protein 
Red blood cells 
Human chorionic 
gonadotropin (female 
subjects only) 
HAV antibodies 
(IgM) 
HBsAg 
HBc antibodies 
HCV antibodies 
HIV antibodies 
types 1 and 2 
Syphilis 
* Serology parameters will be only collected at screening. 
The value of each hematology and biochemistry parameter will be compared to its normal 
range and classified as High, Low or Normal.  Urinalysis parameters will be similarly 
classified as either Normal or Abnormal. 
When calculating changes or shifts in a result from baseline, the value from visit 1 will be 
used as baseline.  If the visit 1 value is missing, the latest pre-baseline value will be used 
(i.e., from Visit 1 or any unscheduled visit conducted between Visit 1 and Visit 2). 
5.4.4 
Physical Examination 
Physical examinations will be performed at visit 1/week -2 (screening) and visit 5/week 12 
(EoT) and whenever there is a medical indication and will include assessments of the main 
body systems. 
The physical examination will be performed per clinic standards and clinically significant 
findings at screening will be recorded as part of the subject’s medical history.  Any abnormal 
finding observed at screening must be assessed and documented as not clinically significant 
if a subject is to be enrolled in the study. 


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After IP administration, new clinically significant findings or a worsening of an ongoing 
clinically significant abnormal condition will be recorded as an AE [see Section 7.3 of 
protocol: Adverse Events and Other Safety Aspects]. 
5.4.5 
12 Lead ECGs 
A 12-lead ECG will be performed as single measurement at visit 1/screening and visit 5/week 
12 (EoT).  ECG traces will be evaluated by the investigator who will give an overall 
interpretation and may leave a qualifying comment in the eCRF.  The overall interpretation 
will be recorded as:  
● 
Normal, or 
● 
Abnormal - not clinically significant, or 
● 
Abnormal - clinically significant 
As well as the overall interpretation, the following ECG variables will be supplied by the 
local laboratory: PR Interval (msec), RR Interval (msec), QRS Duration (msec), QT interval 
(msec) and Heart Rate (HR) (beats/min). 
5.4.6 
Post Void Residual Volume 
PVR volume will be assessed by ultrasonography at visit 1/week -2 (screening) and 
visit 5/week 12 (EoT).  For each subject, the same method should be used throughout the 
study.  The bladder should only be emptied when it was initially filled with preferably > 50% 
of the bladder capacity for age.  Every attempt should be made to measure PVR within a 
minute of voiding.  A PVR of ≤ 100 mL is sufficient and the assessment does not have to be 
repeated.  If the PVR is > 100 mL, the PVR assessment should be repeated (filled with 
preferably > 50% of the bladder capacity for age).  If the subject is unable to complete a 
second measurement, it is up to the investigator to judge whether it can be skipped (and write 
the reason in the eCRF). The lowest PVR volume result measured should be used to evaluate 
the exclusion criterion.  In case the lowest PVR volume measured is ≥ 100 mL at 
visit 1/week -2 (screening), the subject should be excluded from the study.  
5.5 
Other Endpoints 
5.5.1 
Exposure to Study Drug 
The duration of exposure to each dose of study drug (Mirabegron 25 mg and Mirabegron 
50 mg) by visit and for the whole period will be calculated using the following information : 
● Overall start date and stop date of the study medication. 
The first dose of study drug is to be administered on Day 1, the day on visit 2/week 0 
[baseline].  Treatment will be administered once daily orally after meal during a 12-week, 
open-label treatment period. 
● Start date and new dose of study drug at each titration step. 
At visit 3/week 4 or visit 4/week 8 the dose may be up-titrated (from 25 to 50 mg 
according to investigators' discretion), or may remain the same. 
The study does not allow dose reduction from 50 mg to 25 mg as the former is considered 
a safe and effective recommended dose. 


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● Start date and new dose of study drug after each unscheduled dose change. 
● At any time during the treatment period, the subject may have an unscheduled dose 
interruption. At each unscheduled change in dose, the (new) dose, start date and reason 
are recorded.  
In all cases where there is a dose change, either because of dose titration or an unscheduled 
dose interruption, the first and the last dose of the medication at the old level will be collected 
at the CRF. In this way, the subject’s dosing history can be reduced to a series of unbroken 
intervals within each of which, the dose level is constant.  From these, the subject’s exposure 
at each dose can be calculated. 
To illustrate, consider a subject with the following dose information on the eCRF: 
● The dates of the very first and very last dose of the study medication given at D1=1st July 
2020, Dlast=23rd September 2020. 
● Up-titration to 50 mg at Visit 3. The first dose at the new level is given at D2=29th July 
2020. 
● Study drug interrupted at an unscheduled visit. The date of last dose is given at D3=1st 
August 2020. 
● Study drug re-started at an unscheduled visit at D4=5th August 2020. 
● Remains at 50 mg till Visit 5 (Dlast=23rd September 2020).  
From these dates we calculate the following: 
● The duration of exposure to the treatment can be calculated as ETOT=Dlast-D1+1-(D4-D3-1) 
=82 days. 
● Between Visits 2 and 3, the subject is on 25 mg. If the last dose at 25 mg collected in 
CRF is given on D2-1, the day before the subject has the first dose at the new level 
(50 mg), then the exposure at 25 mg between Visits 2 and 3 is, therefore,  
(D2-1)-D1+1=28 days 
● Between Visits 3 and 5, the study drug is temporarily suspended and then restarted.  The 
subject will be considered to be exposed to the 50 mg dose from D2 until D3, i.e.  
D3-D2+1=4 days.  
● For the calculation of the exposure, suspension of the study drug is accounted.  The dose 
will be considered interrupted between D3+1 to D4-1, i.e., (D4-1) - (D3+1) + 1 = 3 days. 
● The study drug is at 50 mg from D4 to Dlast, the date of the last dose on Visit 5, i.e.,  
(Dlast-D4+1)=50 days. 
● The total exposure at 50 mg is E50=54 days, and at 25 mg total exposure is E25=28 days. 
5.5.2 
Compliance to Study Drug 
Compliance will be calculated according to the number of tablets of study medication 
dispensed, the number of tablets used and the duration of exposure between the applicable 
visits and overall. 
The total number of tablets used between Visits i and j (i=2 [baseline], 3, 4, and j=i+1) is 
calculated as: 


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Nused = Total number of tablets dispensed at Visit i - Total number of tablets returned at Visit j 
If some tablets (or part of kits) of IP are lost by the subject or returned later than expected, 
investigator will document the reason and IP compliance will be calculated based on actual 
tablets taken by subjects and IP accountability log.  
When a strip with study drug is not returned/not reconciled, then for the calculations it is 
assumed that all tablets were taken from that strip. 
The amount of expected study drug intake depends on the number of days of study drug 
treatment and the number of prescribed daily tablets.  Since subjects are supposed to take 
1 tablet per day, the total number of expected tablets to be used between Visits i and j (i=2 
{baseline], 3, 4, and j=i+1) is calculated as described below. 
For the compliance calculations it is assumed that on the visit day at Visit 3 (week 4), Visit 4 
(week 8) and Visit 5 (week 12), the tablet is taken at home before going to the clinic.  For the 
baseline visit (Visit 2) the subject takes the tablet at the clinic (Day 1). 
For the period from: 
• Baseline to Week 4 the expected number of tablets taken is equal to: Date of drug 
returned at Week 4 – Date of drug dispensed at Baseline visit + 1. 
• Week 4 to Week 8 and from Week 8 to Week 12 the expected number of tablets taken 
is equal to: Date of drug returned Week (i+4) – Date of drug dispensed (Week i), 
where i=4 or 8.  
Between Visits i and j the compliance to study medication will be calculated as follows: 
Compliance = (Nused / Nprescribed) x 100%. 
For the whole study period, the total amount of study drug used (TOTNused) is equal to the 
sum of the values of Nused at each applicable visit.  Similarly, the total amount of study drug 
prescribed (TOTNprescribed) is equal to the sum of the values of Nprescribed at each applicable 
visit.  Using these total values, the subject’s compliance over the whole study period will be 
calculated as 100% x (TOTNused / TOTNprescribed). 
6 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
Continuous data will be summarized descriptively including the number of subjects (n), 
mean, standard error of the mean (SEM) (efficacy data), standard deviation (SD), median, 
minimum and maximum.  Categorical data will be summarized by frequencies and 
percentages.  Percentages by categories will be based on the number of subjects with no 
missing data, i.e., the percentages for the non-missing categories will add up to 100%. 
All statistical comparisons will be conducted using 2-sided tests at the 5% significance level 
unless stated otherwise.  All null hypotheses will be of no treatment difference, all alternative 
hypotheses will be two-sided, unless specifically stated otherwise. 


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All data summarization and analyses will be performed using SAS® Version 9.4 or higher on 
Linux.  Specifications for table, figures, and data listing formats can be found in the TLF 
specifications. 
6.2 
Study Population 
All study population summaries will be presented showing two treatment groups as: 
● 
Mirabegron 25 mg (Total) 
● 
Mirabegron 50 mg (As-Randomized) 
● 
Total Mirabegron, i.e., the sum of the Mirabegron 25 mg (Total) and of Mirabegron 
50 mg (As-Randomized) 
6.2.1 
Disposition of Subjects 
The following subject data will be presented by treatment arm, unless stated otherwise: 
● 
Number of subjects with informed consent, discontinued before randomization, 
randomized (total only) (All Enrolled Set) 
● 
Number and percentage of subjects randomized in each analysis set, by treatment group 
and total (All Randomized Set) 
● 
Number and percentage of subjects completed and discontinued the screening (including 
COVID-19 reasons), by primary reason for study discontinuation (total only) (All 
Enrolled Set)  
● 
Number and percentage of subjects completed and discontinued treatment, by primary 
reason for treatment discontinuation (including COVID-19 reasons), and by treatment 
group and total (All Randomized Set) 
● 
Number and percentage of subjects who completed the Week 0, Week 4, Week 8 and 
Week 12 visit by treatment group and total (All Randomized Set) 
● 
Number and percentage of subjects completed and discontinued the follow-up period, by 
primary reason for post-study period discontinuation (including COVID-19 reasons), and 
by treatment group and total (All Randomized Set)  
● 
Number and percentages of subjects screened and randomized to each treatment group 
under each protocol version (All Subjects With Informed Consent). 
A listing of inclusion and exclusion criteria, listing of first and last evaluations as well as a 
listing of subjects who were excluded from at least 1 analysis set will be provided for the All 
Enrolled Set. 
6.2.2 
Protocol Deviations  
The number and percentage of subjects with the following protocol deviation criteria will be 
summarized for each criterion and total by treatment group and total as well as by 
investigative site. Subjects deviating from a criterion more than once will be counted once for 
the corresponding criterion. 
The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria 


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PD2 - Developed withdrawal criteria during the study and was not withdrawn 
PD3 - Received wrong treatment or incorrect dose 
PD4 - Received excluded concomitant treatment 
PD5 – Issues related to missing or invalid baseline Diary/OABSS 
6.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by descriptive statistics. 
Summaries will be presented by treatment group and total.  
For the SAF and FAS, descriptive statistics for age will be presented as well as frequency 
tabulations for sex, ethnicity, race (‘Chinese’ or ‘Other’) and prior OAB treatment (Yes/No). 
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) as well as by PT alone, by treatment group for the SAF. 
Demographic data and other baseline characteristics (including medical history) will be 
provided in listing format by site and subject for the All Randomized Set. 
6.2.4 
Previous and Concomitant Medications 
Subjects taking the same medication multiple times will be counted once per medication and 
investigational period.  A medication which can be classified into several chemical and/or 
therapeutic subgroups is presented in all chemical and therapeutic subgroups. 
Previous medications are defined as medications that patients started and ended prior to first 
administration of study medication.  Concomitant medications are defined as any medications 
that subjects took after the first dose of study medication and through Follow-up period 
(EoS).  Medications that started prior to first administration of study drug and continued 
while study drug was given will be counted in both previous and concomitant medications. 
Previous and concomitant medications are coded with WHO-Drug Global data and will be 
provided in listing format by site and subject for the All Randomized Set. 
6.3 
Study Drug Exposure and Compliance 
As per study schedule, all subjects will be assigned to either ‘Mirabegron 25 mg’ or 
‘Mirabegron 50 mg’ at visit 2/week 0. 
At visit 3/week 4 or visit 4/week 8 subjects can be up-titrated from ‘Mirabegron 25 mg’ to 
‘Mirabegron 50 mg’ until the end of the study.  Once up-titrated the dose cannot be adjusted 
back down.  Study drug exposure will be summarized for the following groups: 
● 
Mirabegron 25 mg 
○ 
Never Up-Titrated 
○ 
Later Up-Titrated to 50 mg  
○ 
Total 
● 
Mirabegron 50 mg 
○ 
as Randomized 


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○ 
Up-Titrated from 25 mg  
○ 
Total 
6.3.1 
Exposure 
The following information on drug exposure will be presented by treatment groups described 
in Section 6.3 for the SAF: 
● 
Descriptive statistics for cumulative amount of the drug to which the subject was 
exposed; and 
● 
Number and percent of subject with dose increases or interruptions. 
Duration of exposure will be summarized in two ways. 
● 
Descriptive statistics will be presented by treatment group. 
● 
Exposure time will be categorized according to the following categories by treatment 
group: 
○ at least 1 day, less than 7 days 
○ at least 7 days, less than 14 days 
○ at least 14 days, less than 28 days 
○ at least 28 days, less than 56 days 
○ at least 56 days, less than 83 days 
○ 84 days or more 
○ Unknown. 
● 
Counts and percentages of cumulative exposure will be categorized according to the 
following categories by treatment group for the SAF: 
○ ≥ 7 days 
○ ≥ 14 days 
○ ≥ 28 days 
○ ≥ 56 days 
○ ≥ 84 days 
Exposure details will be listed for each subject by study visit and total for all randomized 
subjects. 
6.3.2 
Treatment Compliance 
Total compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known. 
Percent total compliance will be summarized in two ways for the SAF: 
● 
Descriptive statistics will be presented by treatment group. 
● 
Percent compliance will be categorized according to the following categories by 
treatment group: 
○ less than 70% 
○ at least 70%, less than 80% 
○ at least 80%, less than 120% 
○ at least 120% 


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○ Unknown. 
Treatment compliance details, including all data relevant to the calculation, will be listed for 
each subject by study visit and total for all randomized subjects.  
6.4 
Analysis of Efficacy  
Efficacy analysis of the data from Mirabegron 50 mg group will be conducted on the FAS, 
and interpretation of results from statistical tests will be based on the FAS as well. 
No multiplicity adjustment will be necessary in this study. 
Efficacy data will be summarized by visit (week 0, 4, 8 and 12) and by EoT values unless 
otherwise specified. 
All inferential statistics will be presented by the following treatment groups:  
● 
Mirabegron 25 mg (Total) 
● 
Mirabegron 50 mg (As-Randomized) 
All summary descriptive statistics will be presented by the following treatment groups:  
● 
Mirabegron 25 mg 
○ Never Up-Titrated 
○ Later Up-Titrated to 50 mg  
○ Total 
● Mirabegron 50 mg 
○ as Randomized 
○ Up-Titrated from 25 mg  
○ Total 
6.4.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline to week 12 in mean number of 
micturitions per 24 hours in Mirabegron 50 mg group. 
6.4.1.1 Primary Analysis for Primary Efficacy Endpoint 
The primary estimator for the primary estimand as defined in [Section 2.1.1 Estimand] will 
be calculated according to the evaluation of the primary efficacy endpoint.  The primary 
efficacy endpoint will be analyzed using a Mixed Models Repeated Measures (MMRM).  
The MMRM model will include visit (the repeated term), treatment group (25 mg [total] or 
50 mg [as-randomized]), pooled site, sex and the interaction between treatment group and 
visit as fixed effects and baseline measurement (the mean number of micturitions per 
24 hours) as covariate.  The algorithm to pool sites will be generated and documented prior to 
data base lock (Appendix 9.1).  If the inclusion of pooled sites creates modeling problems, 
then dropping that factor will be considered.  Subject will be identified as subject in the 
repeated statement. 


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The hypothesis for comparisons is given as follows: 
H0: The adjusted mean change from baseline at week 12 in mean number of micturitions per 
24 hours in the 50 mg group is not different from zero. 
H1: The adjusted mean change from baseline at week 12 in mean number of micturitions per 
24 hours in the 50 mg group is not equal zero. 
Statistical testing will be done 2-sided at a 5% significance level. 
The MMRM model results will be presented by treatment least squares (LS) means 
(± standard error [SE]) along with 2-sided 95% confidence intervals (CIs) and associated 
p-value for mean changes from baseline at weeks 4, 8 and 12 (the primary endpoint).  
Data from subjects who switch from 25 to 50 mg mirabegron will not be included in MMRM 
model.  Data from those subjects prior to switching will still be included in the MMRM 
model with treatment equal to 25 mg. 
Model fitting will be visually assessed.  A scatter plot of residuals versus predicted values, 
along with histogram and normal probability plots will be produced. 
6.4.1.2 Graphical Summary of Data from Primary Efficacy Endpoint 
Mean number of micturitions per 24 hours at each visit and change from baseline in mean 
number of micturitions per 24 hours will be plotted for FAS: mean (SEM) values will be 
presented for each visit. 
LS Mean change from baseline in mean number of micturitions per 24 hours at each visit and 
change from baseline in mean number of micturitions per 24 hours will be plotted for FAS: 
mean (95% CI) values will be presented for each visit. 
6.4.1.3 Subgroup Analysis for Primary Efficacy Endpoint 
For the primary efficacy endpoint, descriptive statistics (n, mean,  SD, minimum, median, 
maximum) and the statistical comparison within each group will be calculated for mean 
change from baseline at each visit using the same MMRM model described in Section 6.4.1.1 
for the following subgroup: Prior OAB treatment (Yes vs. No). 
Appendix 9.2 reports a non-exhaustive list of prior OAB treatment (not allowable during the 
study period). 
6.4.2 
Analysis of Secondary Efficacy Endpoints 
6.4.2.1 Analysis of Secondary Efficacy Endpoints at Week 12 
The same primary efficacy analysis (MMRM, with corresponding baseline measurement for 
the endpoint as the covariate) as for the primary endpoint (except for the covariate, i.e., mean 
number of micturitions at baseline) will be applied to change from baseline at the end of the 
12-week treatment period in Mirabegron 50 mg subjects for: 
● 
Mean number of grade 3 or 4 (PPIUS) urgency episodes per 24 hours 
● 
Mean number of daytime incontinence episodes per 24 hours 
● 
Mean number of nighttime incontinence episodes per 24 hours 


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● 
Mean number of urge incontinence episodes per 24 hours 
● 
OAB Symptom Score 
For each of the endpoints above, the covariate included in the model will be the respective 
variable of interest at the baseline, e.g., OAB Symptom Score at baseline for change from 
baseline to week 12 for the OABSS endpoint. 
Data of these secondary efficacy endpoints will be analyzed for the FAS. 
6.4.2.2 Analysis of Secondary Efficacy Endpoints at Weeks 4 and 8 
For each treatment group, separately, least squares (LS) means (± standard error [SE]) along 
with 2-sided 95% Cis, from the same analysis model described in Section 6.4.2.1, will be 
presented for changes from baseline at Weeks 4 and 8. 
6.4.2.3 Analysis of Secondary Efficacy Endpoints for Mirabegron 25 mg Starting Dose 
Secondary efficacy endpoints presented in Section 5.2.6 will be summarized for Mirabegron 
25 mg starting dose by visit (week 0, 4, 8 and 12) following the same statistical methods 
described in Sections 6.4.2.1 - 6.4.2.2 and will be conducted on the FAS. 
6.4.2.4 Graphical Summary of Data from Mean Number of Grade 3 or 4 (PPIUS) 
Urgency Episodes and Urge Incontinence Episodes per 24 hours 
Mean number of grade 3 or 4 (PPIUS) urgency episodes per 24 hours at each visit and mean 
number of urge incontinence episodes per 24 hours at each visit will be plotted for FAS: 
mean (SEM) values will be presented for each visit. 
6.5 
Analysis of Safety 
Safety analysis will be conducted on the SAF.  Safety endpoints will be summarized by 
treatment group and visit, if applicable.  Descriptive statistics will be presented. 
All safety summaries (except for shift tables in Sections 6.5.2 and 6.5.4) will be presented by 
the following: 
● Mirabegron 25 mg 
○ Never Up-Titrated 
○ Later Up-Titrated to 50 mg (at visit 3 or 4) 
○ Total 
● Mirabegron 50 mg 
○ as Randomized 
○ Up-Titrated from 25 mg (at visit 3 or 4) 
○ Total 
● Total Mirabegron, i.e., the sum of the Mirabegron 25 mg (Total) and of Mirabegron 
50 mg (As-Randomized) 


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6.5.1 
Adverse Events 
Summaries and listings of SAEs and Serious TEAEs include SAEs upgraded by the sponsor 
based on review of the Sponsor’s list of Always Serious terms or upgraded according to the 
Important Medical Event process, if any upgrade was done. 
The coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
System Organ Class (SOC) and Preferred Term (PT). 
An overview table will include the following details:  
● Number of TEAEs, 
● Number and percentage of subjects with TEAEs, 
● Number of drug related TEAEs, 
● Number and percentage of subjects with drug related TEAEs,  
● Number of serious TEAEs, 
● Number and percentage of subjects with serious TEAEs, 
● Number of serious drug related TEAEs, 
● Number and percentage of subjects with serious drug related TEAEs, 
● Number of TEAEs leading to withdrawal of treatment, 
● Number and percentage of subjects with TEAEs leading to withdrawal of treatment,  
● Number of drug-related TEAEs leading to withdrawal of treatment, 
● Number and percentage of subjects with drug-related TEAEs leading to withdrawal of 
treatment,  
● Number of TEAEs leading to death, 
● Number and percentage of subjects with TEAEs leading to death, 
● Number of drug-related TEAEs leading the death, 
● Number and percentage of subjects with drug-related TEAEs leading to death, and 
● Number and percentage of subjects who died. 
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group. Summaries will be provided for: 
● TEAEs, 
● Drug related TEAEs,  
● Serious TEAEs,  
● Drug related serious TEAEs,  
● TEAEs leading to withdrawal of treatment,  
● Drug related TEAEs leading to withdrawal of treatment,  
● Frequently Reported (>=5% in Any Treatment Group) TEAEs Excluding SAEs  
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized for each treatment group. 
The number of TEAEs and the number and percentage of subjects with TEAEs, as classified 
by SOC and PT will also be summarized by severity and by relationship to study drug. In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity or relationship, then the subject will be counted only once with the worst severity 


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and highest degree of relationship, however, if any of the severity or relationship values are 
missing then the subject will be counted only once with missing severity or relationship.  In 
the adverse event count, the adverse events will be presented in each category they were 
classified to. Drug related TEAEs will be presented in a similar way by severity only. 
Adverse events of interest will be tabulated by PT. 
AEs will be provided in listing format by site and subject for the SAF. 
6.5.2 
Clinical Laboratory Evaluation 
The baseline value will be the last non-missing value taken on or prior to first dose of study 
drug.  In the “Schedule of Assessment” table in the protocol (Table 1) this “baseline” 
assessment will be done at screening (Visit 1). 
In the eCRF both Blood Urea and Blood Urea Nitrogen (BUN) are presented.  In the event 
that Blood Urea is measured and not BUN, then for summary statistics the BUN value will be 
obtained using the following formulae: BUN(mmol/L) = 2.1428 x Urea(mmol/L) 
Note: BUN values will be summarized and in the listing both Blood Urea and BUN values 
will be presented. 
When corrected serum calcium is not measured, the corrected serum calcium will be 
calculated as (depending on the units used for calcium and albumin):  
Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 [40 (g/L) – albumin 
(g/L)])  
For each local laboratory, separately, the quantitative clinical laboratory variables, i.e., 
hematology, biochemistry, and urinalysis, will be summarized using mean, standard 
deviation, median, minimum and maximum by treatment group and visit [visits 1 and 5] and 
for EoT values.  
In addition, data from the local laboratories will be normalized to a single laboratory for the 
purpose of combining all laboratories and providing an overall summary.  For normalizing 
the data of a laboratory parameter a common reference range for this parameter has to be 
determined.  In this study the common reference range is the normal range coming from the 
site with the highest number of treated subjects. 
Calculating the normalized value of a laboratory parameter:  first all data from the parameter 
assessed in the local laboratories will be transformed into SI units.  Next the data will be 
transformed according to the transformation formula below.  Let x be the value of the 
laboratory parameter from the local laboratory, ULNL the upper limit of the normal range of 
the local laboratory, and ULNC the upper limit of the common reference range, then the 
transformed value (t) from the local laboratory is: 
𝑡= 𝑥.
𝑈𝐿𝑁𝐶
𝑈𝐿𝑁𝐿 
(Scale normalization, Karvanen et al.) 
This value t will be used for reporting normalized laboratory values.  Both the observed and 
normalized values (where applicable) will be reported in listings. 


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Additionally, for groups with both a baseline and week 12 measurement (i.e., Mirabegron 
25 mg [Never Up-Titrated], Mirabegron 50 mg [As-Randomized] and Total Mirabegron) a 
within-subject change will be calculated as the post-baseline measurement minus the baseline 
measurement and summarized in the same way. Each laboratory result will be classified as 
low (L), normal (N), or high (H) at each visit according to the laboratory supplied reference 
ranges.  
The number and percentage of subjects below and above reference range will be summarized 
by treatment group and visit.  
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented by treatment group and visit. 
Summary shifts of reference range (low, normal, high) changes from baseline to week 12 will 
be presented by the following treatment groups: 
● 
Mirabegron 25 mg (Total) 
● 
Mirabegron 50 mg (As-Randomized) 
● 
Total Mirabegron, i.e., the sum of the Mirabegron 25 mg (Total) and of Mirabegron 
50 mg (As-Randomized). 
These shifts are categorized as: 
○ 
“Shift to Low”: shift from normal or high to low 
○ 
“Shift to High”: shift from normal or low to high 
○ 
“Categorized Increase”: shift from low to normal or from normal to high 
○ 
“Categorized No Change”: value stays in the same reference range 
○ 
“Categorized Decrease”: shift from high to normal or from normal to low. 
All clinical laboratory data collected during the study and variables derived from it will be 
listed using SAF. 
6.5.2.1 Liver Safety Assessment 
The liver safety assessments will be summarized by the categories below based on the 
measurements from Alkaline Phosphatase (ALP), Alanine Transaminase (ALT), total 
bilirubin, Aspartate Transaminase (AST) and their combination. These parameters will be 
based on measurements from the local laboratory. 
The subject’s highest value during the investigational period will be used.  
● 
ALT >3xULN, >5xULN, >8xULN, >10xULN, >20xULN 
● 
AST >3xULN, >5xULN, >8xULN, >10xULN, >20xULN 
● 
ALT or AST >3xULN, >5xULN, >10xULN, >20xULN 
● 
ALP >1.5xULN 
● 
Total Bilirubin >2xULN 
● 
(ALT or AST >3xULN) and (Total Bilirubin >2xULN or INR > 1.5) 
● 
(ALT or AST >3xULN) and ALP <2xULN and Total Bilirubin >2xULN 


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Note: ALT, AST, ALP and Total Bilirubin results will be classified using the reference ranges 
supplied by the local laboratories. 
The last 2 criteria where 2 or more parameters are evaluated will be with the measurements 
on the same day or up to 1 day apart (Samples to be taken simultaneously or within a 
maximum of 24 hours).  
The denominator for each criterion will be the number of subjects who have at least one 
value during the investigational period. The number and percentage of subjects meeting the 
criteria during the investigational period will be summarized by treatment group. 
A scatter plot of Peak AST or ALT data vs. Peak Total Bilirubin data will be presented for 
mirabegron subjects.  Data will be presented as fractions of the ULN (of the local 
laboratories).  In this scatter plot the area for Hy’s Law will be presented, where ALT or AST 
>3xULN and Total bilirubin  
>2xULN (ALT, ALT and Total Bilirubin from same blood sample or within a maximum of 
24 hours).  The area for hyperbilirubinemia (ALT and AST <3xULN and Total bilirubin 
>2xULN), Temple’s corollary (ALT or AST >3xULN and Total bilirubin < 2xULN) will 
also be presented in this scatter plot. 
Laboratory data will be provided in listing format by site and subject for the SAF. 
6.5.3 
Vital Signs 
The baseline value will be the last non-missing value taken on or prior to first dose of study 
drug (Visit 2). 
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate and measurement 
for temperature) will be listed and summarized by treatment group and visit using mean, 
standard deviation, median, minimum and maximum. Additionally, for groups with both a 
baseline and a post-baseline 12 measurement, a within-subject change will be calculated per 
visit as the post-baseline measurement minus the baseline measurement and summarized by 
treatment group, total and visit.  Summary of vital signs will be presented for each visit 
[visits 1, 2 (Baseline), 3, 4, and 5], and for EoT values. 
Vital signs data will be provided in listing format by site and subject for the SAF. 
6.5.4 
Electrocardiograms 
The baseline value will be the last non-missing value taken on or prior to first dose of study 
drug.  In the “Schedule of Assessment” table in the protocol (Table 1) this “baseline” 
assessment will be done at screening (Visit 1). 
ECG variables will be summarized using mean, standard deviation, median, minimum, and 
maximum by treatment group total and visit, including changes from baseline for groups with 
both a baseline and week 12 measurement.  Summary of ECG variables will be presented for 
each visit [visits 1 and 5], and for EoT values.  In addition to the ECG variables mentioned in 
Section 5.4.5, QTcF (msec) (=QT (msec)/([RR (msec)/1000]1/3) will be summarized.  
Note: unit for QT and RR reported in CRF is msec.  


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Normal, not clinically significant abnormal, and clinically significant abnormal results as 
assessed by investigator for the 12 lead ECG along with shift tables will be presented for 
changes from baseline to Week 12 including local interpretation categories by the following 
treatment groups: 
● 
Mirabegron 25 mg (Never Up-Titrated) 
● 
Mirabegron 50 mg (As-Randomized) 
● 
Total Mirabegron.  
The QTc interval will be summarized using frequency tables for each treatment visit and time 
point for values of clinical importance using the range criteria below. 
Category 
QTc Interval Criteria Value (msec)  
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450  
> 480  
> 500 
Note that these categories are cumulative in that subjects satisfying criterion for more 
extreme category will also be counted in each applicable less extreme category. 
The corrected QT interval (i.e., QTcF) will also be summarized by treatment group and visit 
showing the frequencies of subjects with the following changes from baseline:  
Variable 
Change from Baseline 
QTc Interval (msec) 
< 0 
≥ 0 and < 30 
≥ 30 and < 60 
≥ 60  
ECG data will be provided in listing format by site and subject for the SAF. 
6.5.5 
Pregnancies 
A detailed listing of all pregnancies will be provided if any occur using All Enrolled Set. 
6.5.6 
Other Safety-Related Assessments 
6.5.6.1 Post Void Residual Volume 
The baseline value will be the last non-missing value taken on or prior to first dose of study 
drug.  In the “Schedule of Assessment” table in the protocol (Table 1) this “baseline” 
assessment will be done at screening (Visit 1). 
PVR will be summarized by treatment group and visit using mean, standard deviation, 
median, minimum, and maximum at each treatment visit, including changes from baseline 
(for groups with both a baseline and week 12 measurement).  In case of 2 measurements at 
the same visit, the lowest (instead of mean) PVR volume will be used for the calculations. 
Summary of PVR values will be presented for each visit [visits 1 and 5], and for EoT values. 
PVR data will be provided in listing format by site and subject for the SAF.  


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6.6 
Analysis of Pharmacokinetics 
Not applicable. 
6.7 
Analysis of Pharmacodynamics  
Not applicable. 
6.8 
Other Analyses  
Not applicable. 
6.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
There is no planned interim analysis but a data cut with summaries (e.g., after 50% of 
subjects planned to be randomized have had their week 12/EoT assessment) and the planned 
primary analysis for the end of the study may be generated at a specific timepoint during the 
study for regulatory reporting purposes. No decisions regarding conduct of the study 
(i.e., stopping) will be based on these results. 
6.10 
Additional Conventions  
6.10.1 Analysis Windows 
The study protocol gives the total study schedule and the permissible intervals for these visits 
expressed as the number of days relative to visit 2/baseline. The total time each subject will 
be in the study will not exceed 16 weeks with a maximum of a screening period of 2 weeks, a 
maximum of 12 weeks for the investigational period and a maximum of a follow-up period of 
2 weeks. 
Analyses will not exclude subject data due to the subject’s failure to comply with the visit 
schedule, see Table 5. 
The data summary by visits will be done following the analysis windows specified in 
Table 5. 
For Bladder e-diary data. using the Subject Visit (SV) domain: for each diary record find the 
date from SV that satisfies the condition (Date from SV-7) <= Diary Date < Date from SV.  
Using the corresponding relative day of that date, assign the analysis visit as specified in 
Table 5. 
Table 5 
Visit Windows for Efficacy and Safety Parameters  
Analysis Visits 
Target day relative to Baseline 
(Visit 2, Day 1) 
Analysis Window (day) 
Bladder e-diary 
Baseline 
Day -1 
Day -12 to Day -1  
Week 4 
Day 28 
Day 7 to Day 42 
Week 8 
Day 56 
Day 43 to Day 70 
Week 12 
Day 84 
Day 71 to Day 97 
EoT 
Day 84 
Day 2 to ≤ Last dose of study drug 


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Analysis Visits 
Target day relative to Baseline 
(Visit 2, Day 1) 
Analysis Window (day) 
OABSS questionnaire 
Baseline 
Day 1 
Day -12 to Day 1  
Week 4 
Day 28 
Day 2 to Day 42 
Week 8 
Day 56 
Day 43 to Day 70 
Week 12 
Day 84 
Day 71 to Day 97 
EoT 
Day 84 
Day 2 to ≤ Last dose of study drug 
Vital signs* 
Week -2 
Day -14 
Day -17 to Day -4 
Week 0/ Baseline 
Last value prior to first dose 
Day -3 to Day 1 (prior to first dose) 
Week 4 
Day 28 
Day 2 to Day 42 
Week 8 
Day 56 
Day 43 to Day 70 
Week 12 
Day 84 
Day 71 to Day 97 
EoT 
Day 84 
Day 1 to ≤ Last dose of study drug 
ECG, Clinical Laboratory Tests (including Pregnancy Test) and PVR* 
Week -2/ Baseline 
Day -14 
Day -17 to Day 1 (prior to first dose) 
Week 12 
Day 84 
Day 2 to Day 97 
EoT 
Day 84 
Day 1 to ≤ Last dose of study drug 
* if an Early Discontinuation visit occurs within any specified visit window, all data collected during this visit 
will be assigned to the respective analysis visit. 
For non-diary data, if a subject has more than one non-missing value within a visit window, 
the non-missing assessment which is closest to the target day within a window will be used. 
If two or more values are equally close and on different days, the latest non-missing value 
will be used. If two or more values are equally close and on the same day, the mean will be 
used for continuous variables or the worst observed case for categorical variables. 
For diary data, the assessment date for the whole diary will be considered to be the date of 
the last valid day of the diary. If more than one diary has an assessment date within the same 
window, and if this results in more than one non-missing value of a diary variable, the 
non-missing value with the diary assessment day that is closest to the target day will be used. 
In case of ties on different days, the later non-missing value will be used. In case of ties 
located on the same side of the target day (i.e., more than one value for the same day), the 
mean of the values will be used for continuous variables and the worst value for categorical 
variables. 
For analyzing diary data the labels of the study visits will not be used, they will be assigned 
based on the dates of assessment. 
A two-day window around the visit date will be applied for the assignment of study period 
for exposure data. 
6.10.2 Imputation Rules for Incomplete Dates  
As a general principle, no imputation of missing data for variables will be done. Exceptions 
are the start and stop dates of AEs and concomitant medication.  The imputed dates will be 
used to allocate the concomitant medication and AEs to a treatment group, in addition to 


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determining whether an AE is/is not treatment emergent. Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be 
shown.  
6.10.2.1 Imputation Rules for Diary Dates  
Not Applicable.  
6.10.2.2 Imputation Rules for Adverse Events  
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 
If an onset date is missing or only the year is known, the imputed onset date will be the date 
of first dose of study drug. 
If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates: 
● 
Date of first dose of study drug 
● 
January 1 of the year of AE onset date 
If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
● 
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date. 
● 
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates: 
○ Date of first dose of study drug 
○ Surrogate onset date 
If the imputed onset date is after the adverse event end date, the imputed onset date will be 
the same as the adverse event end date. 
6.10.2.3 Imputation Rules for Concomitant Medications 
In case of missing partial start and stop dates for concomitant medications, the following 
rules will be used: 
If the start date is missing or partial: 
● if the month is missing, use January 
● if the day is missing, use the first day of the month under consideration 
● if the year is missing, use year of the informed consent date 
● if the entire date is missing, use informed consent date 
If the stop date is missing or partial: 
● if the month is missing, use December 
● if the day is missing, use the last day of the month under consideration 


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● if the year or the entire date is missing, set the stop date to December 31st, 2099 
If the imputed start date is after the stop date, then the imputed start date will be 1 day prior 
to the stop date. 
6.10.3 Outliers 
All values will be included in the planned analyses.  A sensitivity analysis excluding outliers 
may be performed as an additional secondary analysis, if considered appropriate by the study 
statistician or the medical expert. 


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7 
REVISION AND RATIONALE 
7.1 
List of Changes in SAP Version 2.0 from Version 1.0 
The changes from the approved SAP Version 1.0 (Dated 09-Dec-2020) to Version 2.0 that 
impact analyses are listed with the rationale in the table below. 
SAP 
Sections 
Description 
Rationale 
5 
Table for classifying assessments as 
daytime or nighttime is added 
Added for clarification 
 
Text for procedure for calculating 
efficacy endpoints 
Added for clarification 
5.1 
Second paragraph: “total number of” 
should be “mean number of”  
Corrected the definition of mean number of 
micturitions 
5.2 
Summary of efficacy data will also 
be done for EoT values 
Added to be consistent with other studies. 
 
The success rate of efficacy variables 
in each treatment group initiated with 
either 50 mg or 25 mg dose will 
NOT be evaluated at each treatment 
visit 
Not applicable 
5.2.4 
Section 5.2.4 was added to explain 
how the number of urge incontinence 
episodes are calculated 
Was missing in Version 1 
5.2.5 
Text added how to deal if not all 
questions for OABSS are answered. 
Definition of baseline assessment 
was added. 
Added for clarification 
5.4.1 
Corrected definition of TEAE 
To be consistent with protocol 
 
Common TEAEs are defined as 
preferred terms (PTs) that have been 
reported by at least 5% of the 
subjects, in any treatment group.  
Added “in any treatment group” to be 
consistent with other studies. 
 
Table 3 was updated 
Based on new information 
5.5.2 
Text on compliance is updated 
For clarification 
6.4.1.3 
Text on the “statistical comparison 
within each group” was added 
To be consitent with analysis of micturition 
data. 
6.5.1 
Text regardind “upgraded according 
to the Important Medical Event 
process” was added. 
Text added to be consistent with other studies 
6.4, 
6.5.2 – 
6.5.4, 
and 
6.5.6.1 
Summary of efficacy, Lab, ECG, 
Vital signs and PVR data will also be 
done for EoT values  
Added for clarification. 


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SAP 
Sections 
Description 
Rationale 
6.5.2 
Text adjusted for local laboratories 
and how to deal with Blood Urea and 
BUN results 
To clarify how these data will be processed 
 
Text added on normalizing local lab 
data 
To clarify how this will be done 
6.5.4 
Definition of QTcF was added 
Added for clarification 
6.10.1 
Table 5 is updated 
For bladder and questionnaire data no gaps in 
the windows are allowed, see new SAP 
template 
9.1 
The algorithm for pooling sites is 
added 
This should be defined before Database Lock. 
 
7.2 
List of Changes in SAP Version 3.0 from Version 2.0 
The changes from the approved SAP Version 2.0 (Dated 06-May-2021) to Version 3.0 that 
impact analyses are listed with the rationale in the table below. 
SAP 
Sections 
Description 
Rationale 
6.2.3 
Results of Prior OAB Treatment will 
be summarized 
Added for clarification 
 
Medical History data will be 
summarized 
Addional request 
6.4.1.2 
Text added that 2 additional figures 
will be presented 
Added for clarification 
6.4.2.4 
Section added to describe that for 
two secondary endpoints a figure 
will be presented 
Additional request 
 


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8 
REFERENCES 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 
Neurourology and Urodynamics. 2015;34:685–92. 
Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug  
Saf. 2006;15:241-3. 


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9 
APPENDICES 
9.1 
Pooling of Sites Algorithm 
Two hundred and forty-nine (249) subjects were randomized at 15 sites.  When “site” is 
included as a factor in a statistical model, sites that have less than 8 FAS subjects in total will 
be identified and then combined for statistical analysis purposes according to the following 
algorithm:  
▪ Step 1: Divide the sites into two groups with Group 1 including all sites that have at 
least 8 FAS subjects and Group 2 including all remaining sites. Sort each group in 
ascending order by total sample size and site number. 
▪ Step 2: Starting at the top of the Group 2 list (i.e., the first site with the smallest total 
sample size), combine the minimum number of sites required to achieve a “pooled 
site” that has at least 8 FAS subjects in total. Continue forming “pooled sites” in this 
manner until all Group 2 sites have been grouped or it is no longer possible to form a 
“pooled site” with at least 8 FAS subjects in total. 
▪ Step 3: If there is a site (or several sites) left after step 2, combine the site(s) with the 
last “pooled site” that is created. For the situation where no previous “pooled site” is 
created, combine the site(s) with the first site on the sorted Group 1 list. 
▪ “Pooled site” will be assigned names PoolSite01, PoolSite02, etc. For sites not 
needing to be pooled, the original site name will be used such as Site001. For all sites 
that have been combined into pooled sites, the assigned pooled site will be used 
instead of the original site identification in all statistical models that include “site” as 
a factor. However, the original site identification will be used in all summaries of 
subject disposition or discontinuation by site and in all data listings. 
 
 
 






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9.4 
Key Contributors  
Name, Degree And Title And Function 
Department 
 
 
Labcorp 
  
 
Data Science 
 
Medical Affairs, International 
Market 
 
 
Medical Affairs, International 
Market 
  
Medical Affairs, International 
Market 
 
Medical Affairs 
 
Data Science  
 
 
Data Science 
 
 
Labcorp 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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9.5 
Author and Approver Signatures  
Signatures 
 
 
 
 
Prepared by: 
 
Date: 
 
 
 
,  
Labcorp 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
Approved by: 
 
Date: 
 
 
 
 
Data Science 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
Approved by: 
 
Date: 
 
 
 
 
Medical Affairs 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
Approved by: 
 
Date: 
 
 
  
 
Medical Affairs 
 
Date (DD Mmm YYYY) 
 
PPD
PPD
PPD
PPD