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
Phase: PHASE4
Conditions: Urge Incontinence, Overactive Bladder (OAB)
Sponsor: Astellas Pharma China, Inc.

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 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 2 of 68 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 3 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 4 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 5 of 68 
Version 2.0 
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 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 6 of 68 
Version 2.0 
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 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 7 of 68 
Version 2.0 
SIGNATURES 
1. SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in 
[Section 12 Sponsor Signature]. 
 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 8 of 68 
Version 2.0 
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: 
 
 
 
 
 
 
 
 
 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 9 of 68 
Version 2.0 
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 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 10 of 68 
Version 2.0 
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 
 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 11 of 68 
Version 2.0 
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. 
 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL -  
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 12 of 68 
Version 2.0 
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) 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL -  
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 13 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL -  
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 14 of 68 
Version 2.0 
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]). 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 15 of 68 
Version 2.0 
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] 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 16 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 17 of 68 
Version 2.0 
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, 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 18 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 19 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 20 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 21 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 22 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 23 of 68 
Version 2.0 
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). 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 24 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 25 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 26 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 27 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 28 of 68 
Version 2.0 
● 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 29 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 30 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 31 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 32 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 33 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 34 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 35 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 36 of 68 
Version 2.0 
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. 
 
 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 37 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 38 of 68 
Version 2.0 
[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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 39 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 40 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 41 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 42 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 43 of 68 
Version 2.0 
● 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 44 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 45 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 46 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 47 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 48 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 49 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 50 of 68 
Version 2.0 
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 
reporting requirements. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 51 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 52 of 68 
Version 2.0 
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). 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 53 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 54 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 55 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 56 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 57 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 58 of 68 
Version 2.0 
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”). 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 59 of 68 
Version 2.0 
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). 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 61 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 62 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 63 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 64 of 68 
Version 2.0 
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 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 65 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 66 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 67 of 68 
Version 2.0 
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. 

Sponsor: ACN 
ISN/Protocol: 178-MA-2295 
- CONFIDENTIAL - 
Clinical Study Protocol 
22 Mar 2021 
Astellas 
Page 68 of 68 
Version 2.0 
12 
SPONSOR SIGNATURE 
 (Electronic signatures are attached at the end of the document). 
 
 
Signature: ______________________ 
 
 
 
____________________ 
Date (DD Mmm YYYY) 
 
Signature: ______________________ 
 
  
 
 
____________________ 
Date (DD Mmm YYYY) 
Signature: ______________________ 
 
 
 
 
____________________ 
Date (DD Mmm YYYY) 
Signature: ______________________ 
 
 
____________________ 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
Global Protocol Format V9.0 
PPD
PPD
PPD
PPD