Clinical trial NCT02656173
Conditions: Overactive Bladder
Keywords: Tamsulosin Overactive bladder Benign prostatic hypertrophy Mirabegron
Sponsor: Astellas Pharma Inc
Start date: 2016-01-25; Completion date: 2017-07-21
Enrollment: 568 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study was to investigate the efficacy of mirabegron versus placebo in male patients with OAB symptoms while taking the alpha blocker, tamsulosin, for BPH.

Detailed description:

Arms: arm 1: Participants who received mirabegron 50 mg once a day along with tamsulosin 0.2 mg for 12 weeks arm 2: Participants who received matching placebo once a day along with tamsulosin 0.2 mg for 12 weeks.
Interventions: intervention 1: Mirabegron intervention 2: Placebo intervention 3: Tamsulosin
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet intervention 3: Oral tablet

Protocol documents:
Prot_001.pdf: 
A Phase 4, Double-Blind, Randomized, Placebo-controlled 
Multicenter Study to Evaluate the Efficacy, Safety, 
and Tolerability of Mirabegron in Male Subjects with 
OAB Symptoms while taking the Alpha Blocker
Tamsulosin for BPH
ISN/Protocol 178-MA-3016
ClinicalTrials.gov Identifier: NCT02656173
Date of Protocol: 10 May 2016
Sponsor: Astellas Pharma Inc.
2-5-1, Nihonbashi-Honcho, Chuo-ku, 
Tokyo 103-8411, Japan


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
 Page 1 of 94 
 
A Phase 4, Double-Blind, Randomized, Placebo-controlled Multicenter 
Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron 
in Male Subjects with OAB Symptoms while taking the Alpha Blocker 
Tamsulosin for BPH 
Protocol for Phase 4 Study of Mirabegron for Overactive Bladder 
 
 
 
 
 
ISN/Protocol 178-MA-3016 
Version 4.0/ 10 May 2016 
 
 
 
 
 
Sponsor: Astellas Pharma Inc. (API) 
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 
 
 
 
 
 
 
Prepared on May 10, 2016 (Version 4.0) 
 
Investigator:  Investigator information is on file at Astellas. 
---------------------------------------------------------------------------------------------------------------------------------- 
This confidential document is the property of the Sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor. 


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
 Page 2 of 94 
 Table of Contents 
I. 
SIGNATURES ······················································································· 7 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 10 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 12 
IV. 
SYNOPSIS ··························································································· 15 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 24 
VI. 
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS ························ 27 
1 
INTRODUCTION ·················································································· 30 
1.1 
Background ····················································································· 30 
1.2 
Non-clinical and Clinical Data ······························································· 31 
1.3 
Summary of Key Safety Information for Study Drugs ···································· 32 
1.4 
Risk-Benefit Assessment ······································································ 32 
1.4.1 
Foreseeable Risks with Mirabegron ··················································· 32 
1.4.1.1 
Japanese Labeling ·································································· 32 
1.4.1.2 
Korean Labeling ···································································· 36 
1.4.1.3 
Clinically significant adverse drug reactions with mirabegron 
treatment ············································································· 37 
1.4.2 
Foreseeable Risks with Tamsulosin ··················································· 38 
1.4.2.1 
Japanese Labeling ·································································· 38 
1.4.2.2 
Korean Labeling ···································································· 39 
1.4.3 
Potential Risks with Combined Treatment ············································ 40 
1.4.4 
Potential Benefits ········································································· 41 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 41 
2.1 
Study Objectives ··············································································· 41 
2.2 
Study Design and Dose Rationale ··························································· 41 
2.2.1 
Study Design ·············································································· 41 
2.2.2 
Dose Rationale ············································································ 42 
2.3 
Endpoints ························································································ 42 
2.3.1 
Primary Endpoint ········································································· 42 
2.3.2 
Secondary Endpoints····································································· 42 
2.3.3 
Exploratory Endpoints ··································································· 43 
2.3.4 
Safety Endpoints·········································································· 43 
3 
STUDY POPULATION ··········································································· 43 
3.1 
Selection of Study Population ································································ 43 
3.2 
Inclusion Criteria ··············································································· 43 
3.3 
Exclusion Criteria ·············································································· 44 


Sponsor: API  
 
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10 May 2016 
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4 
TREATMENT(S) ··················································································· 46 
4.1 
Identification of Investigational Product(s) ················································· 47 
4.1.1 
Test Drug(s) ··············································································· 47 
4.1.2 
Comparative Drug(s)····································································· 48 
4.1.3 
Drug(s) for Screening Period ··························································· 48 
4.2 
Packaging and Labeling ······································································· 48 
4.2.1 
Packaging ·················································································· 48 
4.2.2 
Labeling ··················································································· 49 
4.3 
Study Drug Handling ·········································································· 49 
4.4 
Blinding ························································································· 49 
4.4.1 
Blinding Method·········································································· 49 
4.4.2 
Confirmation of the Indistinguishability of the Study Drugs ······················· 50 
4.4.3 
Retention of the Assignment Schedule and Procedures for Treatment 
Code Breaking ············································································ 50 
4.4.4 
Breaking the Treatment Code for Emergency ········································ 50 
4.4.5 
Breaking the Treatment Code by the Sponsor ········································ 50 
4.5 
Assignment and Allocation ··································································· 50 
5 
TREATMENTS AND EVALUATION ························································ 51 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 51 
5.1.1 
Dose/Dose Regimen and Administration Period ····································· 51 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) ································ 51 
5.1.3 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································· 51 
5.1.3.1 
Prior Treatment ····································································· 51 
5.1.3.2 
Concomitant Treatment ···························································· 51 
5.1.4 
Treatment Compliance··································································· 52 
5.1.5 
Restrictions During the Study ·························································· 53 
5.2 
Demographics and Baseline Characteristics ················································ 53 
5.2.1 
Demographics ············································································· 53 
5.2.2 
Medical History ··········································································· 54 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 54 
5.3 
Efficacy Assessments ·········································································· 54 
5.3.1 
Micturition Diary ········································································· 54 
5.3.2 
Overactive Bladder Symptom Score (OABSS) ······································ 54 
5.3.3 
Overactive Bladder Questionnaire (OAB-q) ········································· 54 
5.3.4 
International Prostate Symptom Score (IPSS and IPSS [QoL]) ··················· 54 
5.4 
Safety Assessment ············································································· 55 


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5.4.1 
Vital Signs ················································································· 55 
5.4.2 
Adverse Events ··········································································· 55 
5.4.2.1 
Adverse Events of Possible Hepatic Origin ····································· 55 
5.4.3 
Laboratory Assessments ································································· 55 
5.4.4 
Measurement of Residual Urine Volume ············································· 57 
5.4.5 
Measurement of Uroflowmetry ························································· 57 
5.5 
Adverse Events and Other Safety Aspects ·················································· 57 
5.5.1 
Definition of Adverse Events (AEs) ··················································· 57 
5.5.1.1 
Treatment-Emergent Adverse Events (TEAEs) ································ 58 
5.5.2 
Definition of Serious Adverse Events ················································· 58 
5.5.3 
Criteria for Causal Relationship to the Study Drug ·································· 59 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ····························· 59 
5.5.5 
Reporting of Serious Adverse Events ················································· 60 
5.5.6 
Follow-up of Adverse Events ··························································· 60 
5.5.7 
Procedure in Case of Pregnancy ························································ 61 
5.5.8 
Emergency Procedures and Management of Overdose ····························· 61 
5.5.9 
Supply of New Information Affecting the Conduct of the Study ·················· 61 
5.5.10 
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (Unique to Japan) ··································· 62 
5.6 
Test Drug Concentration ······································································ 62 
5.7 
Other Measurements, Assessments or Methods ··········································· 62 
5.8 
Total Amount of Blood Drawn ······························································· 62 
6 
DISCONTINUATION ············································································· 62 
6.1 
Discontinuation of Individual Subject(s) ··················································· 62 
6.2 
Discontinuation of the Site ···································································· 63 
6.3 
Discontinuation of the Study ································································· 63 
7 
STATISTICAL METHODOLOGY ···························································· 64 
7.1 
Sample Size ····················································································· 64 
7.2 
Analysis Set ····················································································· 65 
7.2.1 
Full Analysis Set ········································································· 65 
7.2.2 
Per Protocol Set ··········································································· 65 
7.2.3 
Safety Analysis Set ······································································· 65 
7.3 
Demographics and Other Baseline Characteristics ········································ 65 
7.4 
Analysis of Efficacy ··········································································· 66 
7.4.1 
Analysis of Primary Endpoint ·························································· 66 
7.4.1.1 
Primary Analysis ··································································· 66 
7.4.1.2 
Secondary Analysis ································································ 66 


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7.4.1.3 
Subgroup Analysis ································································· 66 
7.4.2 
Analysis of Secondary Endpoints ······················································ 67 
7.4.3 
Analysis of Exploratory Endpoints ···················································· 67 
7.5 
Analysis of Safety ·············································································· 68 
7.5.1 
Adverse Events ··········································································· 68 
7.5.2 
Laboratory Assessments ································································· 68 
7.5.3 
Vital Signs ················································································· 68 
7.5.4 
Residual Urine Volume ·································································· 69 
7.5.5 
Qmax ······················································································· 69 
7.6 
Analysis of Pharmacokinetics ································································ 69 
7.7 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 69 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 69 
7.8.1 
Missing Data ·············································································· 69 
7.8.2 
Outliers ···················································································· 69 
7.8.3 
Visit Windows ············································································ 69 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 71 
8.1 
Procedure for Clinical Study Quality Control ·············································· 71 
8.1.1 
Data Collection ··········································································· 71 
8.1.2 
Specification of Source Documents ··················································· 72 
8.1.3 
Clinical Study Monitoring ······························································ 73 
8.1.4 
Direct Access to Source Data/Documents ············································ 73 
8.1.5 
Data Management ········································································ 73 
8.1.6 
Protocol Deviations (Unique to Korea) ··············································· 73 
8.1.7 
End of Trial in All Participating Countries ··········································· 74 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 74 
8.2.1 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) ···················································· 74 
8.2.2 
Ethical Conduct of the Study ··························································· 74 
8.2.3 
Informed Consent of Subjects ·························································· 74 
8.2.3.1 
Subject Information and Consent ················································ 74 
8.2.3.2 
Supply of New and Important Information Influencing the 
Subject’s Consent and Revision of the Written Information ················· 75 
8.2.4 
Subject Confidentiality ·································································· 75 
8.3 
Administrative Matters ········································································ 75 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical 
Study ······················································································· 75 
8.3.2 
Documents and Records Related to the Clinical Study ····························· 76 
8.3.3 
Protocol Amendment and/or Revision ················································ 77 


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8.3.4 
Insurance of Subjects and Others ······················································ 78 
8.3.5 
Signatory Investigator for Clinical Study Report ···································· 78 
9 
QUALITY ASSURANCE ········································································· 78 
10 
STUDY ORGANIZATION ······································································· 78 
10.1 
Independent Data-Monitoring Committee (IDMC) ······································· 78 
10.2 
Other Study Organization ····································································· 78 
10.3 
Registration of Subjects ······································································· 79 
11 
REFERENCES ······················································································ 81 
12 
APPENDICES ······················································································· 84 
12.1 
List of Excluded Concomitant Medications ················································ 84 
12.2 
Liver Safety Monitoring and Assessment ··················································· 87 
12.3 
Events Always Considered to be Serious ··················································· 90 
12.4 
OABSS, OAB-q, IPSS and IPSS (QoL) ···················································· 91 
 






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3.  INVESTIGATOR’S SIGNATURE 
A Phase 4, Double-Blind, Randomized, Placebo-controlled Multicenter Study to 
Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Male Subjects with OAB 
Symptoms while taking the Alpha Blocker Tamsulosin for BPH 
ISN/Protocol 178-MA-3016, Version 4.0 
I have read all pages of this clinical study 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 ICH GCP guidelines and applicable 
local regulations. I will also ensure that sub-investigator(s) and other relevant members of my staff 
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: 
 
<Insert name and qualifications of the Investigator> 
 
Printed Name: 
Date (DD Mmm YYYY) 
 
Address: 
 
 
 
 
 
 
 
 
 
 
  


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II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
Contact Information for the Sponsor  
Corporate Name: Astellas Pharma Inc. 
Location: 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
Phone No.: 
  
Fax: 
 
Sponsor’s personnel: 
 
Contact numbers during non-business hours and for emergency:  
Sponsor Personnel (Phone No); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corporate Name: Astellas Pharma Singapore Pte. Ltd. 
Location: 6 Temasek Boulevard #22-03/05 Suntec Tower Four, Singapore 
Phone No.: 
  
Fax: 
 
Sponsor’s personnel: 
 
Contact numbers during non-business hours and for emergency:  
Sponsor Personnel (Phone No); 
 
 
 
Contact Information for the Contract Research Organization (CRO) 
Corporate name:  
 
Location:  
 
 
Phone No.:  
 
 
Fax: 
 
 
 
CRO’s personnel:  
 
Contact numbers during non-business hours and for emergency:  
CRO Contact (Phone No.): 
 
 
Corporate name:  
 
Location:  
 
 
 
Phone No.:  
 
  
Fax: 
 
 
  
CRO’s personnel:  
  
Contact numbers during non-business hours and for emergency:  
CRO Contact (Phone No.): 
 
 


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24h-Contact for Serious Adverse 
Events (SAEs) 
 
See Section 5.5.5 
 
Details will be added locally 
 
 
 
 
 
Medical Expert: 
  
 
, Japan. 
 


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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY 
TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (GPT) 
ANCOVA 
Analysis of Covariance 
API 
Astellas Pharma, Inc. 
AST 
Aspartate aminotransferase (GOT) 
AUC 
Area under drug concentration-time curve 
β-AR 
Beta-adrenergic receptor 
BPH 
Benign prostatic hypertrophy 
BOO 
Bladder outlet obstruction 
BPO 
Benign prostatic obstruction 
BUN 
Blood urea nitrogen 
CA 
Competent Authority 
cAMP 
Cyclic adenosine monophosphate 
CK 
Creatinine kinase 
Cmax 
Maximum observed plasma concentration 
CPK 
Creatine phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Curriculum vitae 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report form 
ED 
Erectile dysfunction 
EDC 
Electronic Data Capture 
EDTA-2K 
Ethylene diaminetetraacetic acid dipotassium salt dihydrate 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
γ-GTP 
gamma-glutamyl transferase  
HUS 
hours of undisturbed sleep 
ICF 
Informed Consent form 
ICH  
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFIS 
Intraoperative Floppy Iris syndrome 
INR 
International normalized ratio 
IPSS 
International Prostate Symptom Score 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISN 
International study number 
LA-CRF 
Liver Abnormality Case Report form 
LUTS 
Lower urinary tract symptoms 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measure 
NASH 
Non-alcoholic steatohepatitis 


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Abbreviations 
Description of abbreviations 
OAB 
Overactive Bladder 
OAB-q 
Overactive Bladder questionnaire 
OABSS 
Overactive Bladder Symptom Score 
OTC 
Over-the-Counter 
PD 
Protocol deviation 
PDE5 
Phosphodiesterase 5 
PI 
Package Insert 
PK 
Pharmacokinetic(s) 
PPS 
Per Protocol Set 
PR 
Pulse rate 
PSA 
Prostate-specific antigen 
PTNS 
Percutaneous Tibial Nerve Stimulation 
PTP 
Press-through Package 
PVR 
Postvoid residual 
Q 
Quartile 
Qmax 
Maximum urine flow rate 
QoL 
Quality of Life 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SFL 
Screening failure log 
SGLT 
Sodium-glucose transporter 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reactions 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TURP 
Transurethral resection of prostate 
UFM 
Uroflowmetry 
ULN 
Upper limit of normal 
US 
United States 
UTI 
Urinary tract infection 
WBC 
White blood cell 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 


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Definition of Key Study Terms 
Terms 
Definition of terms 
Adverse event 
Any untoward medical occurrence in a subject administered a 
study drug, and which does not necessarily have a causal 
relationship to the study drug. 
Baseline 
Observed values/findings that are regarded as the observed 
starting point for comparison.  Visit 2 is the Baseline visit in 
this study. 
Discontinuation 
The act of an enrolled subject concluding study participation 
prior to completion of all protocol-required assessments.  Data 
from discontinued subjects are not necessarily excluded from 
the data analyses. 
Enroll 
To register or enter into a clinical trial. NOTE: Once a subject 
has been enrolled, the clinical trial protocol applies to the 
subject.  
Intervention 
The drug, therapy, or process under investigation in a clinical 
study that is believed to have an effect on outcomes of interest 
(e.g., health-related quality of life, efficacy, safety, 
pharmacoeconomics).  
Investigational period 
Period of time during which protocol objectives are observed, 
and when the test drug and comparative drug (sometimes 
without randomization) is given to subjects, and continues 
until the last assessment after completing administration of the 
test drug or comparative drug. 
Randomization 
The process of assigning study subjects to treatment or control 
groups, using an element of chance to determine treatment 
assignments, in order to reduce bias. 
Screening 
A process of active consideration of potential subjects for 
enrollment in a trial. 
Screen failure 
A potential subject who did not meet one or more criteria 
required for participation in the trial. 
Screening period 
Period of time before the investigational period, from the time 
of informed consent at Visit 1 until just before the test drug or 
comparative drug is given to the subject at Visit 2.  
Study period 
Period of time from the first site’s initiation date to the last 
site’s completion date. 
Subject 
An individual who participates in a clinical study, either as a 
recipient of the study drug or as a control. 
Subject number 
A number assigned to each subject who has agreed to 
participate in a clinical study and has signed the informed 
consent form. 
Treatment period 
For this study, from randomization at Visit 2 through Visit 5 
(Week 12/End of Treatment). 
Variable 
Any quantity that varies; any attribute, phenomenon, or event 
that can have different qualitative or quantitative values. 
 


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IV. 
SYNOPSIS 
Date and Version # of Protocol Synopsis: 
 
Sponsor:  Astellas Pharma Inc. (API) 
Protocol Number: 178-MA-3016  
Name of Study Drug: Mirabegron 
Phase of Development:  4 
Title of Study: A Phase 4, Double-Blind, Randomized, Placebo-controlled Multicenter Study to 
Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Male Subjects with OAB 
Symptoms, while taking the Alpha Blocker, Tamsulosin, for BPH 
Planned Study Period: December 2015 to August 2017  
Study Objective(s):  
Primary Objective: 
To study the efficacy of mirabegron versus placebo in male patients with overactive bladder 
(OAB) symptoms while taking the alpha blocker, tamsulosin, for benign prostatic hypertrophy 
(BPH) 
 
Secondary Objective: 
To assess the safety and tolerability of mirabegron versus placebo in male patients with OAB 
symptoms while taking the alpha blocker, tamsulosin, for BPH   
 
Other Objectives: 
To assess patient-reported outcomes as measured by Symptom Bother, and Total Health-
Related Quality of Life scores as assessed by the Overactive Bladder questionnaire (OAB-q) 
and IPSS (QoL) of mirabegron versus placebo in male subjects with OAB symptoms who are 
taking the alpha blocker, tamsulosin, for BPH. 
 
The hypothesis being tested is that mirabegron is superior to placebo in the treatment of OAB 
symptoms. 
Planned Total Number of Study Centers and Location(s):   
Approximately 55 centers (Japan: ~50 centers; Korea: ~5 centers) 
Study Population:  
Men ≥40 years of age with OAB symptoms and taking the alpha blocker, tamsulosin, for BPH 
Number of Subjects to be Enrolled/Randomized:   
A total of 550 subjects (490 in Japan; 60 in Korea), with 275 subjects randomized (1:1) to each 
treatment group.   
Study Design Overview   
This is a randomized, double-blind, placebo-controlled, parallel group, multi-center study that 
will compare mirabegron with placebo in the treatment of OAB symptoms in men who are 
taking tamsulosin for BPH.  
If a drug for the treatment of BPH (e.g., PDE5 inhibitor or alpha 1 blocker other than 
tamsulosin) is to be changed to tamsulosin to enroll a subject in this clinical study, the change to 
tamsulosin should be done only after ICF signature. 
 
Treatment group 
Screening 
period 
(single-blind)
Treatment 
period 
(double-blind) 
Tamsulosin 0.2 mg / Mirabegron 50 mg
 
●＋□ 
●＋■ 
Tamsulosin 0.2 mg / Placebo 
●＋□ 
 
 


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●：Tamsulosin 0.2mg Tablet 
■：Mirabegron 50mg Tablet 
□：Mirabegron 50mg Placebo Tablet 
At Visit 1 (Screening), subjects will enter into a 4-week single-blind Screening period after 
enrollment and will receive mirabegron 50 mg placebo and tamsulosin 0.2 mg once daily after 
breakfast.  Subjects who meet all entry criteria at the end of the tamsulosin Screening period 
will be randomized at Visit 2 (Baseline) to receive mirabegron 50 mg or matching placebo for 
12 weeks, in addition to daily treatment with tamsulosin 0.2 mg.  
During the treatment period, the subject will complete a 3-day micturition diary 3 days before 
Visit 2 (baseline), Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12/End of Treatment).  
As part of the questionnaire, subjects will complete the Overactive Bladder Symptom Score 
(OABSS) and International Prostate Symptom Score (IPSS) questionnaires at Visit 1 
(Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12/End of 
Treatment); and at Visit 1 (Screening), Visit 2 (Baseline), and Visit 5 (Week 12/End of 
Treatment), subjects will complete the Overactive Bladder questionnaire (OAB-q).  Post-void 
residual (PVR) urine volume will be assessed at Visit 1 (Screening), Visit 2 (Baseline), Visit 3 
(Week 4), Visit 4 (Week 8) and Visit 5 (Week 12/End of Treatment).  The total duration of 
study participation per subject is 16 weeks.  


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Inclusion/Exclusion Criteria:   
 Inclusion:  
Inclusion Criteria assessed at Visit 1 (Screening):   
1. Patient has given written informed consent before starting the study in accordance with the 
informed consent form approved by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) of each study center 
2. Male outpatient >40 years of age at the time of informed consent  
3. Patient has been under treatment with tamsulosin 0.2mg for at least 4 weeks before the start 
of the Screening period 
4. Patient with a history of an average of at least 2 episodes of urgency per 24 hours and an 
average of 8 or more micturitions per 24 hours during the last 3 days before  the start of the 
Screening period (verified by interview). 
5. Patient who has no wish to have children in the future (Unique to Japan). 
6. Male subjects and their female spouses/partners who are of childbearing potential must be 
using highly effective contraception consisting of two forms of birth control* (at least one 
of which must be a barrier method), starting at Screening, continuing throughout the study 
period, and for 28 days after the final study drug administration. 
7. Subject must not donate sperm, starting at Screening, continuing throughout the study 
period, and for 28 days after the final study drug administration. 
8. Patient is willing and able to complete the micturition diary and questionnaires correctly. 
9. Subject agrees not to participate in another interventional study while receiving treatment in 
this study. 
*Highly effective forms of birth control include: 
 Consistent and correct usage of established oral contraception. 
 Established intrauterine device (IUD) or intrauterine system (IUS). 
 Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (Unique to 
Korea: with spermicidal foam/gel/film/cream/suppository). 
 Calendar-based contraceptive methods (Knaus-Ogino or rhythm method). 
Inclusion Criteria assessed at Visit 2 (Baseline) based on the 3-day micturition diary: 
10. Subject with an average of at least 2 episodes of urgency per 24 hours and an average of 8 
or more micturitions per 24 hours based on a 3-day micturition dairy from the Screening 
period.  
11. Subject continues to meet all inclusion criteria of Visit 1. 
Waivers to the inclusion criteria will NOT be allowed.  


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Exclusion:   
Exclusion Criteria assessed at Visit 1 (Screening): 
1. Patient with suspected symptoms of OAB, with onset only transient (e.g., drug-induced, 
psychogenic). 
2. Patient with PVR urine volume >100 mL or Q max <5 mL/sec. 
3. Patient with prostate-specific antigen (PSA) ≥4 ng/mL.  
4. Patient with neurogenic bladder (e.g., spinal-cord lesions or other damage that will clearly 
affect urination; multiple sclerosis; Parkinson’s disease) or a history of surgery that caused 
damage to the pelvic plexus. 
5. Patient with urethral stricture or bladder-neck stenosis. 
6. Patient with diabetic neuropathy complications.  
7. Patient who has undergone a surgical procedure (e.g., transurethral resection of prostate 
[TURP], laser therapy), previous pelvic radiation therapy, or hyperthermia therapy that may 
affect urinary tract function.  
8. Patient with significant stress incontinence (i.e., patients presenting with symptoms of only 
stress urinary incontinence) or postsurgical prostate incontinence, as determined by the 
Investigator.  
9. Patient with an indwelling catheter or practices intermittent self-catheterization. 
10. Patient with 3 or more episodes of recurrent urinary tract infection (UTI) within the last 
6 months. 
11. Patient with a UTI; prostatitis; chronic inflammation, such as interstitial cystitis; urinary 
calculus (e.g. ureteral calculus, urethral calculus, bladder calculus); or previous or current 
malignant disease of the pelvic organs (i.e., within the confines of the pelvis, including the 
bladder, prostate, and rectum; organs of the lower gastrointestinal tract are not necessarily 
considered pelvic organs, as the distal ascending colon, full transverse colon, and proximal 
portion of the descending colon are in the abdomen). 
12. Patient with a concurrent malignancy or history of any malignancy (within the past 5 years), 
except for non-metastatic basal-cell or squamous-cell carcinoma of the skin that has been 
treated successfully.  
13. Patient with serious heart disease (e.g. myocardial infarction, cardiac failure, uncontrolled 
angina pectoris, serious arrhythmia, use of pacemaker), liver disease, kidney disease, 
immunological disease, lung disease.  
14. Patient who has received intravesical injection within the last 12 months with botulinum 
toxin, resiniferatoxin, or capsaicin. 
15. Patient who has received electrostimulation therapy for OAB (e.g., sacral nerve stimulation 
or Percutaneous Tibial Nerve Stimulation [PTNS]).  
16. Patient who has received a bladder training program or pelvic floor exercises <28 days prior 
to the start of the Screening period. 
17. Patient with postural hypotension or syncope, hypokalemia, or closed-angle glaucoma. 
18. Patient with evidence of QT prolongation on electrocardiogram (ECG), defined as QTcF 
>450 msec. 
19. Patient with severe uncontrolled hypertension, defined as sitting systolic blood pressure 
 (SBP) >180 mmHg and/or diastolic blood pressure (DBP) >110 mmHg. 
20. Patient with a clinically significant ECG abnormality, as determined by the Investigator.  
21. Patient who has severe renal impairment, defined as an estimated glomerular filtration rate 
of <29 mL/min/1.73m2; end-stage renal disease; or is undergoing dialysis.  


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22. Patient with aspartate transaminase (AST) or alanine transaminase (ALT) >2 times the 
upper limit of normal (ULN), or gamma-glutamyl transferase (γ-GT) >3 times the ULN. 
23. Patient with moderate or severe hepatic impairment, defined as Child-Pugh Class B or C.  
24. Patient with hypersensitivity to any of the components of mirabegron, other beta-adrenergic 
receptor (β-AR) agonists, or any of the inactive ingredients.  
25. Patient with ongoing alcohol and/or drug abuse. 
26. Patient with or a history of mood disorder, neurotic disorder, or schizophrenia. 
27. Patient with dementia, cognitive dysfunction, or clinically significant cerebrovascular 
disorder 
28. Patient who has been treated with an experimental device <84 days or received an 
investigational agent <84 days prior to the start of the Screening period. 
29. Patient has used any prohibited concomitant medication (defined in Appendix 12.1) 
<28 days (but, <1 year for 5α-reductase inhibitors) before the start of the Screening period. 
30. Patient with any clinically significant condition, which in the opinion of the Investigator, 
makes the subject unsuitable for study participation. 
31. Patient who is involved in the conduct of the study as an employee of the Astellas group, a 
third party associated with the study, or the study site team. 
Exclusion Criteria assessed at Visit 2 (Baseline): 
32. Subject fulfills any exclusion criteria of Visit 1 at Visit 2. 
33. Subject was noncompliant during the 4 week tamsulosin Screening period, defined as taking 
less than 80% or greater than 120% of prescribed dose of study medication. 
34. Subject had an average total daily urine volume >3000 mL, as recorded in the 3-day 
micturition diary. 
35. Subject is found to meet any of the exclusion criteria for enrollment at Visit 1 (Screening) 
 
Waivers to the exclusion criteria will NOT be allowed. 
Investigational Product(s): Mirabegron 50 mg tablet 
Dose(s): 50 mg once daily 
Mode of Administration: Oral route, after breakfast 
Comparative Drug(s): Placebo matched to mirabegron 50 mg tablet 
Dose(s): Once daily 
Mode of Administration: Oral route, after breakfast 
Drug(s) for Screening Period: Mirabegron 50 mg matching placebo along with 
tamsulosin 0.2 mg 
Dose(s): Mirabegron 50 mg placebo and tamsulosin 0.2 mg once daily 
Mode of Administration: Oral route, after breakfast 


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Concomitant Medication Restrictions or Requirements:  
The excluded concomitant meditations (defined in Appendix 12.1) can be allowed to use under 
the conditions below: 
1. From the day following the dispensing of the study drug for the Screening period to the 
end of the Treatment period, none of the prohibited concomitant medications listed in 
Appendix 12.1 should be used.  The following drugs, however, may be concomitantly 
used: 
 
Eye drops 
 
Transdermal formulations, excluding β-agonists and drugs for the treatment of 
urinary storage and voiding dysfunction 
 
Nasal drops, excluding drugs for diabetes insipidus 
 
Topical agents 
 
Inhaled β-agonists used to relieve acute symptoms, such as bronchial asthma 
 
Chinese herbal medicines used for the treatment of conditions other than urinary 
storage and voiding dysfunction 
2. The following drugs may be used concomitantly for a short period of time (up to a total 
of 5 days during the interval from the day following a visit to the next visit), except 
during the micturition diary period:  
 
Parasympathetic inhibitors/parasympatholytic drugs for peptic ulcer, etc. 
 
Antihistamines, ephedrine hydrochloride, and methylephedrine hydrochloride 
for common cold, etc. 
3. Transient concomitant use of parasympathetic inhibitors/parasympatholytic drugs will 
be allowed, if used in preparation for an examination, except during the micturition 
diary period.  
4. Concomitant treatment with 5α-reductase inhibitors will be allowed (the dosage shall 
not be changed for study period), if the subject has been on treatment for a year or 
more. 
5. Transient concomitant use of phosphodiesterase 5 (PDE5) inhibitor for treatment of 
erectile dysfunction (ED) will be allowed, except during the micturition diary period.  
6. Nonpharmacological therapy for OAB, such as biofeedback therapy, bladder training, 
or pelvic-floor muscle exercise will be prohibited from 4 weeks before (<28 days) the 
start of the Screening period to the end of the Treatment period. 
Duration of Treatment: Subjects will receive mirabegron 50 mg or matching placebo (along 
with tamsulosin 0.2 mg) once daily for 12 weeks after a 4-week Screening period on tamsulosin 
0.2 mg + mirabegron 50 mg placebo.  Subject participation will last approximately 16 weeks. 


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Endpoints for Evaluation:   
Primary: 
 
Change from Baseline to End of Treatment in mean number of micturitions/24 hours, 
based on a 3-day micturition diary. 
Secondary: 
Change from Baseline to End of Treatment in: 
 
Mean number of urgency episodes/24 hours 
 
Mean number of urgency incontinence episodes/24 hours 
 
Mean number of incontinence episodes/24 hours 
 
Mean number of nocturia episodes 
 
Mean volume voided per micturition 
 
Total OABSS score  
 
Subscale score from OABSS score 
 
Total IPSS score  
 
Subscale score from IPSS score 
 
Symptom Bother and Total Health-Related Quality of Life scores, as assessed by the 
OAB-q questionnaire. 
 
Exploratory: 
Change from Baseline to End of Treatment in: 
 
Hours of undisturbed sleep (HUS) 
 
First nighttime voided volume 
 
Subscale scores from OAB-q 
 
Normalization rate of OABSS 
 
Normalization rate of micturition diary (number of episodes of 
micturition/urgency/urgency incontinence/incontinence/nocturia) 
 
Safety Variables: 
 
Incidence and severity of treatment-emergent adverse events (TEAEs)  
 
Vital signs: sitting systolic and diastolic blood pressure and pulse rate (home based 
self-measurements and office measurements) 
 
Laboratory parameters (serum chemistry, hematology, and urinalysis) 
 
Post-voiding residual (PVR) urine volume 
 
Maximum urine flow rate (Qmax) 


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Statistical Methods: 
Sample size justification:  
The primary endpoint for this study is the change from Baseline to End of Treatment in mean 
number of micturitions/24 hours, based on the 3-day micturition diary.  
For the Full Analysis set (FAS), 248 subjects per treatment group will provide 90% power to 
detect a 0.7 reduction in the mean number of micturitions/24 hours in the mirabegron group 
compared with the placebo group, at a two-sided alpha level of 0.05.  A standard deviation (SD) 
of 2.4 is assumed. 
Assumptions for the mean reduction and SD are based on data from previous studies (i.e., 178-
CL-048, 178-CL-090 and 905-JC-001).  If 90% of the randomized subjects are evaluable for 
efficacy, 550 subjects should be randomized, with 275 subjects randomized to each treatment 
group. 
Efficacy:   
The primary analysis set is the FAS, which will include all subjects who meet the following 
criteria: 
 
Those who took at least one dose of double-blind study medication after randomization 
 
Those who had a micturition measurement in the Baseline visit diary and at least one 
micturition measurement in the post- Baseline visit diary 
Subjects who are included in the FAS and who meet all of the following criteria will be 
included in the Per Protocol Set (PPS): 
 
Those subjects who did not violate the inclusion or exclusion criteria 
 
Those subjects with no less than 80% drug compliance during the Screening and 
Treatment period 
 
Those subjects who took the study drug for at least 42 days during the Treatment 
period, from the day following dispensing.  However, any subjects who discontinued 
the study for efficacy-related reasons, such as insufficient therapeutic effect, will be 
included in the PPS, even if the drug was taken for fewer than 42 days. 
 
Those subjects whose diary was completed for at least 2 of the 3 consecutive days for 
Visit 2 and the last visit during the Treatment period. 
 
Those subjects who did not receive any of the prohibited concomitant 
medications/therapies that could affect the evaluation of efficacy. 
The End-of-Treatment assessment will be analyzed to account for subjects who prematurely 
discontinued from the study.  The End-of-Treatment assessment is defined as the last post-
Baseline visit assessment during the double-blind study period for which data for the primary 
efficacy variable is available.   
Continuous variables will be summarized using descriptive statistics (i.e., mean, SD, minimum, 
median, Quartile 1 [Q1], Q3, and maximum).  Categorical variables will be described using 
absolute and relative frequency. 
The primary efficacy variable is the change from Baseline to End-of-Treatment in the mean 
number of micturitions/24 hours, based on the 3-day micturition diary.  It will be analyzed using 
an Analysis of Covariance (ANCOVA), including treatment group and region as fixed factors 
and baseline as a covariate.  Within the framework of the ANCOVA model, point estimates and 
two-sided 95% confidence intervals for the mean change from Baseline within each treatment 
group, as well as for the difference in mean change from Baseline between the mirabegron 
treatment group and placebo, will be calculated.   
The primary endpoint and all secondary endpoints will be analyzed using the FAS, with the PPS 
used as a supportive analysis for the secondary endpoints. 
Pharmacokinetics: Not applicable. 
Pharmacodynamics: Not applicable. 


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Safety:  
The safety analyses will be done on the Safety Analysis Set (SAF), which consists of subjects 
who received at least one dose of double-blind study medication.  Treatment-emergent AEs will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary and will 
be summarized by treatment group.  All laboratory data, including clinical chemistry, 
hematology, and urinalysis will be descriptively summarized for Baseline, Visits 3, 4, and 5, as 
well as the change from Baseline to each visit.  Changes from Baseline in vital signs will be 
summarized by treatment group.  In addition, PVR volume, as measured by ultrasonography 
and bladder scanning, will be summarized by change from Baseline. 
Interim analyses: Not applicable.  
 


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V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Figure 1 
Study Design Flow Chart 
 
Study Schematic Diagram  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Period 
(12 weeks) 
Randomization
Single-blind 
V3 
V1 
V2 
V4 
V5 
Screening Period 
(4 weeks) 
Mirabegron 50 mg 
plus Tamsulosin 0.2 mg 
Double-blind 
Placebo matched to Mirabegron 50 mg  
plus Tamsulosin 0.2 mg 
4 weeks
4 weeks
4 weeks
Placebo matched to 
Mirabegron 50 mg  
plus Tamsulosin  
0.2 mg 


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Table 1: Schedule of Assessments  
Screening/ 
Tamsulosin 
Screening
Treatment Period 
Visit
1 
2 
3 
4 
5 
Day
-28 
1 
29 
57 
85 
Week
-4 
0 
4 
8 
12 
Visit Windows
+/- 7d 
- 
+/- 7 d 
+/- 7 d 
+/- 7 d 
Visit Windows (Study Days) a 
-35 to -21 
- 
22 to 36 
50 to 64 
78 to 92 
Informed Consent 
X b
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Medical History and OAB History 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Enter 4-week Tamsulosin Screening c 
X 
 
 
 
 
Enrollment 
X 
 
 
 
 
Randomization d 
 
X 
 
 
 
Physical Exam  
X 
 
 
 
 
Weight and Height 
X 
 
 
 
 
Vital Signs (includes pulse and blood pressuree) 
X 
X 
X 
X 
X 
Serum PSA 
X 
 
 
 
 
Prostate volume 
X 
 
 
 
 
Serum chemistry f, hematology f, urinalysis 
X 
X d 
 
 
X 
12-Lead ECG (QTcF interval) 
X 
 
 
 
 
Ultrasonography or Bladder Scan (PVR) 
X 
X 
X 
X 
X 
Uroflowmetry g 
X 
X 
 
 
X 
Medication History and OAB Medication History 
X 
 
 
 
 
Concomitant Medications Assessment 
X 
X 
X 
X 
X 
Adverse Event Assessment 
 
X 
X 
X 
X 
Dispense Study Drug  
X 
X 
X 
X 
 
Drug Accountability 
X 
X 
X 
X 
X 
Instruct Subject on 3-day Micturition Diary h 
X 
X 
X 
X 
 
Subject Completes 3-day Micturition Diary  
 
X i 
X i 
X i 
X i 


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Screening/ 
Tamsulosin 
Screening
Treatment Period 
Visit
1 
2 
3 
4 
5 
Day
-28 
1 
29 
57 
85 
Week
-4 
0 
4 
8 
12 
Visit Windows
+/- 7d 
- 
+/- 7 d 
+/- 7 d 
+/- 7 d 
Visit Windows (Study Days) a 
-35 to -21 
- 
22 to 36 
50 to 64 
78 to 92 
OABSS 
X 
X 
X 
X 
X 
IPSS & IPSS (QoL) 
X 
X 
X 
X 
X 
OAB-q  
X 
X 
 
 
X 
Review Micturition Diary j 
 
X 
X 
X 
X 
Abbreviations: ECG =electrocardiogram; IPSS = International Prostate Symptom Score; OAB = Overactive bladder; OAB-q = Overactive Bladder questionnaire; OABSS = Overactive 
Bladder Symptom Score; PVR = Post-void residual (volume); QoL = Quality of Life; UFM = uroflowmetry 
a. 
Visit windows/study days will be calculated based on Day 1 (Visit 2). 
b. If a drug for the treatment of BPH is to be changed to tamsulosin to enroll a subject in this clinical study, the change to tamsulosin should be done only after ICF signature and a new 
informed consent is to be obtained at Visit 1 (Screening). 
c. 
Subjects must take tamsulosin for at least 28 days before the Screening period. 
d. Randomization is to occur after confirming all eligibility criteria and after performing all other visit procedures at Visit 2. 
e. 
Measured during the patient diary period and at each visit (only at visit for discontinued subjects if there is no entry in the patient diary) 
f. 
Blood samples need not be under fasting conditions.  
g. Any UFM results obtained within 28 days prior to the start of the Screening period may be used, with the subject’s consent, instead of the Visit 1 data. 
h. At the Tamsulosin Screening visit (Visit 1), all subjects will be provided a micturition diary that will be used to record the date and time of each of their micturitions, episodes of 
incontinence, urgency, and voiding volume. Voiding volumes will be collected at Visit 2 (Baseline) and Visit 5 (Week 12). Additionally, the diary will be used to record daily medication 
intake and self-measurement of blood pressure and pulse rate. Subjects will be instructed to begin completing the micturition diary 3 days prior to each in-office study visit, including 
Visit 2 (Baseline) and Visits 3 through 5 (Treatment Period), and to complete the diary for the full 3 days.   
i. 
For Visits 2, 3, 4, and 5, subjects should complete the micturition diary on the 3 days immediately prior to the study visit, but in any case, on consecutive days within 1 week prior to the 
study visit. 
j. 
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VI. 
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS 
Acceptable Time Ranges for Efficacy Assessments 
A. Micturition Diary: 
Time point 
Scheduled day 
Acceptable time range 
Diary retrieved at Visit 2 
1 
Day -7 to Day 1 (AM 5:59) 
Diary retrieved at Visit 3 
29 
Day 19 to Day 36 (AM 5:59) 
Diary retrieved at Visit 4 
57 
Day 47 to Day 64 (AM 5:59) 
Diary retrieved at Visit 5 
85 
Day 75 to Day 92 (AM 5:59) 
The diary is to be retrieved at the final 
evaluation during the Treatment 
period. 
The final diary must be completed within 7 days after 
the last dose of study drug. 
If the subject cannot complete the diary for the 3 days immediately prior to the visit, the diary 
entries may be for any 3 days within 7 days prior to the visit. 
 
B. OABSS, IPSS and IPSS (QoL), OAB-q* 
Time Point 
Scheduled Day 
Acceptable Time Range 
Completed at Visit 1 
-28 
Day -35 to Day -21 
Completed at Visit 2 
1 
- 
Completed at Visit 3 
29 
Day 22 to Day 36 
Completed at Visit 4 
57 
Day 50 to Day 64 
Completed at Visit 5 
85 
Day 78 to Day 92 
The questionnaires must be completed 
at the final evaluation during the 
Treatment period. 
The final diary must be completed within 7 days after 
the last dose of study drug. 
*OAB-q not performed at Visit 3 and Visit 4. 
 


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Acceptable Time Ranges for Safety Tests 
Vital Signs 
Time Point 
Scheduled Day 
Acceptable Time Range 
Visit 1 
-28 
Day-35 to Day -21 
Visit 2 
1 
- 
Visit 3 
29 
Day 22 to Day 36 
Visit 4 
57 
Day 50 to Day 64 
Visit 5 
85 
Day 78 to Day 92 
Final evaluation during 
Treatment period 
Must be performed within 7 days after the last dose of study 
drug 
 
Hematology and Serum Chemistry 
Time Point 
Scheduled Day 
Acceptable Time Range 
Visit 1 
-28 
Day-35 to Day -21 
Visit 2 
1 
- 
Visit 5 
85 
Day 78 to Day 92 
Final evaluation during 
Treatment period 
Must be performed within 7 days after the last dose of study 
drug 
 
Urinalysis 
Time Point 
Scheduled Day 
Acceptable Time Range 
Visit 1 
-28 
Day -35 days to Day -21 days 
Visit 2 
1 
- 
Visit 5 
85 
Day 78 to Day 92 
Final evaluation during 
Treatment period 
Must be performed within 7 days after the last dose of study 
drug 
 
Residual Urine Volume 
Time Point 
Scheduled Day 
Acceptable Time Range 
Visit 1 
-28 
Day -35 days to Day -21 days 
Visit 2 
1 
- 
Visit 3 
29 
Day 22 to Day 36 
Visit 4 
57 
Day 50 to Day 64 
Visit 5 
85 
Day 78 to Day 92 
Final evaluation during 
Treatment period 
Must be performed within 7 days after the last dose of study 
drug 
 
 


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Uroflowmetry 
Time Point 
Scheduled Day 
Acceptable Time Range 
Visit 1 
-28 
Day-35 to Day -21 
Visit 2 
1 
- 
Visit 5 
85 
Day 78 to Day 92 
Final evaluation during 
Treatment period 
Must be performed within 7 days after the last dose of study 
drug 
 
Self-measurement of blood pressure and pulse rate by patients 
Time point 
Scheduled day 
Acceptable time range 
Diary retrieved at Visit 2 
1 
Day -7 to Day -1 
Diary retrieved at Visit 3 
29 
Day 19 to Day 35 
Diary retrieved at Visit 4 
57 
Day 47 to Day 63 
Diary retrieved at Visit 5 
85 
Day 75 to Day 91 
The diary is to be retrieved at the final 
evaluation during the Treatment 
period. 
The final diary must be completed within 7 days after 
the last dose of study drug. 


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1 
INTRODUCTION 
1.1 
Background 
Benign prostatic hyperplasia (BPH) is associated with lower urinary tract symptoms 
(LUTS) caused by benign enlargement of the prostate gland.  The prevalence of LUTS is 
increasing with advancement of   the aging society (especially, ≥50 years of age).  These 
symptoms may be related to the obstructive effect of prostate enlargement, secondary 
effects on the bladder, or complications of BPH, and include symptoms associated with 
voiding, post-micturition, and bladder storage.  The LUTS associated with BPH have 
been shown to be highly bothersome to patients, resulting in a negative impact on sleep, 
mental health, work productivity, and overall health-related quality of life (QoL)1-4.  
Therefore, a decrease in the level of bothersome symptoms may be a better indicator of 
patient satisfaction with BPH treatment in addition to the measures of symptom frequency.   
Recommended first-line pharmacotherapy for LUTS associated with BPH is with an 
alpha1-adrenergic receptor antagonist (alpha1-blocker), which can alleviate both voiding 
symptoms and storage symptoms5.  Tamsulosin is the most commonly used alpha1-
blocker for this indication.  However, LUTS in patients with both bladder outlet 
obstruction and detrusor overactivity may not sufficiently improve with alpha1-blocker 
monotherapy, and as a result, overactive bladder (OAB) symptoms may persist.  
OAB is a symptom complex that is characterized by urinary urgency, with or without 
urinary incontinence, and is often associated with urinary frequency and nocturia6.  The 
etiology of OAB is multifactorial, with urgency symptoms associated with overactivity of 
the detrusor muscle, which can be of neurogenic, myogenic, or idiopathic origin.  
Antimuscarinics (AMs) are the mainstay of pharmacological treatment of OAB, and 
represent the most commonly prescribed drugs for this condition, as there is substantial 
evidence of their efficacy.   
A number of studies7-13, have reported efficacy of AMs as add-on therapy to an alpha1-
blocker for the treatment of residual OAB symptoms.  The ASSIST (add-on therapy of 
solifenacin succinate for BPH with OAB symptoms treated by tamsulosin hydrochloride) 
study7, which involved combined treatment with tamsulosin and solifenacin, is the only 
randomized, controlled, double-blind, placebo-controlled clinical trial of tamsulosin and 
an AM, and one of the most important studies in Japan that support the efficacy of add-on 
therapy for OAB.  However, there are tolerability concerns with AMs, due to their actions 
on the salivary gland, intestine, and eye, resulting in side effects such as dry mouth, 
constipation, and blurred vision, all of which limits their chronic use.  Also, combination 
therapy with an alpha1-blocker increases the risk of urinary retention, which occurs with 
an estimated incidence in men of 6.8 per 1000 person-years14.  Urinary retention is 
painful, and significantly reduces QoL. 
Mirabegron, discovered by Astellas Pharma Inc. (API) and approved in Japan in 2011 and 
Korea in 2014, is a highly selective β3-adrenergic receptor (β3-AR) agonist that offers a 
new treatment option for patients with OAB.  Mirabegron has been demonstrated to 
improve OAB symptoms by stimulating β3-AR in the bladder smooth muscle, resulting in 
relaxation of the bladder and enhanced urine storage15, 16.  In the Phase 3 studies for 


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mirabegron, the incidence of adverse events (AEs) among subjects receiving mirabegron 
was no greater than among subjects receiving placebo17-21.   
It is expected that mirabegron will be better tolerated than AMs, and therefore, add-on 
treatment with mirabegron may offer a safer alternative to the use of AMs for the 
treatment of OAB. There are two studies on the add-on therapy in Japan. The one is an 
open-label, randomized, controlled study that compared co-administration of mirabegron 
and tamsulosin to tamsulosin monotherapy22. The other is a nonrandomized, open-label 
study of mirabegron as add-on treatment to tamsulosin23. The add-on therapy of 
mirabegron to tamsulosin proved the effectiveness in the studies, otherwise, these were 
non-placebo and non-double-blind studies. Therefore, this study will be the first double-
blind, placebo-controlled study to assess the efficacy, safety, and tolerability of 
mirabegron as add-on treatment to tamsulosin in subjects with BPH and residual OAB 
symptoms.  
 
1.2 
Non-clinical and Clinical Data 
Nonclinical data: 
1. β3-AR stimulatory effect: 
In an experiment using cells expressing human β3-AR, mirabegron induced a 
concentration-dependent increase of cyclic adenosine monophosphate (cAMP) 
levels in the cells.  In cells expressing human β1-AR and β2-AR, mirabegron led 
to a minor increase of intracellular cAMP levels. 
2. Bladder relaxing effect: 
In an experiment using isolated rat bladder, mirabegron induced an increase of 
cAMP levels in the tissues. In isolated rat and human bladders with carbachol-
induced sustained contraction, mirabegron demonstrated a relaxing effect. 
3. Effect on intravesical pressure: 
In anesthetized rats, mirabegron decreased the resting intravesical pressure. 
4. Effects on bladder function: 
In conscious Cynomolgus monkeys, mirabegron led to an increased mean volume 
voided per micturition as well as decreased micturition frequency.  In conscious 
rats with cerebral infarction, mirabegron led to an increased mean volume voided 
per micturition. 
Please refer to the Package Insert (PI) for further information on nonclinical studies of 
mirabegron.  
Clinical data: 
Co-administration of mirabegron with tamsulosin: 
In an open-label, randomized, controlled study that compared co-administration of 
mirabegron and tamsulosin to tamsulosin monotherapy in 94 subjects with OAB induced 
by benign prostatic obstruction (BPO), efficacy was assessed by changes from baseline in 
the Overactive Bladder Symptom Score (OABSS) and International Prostate Symptom 


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Score (IPSS).  The efficacy results demonstrated a significant improvement in the 
combination therapy group compared to the tamsulosin monotherapy group in OABSS 
total score (-2.21 vs. - 0.87; p=0.012) and OABSS urgency score (-1.34 vs. -0.55; 
p=0.006).  The changes from baseline in scores for OABSS daytime frequency, the IPSS 
storage symptom subscore, and the QoL Index after 8 weeks of treatment were all 
significantly greater in the combination treatment group than in the tamsulosin 
monotherapy group.  Also, the change in post-void residual urine volume was 
significantly greater in the combination therapy group than in the tamsulosin 
monotherapy group.  Urinary retention was observed in 1 subject in the combination 
therapy group.  The authors concluded that mirabegron combined with tamsulosin was an 
effective and safe treatment for patients with BPO with OAB symptoms after tamsulosin 
monotherapy22. 
In a nonrandomized, open-label study of mirabegron as add-on treatment to tamsulosin in 
26 Japanese male subjects with OAB, efficacy was assessed by changes from baseline in 
OABSS, IPSS, free uroflowmetry (UFM), filling cystometry, and pressure-flow study 
(PFS).  The results showed that mirabegron treatment significantly improved the OABSS 
(from 8.5 ± 2.3 to 4.7 ± 2.5; p <0.001), voided volume (from 135 ± 47 to 181 ± 102 mL; 
p = 0.01), maximum flow rate (from 10.7 ± 3.7 to 13.5 ±6.4 mL/sec; p<0.01), and average 
flow rate (from 5.5 ± 1.9 to 7.1 ±3.3 mL/sec; p<0.01).  Also, maximum cystometric 
capacity significantly increased from 170 ±98 to 212 ±95 mL (p = 0.01).  No subject 
discontinued mirabegron treatment due to an adverse event (AE).  The authors concluded 
that the combined use of mirabegron and tamsulosin was a safe and effective treatment 
option for male patients with OAB, as it improved urine storage and voiding symptoms, 
urodynamic bladder storage, and urine flow rate, with no significant deleterious effect on 
bladder contractility23. 
1.3 
Summary of Key Safety Information for Study Drugs 
For detailed safety information on the study medications, please refer to the Package 
Inserts for mirabegron and tamsulosin. 
1.4 
Risk-Benefit Assessment 
1.4.1 
Foreseeable Risks with Mirabegron 
1.4.1.1 Japanese Labeling  
The following information on adverse reactions is from the Japanese labeling for 
Betanis®Tablets 25 mg and 50 mg (August 2015, 8th version): 
Adverse Reactions 
Adverse reactions to this product including abnormal laboratory values were reported in 
313 (25.9%) of 1,207 patients with OAB in the safety evaluation in Japan.  Major adverse 
reactions included 45 cases (3.7%) of γ-GTP increased, 35 cases (2.9%) of constipation, 
31 cases (2.6%) of CK (CPK) increased, 30 cases (2.5%) of ALP increased, 21 cases 
(1.7%) of dry mouth, 21 cases (1.7%) of ALT (GPT) increased, 19 cases (1.6%) of AST 
(GOT) increased, 17 cases (1.4%) of protein urine present and 15 cases (1.2%) of white 
blood cell count decreased (At the time of approval: July 2011). 
(1) Clinically significant adverse reactions 


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Urinary retention (incidence unknown): Since urinary retention may occur, patients 
should be monitored carefully.  If any symptom is observed, this product should be 
discontinued and appropriate measures should be taken. 


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(2) Other Adverse Drug Reactions 
System Organ 
Class 
Preferred Term 
Incidence ≥1%, 
<5% 
Preferred Term 
Incidence <1% 
Preferred Term
Incidence 
unknown 
Blood and 
lymphatic system 
disorders 
White blood cell 
count decreased 
Platelet count increased 
White blood cell count 
increased 
Platelet count decreased 
 
Cardiac disorders 
 
Bundle branch block right 
Palpitations 
Supraventricular 
extrasystoles Tachycardia 
Ventricular extrasystoles 
Blood pressure increased 
Heart rate increased 
 
Ear and labyrinth 
disorders 
 
Vertigo 
 
Eye disorders 
 
 
Vision blurred 
Gastrointestinal 
disorders 
Constipation 
Dry mouth 
Abdominal discomfort 
Abdominal distension 
Diarrhoea 
Duodenal ulcer 
Gastritis 
Stomatitis 
Nausea 
Vomiting 
Abdominal pain 
Abdominal pain 
upper 
Abdominal pain 
lower 
General disorders 
and 
administration 
site conditions 
 
Malaise 
Oedema 
Thirst 
Chest discomfort 
Chest pain 
Hepatobiliary 
disorders 
AST (GOT) 
increased  
ALT (GPT) 
increased 
γ-GTP increased 
ALP increased 
Bilirubin increased 
 
Infections 
 
Cystitis 
Urinary sediment abnormal
 
Metabolism and 
nutrition disorders
CK (CPK) increased 
CK (CPK) decreased 
Blood glucose increased 
Blood glucose decreased 
Cholesterol increased, 
Uric acid increased 
Decreased 
appetite 
Nervous system 
disorders 
 
Dizziness 
Headache 
Tremor 
Hypoaesthesia 
Somnolence 
Renal and urinary 
disorders 
Protein urine present 
Glucose urine present 
Creatinine increased 
BUN increased 
BUN decreased 
Residual urine 
 
Skin and 
subcutaneous 
tissue disorders 
 
Rash 
Urticaria 
Pruritus 


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System Organ 
Class 
Preferred Term 
Incidence ≥1%, 
<5% 
Preferred Term 
Incidence <1% 
Preferred Term
Incidence 
unknown 
Vascular 
disorders 
 
Hypertension 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK 
= creatine kinase; CPK = creatine phosphokinase; GTP = glutamyl transpeptidase 


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1.4.1.2 Korean Labeling 
The following information on adverse reactions is from the Korean labeling for Betmiga 
(mirabegron) prolonged-release 25 mg and 50 mg tablets (April 2015): 
Adverse reactions 
(1) Adverse reactions reported in foreign clinical trials 
The safety of mirabegron was evaluated in 8433 subjects with OAB, of which 5648 
received at least 1 dose of mirabegron in the Phase 2/3 program, and 622 subjects 
received mirabegron for at least 1 year.  In the three 12-week Phase 3 double-blind, 
placebo-controlled studies, 88% of the subjects completed treatment with mirabegron and 
4% discontinued from the study due to AEs.  Most adverse drug reactions were mild-to-
moderate in severity. 
The most common adverse reactions reported in subjects treated with mirabegron 50 mg 
were urinary tract infections (UTI; 2.9%) and tachycardia (1.2%).  Tachycardia led to 
discontinuation in 0.1% of subjects receiving mirabegron 50 mg.  No cases of UTI in 
patients receiving mirabegron 50 mg led to discontinuation from the study.  Serious 
adverse reactions included atrial fibrillation (0.2%).  
The adverse reactions observed during the long-term (1-year) active-controlled 
(muscarinic antagonist) study were similar in nature and severity to those observed in the 
three 12-week placebo-controlled studies. 
 


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Adverse Reactions Observed in Subjects Treated with Mirabegron in Three Phase 3, 
Double-Blind, Placebo-Controlled Studies 
MedDRA 
 System Organ Class
Common ARs 
(1/100≤ , <1/10) 
Uncommon ARs 
(1/1,000≤ , <1/100) 
Rare ARs 
(1/10,000≤ , <1/1,000)
Infections and 
infestations 
Urinary tract infection
Vaginal infection 
 
Eye disorders 
 
 
Eyelid oedema 
Cardiac disorders 
Tachycardia 
Palpitation 
Atrial fibrillation 
Blood pressure 
increased 
 
Gastrointestinal 
disorders 
 
Dyspepsia 
Gastritis 
Lip oedema 
Skin and 
subcutaneous tissue 
disorders 
 
Urticaria 
Rash 
Macular rash 
Papular rash 
Pruritus 
Leukocytoclastic 
vasculitis 
Purpura 
Musculoskeletal and 
connective tissue 
disorders 
 
Joint swelling 
 
Urinary and 
reproductive system 
disorders 
 
Vulvovaginal pruritus
Cystitis 
 
Metabolism and 
nutrition system 
disorders 
 
GGT increased 
AST increased 
ALT increased 
 
ALT = alanine aminotransferase; AR = adverse reaction; AST = aspartate aminotransferase; GGT = 
gamma-glutamyl transferase; MedDRA = Medical Dictionary for Regulatory Activities 
In clinical trials conducted in Asia, the safety of mirabegron was evaluated in 1103 
patients with OAB in Phase 3, double-blind placebo- and active-controlled studies.  The 
most common (≥2.0%) treatment-emergent adverse reactions reported in Asian patients 
treated with mirabegron 50 mg for 12 weeks was dry mouth (4.1%).  The incidence of dry 
mouth was similar in the placebo group (4.4%), but higher in the active control group 
(8.1%), which was consistent with the pharmacological effects of antimuscarinics. 
Global post-marketing experience with mirabegron includes spontaneous reports of 
urinary retention and nausea, although the frequency and causality of these reported 
adverse reactions cannot be reliably determined. 
In a Phase 3, 12-week, multicenter, randomized, double-blind, placebo- and active-
controlled parallel-group study, the most common treatment-emergent adverse reaction 
(≥2% in any treatment group) was dry mouth, reported in 15/366 (4.1%) subjects 
receiving mirabegron, 16/366 (4.4%) subjects receiving placebo, and 30/371 (8.1%) of 
subjects receiving the antimuscarinic, tolterodine. 
1.4.1.3 Clinically significant adverse drug reactions with mirabegron treatment 
Identified risks with mirabegron treatment include increased heart rate and tachycardia as 
well as hypersensitivity reactions.  Potential risks include QT prolongation, increased 


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blood pressure, UTI, urinary retention, fetal disorders after exposure during pregnancy, 
and events induced by increased exposure to CYP2D6 substrates.  The risks of QT 
prolongation, increased heart rate, or increased blood pressure are greater with increasing 
exposure at supratherapeutic doses, and can be mitigated with optimal dose selection.  
The maximum therapeutic dose of mirabegron, based on the overall benefit-risk is 50 mg 
once daily.  In patients with severe renal impairment or moderate hepatic impairment, the 
dose of mirabegron is 25 mg once daily.  Further dose adjustments for renal impairment, 
hepatic impairment and concomitant use of strong CYP3A4 inhibitors may be required. 
Overall, mirabegron at the therapeutic oral doses of 25 mg and 50 mg once daily is 
considered to be a safe and effective for the treatment of adult patients with OAB.  The 
benefits of treatment exceed the risk associated with the use of the product. Mirabegron 
was approved in Japan in 2011, and to date has been approved in more than 50 countries, 
including the United States and European Union.  
1.4.2 
Foreseeable Risks with Tamsulosin 
1.4.2.1 Japanese Labeling 
The following information on adverse reactions is from the Japanese labeling for 
Harnal® D (tamsulosin hydrochloride) 0.1 mg and 0.2 mg tablets (January 2013, 9th 
version): 
Adverse Reactions 
Adverse reactions, including abnormalities in clinical laboratory findings, were observed 
in 104 (2.2%) of 4,724 subjects in clinical trials prior to approval and in drug-use surveys 
for HARNAL Capsules.  The major adverse reactions associated with tamsulosin use 
were dizziness and stomach discomfort. 
Clinically Significant Adverse Reactions 
Syncope/unconsciousness (incidence unknown): Since transient unconsciousness may 
appear with a decrease in blood pressure, patients should be carefully observed.  If any 
abnormal findings are observed during treatment, administration should be discontinued 
and appropriate measures should be taken. 
Hepatic function disorder or jaundice (incidence unknown for each): Since increases of 
AST (GOT), ALT (GPT), or jaundice may appear, patients should be carefully observed.  
If any abnormal findings are observed during treatment, appropriate measures, such as 
drug discontinuation, should be taken. 


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Other Adverse Reactions 
System Organ Class
Incidence 
≥0.1% ,  <5% 
<0.1% 
Unknown 
Psychoneurologic 
Dizziness 
Swaying feeling 
Dizziness on 
standing up 
Headache 
Sleepiness 
Bad mood 
Numbness 
Cardiovascular 
 
Blood pressure 
decreased 
Orthostatic 
hypotension 
Tachycardia 
Palpitations 
Arrhythmia 
Hypersensitivity* 
 
Itching 
Rash 
Urticaria 
Erythema multiforme 
Gastrointestinal 
Stomach discomfort 
Queasy 
Vomiting 
Thirst 
Constipation 
Stomach heaviness 
Gastralgia 
Anorexia 
Diarrhea 
Dysphagia 
 
Others 
 
Nasal congestion 
Oedema 
Urinary incontinence
Burning sensation of 
pharynx 
General malaise 
Dysgeusia 
Gynecomastia 
Priapism 
Ejaculation disorder 
Intraoperative floppy 
iris syndrome 
Vision blurred 
Visual impairment 
Hot flush 
Feeling hot 
Burning sensation 
* If hypersensitivity reactions are observed, treatment should be discontinued. 
 
1.4.2.2 Korean Labeling 
The following information on adverse reactions is from the Korean labeling for Harnal®D 
(tamsulosin hydrochloride) 0.2 mg tablets (June 2015): 
Adverse Reactions 
Syncope/unconsciousness (incidence unknown): Since transient unconsciousness etc. may 
appear with the decrease of blood pressure, patient should be carefully observed.  If such 
reactions are observed during treatment, administration should be discontinued and 
appropriate measures should be taken. 
Nervous system: Dizziness, giddiness, dizziness on standing up, headache, somnolence, 
nervousness, insomnia, libido, bad mood (incidence unknown), and numbness (incidence 
unknown) decreased may occasionally appear. 


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Cardiovascular system: Tachycardia, blood pressure dropped, orthostatic hypotension, 
palpitation, and arrhythmia may occasionally appear. 
Hypersensitivity: Rash, itching, and urticarial may occasionally appear.  If such reactions 
are observed during treatment, administration should be discontinued.  
Digestive system: Nausea, vomiting, stomach discomfort, stomach heaviness, stomach 
ache, appetite decreased, dipsosis, obstipation, diarrhea, tooth disorder, and dysphagia 
may occasionally appear. 
Hepatic dysfunction or jaundice (Incidence unknown for each): Since increases of AST, 
ALT, or jaundice may appear, patient should be carefully observed.  If such reactions are 
observed during treatment, appropriate measures, such as drug discontinuation, should be 
taken. 
Others: Dysphagia, burning sensation of pharynx, generalized fatigue, nasal obstruction, 
epistaxis, edema, urinary incontinence, dysgeusia, gynaecomastia, priapism, infection, 
asthenia, back pain, chest pain, rhinitis, pharyngitis, cough increased, sinusitis, abnormal 
ejaculation, amblyopia, Intraoperative Floppy Iris Syndrome (IFIS), vision blurred, visual 
impairment, erythema multiforme, and dermatitis exfoliative may occasionally appear. 
The following ARs have been identified in post-marketing surveillance reports in the 
United States: allergic-type reactions, such as skin rash; pruritus; angioedema of tongue, 
lips, and face and urticaria have been reported with positive rechallenge in some cases.  
Priapism has been rarely reported.  Infrequent reports of palpitations, hypotension, skin 
desquamation, constipation, and vomiting have been received during the post-marketing 
period.  During cataract and glaucoma surgery, a variant of small-pupil syndrome known 
as IFIS has been reported in association with alpha1 blocker therapy.  As these reactions 
are reported voluntarily from a population of uncertain size, it is not always possible to 
reliably estimate their frequency or establish a causal relationship to drug exposure.  
Decisions to include these reactions in labeling are typically based on one or more of the 
following factors: 1) the seriousness of the reaction; 2) the frequency of reporting; or 3) 
the strength of causal connection to the drug. 
As elderly patients are more likely to experience renal dysfunction, they should be started 
on a lower dose of tamsulosin (0.1 mg) and be carefully monitored.  If no abnormalities 
are detected, the dose can be increased to 0.2 mg. 
1.4.3 
Potential Risks with Combined Treatment 
Alpha-adrenergic receptor antagonists, like tamsulosin, are associated with cardiovascular 
side effects, such as orthostatic hypotension, syncope, tachycardia, and palpitations.  An 
open-label, randomized, two-arm, two-sequence, crossover Phase 1 study in 48 healthy 
men aged 44 to 72 years of age evaluated the potential pharmacokinetic (PK) and 
cardiovascular interactions with concomitant tamsulosin and mirabegron treatment24. 
The effect of steady-state mirabegron 100mg/day on single-dose 0.4mg/day tamsulosin 
was evaluated in 1 treatment arm, and the effect of steady-state tamsulosin on single-dose 
mirabegron was evaluated in the second treatment arm.  The PK results showed that with 
combined treatment, the maximum observed plasma concentration (Cmax) and area under 
the drug concentration-time curve (AUC) for tamsulosin increased ~60%, and mirabegron 
exposure decreased by ~16%.   


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With respect to cardiovascular safety, the combined treatment resulted in no statistically 
significant changes in pulse rate (PR) or systolic blood pressure (SBP), compared to 
monotherapy, up to 12 hours after dosing.  Although mean diastolic blood pressure (DBP) 
was significantly lower with combination treatment, the effect was small and not 
associated with orthostatic symptoms or an increase in positive orthostatic stress tests.  
Furthermore, orthostatic events were balanced across the treatment groups.  
Thus, the results of this study showed that with co-administration, the increase in 
tamsulosin exposure and decrease in mirabegron exposure were not associated with 
clinically relevant pharmacodynamic interactions between the two drugs. 
1.4.4 
Potential Benefits 
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. 
Tamsulosin is an alpha adrenergic blocker indicated for the treatment of BOO associated 
with BPH.  Its mechanism of action is inhibition of alpha1 ARs in the urethra and prostate. 
Mirabegron should be an effective add-on treatment to mitigate OAB symptoms that 
persist in patients treated with tamsulosin for BPH-associated BOO. 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objectives 
To study the efficacy of mirabegron versus placebo in male patients with OAB symptoms 
while taking the alpha blocker, tamsulosin, for BPH.  
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is a randomized, double-blind, placebo-controlled study of the efficacy, safety, and 
tolerability of treatment with mirabegron for OAB in male subjects at least 40 years of 
age who are taking tamsulosin for BPH.  Eligible subjects must have a history of (on 
average) at least 2 urgency episodes and 8 or more micturitions in a 24-hour period during 
the 3 days prior to the start of the Screening period.   
The study will consist of a 4-week single-blind Screening period followed by a 12-week 
double-blind Treatment period.  During the Screening period and beginning with Visit 1, 
all subjects will receive tamsulosin 0.2 mg along with mirabegron 50 mg matching 
placebo once daily after breakfast.   
At the conclusion of the 4-week tamsulosin Screening period, subjects will complete a 3-
day micturition diary just prior to Visit 2 (Baseline).  Subjects who meet entry criteria at 
the end of the tamsulosin Screening period will be randomized (at Visit 2) to receive 


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either mirabegron 50 mg or matching placebo for 12 weeks of double-blind treatment, 
while continuing their treatment with tamsulosin 0.2 mg daily.  Randomization will be in 
a 1:1 ratio, with 275 subjects randomized to each treatment group.  The key efficacy 
assessments are as follows: 
● 
Subjects will complete a 3-day micturition diary 3 days before Visit 3 (Week 4), 
Visit 4 (Week 8), and Visit 5 (Week 12).  
● 
Subjects will complete the Overactive Bladder Symptom Score (OABSS) and 
International Prostate Symptom Score (IPSS) at Visit 1 (Screening), Visit 2 
(Baseline), Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12).  
● 
Subjects will complete the Overactive Bladder questionnaire (OAB-q) at Visit 1 
(Screening), Visit 2 (Baseline), and Visit 5 (Week 12).  
Safety and tolerability of mirabegron administered concomitantly with tamsulosin will be 
assessed by the incidence and severity of treatment-emergent adverse events (TEAEs), 
laboratory parameters (i.e., serum chemistry, hematology, and urinalysis), vital signs 
measurements (i.e., sitting systolic and diastolic blood pressure and pulse rate), post-void 
residual (PVR) urine volume, and maximum urine flow rate (Qmax). 
Individual subject participation in the study will be ~16 weeks, which includes the 4-week 
Screening period and the 12-week double-blind Treatment period. 
The study will be conducted in Japan (~50 centers) and Korea (~5 centers).  The target 
enrollment is 550 subjects, with 275 randomized to each treatment group. 
2.2.2 
Dose Rationale 
As this study is being conducted in adult men with OAB, it will employ the approved 
dose and dosing regimens prescribed in the respective Package Inserts for each drug: 
● 
The dose of mirabegron is 50 mg once daily by the oral route. 
● 
The dose of tamsulosin is 0.2 mg once daily by the oral route. 
The 4-week Screening period will be sufficient for evaluation of baseline symptoms with 
tamsulosin monotherapy. 
The 12-week double-blind Treatment period for mirabegron versus placebo will allow 
sufficient time to assess the treatment effect, as well as safety and tolerability of 
mirabegron administered concomitantly with tamsulosin. 
2.3 
Endpoints  
2.3.1 
Primary Endpoint 
The primary endpoint is the change from Baseline to End-of-Treatment in the mean 
number of micturitions in 24 hours, based on a 3-day micturition diary. 
2.3.2 
Secondary Endpoints  
The secondary endpoints include the change from Baseline to End of Treatment in:  
● 
Mean number of urgency episodes/24 hours 
● 
Mean number of urgency incontinence episodes/24 hours 
● 
Mean number of incontinence episodes/24 hours 
● 
Mean number of nocturia episodes 


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● 
Mean volume voided per micturition 
● 
Total OABSS score  
● 
Subscale score from OABSS score 
● 
Total IPSS score  
● 
Subscale score from IPSS score 
● 
Symptom Bother and Total Health-Related Quality of Life scores, as assessed by 
OAB-q questionnaire. 
Subjects should be instructed to complete the 3-day micturition diary on the 3 days 
leading up to the visit for Visit 2 (Day 1), Visit 3 (Day 29 ± 7 days), Visit 4 
(Day 57 ±7 days), and Visit 5 (Day 85 ±7 days).  If the subject is unable to fill out the 
diary on the 3 days prior to the visit, then the diary should be completed on any 3 days 
within the 7 days prior to the visit. 
Subjects will complete the OABSS and IPSS/IPSS (QoL) assessments at Visit 1, Visit 2, 
Visit 3, Visit 4, and Visit 5. 
Subjects will complete the OAB-q at Visit 1, Visit 2, and Visit 5. 
2.3.3 
Exploratory Endpoints 
The exploratory endpoints will include the change from Baseline to End of Treatment in: 
● 
Hours of undisturbed sleep (HUS)  
● 
First nighttime voided volume 
● 
Subscale scores from OAB-q scores 
● 
Normalization rate of OABSS 
● 
Normalization rate of micturition diary (number of episodes of 
micturition/urgency/urgency incontinence/incontinence/nocturia) 
2.3.4 
Safety Endpoints 
● 
Incidence and severity of TEAEs 
● 
Vital signs: sitting systolic and diastolic blood pressure and pulse rate (home based 
self-measurements and office measurements) 
● 
Laboratory parameters (serum chemistry, hematology, and urinalysis) 
● 
PVR urine volume 
● 
Qmax 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
Patients with OAB will be eligible for enrollment in the study, based on the following 
inclusion and exclusion criteria. 
3.2 
Inclusion Criteria 
A patient is eligible for enrollment in the study if all of the following apply: 
Inclusion Criteria assessed at Visit 1 (Screening):   
1) Patient has given written informed consent before starting the study in accordance 
with the informed consent form approved by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) of each study center 


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2) Male outpatient ≥40 years of age at the time of informed consent  
3) Patient has been under treatment with tamsulosin 0.2mg for at least 4 weeks before 
the start of the Screening period 
4) Patient with a history of an average of at least 2 episodes of urgency per 24 hours 
and an average of 8 or more micturitions per 24 hours during the last 3 days before 
the start of the Screening period (the conditions are checked by interview). 
5) Patient who has no wish to have children in the future (Unique to Japan). 
6) Male subjects and their female spouses/partners who are of childbearing potential 
must be using highly effective contraception consisting of two forms of birth 
control* (at least one of which must be a barrier method) starting at Screening, 
continuing throughout the study period, and for 28 days after the final study drug 
administration. 
7) Subject must not donate sperm, starting at Screening, continuing throughout the 
study period, and for 28 days after the final study drug administration. 
8) Patient is willing and able to complete the micturition diary and questionnaires 
correctly. 
9) Subject agrees not to participate in another interventional study while receiving 
treatment in this study. 
Inclusion Criteria assessed at Visit 2 (Baseline), based on the 3-day micturition diary: 
1) Subject with an average of at least 2 episodes of urgency per 24 hours and an 
average of 8 or more micturitions per 24 hours, based on the 3-day micturition diary 
from the Screening period.  
2) Subject continues to meet all inclusion criteria of Visit 1. 
Waivers to the inclusion criteria will NOT be allowed. 
 
*Highly effective forms of birth control include: 
 Consistent and correct usage of established oral contraception. 
 Established intrauterine device (IUD) or intrauterine system (IUS). 
 Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository (Unique to Korea: with spermicidal 
foam/gel/film/cream/suppository). 
 Calendar-based contraceptive methods (Knaus-Ogino or rhythm method) 
 
3.3 
Exclusion Criteria 
Exclusion Criteria assessed at Visit 1 (Screening): 
1. Patient with suspected symptoms of OAB, with onset only transient (e.g., drug-
induced, psychogenic). 
2. Patient with PVR urine volume >100 mL or Qmax <5 ml/sec. 
3. Patient with prostate-specific antigen (PSA) ≥4 ng/mL.  


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4. Patient with neurogenic bladder (e.g., spinal cord lesions or other damages that 
will clearly affect urination; multiple sclerosis; Parkinson’s disease) or a history of 
surgery that caused damage to the pelvic plexus. 
5. Patient with urethral stricture or bladder-neck stenosis. 
6. Patient with diabetic neuropathy complications.  
7. Patient who has undergone a surgical procedure (e.g., transurethral resection of 
prostate [TURP], laser therapy), previous pelvic radiation therapy, or 
hyperthermia therapy that may affect urinary tract functions.  
8. Patient with significant stress incontinence (i.e., patients presenting with only 
symptoms of stress urinary incontinence) or postsurgical prostate incontinence, as 
determined by the Investigator.  
9. Patient with an indwelling catheter or practices intermittent self-catheterization. 
10. Patient with 3 or more episodes of recurrent urinary tract infection (UTI) within 
the last 6 months. 
11. Patient with a UTI; prostatitis; chronic inflammation, such as interstitial cystitis; 
urinary calculus (e.g., ureteral calculus, urethral calculus, bladder calculus); or 
previous or current malignant disease of the pelvic organs (i.e., within the confines 
of the pelvis, including the bladder, prostate, and rectum; organs of the lower 
gastrointestinal tract are not necessarily considered pelvic organs, as the distal 
ascending colon, the full transverse colon, and proximal portion of the descending 
colon are in the abdomen). 
12. Patient with a concurrent malignancy or history of any malignancy (within the 
past 5 years), except for nonmetastatic basal-cell or squamous-cell carcinoma of 
the skin that has been treated successfully.  
13. Patient with serious heart disease (e.g., myocardial infarction, cardiac failure, 
uncontrolled angina pectoris, serious arrhythmia, use of pacemaker), liver disease, 
kidney disease, immunological disease, lung disease.  
14. Patient who has received intravesical injection within the last 12 months with 
botulinum toxin, resiniferatoxin, or capsaicin. 
15. Patient who has received electrostimulation therapy for OAB (e.g., sacral nerve 
stimulation or Percutaneous Tibial Nerve Stimulation [PTNS]).  
16. Patient who has received a bladder training program or pelvic floor exercises 
<28 days prior to the start of the Screening period. 
17. Patient with postural hypotension or syncope, hypokalemia, or closed-angle 
glaucoma. 
18. Patient with evidence of QT prolongation on electrocardiogram (ECG), defined as 
QTcF >450 msec. 
19. Patient with severe uncontrolled hypertension, defined as a sitting SBP >180 
mmHg and/or DBP >110 mmHg. 


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20. Patient with a clinically significant ECG abnormality, as determined by the 
Investigator. 
21. Patient with severe renal impairment, defined as estimated glomerular filtration 
rate <29 mL/min/1.73m2; end-stage renal disease; or is undergoing dialysis.  
22. Patient with AST or ALT >2 times the upper limit of normal (ULN), or gamma-
glutamyl transferase (γ-GT) >3 times the ULN. 
23. Patient with moderate or severe hepatic impairment, defined as Child-Pugh Class 
B or C.  
24. Patient with hypersensitivity to any components of mirabegron, other β-AR 
agonists, or any of the inactive ingredients.  
25. Patient with ongoing alcohol and/or drug abuse. 
26. Patient with or a history of mood disorder, neurotic disorder, or schizophrenia. 
27. Patient with dementia, cognitive dysfunction, or clinically significant 
cerebrovascular disorder. 
28. Patient has been treated with an experimental device <84 days or received an 
investigational agent <84 days prior to the start of the Screening period. 
29. Patient has used any prohibited concomitant medication (defined in Appendix 
12.1) <28 days (but, <1 year for 5α-reductase inhibitors) before the start of the 
Screening period. 
30. Patient with any clinically significant condition, which in the opinion of the 
Investigator, makes the subject unsuitable for study participation. 
31. Patient who is involved in the conduct of the study as an employee of the Astellas 
group, a third party associated with the study, or the study site team. 
Exclusion Criteria assessed at Visit 2 (Baseline): 
32. Subject fulfills any exclusion criteria of Visit 1 at Visit 2. 
33. Subject was noncompliant during the 4 week tamsulosin Screening period, defined 
as taking less than 80% or greater than 120% of the prescribed dose of study 
medication. 
34. Subject had an average total daily urine volume >3000 mL, as recorded in the 3-
day micturition diary. 
35. Subject is found to meet any of the exclusion criteria for enrollment at Visit 1 
(Screening) 
Waivers to the exclusion criteria will NOT be allowed. 
4 
TREATMENT(S) 
During the 4 week, single-blind Screening period, all subjects will receive tamsulosin 
0.2 mg along with mirabegron matching placebo once daily after breakfast. 


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During the 12 week, double-blind Treatment period, subjects will receive their 
randomized treatment (mirabegron 50 mg or matching placebo) along with tamsulosin 
0.2 mg once daily after breakfast. 
4.1 
Identification of Investigational Product(s) 
Study drugs to be administered during the single-blind Screening period: 
● 
Mirabegron 50 mg matching placebo tablet 
 
and 
● 
Tamsulosin 0.2 mg tablet 
Study drugs to be administered during the double-blind Treatment period: 
● 
Mirabegron 50 mg tablet 
 
or 
● 
Mirabegron 50 mg matching placebo tablet 
 
and 
● 
Tamsulosin 0.2 mg tablet 
4.1.1 
Test Drug(s) 
Mirabegron 50 mg, tamsulosin 0.2 mg, and placebo are tablets, to be administered by the 
oral route. 
Mirabegron 50 mg tablet: 
Nonproprietary name
Mirabegron 
Chemical name 
2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-
phenylethyl]amino}ethyl)phenyl]acetamide 
Molecular formula 
and molecular weight
C21H24N4O2S  
Molecular weight: 396.51 
Content and dosage 
form 
Mirabegron 50 mg tablet for the Treatment period: 
Each tablet contains 50 mg of mirabegron.  
Size 
Major axis, approx. 12.1 mm; minor axis, approx. 6.1 mm; thickness, 
approx. 5.2 mm 
Lot number 
Information described in Pharmacy Manual (written procedures for 
handling of study drugs) 
Storage conditions 
Room temperature 
Manufacturer 
Astellas Pharma Inc. 
 


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Tamsulosin 0.2 mg tablet: 
Nonproprietary name
Tamsulosin 
Chemical name 
5-{(2R)-2-[2-(2-ethoxyphenoxy)ethylamino]propy}-2-
methoxybenzenesulfonamide monohydrochloride 
Molecular formula 
and molecular weight
C20H28N2O5S·HCl 
Molecular weight: 444.97 
Content and dosage 
form 
Tamsulosin 0.2 mg tablet for the Screening period and double-blind 
treatment period: 
Each round, white tablet contains 0.2 mg of tamsulosin hydrochloride.  
Size 
8.5mm in diameter; 4.2 mm thickness 
Lot number 
Information described in Pharmacy Manual (written procedures for 
handling of study drugs) 
Storage conditions 
Room temperature 
Manufacturer 
Astellas Pharma Inc. 
 
4.1.2 
Comparative Drug(s)  
The placebo for mirabegron 50 mg will be supplied as a matching tablet, visually 
indistinguishable from the active drug. 
Mirabegron 50 mg Placebo: 
Content and dosage 
form 
Mirabegron 50 mg placebo tablet for the Screening period and double-blind 
treatment period. 
Size 
Major axis, approx. 12.1 mm; minor axis, approx. 6.1 mm; thickness, 
approx. 5.2 mm 
Lot number 
Information described in Pharmacy Manual (written procedures for 
handling of study drugs) 
Storage conditions 
Room temperature 
Manufacturer 
Astellas Pharma Inc. 
4.1.3 
Drug(s) for Screening Period 
A daily dose of tamsulosin 0.2 mg along with mirabegron 50 mg matching placebo will 
be administered to all subjects during the 4-week Screening period.  Both study drugs are 
in tablet form to be administered orally. 
4.2 
Packaging and Labeling 
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at API or the Sponsor’s designee in accordance with API 
or Sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing 
Practice (GMP) guidelines, Internation Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines, and applicable local laws/regulations. 
Each carton will bear a label conforming to regulatory guidelines, GMP, and local laws 
and regulations, and which identifies the contents as an investigational drug. 
4.2.1 
Packaging 
Mirabegron 50 mg tablets/matching placebo: 10 mirabegron 50 mg tablets or matching 
placebo will be included in 1 Press-Through Package (PTP) sheet; 4 PTP sheets will be 
packed in a small box. 


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Tamsulosin 0.2 mg tablets: 14 tamsulosin 0.2 mg tablets will be included in 1 PTP sheet; 
2 PTP sheets will be in an aluminum pouch, which will be packed in a small box. 
4.2.2 
Labeling 
The study drug labeling will be in the same language as the translated protocol. 
4.3 
Study Drug Handling  
Current GCP guidelines require the Head of the study site to ensure that the study drug 
deliveries from the Sponsor are received by a responsible person (e.g., pharmacist) and 
that the following measures take place (Unique to Japan): 
Current GCP guidelines require the Investigator to ensure that the study drug deliveries 
from the Sponsor are received by a responsible person (e.g., pharmacist) and that the 
following measures take place (Unique to Korea): 
● 
The deliveries are recorded 
● 
The study drug is handled and stored safely and properly 
● 
The study drug is dispensed to study subjects in accordance with the protocol 
● 
Any unused study drugs (including those returned from study subjects) are returned 
to the Sponsor 
Either the Head of the study site (Unique to Japan), the investigator (Unique to Korea) or 
the study drug storage manager is accountable for the study drugs as follows: 
● 
The study drugs will be stored and accounted for according to the Sponsor’s written 
procedures for handling the study drugs. 
● 
Records of receipt of the study drugs, the inventory at the study site, the use by each 
subject, and the return to the Sponsor or alternative disposal of unused study drugs 
will be prepared and retained.  These records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and the unique code numbers 
assigned to the study drugs and subjects. 
● 
Records will be prepared and retained that document that the subjects were 
adequately provided the doses specified in the protocol, and that all the study drugs 
supplied from the Sponsor are reconciled. 
4.4 
Blinding 
4.4.1 
Blinding Method  
Subjects will be randomized to receive mirabegron 50 mg or matching placebo in a 
double-blind fashion such that neither the Investigator, the Sponsor’s study management 
team, clinical staff, nor the subject will know which agent is being administered.  The 
randomization number will be assigned to each subject, based on information obtained 
from the Interactive Response Technology (IRT). 
The mirabegron 50 mg tablet and the placebo tablet, as well as the packaging for each 
treatment, are visually indistinguishable.  


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4.4.2 
Confirmation of the Indistinguishability of the Study Drugs 
The active mirabegron 50 mg tablet and the matching placebo tablet, as well as the 
packaging, are visually indistinguishable.  Both tablets are ~12.1 mm long, ~6.1 mm wide, 
and 5.2 mm in thickness. 
4.4.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking  
The randomization list and study medication blind will be maintained by the IRT system. 
4.4.4 
Breaking the Treatment Code for Emergency  
The treatment assignment may be unblinded for a study subject who experiences a serious 
adverse event (SAE), and for whom, knowledge of the study treatment is required for 
appropriate management/treatment of the SAE. 
4.4.5 
Breaking the Treatment Code by the Sponsor  
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual 
case or a group of cases requires expedited regulatory reporting.  Individual Emergency 
Codes will be provided to the limited staff who are responsible to break the codes for all 
SUSAR cases for reporting purposes. 
The treatment code for each randomized subject will be provided by the IRT in the event 
of a medical emergency requiring knowledge of the treatment assigned to the subject.  
The time, date, subject number and reason for obtaining any of these codes, and therefore 
breaking the blind, must be documented in the study file.  They must only be requested by 
the Investigator or other persons designated as Sub-investigators.  No subjects or other 
study personnel will be made aware of the treatment given to any subject unless a medical 
emergency necessitates such disclosure. 
Unblinding of the study medication should only be considered for subject safety or when 
critical therapeutic decisions are contingent upon knowing the blinded study drug 
assignment.  Any unblinding by the investigational staff must be reported immediately to 
the Sponsor and must include an explanation of why the study medication was unblinded.  
If possible, the Sponsor should be contacted prior to unblinding of the study medication. 
4.5 
Assignment and Allocation 
Subjects will be randomized 1:1 to receive mirabegron 50 mg or matching placebo once 
daily during the 12-week treatment period. The randomization will be stratified by site. 
Randomization will be performed via IRT.  Prior to the initiation of the study treatment, 
the site staff will contact the IRT in order to determine the randomly assigned treatment 
for each subject.  Specific procedures for randomization through the IRT are described in 
the study procedures manual. 


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5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug(s) and Other 
Medication(s) 
5.1.1 
Dose/Dose Regimen and Administration Period 
Screening Period: 
During the 4-week Screening period, all subjects will receive 1 tamsulosin 0.2 mg tablet 
along with 1 mirabegron 50 mg matching placebo tablet once daily after breakfast. 
Treatment Period: 
During the 12-week Treatment period, all subjects will receive their randomized 
treatment (1 mirabegron 50 mg tablet or 1 matching placebo tablet) along with 
1 tamsulosin 0.2 mg tablet, to be taken once daily after breakfast. 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) 
No dose increases or decreases are allowed in this study, as the study subjects are to 
receive the approved doses for mirabegron and tamsulosin, as stated in the respective 
Package Inserts. 
5.1.3 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) 
5.1.3.1 Prior Treatment 
All prior medications and non-medication therapies for BPH and OAB received by a 
study subject within 4 weeks prior to Visit 1 (Screening) will be recorded on the 
electronic Case Report Form (eCRF), as described below.  Any prior treatment with 
tamsulosin will be recorded, regardless of the time frame in which it was taken. 
Previous treatment 
Investigation period 
Data to be entered on the 
eCRF 
Previous medication 
(For BPH and OAB) 
From 4 weeks before 
Visit 1 (Screening) to 
Visit 1 
Drug name, daily dose, route of 
administration, administration 
period, reason for use, time of 
administration 
Previous therapy 
(For BPH and OAB) 
Therapy name, treatment period, 
reason for use, time of treatment
5.1.3.2 Concomitant Treatment 
Drug classes and specific medications that are prohibited during the study are provided in 
Appendix 12.1 List of Excluded Concomitant Medications. 
All concomitant medications and non-medication therapies received by a subject from 
Baseline to the end of the Treatment period will be entered on the eCRF, as described 
below: 


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Concomitant treatment 
Investigation period 
Data to be entered on the eCRF
Concomitant medication 
(all drugs) 
From Visit 1 to the end of 
the Treatment period 
Drug name, route of 
administration, administration 
period, reason for use 
Concomitant therapy 
(all non-medication therapies) 
Therapy name, treatment period, 
reason for use 
The excluded concomitant meditations (defined in Appendix 12.1) can be allowed to use 
under the conditions below: 
1) From the day following the dispensing of the study drug for the Screening period to 
the end of the Treatment period, none of the prohibited concomitant medications 
listed in Appendix 12.1 should be concomitantly used.  However, the following drugs 
may be concomitantly used: 
 Eye drops 
 Transdermal formulations, excluding β-agonists and drugs for the treatment of 
urinary storage and voiding dysfunction 
 Nasal drops, excluding drugs for diabetes insipidus 
 Topical agents 
 Inhaled β-agonists used to relieve acute symptoms such as bronchial asthma 
 Chinese herbal medicines used for the treatment of conditions other than urinary 
storage and voiding dysfunction 
2) The following drugs may be used concomitantly for a short period of time (i.e., up to 
a total of 5 days during the interval from the day following a visit to the next visit), 
except during the micturition diary period: 
 Parasympathetic inhibitors/parasympatholytic drugs for peptic ulcer, etc. 
 Antihistamines, ephedrine hydrochloride, and methylephedrine hydrochloride for 
common cold, etc.  
3) Transient concomitant use of parasympathetic inhibitors/parasympatholytic drugs 
will be allowed, if used in preparation for an examination, except during the 
micturition diary period. 
4) Concomitant use of 5α-reductase inhibitors will be allowed (the dosage shall not be 
changed for study period), if the subject has been on treatment for a year or more. 
5) Transient concomitant use of PDE5 inhibitor for ED treatment will be allowed, 
except during the micturition diary period. 
6) Nonpharmacological therapy for OAB, such as biofeedback therapy, bladder training, 
or pelvic floor muscle exercise will be prohibited from 4 weeks (<28 days) before the 
start of the Screening period to the end of the Treatment period. 
5.1.4 
Treatment Compliance 
The Investigator or designee will confirm treatment compliance of each study subject 
throughout the study period.  At each visit, treatment compliance will be evaluated based 
on the information provided by the subject (i.e., amount of prescribed drugs, returned 
unused drugs, lost drugs, etc.) and recorded in the medical record or other source 
documents, with the amounts of prescribed, returned, and lost drugs entered into the 
eCRF.  Consistency with drug accountability logs will be checked, as required.  
If treatment compliance is found to be poor as the result of the evaluation, the reason for 
poor compliance will be investigated, and the subject will be given instructions to 
improve compliance. 


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Treatment compliance should be monitored closely, and any deviation in compliance 
should be reported to the Sponsor. 
5.1.5 
Restrictions During the Study 
(1) Medication 
When prescribing the study medication, the Investigator or Sub-investigator will 
explain to the subjects how to take the study medication, with emphasis on the 
following: 
● 
The subject should take the study medication with water, once daily after 
breakfast. 
● 
The subject should start taking the prescribed study medication on the day 
following dispensing of the study drug(s). 
● 
The subject should return any unused study medication at the next visit, and 
report their compliance to the Investigator or Sub-investigator. 
● 
If the subject has discontinued taking the study medication at his/her own 
discretion, he/she must visit the study site at the earliest possible time to undergo 
examination by the Investigator or Sub-investigator. 
(2) Micturition diary 
The Investigator or Sub-investigator will provide each subject with a micturition 
diary, after entering into the diary the date of the next scheduled visit, the dates on 
which the diary should be completed, and the subject number.  When providing the 
micturition diary to the subject, the Investigator or Sub-investigator will explain to 
the subject how to complete the micturition diary, with emphasis on the following: 
● 
As a rule, the subject will complete the micturition diary during the 3 days 
immediately before each of the scheduled visits (i.e., at Visits 2, 3, 4, and 5/End 
of Treatment.  Each diary day starts at 06:00 and ends at 05:59 on the following 
day. 
● 
For the 3 days of recording in the micturition diary, the subject will record their 
awakening and bedtime hours; time of each micturition; number of micturition 
episodes, urgency episodes, urinary incontinence episodes, voided volume, 
sitting blood pressure (SBP and DBP) and pulse rate with the times of 
measurements. In addition, the subject will record the time of medication. 
Voided volume will be recorded at Visits2, and 5 only. 
● 
Sitting blood pressure and pulse rate will be measured twice consecutively on 
awakening and before bedtime. The second measured value will be recorded in 
the patient diary. When measurements on awakening are not possible, these 
should be taken before taking medication for the day as far as possible. 
● 
The subject should bring their completed micturition diary to the next visit. 
 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
At Visit 1, the following subject background data will be obtained and entered into the 
eCRF: the subject’s date of birth, sex, race, ethnicity, height, body weight, information on 


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the target disease, medical history, previous treatment, disease duration of BPH, prostate 
volume, ECG (QTcF), and PSA. 
Please refer to Section 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of 
Disease for information on the target disease, and Section 5.2.2 Medical History for past 
and concurrent diseases, and Section 5.1.3 Previous and Concomitant Treatment. 
5.2.2 
Medical History 
Both past and concurrent diseases will be recorded at Visit 1.  Past diseases are defined as 
diseases that resolved by the day of dispensing of the study drug.  For recent past diseases 
that resolved within 1 year prior to Visit 1, the diagnosis, time of onset, and time of 
resolution will be entered into the eCRF.  As a rule, no entries should be made on the 
eCRF for non-urological temporary diseases (e.g., common cold), or 
otorhinolaryngological, dental, dermatological, or ocular diseases.  The duration of the 
disease should be indicated in months or years. 
Concurrent diseases are defined as diseases that have not resolved as of the day of 
dispensing of the study drug during the Screening period.  For all concurrent diseases, the 
diagnosis and time of onset are to be entered into the eCRF. 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease 
At Visit 1, the following information on OAB and BPH will be confirmed, with the 
information entered into the eCRF: 
● 
Diagnosis: OAB, BPH 
● 
Time of onset (i.e., time when symptoms were apparent) 
● 
Type of urinary incontinence (e.g., urge or mixed) 
5.3 
Efficacy Assessments 
5.3.1 
Micturition Diary 
The micturition diary will be used to record the date and time of each micturition, 
incontinence episodes, urgency episodes, and voiding volume.  Voiding volume will be 
recorded at Visits  2, and 5 only.  The diary will also be used to record daily medication 
intake.  The diary must be completed for at least 2 days in order to be included in the 
efficacy assessment for that visit. 
5.3.2 
Overactive Bladder Symptom Score (OABSS) 
The OABSS is a 4-item questionnaire that assesses urinary frequency (Appendix 12.4).  
The subject is to fill out the questionnaire at each study visit. 
5.3.3 
Overactive Bladder Questionnaire (OAB-q) 
The OAB-q is a 33-item questionnaire that assesses Symptom Bother and the effect of the 
symptoms on the subject’s life (Appendix 12.4).  The subject is to fill out the 
questionnaire at Visit 1, Visit 2, and Visit 5. 
5.3.4 
International Prostate Symptom Score (IPSS and IPSS [QoL]) 
The IPSS and IPSS (QoL) includes an 8-item questionnaire that assesses urinary 
frequency and incomplete voiding along with a QoL assessment (Appendix 12.4).  The 
subject is to fill out the questionnaire at each study visit. 


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5.4 
Safety Assessment 
5.4.1 
Vital Signs 
Office-measured sitting BP and PR (at rest): 
At all visits, sitting BP and pulse rate will be measured at the study site and entered into 
the eCRF.  The values obtained at Visit 1 and Visit 2 will be used for eligibility 
determination by the Investigator or Sub-investigator. 
Self-measured sitting blood pressure and pulse rate (at rest): 
Subjects will measure sitting blood pressure and pulse rate using an automatic 
sphygmomanometer for 3 days immediately before each of the scheduled visits [at Visit 2, 
3, 4 and 5(or End of Treatment)], and record the measured values with the times of 
measurements in the patient diary. For details, refer to Section 5.1.5 “Restrictions During 
the Study” Part (2). 
5.4.2 
Adverse Events 
See Section 5.5 Adverse Events and Other Safety Aspects for information regarding 
AE collection and data handling.  
5.4.2.1 Adverse Events of Possible Hepatic Origin 
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information 
on liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a 
study and receiving study drug is accompanied by increases in liver function tests (LFTs; 
AST, ALT, bilirubin) or is suspected to be due to hepatic dysfunction.  
Any subjects with AEs of hepatic origin accompanied by LFT abnormalities should be 
carefully monitored.   
5.4.3 
Laboratory Assessments 
 (1) 
Test parameters 
Table 2 shows the listing of laboratory tests to be performed during the study.  Refer to 
“V. FLOW CHART AND SCHEDULE OF ASSESSMENTS” for the test schedule by 
visit.  
The sampling and measurement for biochemistry, hematology and Coagulation tests will 
be performed centrally at 
 (
, Japan) and 
 
(
, Korea) under coordination with the study site, investigator, and sub-investigators.  
In principle, urinalysis will be performed at the study site. 


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Table 2 
Laboratory Tests to be Performed During the Study 
Laboratory Test 
Visit(s) 
Analytes 
Collection Tube 
Serum Chemistry 
Visit 1 
PSA 
Blood collection tube 
for serum separation 
(4 mL) 
Visit 1, Visit 2, and 
Visit 5 (or 
discontinuation) 
AST (GOT) 
ALT (GPT) 
γ-GTP 
ALP 
CK 
Creatinine 
Total bilirubin 
BUN 
Uric acid 
Total protein 
Total cholesterol 
Albumin 
Sodium 
Potassium 
Chloride 
 
Blood collection tube 
for serum separation 
(4 mL) 
Hematology 
Visit 1, Visit 2, and 
Visit 5 (or 
discontinuation) 
RBC count 
WBC count 
Hemoglobin 
Hematocrit 
Platelet count 
Blood collection tube 
containing EDTA-2K 
(2 mL) 
Coagulation 
Visit 1 
Prothrombin 
Blood collection tube 
containing Sodium 
citrate 3.2%  (3 mL) 
Urinalysis 
Visit 1, Visit 2, and 
Visit 5 (or 
discontinuation) 
Glucose (qualitative) 
Protein (qualitative) 
Dipstick 
Sediment 
Urine collection tube 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = 
blood urea nitrogen; CK = creatinine kinase; EDTA-2K = ethylenediaminetetraacetic acid dipotassium salt 
dihydrate; γ-GTP = gamma glutamyl transpeptidase; RBC = red blood cell; WBC = white blood cell  
 
(2) 
Measurement results 
 (
, Japan) will send the central laboratory test results by mail to the 
Investigator or Sub-investigator.  The Investigator or Sub-investigator will determine the 
eligibility of each subject, based on the laboratory values at Visit 1.  If any test parameters 
specified in the exclusion criteria (i.e., AST, ALT, GGT, creatinine, PSA) cannot be 
measured in the sample collected at Visit 1, they will be re-measured to evaluate the test 
values by Visit 2. 
For parameters locally measured at the study site, results will be entered into the eCRF.  
Urinary sediment (normal or abnormal) will be determined according to the normal 
ranges used by the study center, and results will be entered into the eCRF. 
The clinical significance of out-of-range laboratory findings is to be determined and 
documented by the Investigator/Sub-investigator. 


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5.4.4 
Measurement of Residual Urine Volume 
Residual urine volume will be measured at all visits and recorded in the eCRF. The 
measurement of residual urine volume will be performed using either ultrasonography or 
bladder scan; however, the same measurement method must be used for a given subject 
throughout the study period. 
5.4.5 
Measurement of Uroflowmetry 
Uroflowmetry (UFM) will be performed at Visits 1, 2 and 5/End of Treatment, and the 
results will be entered on the eCRF.  To ensure that an adequate volume of urine can be 
voided for the test, subjects will be instructed to drink approximately 180 mL of water 
approximately 1.5 hours before the test.  Subjects will also be instructed to void as usual 
(i.e., without abdominal pressure). 
Any UFM results obtained within 28 days prior to the start of the Screening period may 
be used instead of the Visit 1 data, with the subject’s agreement. 
The Investigator or Sub-investigator will submit a copy of the uroflowmetrogram to the 
Sponsor. 
● 
Average flow rate: volume voided per micturition (voided volume) divided by time 
for the micturition (flow time)*1 
● 
Maximum flow rate (Qmax)*2 
● 
Volume voided per micturition*3 
*1 The time over which measurable flow actually occurs (i.e., not including the time for 
interruption of micturition) 
*2 If a value exceeding 3 times the average flow rate is noted, the urinary flow pattern will 
be reviewed.  If a spike or other patterns suggestive of abdominal pressure is seen, such 
abnormally high value(s) will be excluded when determining the maximum flow rate. 
*3 If the voided volume is too small, re-testing will be considered. 
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a subject administered a study 
drug or has undergone study procedures and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE.  In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are 
followed and the information is appropriately recorded in the eCRF accordingly.   
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, 
ECG data, physical examination) should be defined as an AE only if the abnormality 
meets one of the following criteria: 


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● 
Induces clinical signs or symptoms 
● 
Requires active intervention 
● 
Requires interruption or discontinuation of study medication 
● 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
5.5.1.1 Treatment-Emergent Adverse Events (TEAEs) 
For the purposes of analysis of the safety data following the completion of the study, a 
TEAE is defined as follows: 
● 
An AE with onset during the double-blind Treatment period 
● 
An AE with onset during the Screening period, with worsening severity during the 
double-blind Treatment period 
Thus, AEs with onset during the Screening period that either resolved during that period 
or continued into the double-blind Treatment period with the same or lesser severity will 
NOT be counted as TEAEs. 
5.5.2 
Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it 
results in any of the following outcomes:  
● 
Results in death 
● 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death. 
It does not include an AE that, had it occurred in a more severe form, might have 
caused death) 
● 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions  
● 
Results in congenital anomaly, or birth defect 
● 
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be 
considered as serious)  
● 
Other medically important events 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 intervention to prevent one of the other outcomes listed in the 
definition above.  These events, including those that may result in disability/incapacity, 
should also usually be considered serious.  Examples of such events are 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.  
Safety events of interest in case the medicinal products administered to the subject as part 
of the study (e.g., study drug, comparator, background therapy) that may require 
expedited reporting and/or safety evaluation include, but are not limited to: 
● 
Overdose of the medicinal product(s) 


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● 
Suspected abuse/misuse of the medicinal product(s) 
● 
Inadvertent or accidental exposure to the medicinal product(s) 
● 
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion) 
All of the events of interest noted above should be recorded on the eCRF.  Any situation 
involving these events of interest that also meets the criteria for an SAE should be 
recorded on the AE page of the eCRF and marked ‘serious’ and on the SAE 
worksheet/report.  
The Sponsor has a list of events that they classify as “always serious” events.  If an 
adverse event is reported that is considered to be an event per this classification as 
“always serious”, additional information on the event may be requested (See Appendix 
12.3). 
If a female partner of a study subject becomes pregnant during the study, the pregnancy is 
to be reported as an SAE (See Section 5.5.7 Procedure in Case of Pregnancy). 
5.5.3 
Criteria for Causal Relationship to the Study Drug 
The Investigator or Sub-investigator will assess the causal relationship between each AE 
and the study drugs (mirabegron and tamsulosin) to record the results in the eCRF.  
Adverse events that fall under either “Possible,” “Probable,” or “Not Assessable” should 
be defined as “AEs whose relationship to the study drugs could not be ruled out.” 
 
Causal relationship 
to the study drug 
Criteria for causal relationship 
Not related 
A clinical event, including a laboratory test abnormality, with a 
temporal relationship to study drug administration that makes a causal 
relationship improbable and/or in which other drugs, chemicals, or 
underlying disease provide plausible explanations of causality. 
Possible 
A clinical event, including a laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, but 
which could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
Probable 
A clinical event, including a laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, and 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on re-
administration (rechallenge) or withdrawal (dechallenge). 
Not assessable 
A report suggesting an adverse reaction, but which cannot be judged as 
information is insufficient or contradictory, and cannot be 
supplemented or verified. 
5.5.4 
Criteria for Defining the Severity of an Adverse Event 
The Investigator will use the following definitions to rate the severity of each AE: 
● 
Mild: No disruption of normal daily activities 
● 
Moderate: Affects normal daily activities 
● 
Severe: Inability to perform daily activities 


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The severity will also be determined by reference to the grading specified in the 
“Standards for Classification of Serious Adverse Drug Reactions,” PAB/SD Notification 
No. 80, dated 29 Jun 1992 (Appendix 12.5. Classification of Seriousness of Adverse Drug 
Reaction). (Unique to Japan) 
5.5.5 
Reporting of Serious Adverse Events 
In the case of an SAE, the investigator or sub-investigator must report to the head of the 
study site and must contact the Sponsor/delegated Contract Research Organization (CRO) 
by telephone or fax immediately (within 24 hours of becoming aware of the event).  
The Investigator should complete and submit an SAE Worksheet containing all 
information that is required by the Regulatory Authorities to the Sponsor/delegated CRO 
by fax immediately (within 24 hours of awareness) and to the Head of the hospital.  If the 
faxing of the SAE Worksheet is not possible or is not possible within 24 hours, the 
Sponsor/delegate should be informed by phone. 
For contact details, see Section II Contact Details of Key Sponsor's Personnel.  
Please fax SAE Worksheet to: 
CRO:  
  
 
  
 
 
5.5.6 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be 
followed up until resolved or judged to be no longer clinically significant, or until they 
become chronic to the extent that they can be fully characterized.  
If during AE follow-up, the AE progresses to an "SAE", or if a subject experiences a new 
SAE, the investigator must immediately report the information to the Sponsor.  
Even if the subject does not return to normal or baseline level, the follow-up can be 
considered unnecessary or finished when the following procedures have been taken:  
1. Unnecessary: for AEs unrelated to the study drug, the 
Investigator/Sub-investigator judges that further follow-up is no longer necessary 
and the Sponsor judges that the reason is acceptable. 
2. Finished: based on the clinical course during the follow-up period, the 
Investigator/Sub-investigator judges that further follow-up is not necessary and 
the rationale for this judgment is recorded in follow-up report or other relevant 
documents.  The Sponsor judges the rationale is acceptable in consideration of 
safety of the subject. 
Please refer to Appendix 12.2 Liver Safety Monitoring and Assessment for detailed 
instructions on Drug Induced Liver Injury. 


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5.5.7 
Procedure in Case of Pregnancy 
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the 
subject should report the pregnancy to the Investigator.  The Investigator will report the 
pregnancy to the Sponsor/delegated CRO as an SAE. 
Information should be obtained by the Investigator on the estimated date of conception, 
estimated delivery date, and pregnancy outcome. 
5.5.8 
Emergency Procedures and Management of Overdose 
Mirabegron 
In a Japanese Phase 1 clinical study, mirabegron was administered to healthy adult males 
at doses of up to 400 mg/day.  In the 400 mg/day group, there were 3 cases of ‘heart rate 
increased’, 1 case of palpitations, and 1 case of ‘ALT increased’ reported as adverse drug 
reactions.  Only supportive treatment is available for overdose of mirabegron.  If a subject 
has inadvertently taken an overdose of mirabegron, the Investigator or Sub-investigator 
will provide emergency treatment and general maintenance therapy, as required according 
to the symptoms, and will perform appropriate examinations, such as vital sign 
measurements and 12-lead ECG. 
Tamsulosin 
Overdosage of tamsulosin may cause a decrease in blood pressure.  Should an overdose 
occur, restoration of blood pressure and normalization of heart rate may be accomplished 
by keeping the patient in the supine position.  If this measure is inadequate, then 
administration of intravenous fluids should be considered.  If necessary, vasopressors 
should then be used, and renal function should be monitored and supported as needed.  
Laboratory data indicate that tamsulosin hydrochloride is 94% to 99% protein bound; 
therefore, dialysis is unlikely to be of benefit. 
5.5.9 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that is necessary for proper conduct of the 
study, the Sponsor will inform all investigators involved in the study, as well as 
regulatory authorities.  The investigators should inform the IRB/IEC of such information. 
1. When information is obtained regarding serious and unexpected adverse drug 
reactions (or other) that are specified in Article 273 of the Enforcement Regulations 
of the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics, in compliance with Article 68-10 Paragraph 1 of the Pharmaceutical 
Affairs Law, the Sponsor should inform all the investigators involved in the clinical 
study, the Head of the study site, and the Regulatory Authorities of such information.  
The Head of the study site who receives such information will decide whether the 
clinical study should be continued after hearing the opinions of the IRB.  The 
Investigator will supply the new information to the subjects, in compliance with 
Section 8.2.3.2 Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information. (Unique to Japan) 
2. In addition to the above item (1), when the Head of the study site receives the 
revisions of the Package Insert, protocol, or written information, information on the 


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matters covering the quality of the study drug, efficacy and safety, information 
necessary for conducting the clinical study properly, or documents to be examined by 
the IRB should be sent to the IRB. (Unique to Japan) 
5.5.10 Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (Unique to Japan) 
The Investigator must not deviate from or amend the protocol, excluding an emergency 
case for avoiding risks to the subjects.  When the Investigator does not follow the 
protocol in order to avoid urgent risks for subjects, the Investigator should take the 
following actions:  
1. Describe the contents of the deviation or amendment and the reasons for it in a 
written notice, and immediately send the document stating the deviation or 
amendment and the reasons to the Sponsor and the Head of the study site.  Keep a 
copy of the notice. 
2. Consult with the Sponsor at the earliest possibility for cases in which it is necessary 
to amend the protocol.  Obtain approval for a draft of the amended protocol from the 
IRB and the Head of the study site as well as written approval from the Sponsor. 
5.6 
Test Drug Concentration 
Not applicable to this study. 
5.7 
Other Measurements, Assessments or Methods 
Not applicable to this study. 
5.8 
Total Amount of Blood Drawn 
Table 3 shows the specifics of blood sample collection, including the category/type of test, 
time points for blood collection, and the volume of blood samples.  The total volume of 
blood to be drawn from each subject is 25 mL. 
Table 3 
Blood Sample Collection During the Study 
Test 
Time Point 
Volume of 
Blood per 
Collection 
Scheduled 
Number of 
Collections 
Total 
Volume 
Total Volume of 
Blood Per 
Subject 
Serum 
Chemistry 
Visit 1 
Visit 2 
Visit 5 
4 mL 
3 
12 mL 
 
 
 
25 mL 
Hematology 
Visit 1 
Visit 2 
Visit 5 
2 mL 
3 
6 mL 
Coagulation 
Visit 1 
3 mL 
1 
3 mL 
Serum PSA 
Visit 1 
4 mL 
1 
4 mL 
PSA = prostate-specific antigen 
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s)  
A discontinuation is a subject enrolled in the study for whom study treatment is 
prematurely discontinued, for any reason.   


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The subject is free to withdraw from study treatment and/or the 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 terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it. 
If a subject is discontinued from the study and has an ongoing AE or an unresolved 
laboratory result that is significantly outside of the reference range, the Investigator will 
attempt to provide follow-up until the condition stabilizes or is no longer clinically 
significant.  
Treatment Discontinuation Criteria for Individual Subjects: 
● 
Due to an AE 
o When continuation in the study is judged to be difficult due to 
development of an AE or SAE 
o When continuation in the study is judged to be difficult due to aggravation 
of a concurrent disease requiring a change in treatment from the protocol 
● 
Lack of efficacy 
● 
Withdrawn consent 
● 
Lost to follow-up 
● 
Deviation from the inclusion or exclusion criteria during the Screening period 
● 
Protocol deviations 
o When a subject is found not to have met the inclusion criteria at enrollment, 
or to have met the exclusion criteria after enrollment and therefore, was 
determined to be ineligible for the study 
o Any other serious violation of the protocol 
● 
Other 
o When the Investigator judges that the subject must be withdrawn from the 
study, for any reason. 
For those subjects who are withdrawn from the study after study drug administration, the 
examinations and evaluations scheduled for the final visit of the treatment period will be 
performed at the time of discontinuation, as much as possible (See Section V, Figure 
1 Study Design Flow Chart and Table 1 Schedule of Assessments).  If the subject is 
discontinued due to an AE, appropriate treatment will be provided, as necessary. 
The Investigator will record the date and reason for the subject discontinuation and enter 
in the eCRF. 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor and the Head of the study site. 
6.3 
Discontinuation of the Study 
The Sponsor may terminate this study prematurely, either in its entirety or at any study 
site, for reasonable cause provided that written notice is submitted in advance of the 
intended termination.  Advance notice is not required if the study is stopped due to safety 


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concerns.  If the Sponsor terminates the study for safety reasons, the Sponsor will 
immediately notify the Investigator and subsequently provide written instructions for 
study termination. 
7 
STATISTICAL METHODOLOGY 
The statistical analysis will be coordinated by the responsible biostatistician of API.  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.  The SAP will be 
finalized before breaking the treatment code.  Any changes from the planned analyses in 
the SAP will be described and justified in the Clinical Study Report.  
7.1 
Sample Size 
The sample size for this study was based on 248 subjects per treatment group (using the 
Full Analysis Set [FAS]) to provide 90% power to detect a 0.7 reduction in the mean 
number of micturitions/24 hours in the mirabegron group compared to the placebo group, 
at a two-sided alpha level of 0.05.  A standard deviation (SD) of 2.4 is assumed.  
Assumptions for the mean reduction and SD are based on data from previous studies 
(178-CL-048, 178-CL-090 and 905-JC-001; Table 4-6).  If 90% of the randomized 
subjects are evaluable for efficacy, 550 subjects should be randomized, with 275 subjects 
randomized to each treatment group. 
Table 4 
178-CL-04817   Change from Baseline in the Mean Number of 
Micturitions at the Final Assessment 
 
Placebo (n = 368) 
Mirabegron 50 mg (n = 369) 
Baseline 
11.29 ± 2.748 
11.15 ± 2.650 
Final assessment 
10.44 ± 2.777 
9.48 ± 2.528 
Change 
−0.86 ± 2.354 
−1.67 ± 2.212 
*Mean ± SD 
 
Table 5 
178-CL-09021   Change from Baseline to Last Visit in Mean Number of  
Micturitions Per 24-hour 
 
Placebo 
Mirabegron 50mg 
N 
mean 
SE 
95% CI 
N 
mean 
SE 
95% CI 
Overall 
323 
-1.48 
0.178 
(-1.83, -1.13)
338
-2.04 
0.174 
(-2.38, -1.70) 
China 
 
 
 
 
 
 
 
India 
 
 
 
 
 
 
 
Korea 
 
 
 
 
 
 
Taiwan 
 
 
 
 
 
 
 
* Adjusted change from baseline results are generated from the ANCOVA model with treatment group as a 
fixed factor and baseline as a covariate.  
 
Table 6 
905-JC-0017    Changes in average 24-hour frequency of urination 


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Tamsulosin 0.2mg + Placebo 
(n = 209) 
Tamsulosin 0.2mg + Vesicare 5.0mg
(n = 208) 
Adjusted mean 
(95% confidence interval) 
-0.22   (-0.51, 0.06) 
-1.06   (-1.34, -0.77) 
*Analysis of covariance was performed with the treatment group as a factor and baseline average 24-hour 
frequency of urgency as a covariate, and multiplicity was adjusted by a closed testing procedure to start 
with comparison of the Ha0.2mg+Vc5.0mg group. 
 
7.2 
Analysis Set 
The analysis will be performed using the following analysis populations, based on ICH 
guidelines E3 and E9.  The final handling of the analysis sets will be decided with the 
decisions based on the opinions and advice of medical experts prior to breaking of the 
randomization code. 
7.2.1 
Full Analysis Set 
The primary analysis dataset is the FAS, which will consist of all subjects who are 
randomized and receive at least 1 dose of double-blind study drug and have a Baseline 
micturition measurement and at least 1 post-Baseline micturition measurement. 
All secondary efficacy analyses will be performed on the FAS. 
7.2.2 
Per Protocol Set 
Subjects from the FAS who meet all of the following criteria will be included in the Per 
Protocol Set (PPS):  
1. Those subjects who did not violate the inclusion criteria. 
2. Those subjects who did not violate the exclusion criteria.  
3. Those subjects with drug compliance during the Screening period and Treatment 
period of not less than 80%. 
4. Those subjects who took the study drug during the Treatment period for 42 days 
or longer from the day following dispensing.  However, subjects who discontinued 
the study for efficacy-related reasons, such as insufficient therapeutic effect, will 
be included in the PPS, even if the drug was taken for less than 42 days. 
5. Subjects with diary entries for at least 2 of the 3 consecutive days at Visit 2 and 
the last visit during the Treatment period. 
6. Subjects who did not receive any of the prohibited concomitant 
medications/therapies that may affect the evaluation of efficacy.  
7.2.3 
Safety Analysis Set 
The analysis of safety data will be performed on the Safety Analysis Set (SAF), which 
will include all subjects who received at least 1 dose of double-blind study medication. 
7.3 
Demographics and Other Baseline Characteristics  
Demographics and other baseline characteristics will be summarized by treatment group 
for the FAS, PPS, and SAF.  Descriptive statistics will include: number of subjects; mean, 


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SD, minimum, Q1, median, Q3 and maximum for continuous endpoints; and frequency 
and percentage for categorical endpoints.  
7.4 
Analysis of Efficacy  
The efficacy analysis will be conducted on the FAS, with the PPS as a supportive 
analysis.  
7.4.1 
Analysis of Primary Endpoint  
7.4.1.1 Primary Analysis 
The primary efficacy endpoint, change from Baseline to End of Treatment in the mean 
number of micturitions per 24 hours, will be analyzed using an Analysis of Covariance 
(ANCOVA), including treatment group and region as fixed factors and baseline as a 
covariate.  Within the framework of the ANCOVA model, point estimates and two-sided 
95% confidence intervals for the mean change from Baseline both within and between 
treatment groups will be calculated.  The two-sided significance level will be set at 5%.  
The hypotheses for the treatment group comparisons are as follows: 
H0: The change from Baseline to End of Treatment in the mean number of micturitions 
over 24 hours is the same in subjects who received mirabegron compared to those who 
received placebo. 
H1: The change from Baseline to End of Treatment in the mean number of micturitions 
over 24 hours is not the same in subjects who received mirabegron compared to those 
who received placebo. 
The primary and secondary efficacy analyses will be conducted using the FAS, which 
includes all subjects who receive at least 1 dose of double-blind study medication and 
have both a Baseline and post-Baseline micturition assessment. 
For those subjects who discontinue the study prematurely, the End-of-Treatment 
assessment will be analyzed.  The End-of-Treatment assessment is defined as the last 
post-Baseline assessment during the double-blind study period for which primary efficacy 
data are available. 
Continuous variables will be summarized using descriptive statistics, including mean, 
standard deviation, minimum, Q1, median, Q3 and maximum.  Categorical variables will 
be described using absolute and relative frequency. 
7.4.1.2 Secondary Analysis 
The primary efficacy endpoint, change from Baseline to End of Treatment in the mean 
number of micturition episodes per 24 hours, will be analyzed using a Mixed Model 
Repeated Measure (MMRM) for the secondary analysis.  Further details on the MMRM 
analyses will be provided in the Statistical Analysis Plan (SAP). 
7.4.1.3 Subgroup Analysis 
Subgroup analyses will include analyses by geographic region and by urgency 
incontinence at Baseline.  Further details on subgroup analyses will be provided in the 
SAP. 


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7.4.2 
Analysis of Secondary Endpoints  
The secondary endpoints include the change from Baseline to End of Treatment in:  
● 
Mean number of urgency episodes/24 hours 
● 
Mean number of urgency incontinence episodes/24 hours 
● 
Mean number of incontinence episodes/24 hours 
● 
Mean number of nocturnal episodes 
● 
Mean volume voided per micturition 
● 
Total OABSS score  
● 
Subscale score from OABSS score 
● 
Total IPSS score  
● 
Subscale score from IPSS score 
● 
Symptom Bother and total Health-Related QoL scores, as assessed by the OAB-q 
questionnaire. 
The secondary endpoints will be analyzed using the FAS, with the PPS as a supportive 
analysis.  For the changes in mean number of incontinence and urge incontinence 
episodes, the analysis will be based on those subjects who have at least 1 incontinence 
episode at Baseline. 
For the change in the mean number of nocturia episodes, the analysis will be based on 
those subjects who had at least 1 nocturia episode at Baseline. 
The secondary efficacy endpoints, except for the changes in mean number of incontinence 
and urge incontinence episodes, will be analyzed using an Analysis of Covariance 
(ANCOVA), including treatment group and region as fixed factors and baseline as a 
covariate. Within the framework of the ANCOVA model, point estimates and two-sided 
95% confidence intervals for the mean change from Baseline both within and between 
treatment groups will be calculated. The two-sided significance level will be set at 5%. 
The changes in mean number of incontinence and urge incontinence episodes will be 
analyzed using a Stratified Rank Analysis of Covariance (RANCOVA). Details on the 
RANCOVA analyses will be provided in the Statistical Analysis Plan (SAP). 
7.4.3 
Analysis of Exploratory Endpoints  
The exploratory endpoints will include the change from Baseline to End of Treatment 
in: 
● 
Hours of undisturbed sleep (HUS) 
● 
First nighttime voided volume 
● 
Subscale scores from OAB-q 
● 
Normalization rate of OABSS 
● 
Normalization rate of micturition diary (number of episodes of 
micturition/urgency/urgency incontinence/incontinence/nocturia 
The exploratory endpoints will be analyzed using the FAS. 
Based on the following definitions of normalization, the percentage of subjects 
normalized were of the subjects who were not normalized at Baseline: 
● 
OABSS: 1 point or less on Question 3, or a total score of ≤2 points 
● 
Micturition episodes: mean number per 24 hours of <8 


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● 
Urgency episodes: mean number per 24 hours of zero 
● 
Urgency incontinence episodes: mean number per 24 hours of zero 
● 
Incontinence episodes: mean number per 24 hours of zero 
● 
Nocturia episodes: mean number per 24 hours of zero 
Details on the analyses will be provided in the Statistical Analysis Plan (SAP). 
7.5 
Analysis of Safety 
The safety analysis will be performed on the SAF. 
7.5.1 
Adverse Events  
Adverse events will be recorded at each visit.  The incidence and severity (mild, 
moderate, or severe) of TEAEs will be tabulated. 
Adverse events will be coded using the MedDRA dictionary.   
Adverse events reported during the double-blind Treatment period will be analyzed as 
follows:  
● 
The number and percentage of subjects with AEs, SAEs, AEs leading to 
discontinuation, and AEs related to study drug will be summarized by System Organ 
Class (SOC), Preferred Term (PT), and treatment group.  The treatment groups will 
be compared using Fisher’s Exact test, with a two-sided 95% confidence interval and 
5% significance level.  The number and percentage of AEs, by severity, will also be 
summarized.  All AEs will be displayed in a listing, by subject. 
Adverse events reported during the Screening period will be analyzed as follows: 
● 
The number and percentage of subjects with AEs and the number and percentage of 
subjects with SAEs will be summarized by SOC and PT.  A two-sided 95% 
confidence interval will be presented.  The number and percentage of subjects with 
AEs by severity will also be summarized. 
7.5.2 
Laboratory Assessments 
Laboratory tests, including serum chemistry, hematology, and urinalysis, will be 
performed at Visit 1 (Screening), prior to dosing on Visit 2 (Baseline), and at Visit 5 
(Week 12/End of Treatment). 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment group and time point.  Shifts in laboratory 
test values relative to the normal range from Baseline to each time point during the 
Treatment period will also be tabulated.  Laboratory data will be displayed in listings. 
7.5.3 
Vital Signs 
Vital signs, including SBP, DBP, and PR will be measured at each visit. 
Descriptive statistics will be used to summarize vital sign measurements and changes 
from Baseline by treatment group and time point.  Vital signs data will be displayed in 
listings, by subject. 


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7.5.4 
Residual Urine Volume 
For residual urine volume, descriptive statistics will be used to summarize the 
measurement values and changes from Baseline, by treatment group and time point.  
Residual urine volume data will be provided in a listing, by subject. 
7.5.5 
Qmax 
For Qmax, descriptive statistics will be used to summarize the measurements and changes 
from Baseline, by time point and treatment group.  Qmax data will be provided in a 
listing, by subject. 
7.6 
Analysis of Pharmacokinetics 
Not applicable to this study.  
7.7 
Interim Analysis (and Early Discontinuation of the Clinical 
Study) 
No formal interim analysis is planned. 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
7.8.1 
Missing Data 
The final handling of missing data will be decided by the time of database lock, and will 
be based on the opinion and advice of a medical expert.  If multiple observed values have 
been obtained within the same visit window for 1 subject, the value closer to the 
scheduled date will be used for analysis.  If the number of days deviated from the 
scheduled date is equal between these values, the value obtained on the later date will be 
used for the analysis.  
The day of prescription of the study drug for the treatment period is defined as Day 1, 
and the following day is defined as Day 2.   
As a general rule, missing efficacy data will not be imputed.  Exceptions to this are the 
start and stop dates of AEs and concomitant medications.  
Listings of AEs and concomitant medications will show the actual partial dates; imputed 
dates will not be shown.  The SAP will define the visit windows to be used for analyses 
by visit. 
7.8.2 
Outliers 
The final handling of outliers will be decided by the time of database lock, and will be 
based on the opinion and advice of a medical expert. 
7.8.3 
Visit Windows 
As indicated in Section 7.8.2, the final handling of outliers will be decided by the time of 
database lock, and will be based on the opinion and advice of a medical expert.  However, 
the policy described below will be followed as a general rule: 


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If multiple observed values have been obtained within the same visit window for a subject, 
the value closest to the scheduled date will be used.  If there are similar deviations from 
the scheduled date, the value obtained on the later date will be used.   
Data obtained as early as possible within the allowable range for each visit and within a 
7-day period from the final dose will be used. 
Micturition Diary: 
The mean number of: micturition episodes per 24 hours, urgency episodes per 24 hours, 
urinary incontinence episodes per 24 hours, urgency incontinence episodes per 24 hours, 
as well as mean volume voided per micturition and mean number of nocturia episodes 
will be calculated on the basis of the micturition diary and handled as follows:  
The information in the diary (recorded within 3 days before each visit, in principle) 
measured and recorded in the time windows specified below will be used as the data for 
that time point. 
Time Point 
Scheduled Day 
Acceptable Time Range 
Diary retrieved at Visit 2 
1 
Day -7 to Day 1 (AM 5:59) 
Diary retrieved at Visit 3 
29 
Day 19 to Day 36 (AM 5:59) 
Diary retrieved at Visit 4 
57 
Day 47 to Day 64 (AM 5:59) 
Diary retrieved at Visit 5 
85 
Day 75 to Day 92 (AM 5:59) 
Diary retrieved at the final evaluation in 
the Treatment period 
The final diary must be completed within 7 days after 
the last dose of study drug. 
If the subject cannot complete the diary during the 3 days immediately prior to the visit, the diary 
entries must be recorded for any 3 days within 7 days prior to the visit. 
 
If for some reason, information cannot be recorded in the diary during the 3 days before a 
given visit, data will be assessed based on the diary entries recorded within 7 days before 
the visit and within the above-specified time windows. 
 
OABSS, IPSS, IPSS (QoL), and OAB-q* 
The information measured and recorded within the time windows specified below will be 
used as the data for that time point. 
Time Point 
Scheduled Day 
Acceptable Time Range 
Completed at Visit 1 
-28 
Day -35 to Day -21 
Completed at Visit 2 
1 
- 
Completed at Visit 3 
29 
Day 22 to Day 36 
Completed at Visit 4 
57 
Day 50 to Day 64 
Completed at Visit 5 
85 
Day 78 to Day 92 
Questionnaires are to be completed at 
the final evaluation during the Treatment 
period. 
Final diary must be completed within 7 days after the 
last dose of study drug. 
*OAB-q not performed at Visit 3 and Visit 4. 
 
Safety Assessments 
The time windows for the analysis of residual urine volume, laboratory tests*, and 
measurement of BP and PR are described below: 


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Time Point for Evaluation 
Scheduled Day 
Acceptable Time Range 
Visit 1 
-28 
Day -35 to Day -21 
Visit 2 
1 
- 
Visit 3 
29 
Day 22 to Day 36 
Visit 4 
57 
Day 50 to Day 64 
Visit 5 
85 
Day 78 to Day 92 
Final 
evaluation 
during 
the 
Treatment period 
Final evaluation must be performed within 7 days after the 
last dose of study drug. 
* Performed only at Week -4, Week 0, and Week 12/early termination 
 
The time windows for the analysis of self-measurement of BP and PR are described 
below: 
Time point 
Scheduled day 
Acceptable time range 
Diary retrieved at Visit 2 
1 
Day -7 to Day -1 
Diary retrieved at Visit 3 
29 
Day 19 to Day 35 
Diary retrieved at Visit 4 
57 
Day 47 to Day 63 
Diary retrieved at Visit 5 
85 
Day 75 to Day 91 
The diary is to be retrieved at the final 
evaluation during the Treatment period. 
The final diary must be completed within 7 days after the last 
dose of study drug. 
 
 
8 
OPERATIONAL AND ADMINISTRATIVE 
CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
Electronic Case Report Form (eCRF) 
The Investigator, Sub-investigator, or collaborator will promptly enter individual subject 
data into the computer using the Electronic Data Capture (EDC) system in accordance 
with the protocol instructions for each visit (including laboratory findings if necessary).  
For a subject who discontinues the study after informed consent, but prior to the 
dispensing of the study drug for the Screening period, minimum necessary demographic 
information (subject number, sex, date of birth, and date of obtaining consent) and the 
reason for discontinuation will be entered into the SFL using the EDC system.  
The Investigator must ensure that all data on the eCRF (including SFL) are submitted to 
the Sponsor, the responses to queries are accurate and complete, and the entries are 
verifiable against the source documents.  In addition, the source documents must be 
properly retained at the study site. 
The Monitor will verify the data on the eCRF against the source documents to confirm 
that they are consistent. If any correction of data is found, the Monitor will confirm that 
the data correction is appropriately recorded. 
OABSS, OAB-q, IPSS with IPSS QoL, and Micturition Diary 
At each visit, the Investigator or Sub-investigator will review the OABSS, OAB-q, IPSS 
with IPSS QoL, and micturition diary recorded by the subjects.  If there is any unclear 


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entry, the Investigator, Sub-investigator or their designee will inquire of the subject for 
the entry and request the subject to make necessary additions or corrections.  If the 
Investigator or Sub-investigator makes any additions or corrections, he/she will place the 
date of correction, and signature or seal to the added or corrected portions.  Finally, the 
Investigator or Sub-investigator will review all entries, place the date of review, and 
signature or seal on the OABSS, OAB-q, IPSS with IPSS QoL, and micturition diary and 
then will submit copies of these documents to the Sponsor. 
The Investigator or Sub-investigator will enter the data from the micturition diary and 
questionnaire into the computer using the EDC system as follows with the data from the 
eCRF. 
Laboratory Data 
Laboratory tests will be performed at a central laboratory.  Laboratory data will be 
transferred electronically to the Sponsor or designee at predefined intervals during the 
study.  The laboratory will provide the Sponsor or designee with a complete and clean 
copy of the data. 
8.1.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study 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.   
The following information should be included in the source medical records: 
● 
Demographic data (age, sex, race, ethnicity, height and body weight) 
● 
Inclusion and exclusion criteria details 
● 
Participation in study and original signed and dated informed consent forms 
● 
Source medical records and attached records (Investigator will submit copies of UFM 
chart to Sponsor, while retaining the originals)  
● 
Visit dates 
● 
Medical history and physical examination details 
● 
Key efficacy and safety data, if applicable (as specified in the protocol) 
● 
OABSS, OAB-q, IPSS and IPSS (QoL), and micturition diary (the Investigator will 
review all entries, date the review, apply a signature/seal to the documents, and 
submit copies of the documents to the Sponsor, while retaining the originals.) 
● 
Adverse events and concomitant medication  
● 
Results of relevant examinations (e.g., ECG charts, X-ray films etc.) 
● 
Laboratory printouts 
● 
Dispensing and return of study drug details 
● 
Reason for premature discontinuation  
● 
Randomization number 
 
The eCRF will serve as the source data for the following information, unless there are any 
records in the medical chart:  
● 
Route of administration of a prior or concomitant medication and reason for and time 
of use 


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● 
Reason for and time of prior or concomitant therapy 
● 
Details of ECG charts, images, etc., if used for diagnosis or evaluation at enrollment 
● 
Details of AEs (outcome, severity, seriousness, treatment, other measures taken, and 
causal relationship to the study drug), date of the final observation, date and reason 
for discontinuation 
Other comments in the eCRF (or comments in the CRF for follow-up when a follow-up of 
adverse events is conducted)  
8.1.3 
Clinical Study Monitoring 
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure 
that subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents.  The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring.  They will monitor the study in 
accordance with planned monitoring procedures.   
8.1.4 
Direct Access to Source Data/Documents 
The Investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory 
authorities.  In these instances, they must provide all study-related records, such as source 
documents (refer to Section 8.1.2 Specification of Source Documents) when they are 
requested by the Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities.  
The confidentiality of the subject's identities shall be well protected consistent with local 
and national regulations when the source documents are subject to direct access. 
8.1.5 
Data Management 
Data management will be coordinated by the Data Science department of the Sponsor in 
accordance with the SOPs for data management.  All study specific processes and 
definitions will be documented by the Data Management department.  The eCRF retrieval 
and correction process will be referenced in the eCRF instructions.  Coding of medical 
terms and medications will be performed using MedDRA and the 
World Health Organization Drug Dictionary Enhanced (WHODDE) drug dictionary. 
8.1.6 
Protocol Deviations (Unique to Korea) 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  The Investigator is responsible for 
ensuring the study is conducted in accordance with the procedures and evaluations 
described in this protocol and must protect the rights, safety, and welfare of subjects.  The 
Investigator should not implement any deviation from or changes of the protocol, unless it 
is necessary to eliminate an immediate hazard to study subjects.   
A protocol waiver is a documented prospective approval of a request from an investigator 
to deviate from the protocol.  Protocol waivers are strictly prohibited. 
For the purposes of this protocol, deviations requiring notification to Sponsor are defined 
as any subject who:  


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● 
Entered into the study even though they did not satisfy entry criteria.  
● 
Developed withdrawal criteria during the study and were not withdrawn 
● 
Received wrong treatment or incorrect dose.  
● 
Received excluded concomitant treatment.    
When a deviation from the protocol is identified for an individual subject, the Investigator 
or designee must ensure that the Sponsor is notified.  The Sponsor will follow up with the 
Investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or efficacy of the subject to determine subject continuation in the study.  
If a deviation impacts the safety of a subject, the Investigator must contact the Sponsor 
immediately. 
The Investigator will also assure that deviations meeting IRB/IEC and applicable 
Regulatory Authority criteria are documented and communicated appropriately.  All 
documentation and communications to the IRB/IEC and applicable regulatory authorities 
will be provided to the Sponsor and maintained within the Trial Master File.   
NOTE: Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable. 
8.1.7 
End of Trial in All Participating Countries 
The end of the trial in all participating countries is defined as the Last Subject’s Last Visit. 
8.2 
Ethics and Protection of Subject Confidentiality  
8.2.1 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) 
Prior to concluding the study contract, the IRB/IEC of the respective study site will 
review and approve the protocol and several documents used to obtain a patient’s consent 
in order to secure the patient’s human rights, safety, and well-being. 
8.2.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  
8.2.3 
Informed Consent of Subjects 
8.2.3.1 Subject Information and Consent 
The Investigator or his/her representative will explain the nature of the study to the 
subject or his/her guardian or legal representative, and answer all questions regarding this 
study.  Prior to any study-related screening procedures being performed on the subject, 
the informed consent statement will be reviewed and signed and dated by the subject or 
his/her guardian or legal representative, the person who administered the informed 
consent and any other signatories according to local requirements.  A copy of the signed 
informed consent form will be given to the subject and the original will be placed in the 
subject’s medical record.  An entry must also be made in the subject’s dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy. 


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The signed consent forms will be retained by the Investigator and made available (for 
review only) to the study monitor and auditor, regulatory authorities, and other applicable 
individuals, upon request. 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information 
1. The Investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the 
study (e.g., report of serious drug adverse drug reaction).  The communication must 
be documented in the subject’s medical records and must document whether the 
subject is willing to remain in the study or not. 
2. The Investigator must update their 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 re-consent subjects with the updated ICF even 
if relevant information was provided orally.  The Investigator or his/her 
representative who obtained the written informed consent and the subject should sign 
and date the informed consent form and place a personal seal.  A copy of the 
signed/sealed informed consent form 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 re-consent process. 
8.2.4 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited.  Such medical information may 
be given only after approval of the subject to the subject's physician or to other 
appropriate medical personnel responsible for the subject's well-being. 
The Sponsor shall not disclose any confidential information on subjects obtained during 
the performance of their duties in the clinical study without justifiable reasons. 
All individuals and organizations involved in the study must pay very careful attention to 
protect subjects’ privacy with appropriate measures, for example, by prohibiting the use 
of any private information that may identify a subject (e.g., name or address).  These 
details shall be processed in accordance with the applicable local and regional laws. 
Even though any individuals involved in the study, including the study monitors and 
auditors, may get to know matters related to subject's privacy due to direct access to 
source documents, or from other sources, they may not leak the content to third parties.  
8.3 
Administrative Matters 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished 
scientific data, the IB 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 


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the information obtained during the clinical study in connection with the development of 
the drug 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 
clinical study, the Investigator 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 Clinical Study Agreement. 
After agreement between Investigator(s) and Sponsor, the manuscript can be submitted 
for publication. 
8.3.2 
Documents and Records Related to the Clinical Study 
The Sponsor will provide the Investigator and/or institution with the following: 
● 
Study protocol (and amendments, where applicable) 
● 
PI (and amendments, where applicable) 
● 
CRFs and SAE Worksheet 
● 
Study medication, with all necessary documentation 
● 
Study contract 
In order to start the study, the Investigator and/or study site is required to provide the 
following documentation to the Sponsor:  
● 
Signed Investigator's Statement in this protocol and CRF 
● 
Current Curricula Vitae (CV) of all investigators 
● 
List of sub-investigators and collaborators  
● 
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY) 
● 
Instruction and decision of the head of the study site 
● 
Study contract 
● 
Laboratory normal reference ranges (if applicable, signed and dated by the 
responsible laboratory employee) 
At the end of the study, the Sponsor is responsible for the collection of: 
● 
Unused CRFs and other study documentation, 
● 
Unused study drug 
The Investigator will archive all study data (e.g., Subject Identification Code List, source 
data, CRFs, and Investigator's File) and relevant correspondence.  These documents are to 
be kept on file for the appropriate term determined by local regulation.   
The records to be retained at the study sites are the ones listed as essential documents in 
GCP.  These records shall be retained by the Head of the study site or the record keeper 
designated by the Head until notice issued by the Sponsor on completion of the retention 
period is received.  These documents are also subject to direct access and should be 
provided upon request from the Sponsor or regulatory authorities. 
The Head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site concerned until 
the date defined in 1 or 2 below, whichever comes later. 


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1. Approval date of marketing of the test drug (if development of the drug is stopped, 
until three years after the decision to discontinue development is notified) 
2. Until 3 years after discontinuation or termination of the study. 
The following are the major documents to be retained at the study site. 
1. Source documents (clinical data, documents, and records for preparing the CRF), 
hospital records, medical records, test records, memoranda, micturition diary or 
check lists for evaluation, administration records, data recorded by automatic 
measuring instruments, reproductions or transcripts verified as precise copies, 
microfiche, negative films, microfilms/magnetic media, X-ray films, subject files and 
study-related records kept at either a pharmacy, a laboratory, or medical technical 
office, as well as subject registration forms, laboratory test slips including central 
measurement, worksheets specified by the Sponsor, records of clinical coordinators, 
and records related to the clinical study selected from those verified in other 
departments or hospitals.  
2. Contracts, written informed consent forms, written information, and other documents 
or their copies prepared by the study personnel. A letter of request for clinical study 
(including a request for continuation/amendment), letter of request for review, notice 
of clinical study contract, clinical study contract, notification of discontinuation or 
completion of clinical study, written information for informed consent (including 
revisions), signed and dated written informed consent (including revisions), CVs of 
investigators, list of sub-investigators, list of signatures and print of seals (copy), and 
case report forms (copy), etc.  
3. The protocol, documents obtained from the IRB related to the adequacy of 
conducting the clinical study by the head of the study sites (Article 32-1, MHW 
Ordinance No. 28), documents obtained from the IRB related to the adequacy of 
conducting a clinical study whose period exceeds one year or the adequacy of 
continuously conducting the clinical study from which information on adverse drug 
reactions is obtained, and other documents obtained. An agreed-upon protocol 
(including revisions), IB (including revisions), operational procedures for the 
investigator, materials and information supplied by the Sponsor (e.g., AE report), 
matters reported by the investigator (revisions of the protocol, AE reports, etc.), 
operational procedures for the IRB, the list of names of the IRB members, materials 
for IRB review (including continuous deliberation), IRB review records (including 
continuous deliberation), and the review result report of the IRB (including 
continuous deliberation), etc.  
4. Records of control for study drugs and other duties related to the clinical study. 
Procedure for controlling the study drugs, drug inventory and accountability record, 
vouchers for the receipt and return of the study drugs, and the prescriptions for 
concomitant medications 
8.3.3 
Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments and/or revisions.  Depending on the nature of the amendment, 
either approval or notification of the IRB and Competent Authority may be required.  The 
changes will become effective only after the approval of the Sponsor, the Investigator, 
and the IRB (if applicable), followed by the approval of the Head of the study site. 


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8.3.4 
Insurance of Subjects and Others 
If a subject suffers any study-related injury, the Sponsor will compensate appropriately 
according to the severity and duration of the damage.  However, if it was caused 
intentionally or was due to gross negligence by the study site, the Sponsor will consult 
with the study site about handling the injury, based on the agreed study contract.  
Compensation for the study-related injury is provided by the following procedures: 
1. If a subject incurs a injury as a result of participation in the clinical study, the study 
site should provide medical treatment and other necessary measures.  The Sponsor 
should be notified of the injury.  
2. When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the Sponsor.  Both parties should work together towards 
compensation settlement.  
3. The Sponsor shall pay compensation or indemnification and bear expenses necessary 
for the settlement as provided in the clinical contract.  
4. The Sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above. 
8.3.5 
Signatory Investigator for Clinical Study Report 
The Medical Expert and/or 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 signatory will be the Medical Expert and/or the representative for the 
Coordinating Investigator(s) or the Principal Investigator(s), and Vice President, Clinical 
Development Administration. 
9 
QUALITY ASSURANCE 
The Sponsor is implementing and maintaining quality assurance and quality control 
systems with written SOPs to ensure that trials are conducted and data are generated, 
documented, recorded, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirement(s). 
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities.  The audit may include on-site review of regulatory 
documents, eCRFs, and source documents.  Direct access to these documents will be 
required by the auditors. 
10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee (IDMC) 
Not applicable. 
10.2 
Other Study Organization 
Not applicable. 


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10.3 
Registration of Subjects 
The Investigator or Sub-investigator will obtain written informed consent from each 
screened patient after investigating his/her background. 
After confirming that the subject meets all the inclusion criteria and none of the exclusion 
criteria, the Investigator or Sub-investigator will enter necessary information on the 
registration screen of the web registration system.  On receiving registration information, 
the Registration Center will confirm whether the subject meets all the inclusion criteria 
and none of the exclusion criteria.  The study drugs will be allocated to eligible subjects 
after enrollment at Visit 2/Baseline.  The Registration Center will notify the study site of 
registration results and allocated drugs via the web registration system. 
The Investigator or Sub-investigator will confirm that the subject is eligible for 
enrollment at Visit 1/Screening and prescribe the study medication (tamsulosin 0.2 mg 
tablet + mirabegron 50 mg placebo tablet) for the Screening period at enrollment.  Prior to 
Visit 2/Baseline, subjects will be randomized to receive mirabegron 50 mg or matching 
placebo along with tamsulosin 0.2 mg for the Treatment period. 
If the subject is determined to be ineligible for enrollment at Visit 1/Screening or 
Visit 2/Baseline, the subject will be discontinued from the study. 
 
 


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Flow of Subject Registration: 
 
 
Informed consent 
Screening 
Confirming the inclusion/exclusion criteria 
(enrollment at visit 2/baseline) 
Confirming the inclusion/exclusion criteria 
(enrollment at visit 1/screening) 
Enrollment at 
visit 1/ 
screening 
Registration of subject 
information 
Confirming eligibility for 
registration 
Prescribe the study drug for the 
screening period 
Enrollment at 
visit 2/ 
baseline 
Registration of subject 
information 
Confirming eligibility for 
registration 
Prescribe the designated study 
drugs for the treatment period 
Screening period 
Treatment period 
Web 
Web 
Web 
Web 
Study drug allocation 


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11 
REFERENCES  
1. Coyne KS, Sexton CC, Irwin DE, Kopp ZS, Kelleher CJ, Milsom I, The impact of 
overactive bladder, incontinence and other lower urinary tract symptoms on 
quality of life, work productivity, sexuality and emotional well-being in men and 
women: results from the EPIC study. BJU Int. 2008; 101(11): 1388-95 
2. Irwin DE, Milsom I, Kopp Z, Abrams P; EPIC Study Group, Symptom bother and 
health care-seeking behavior among individuals with overactive bladder. Eur Urol. 
2008; 53(5): 1029-37 
3. Kannan H, Radican L, Turpin RS, Bolge SC, Burden of illness associated with 
lower urinary tract symptoms including overactive bladder/urinary incontinence. 
Urology. 2009; 74(1): 34-8 
4. Sexton CC, Coyne KS, Kopp ZS, Irwin DE, Milsom I, Aiyer LP, et al. EpiLUTS 
Team. The overlap of storage, voiding and postmicturition symptoms and 
implications for treatment seeking in the USA, UK and Sweden: EpiLUTS. BJU 
Int. 2009; 103 Suppl 3: 12-23 
5. The Japanese Urological Association, BPH Guideline Clinical Guideline for 
Benign Prostatic Hyperplasia 2011  
6. 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. 
7. Yamaguchi O, Kakizaki H, HommaY, Takeda M, Nishizawa O, Gotoh, et al. 
Solifenacin as Add-on Therapy for Overactive Bladder Symptoms in Men Treated 
for Lower Urinary Tract Symptoms – ASSIST, Randomized Controlled Study. 
Urology 2011; 78(1): 126-33 
8. Nishizawa O, Yamaguchi O, Takeda M, Yokoyama O. Randomized Controlled 
Trial to Treat Benign Prostatic Hyperplasia with Overactive Bladder Using an 
Alpha-blocker Combined with Anticholinergics. LUTS 2011; 3: 29-35 
9. Takeda M, Nishizawa O, Gotoh M, Yoshida M, Takahashi S, Masumori N. 
Clinical efficacy and safety of imidafenacin as add-on treatment for persistent 
overactive bladder symptoms despite α-blocker treatment in patients with BPH: 
the ADDITION study. Urology. 2013; 82(4): 887-93 
10. Yokoyama O, Tsujimura A, Akino H, Segawa N, Tamada S, Oguchi N, et al. 
Add-on anticholinergic therapy for residual nocturia in patients with lower urinary 
tract symptoms receiving α1-blocker treatment: a multi-centre, prospective, 
randomised study. World J Urol. 2015; 33(5): 659-67 
11. Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W. Safety and tolerability 
of solifenacin add-on therapy to alpha-blocker treated men with residual urgency 
and frequency. J Urol. 2009; 182(6): 2825-30 
12. Kaplan SA, Roehrborn CG, Chancellor M, Carlsson M, Bavendam T, Guan Z. 
Extended-release tolterodine with or without tamsulosin in men with lower 


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urinary tract symptoms and overactive bladder: effects on urinary symptoms 
assessed by the International Prostate Symptom Score. BJU Int. 2008; 102(9): 
1133-9 
13. Chapple C, Herschorn S, Abrams P, Sun F, Brodsky M, Guan Z. Tolterodine 
treatment improves storage symptoms suggestive of overactive bladder in men 
treated with alpha-blockers. Eur Urol. 2009; 56(3): 534-41 
14. Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, et al. 
Natural history of prostatism: risk factors for acute urinary retention. J Urol. 1997; 
158(2): 481-7. 
15. Hatanaka T, Ukai M, Watanabe M, Someya A, Ohtake A, Suzuki M, et al .Effect 
of mirabegron, a novel β3-adrenoceptor agonist, on bladder function during 
storage phase in rats. Naunyn Schmiedebergs Arch Pharmacol. 2013; 386(1): 71-8 
16. Hatanaka T, Ukai M, Watanabe M, Someya A, Ohtake A, Suzuki M, et al. 
Pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in 
cynomolgus monkeys. Naunyn Schmiedebergs Arch Pharmacol. 2013; 386(11): 
1001-8 
17. Yamaguchi O, Marui E, Kakizaki H, Homma Y, Igawa Y, Takeda M, et al. Phase 
III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor 
agonist mirabegron, 50 mg once daily, in Japanese patients with overactive 
bladder. BJU Int. 2014; 113(6): 951-60 
18. Herschorn S, Barkin J, Castro-Diaz D, Frankel JM, Espuna-Pons M, Gousse AE, 
et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, 
multicentre study to assess the efficacy and safety of the β₃ adrenoceptor agonist, 
mirabegron, in patients with symptoms of overactive bladder. Urology. 2013; 
82(2): 313-20 
19. Khullar V, Amarenco G, Angulo JC, Cambronero J, Høye K, Milsom I, et al. 
Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients 
with overactive bladder: results from a randomised European-Australian phase 3 
trial. Eur Urol. 2013; 63(2): 283-95 
20. Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a 
randomized phase III trial of mirabegron in patients with overactive bladder. J 
Urol. 2013; 189(4): 1388-95 
21. Kuo HC, Lee KS, Na Y, Sood R, Nakaji S, Kubota Y, et al. Results of a 
Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, 
Multicenter Study of Mirabegron, a β3-adrenoceptor Agonist, in Patients With 
Overactive Bladder in Asia. Neurourol Urodyn 2014. 
http://dx.doi.org/10.1002/nau.22645.  
22. Ichihara K, Masumori N, Fukuta F, Tsukamoto T, Iwasawa A, Tanaka Y. A 
randomized controlled study of the efficacy of tamsulosin monotherapy and its 
combination with mirabegron for overactive bladder induced by benign prostatic 
obstruction. J Urol 2015; 193: 921-6. 


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23. Wada N, Iuchi H, Kita M, Hashizume K, Matsumoto S, Kakizaki H. Urodynamic 
efficacy and safety of mirabegron add-on treatment with tamsulosin for Japanese 
male patients with overactive bladder. LUTS 2015 Wiley Publishing Asia Pty Ltd. 
24. Van Gelderen M, Tretter R, Meijer J, Dorrepaal C, Gangaram-Panday S, Brooks 
A, et al. Absence of clinically relevant cardiovascular interaction upon add-on of 
mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in 
healthy middle-aged to elderly men. Int’l J Clin Pharm Ther 2014 DOI 
10.5414/CP201979. 


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12 
APPENDICES 
12.1 
List of Excluded Concomitant Medications 
 
Therapeutic agents for urinary incontinence/pollakiuria: 
Anticholinergics 
Oxybutynin  
Flavoxate 
Fesoterodine  
Propiverine  
Imidafenacin 
Solifenacin 
Tolterodine 
etc. 
β2-agonist 
Clenbuterol 
etc. 
 
β3-agonist 
Mirabegron 
etc. 
 
PDE5 inhibitor 
 
Agents that have anticholinergic effects: 
Antidepressants 
Imipramine 
Amitriptyline 
etc. 
 
Antihistamines 
Diphenylpyraline 
Cyproheptadine 
etc. 
 
Anti-vertigenous drugs 
Difenidol  
etc. 
 
 
Antiparkinsonian drugs 
Piroheptine 
Mazaticol 
etc. 
 
Parasympathetic inhibitors/parasympatholytic drugs 
(including narcotic drugs) 
Tiquizium  
Piperidolate  
etc. 
 
Gastrointestinal drugs 
Mepenzolate  
Pipethanate 
etc. 
Other drugs: 
Sympathomimetic drugs 
Amezinium  
etc. 
 
α-agonists 
Methoxamine 
Midodrine 
etc. 
 
α- and β-agonists 
Etilefrine 
Methylephedrine 
etc. 
 
β-agonists 
Isoproterenol  
Methoxyphenamine 
etc. 
 
α-blockers 
Doxazosin 
Bunazosin 
etc. 
 
α- and β-blockers 
Amosulalol 
Labetalol 
etc. 
 
β-blockers 
Penbutolol 
Bopindolol 
etc. 
 
Cholinesterase inhibitors 
Donepezil 
Ambenonium 
etc. 


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Other drugs (cont’d): 
Cholinergics 
Acetylcholine 
Bethanechol 
etc. 
 
Therapeutic agents for prostatic hypertrophy 
Allylestrenol 
Oxendolone 
Tadalafil 
etc. 
 
Chinese herbal medicines for urinary storage 
and voiding dysfunction 
 
Therapeutic agents for diabetes insipidus 
Desmopressin  
Vasopressin 
etc. 
 
MAO inhibitors 
Selegiline 
etc. 
 
5α-reductase inhibitors 
Dutasteride 
Finasteride 
etc. 
 
Class Ia antiarrhythmics 
Procainamide 
Disopyramide 
etc. 
 
Class III antiarrhythmics 
Amiodarone 
Sotalol 
etc. 
 
SGLT(sodium-glucose transporter) 2 inhibitor 
Ipragliflozin 
Dapagliflozin 
etc. 
 
OTC drugs for urinary storage and voiding 
dysfunction 
 
Loop diuretics 
Furosemide  
Bumetanide 
etc. 
 
Narcotics 
Opium 
Opium ipecac 
etc. 
 
 
 
CYP2D6 substrates 
Flecainide 
Propafenone 
etc. 
 
Phenothiazine antipsychotics 
Perphenazine 
Chlorpromazine 
etc. 
 
Strong CYP3A4 inhibitors 
Clarithromycin  
Erythromycin 
Atazanavir 
Indinavir  
etc. 
 
Other drugs 
Cyclosporine 
Tacrolimus 
Pimozide  
Digoxin 
 
The above excluded concomitant meditations however, can be allowed to use under the 
conditions below: 
1. From the day following dispensing of the study drug for the Screening period to the 
end of the Treatment period, none of the prohibited concomitant medications listed in 
Appendix 12.1 should be concomitantly used.  However, the following drugs may be 
concomitantly used: 
 Eye drops 
 Transdermal formulations, excluding β-agonists and drugs for the treatment of 


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urinary storage and voiding dysfunction 
 Nasal drops, excluding drugs for diabetes insipidus 
 Topical agents 
 Inhaled β-agonists used to relieve acute symptoms such as bronchial asthma 
 Chinese herbal medicines used for the treatment of conditions other than urinary 
storage and voiding dysfunction 
2. The following drugs may be used concomitantly for a short period of time (up to a 
total of 5 days during the interval from the day following a visit to the next visit), 
except during the micturition diary period: 
 Parasympathetic inhibitors/parasympatholytic drugs for peptic ulcer, etc. 
 Antihistamines, ephedrine hydrochloride, and methylephedrine hydrochloride for 
common cold, etc. 
3. Transient concomitant use of parasympathetic inhibitors/parasympatholytic drugs 
will be allowed, if used in preparation for an examination, except during the 
micturition diary period. 
4. Concomitant treatment with 5α-reductase inhibitors will be allowed (the dosage shall 
not be changed for study period), if the subject has been on treatment for a year or 
more. 
5. Transient concomitant use of PDE5 inhibitor for ED treatment will be allowed except 
during the micturition diary period. 
6. Nonpharmacological therapy for OAB, such as biofeedback therapy, bladder training, 
or pelvic floor muscle exercise will be prohibited from 4 weeks (<28 days) before the 
start of the screening period to the end of the treatment period. 
 
 


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12.2 
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical 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 ALT, AST, ALP, and total bilirubin).  
Testing should be repeated within 48 to 72 hours of notification of the test results.  For 
studies for which a central laboratory is used, alerts will be generated by the central lab 
regarding moderate and severe liver abnormality to inform the Investigator, study monitor, 
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 according to the 
following criteria: 
 
 
ALT or AST 
 
Total Bilirubin 
Moderate 
 
> 3× ULN  
or 
> 2× ULN 
 
 
 
 
 
Severe* 
 
> 3× ULN 
and
> 2× ULN 
In addition, the subject should be considered to have severe hepatic abnormalities with 
any of the following criteria: 
● 
ALT or AST >8× ULN 
● 
ALT or AST >5× ULN for more than 2 weeks   
● 
ALT or AST >3× ULN and INR >1.5 (If International Normalized Ratio [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%).  
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 laboratory tests.  The site should complete the Liver 
Abnormality Case Report Form (LA-CRF) that has been developed globally and can be 
activated for any study. Subjects with confirmed abnormal liver function testing should be 
followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly, then 
weekly or less if abnormalities stabilize, or the study drug 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 an SAE.  
The Sponsor should be contacted and informed of all subjects for whom severe hepatic 
liver function abnormalities possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 


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● 
Obtain a more detailed history of symptoms and prior or concurrent diseases.  
Symptoms and new onset-diseases should be recorded as ‘adverse events’ on the AE 
page of the eCRF.  Illnesses and conditions such as hypotensive events, and 
decompensated cardiac disease that may lead to secondary liver abnormalities should 
be noted.  Non-alcoholic steatohepatitis (NASH) is seen in obese 
hyperlipoproteinemic, and/or diabetic patients and may be associated with fluctuating 
aminotransferase levels.  The investigator should ensure that the medical history form 
captures any illness that pre-dates study enrollment that may be relevant in assessing 
hepatic function.  
● 
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets.  Medications, including dose, should be entered on the concomitant 
medication page of 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 laboratory tests including INR, 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 Discontinuation 
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing 
or acute liver disease or exposure to other agents associated with liver injury, the subject 
may be discontinued from the study.  The investigator may determine that it is not in the 
subject’s best interest to continue study enrollment.  Discontinuation of 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 >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).  
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory 
tests is not possible, drug 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 two “requirements” for Hy’s Law are: 1) Evidence that a 
drug can cause hepatocellular-type injury, generally shown by transaminase elevations 
greater than 3 times the upper limit of normal (“2 x ULN elevations are too common in 
treated and untreated patients to be discriminating”); 2) Cases of increased bilirubin (at 
least 2 x ULN) with concurrent transaminase elevations at least 3x ULN and no evidence 
of intra- or extra-hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s 


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
Page 89 of 94 
syndrome. [Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol 
Drug Saf 2006 15(4):241-3.] 
Reference 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation” issued by FDA on July 2009.   
 


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
Page 90 of 94 
12.3 
Events Always Considered to be Serious 
If any of the following AEs occurs during the study, they will be considered SAEs and are 
to be reported as described in Section 5.5.5 Reporting of Serious Adverse Events: 
● 
Acute liver failure 
● 
Renal failure acute 
● 
Acute respiratory failure 
● 
Agranulocytosis 
● 
Anaphylaxis 
● 
Any malignancy 
● 
Aplastic anemia 
● 
Confirmed or suspected transmission of an infectious agent via product 
● 
Congenital anomalies 
● 
Hepatic necrosis 
● 
Malignant hypertension 
● 
Pulmonary hypertension 
● 
Convulsion 
● 
Torsades de pointes 
● 
Toxic epidermal necrolysis 
● 
Ventricular fibrillation 
● 
Hemolytic anemia 
● 
Bone marrow failure 
● 
Myocardial infarction 
● 
Cardiac arrest 
● 
Deafness 
● 
Blindness 
● 
Pancreatitis acute 
● 
Acute graft versus host disease 
● 
Septic shock 
● 
Sepsis 
● 
Rhabdomyolysis 
● 
Respiratory failure 
● 
Stevens-Johnson syndrome 


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
Page 91 of 94 
12.4 
 OABSS, OAB-q, IPSS and IPSS (QoL) 
Overactive Bladder Symptom Score (OABSS): 
 
Overactive Bladder Questionnaire (OAB-q): 


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
Page 92 of 94 


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
Page 93 of 94 
 
 


Sponsor: API  
 
ISN/Protocol 178-MA-3016 
CONFIDENTIAL 
 
 
10 May 2016 
Astellas 
Page 94 of 94 
International Prostate Symptom Score (IPSS): 
In the past 
month: 
Not at 
All 
Less 
than 
1 in 5 
Times 
Less 
than 
Half the
Time 
About 
Half 
the 
Time 
More 
than 
Half 
the 
Time 
Almost
Always 
1. Incomplete Emptying 
How often have you had the 
sensation of not emptying your 
bladder? 
0 
1 
2 
3 
4 
5 
2. Frequency 
How often have you had to 
urinate less than every two 
hours? 
0 
1 
2 
3 
4 
5 
3. Intermittency 
How often have you found you 
stopped and started again several 
times when you 
urinated? 
0 
1 
2 
3 
4 
5 
4. Urgency 
How often have you found it 
difficult to postpone urination? 
0 
1 
2 
3 
4 
5 
5. Weak Stream 
How often have you had a weak 
urinary stream? 
0 
1 
2 
3 
4 
5 
6. Straining 
How often have you had to strain 
to start urination? 
0 
1 
2 
3 
4 
5 
 
None 
1 Time
2 Times
3 Times
4 Times 
≥5 
Times 
7. Nocturia 
How many times did you 
typically get up at night to 
urinate? 
0 
1 
2 
3 
4 
5 
 
Quality of Life Due to 
Urinary Symptoms 
Delighted 
Pleased 
Mostly 
satisfied 
Mixed 
Mostly 
dissatisfied 
Unhappy 
Terrible 
If you were to spend the rest of 
your life with your urinary 
condition just the way it is now, 
how would you feel about that? 
0 
1 
2 
3 
4 
5 
6 
 
 
 
(GPF 4.1) 


ISN 178-MA-3016                                                       ：10/May/2016 
178-MA-3016 
 1 / 2 
 
 
Ver. 3.0 
Ver. 4.0 
Reason for amendment 
1 
SIGNATURES 
1.SPONSOR’S SIGNATURE 
ISN/Protocol 178-MA-3016, Version 3.0 
Printed Name:  
 
ISN/Protocol 178-MA-3016, Version 4.0 
Printed Name:  
 
Change of organization 
2 
CONTACT DETAILS OF 
KEY SPONSOR’S 
PERSONNEL 
Corporate Name: Astellas Pharma Singapore Pte. Ltd. 
Location: 6 Temasek Boulevard #22-04/05 Suntec Tower 
Four, Singapore 
Phone No.: 
  
Fax: 
 
Sponsor’s personnel: 
 
Contact numbers during non-business hours and for 
emergency:  
Sponsor Personnel (Phone No)
 
                         
 
 
Corporate Name: Astellas Pharma Singapore Pte. Ltd. 
Location: 6 Temasek Boulevard #22-03/05 Suntec Tower 
Four, Singapore 
Phone No.: 
  
Fax: 
 
Sponsor’s personnel: 
 
Contact numbers during non-business hours and for 
emergency:  
Sponsor Personnel (Phone No);
 
 
Change of organization 
3 
SYNOPSIS 
Inclusion:  
 
Highly effective forms of birth control include: 
 
Consistent and correct... 
 
Established intrauterine device (IUD)... 
 
Barrier methods of contraception: condom... 
 
Calendar-based contraceptive methods (Knaus-Ogino 
or rhythm method). (Unique to Japan) 
Highly effective forms of birth control include: 
 
Consistent and correct... 
 
Established intrauterine device (IUD)... 
 
Barrier methods of contraception: condom... 
 
Calendar-based contraceptive methods 
(Knaus-Ogino or rhythm method). 
Confirmed it is also 
acceptable in Korea 
4 
SYNOPSIS 
Exclusion: 
22．Patient with aspartate transaminase (AST) or alanine 
transaminase (ALT) >2 times the upper limit of normal 
(ULN), or gamma-glutamyl transferase (γ-GT) >3 times 
the ULN and considered clinically significant by the 
Investigator. 
 
22．Patient with aspartate transaminase (AST) or alanine 
transaminase (ALT) >2 times the upper limit of normal 
(ULN), or gamma-glutamyl transferase (γ-GT) >3 times 
the ULN. 
 
Correction of intention er
roneous  
5 
3.2 
Inclusion Criteria 
*Highly effective forms of birth control include: 
 
Consistent and correct... 
 
Established intrauterine device (IUD)... 
 
Barrier methods of contraception: condom... 
 
Calendar-based contraceptive methods (Knaus-Ogino 
or rhythm method). (Unique to Japan) 
*Highly effective forms of birth control include: 
 
Consistent and correct... 
 
Established intrauterine device (IUD)... 
 
Barrier methods of contraception: condom... 
 
Calendar-based contraceptive methods 
(Knaus-Ogino or rhythm method). 
Confirmed it is also 
acceptable in Korea  


ISN 178-MA-3016                                                       ：10/May/2016 
178-MA-3016 
 2 / 2 
 
 
Ver. 3.0 
Ver. 4.0 
Reason for amendment 
6 
3.3 
Exclusion Criteria 
22．Patient with aspartate transaminase (AST) or alanine 
transaminase (ALT) >2 times the upper limit of normal 
(ULN), or gamma-glutamyl transferase (γ-GT) >3 times 
the ULN and considered clinically significant by the 
Investigator. 
 
22．Patient with aspartate transaminase (AST) or alanine 
transaminase (ALT) >2 times the upper limit of normal 
(ULN), or gamma-glutamyl transferase (γ-GT) >3 times 
the ULN. 
 
Correction of intention er
roneous 
7 
5.3.1 
Micturition Diary 
The micturition diary will be used to record the date and 
time of each micturition, incontinence episodes, urgency 
episodes, and voiding volume.  Voiding volume will be 
recorded at Visits 1, 2, and 5 only.  The diary will also be 
used to record daily medication intake.... 
The micturition diary will be used to record the date and 
time of each micturition, incontinence episodes, urgency 
episodes, and voiding volume.  Voiding volume will be 
recorded at Visits 2, and 5 only.  The diary will also be 
used to record daily medication intake.... 
Correction of description
 erroneous 
 
5.5.4 
Criteria for Defining 
the Severity of an Adverse 
Event 
The severity will also be determined by reference to the 
grading specified in the “Standards for Classification of 
Serious Adverse Drug Reactions,” PAB/SD Notification 
No. 80, dated 29 Jun 1992 (Appendix 12.4. Classification 
of Seriousness of Adverse Drug Reaction). (Unique to 
Japan) 
 
The severity will also be determined by reference to the 
grading specified in the “Standards for Classification of 
Serious Adverse Drug Reactions,” PAB/SD Notification 
No. 80, dated 29 Jun 1992 (Appendix 12.5. Classification 
of Seriousness of Adverse Drug Reaction). (Unique to 
Japan) 
 
Correction of description
 erroneous 
8 
5.5.9 
Supply of New 
Information Affecting the 
Conduct of the Study 
1. When information is obtained regarding serious and 
unexpected adverse drug reactions (or other) that are 
specified in Article 273 of the Enforcement 
Regulations of the Pharmaceutical Affairs Law, in 
compliance with Article 80-2 Paragraph 6 of the 
Pharmaceutical Affairs Law, the Sponsor should 
inform all the investigators involved in the clinical 
study, the Head of the study site,.... 
1. When information is obtained regarding serious and 
unexpected adverse drug reactions (or other) that are 
specified in Article 273 of the Enforcement 
Regulations of the Act on Securing Quality, 
Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and 
Cosmetics, in compliance with Article 68-10 
Paragraph 1 of the Pharmaceutical Affairs Law, the 
Sponsor should inform all the investigators involved 
in the clinical study, the Head of the study site,... 
Correction of description
 erroneous 
9 
7.2 
Analysis Set 
The analysis will be performed using the following 
analysis populations, based on ICH guidelines E3 and E9.  
The final handling of the analysis sets will be decided at 
the Blind Data Review Meeting, with the decisions based 
on the opinions and advice of medical experts prior to 
breaking of the randomization code. 
The analysis will be performed using the following 
analysis populations, based on ICH guidelines E3 and E9.  
The final handling of the analysis sets will be decided 
with the decisions based on the opinions and advice of 
medical experts prior to breaking of the randomization 
code. 
Correction of description
 erroneous 
 






Astellas Pharma Inc. 
ISN/Protocol＜178-MA-3016＞ 
－CONFIDENTIAL－ 
 
Protocol Ver. 4.00 Addendum_26 May 2016 
 
26 May 2016 
Astellas 
 
INVESTIGATOR’S SIGNATURE 
A Phase 4, Double-Blind, Randomized, Placebo-controlled Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Male Subjects with 
OAB Symptoms while taking the Alpha Blocker Tamsulosin for BPH 
ISN/Protocol 178-MA-3016, Version 4.0 Addendum 
I have read all pages of this clinical study 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 ICH GCP guidelines and applicable local regulations. I will also 
ensure that sub-investigator(s) and other relevant members of my staff 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: 
 
<Insert name and qualifications of the Investigator> 
 
Printed Name: 
Date (DD Mmm YYYY) 
 
Address: 
 
 
 
 
 
 
 
 
 
 
  
 





















SAP_000.pdf: 
A Phase 4, Double-Blind, Randomized, Placebo-controlled 
Multicenter Study to Evaluate the Efficacy, Safety, 
and Tolerability of Mirabegron in Male Subjects with 
OAB Symptoms while taking the Alpha Blocker
Tamsulosin for BPH
ISN/Protocol 178-MA-3016
ClinicalTrials.gov Identifier: NCT02656173
Date of Statistical Analysis Plan: 14 Nov 2017
Sponsor: Astellas Pharma Inc.
2-5-1, Nihonbashi-Honcho, Chuo-ku, 
Tokyo 103-8411, Japan


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00, 14- Nov-2017
ISN/Protocol: 178-MA-3016
<14-Nov-2017>
Astellas
Page 1 of 38
STATISTICAL ANALYSIS PLAN
Final Version 1.00, dated 14-Nov 2017
A Phase 4, Double-Blind, Randomized, Placebo-controlled Multicenter Study 
to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Male Subjects 
with OAB Symptoms while taking the Alpha Blocker Tamsulosin for BPH
ISN: 178-MA-3016
Astellas Pharma Inc. (API)
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00, 14- Nov-2017
ISN/Protocol: 178-MA-3016
<14-Nov-2017>
Astellas
Page 2 of 38
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
FLOW CHART AND VISIT SCHEDULE···················································· 7
3
STUDY OBJECTIVE(S) AND DESIGN······················································11
3.1
Study Objective(s) ············································································11
3.1.1
Primary Objective ·······································································11
3.1.2
Secondary Objective ····································································11
3.1.3
Other Objectives·········································································11
3.2
Study Design···················································································11
3.3
Randomization·················································································12
4
SAMPLE SIZE ····················································································12
5
ANALYSIS SETS ·················································································12
5.1
Full Analysis Set (FAS) ······································································12
5.2
Per Protocol Set (PPS)········································································12
5.2.1
Reasons for Exclusion From PPS ·····················································13
5.3
Safety Analysis Set (SAF) ···································································13
6
ANALYSIS VARIABLES ·······································································13
6.1
Efficacy Endpoints············································································13
6.1.1
Primary Efficacy Endpoint·····························································13
6.1.2
Secondary Efficacy Endpoints·························································13
6.1.3
Exploratory Efficacy Endpoints ·······················································16
6.1.4
Other Efficacy Variables ·······························································17
6.2
Safety Variables···············································································17
6.3
Other Variables················································································17
7
STATISTICAL METHODOLOGY ···························································18
7.1
General Considerations·······································································18
7.2
Study Population ··············································································20
7.2.1
Disposition of Subjects ·································································20
7.2.2
Protocol Deviations ·····································································20
7.2.3
Demographic and Other Baseline Characteristics ···································21
7.2.4
Previous and Concomitant Medications ··············································21


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00, 14- Nov-2017
ISN/Protocol: 178-MA-3016
<14-Nov-2017>
Astellas
Page 3 of 38
7.3
Study Drugs····················································································22
7.3.1
Exposure··················································································22
7.3.2
Treatment Compliance··································································22
7.4
Analysis of Efficacy ··········································································22
7.4.1
Analysis of Primary Endpoint(s) ······················································22
7.4.2
Analysis of Secondary Endpoints ·····················································25
7.4.3
Analysis of Exploratory Endpoints····················································26
7.4.4
Subgroup Analysis of Efficacy Endpoints············································27
7.5
Analysis of Safety·············································································27
7.5.1
Adverse Events ··········································································27
7.5.2
Clinical Laboratory Evaluation ························································31
7.5.3
Vital Signs················································································32
7.5.4
Pregnancies···············································································32
7.5.5
Other Safety-Related Observations ···················································33
7.6
Analysis of PK·················································································33
7.7
Analysis of PD·················································································33
7.8
Subgroups of Interest ·········································································33
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················34
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········34
7.10.1
Missing Data ·············································································34
7.10.2
Outliers ···················································································34
7.10.3
Visit Windows ···········································································34
8
DOCUMENT REVISION HISTORY·························································36
9
REFERENCES ····················································································36
10
APPENDICES ·····················································································37
10.1
Appendix 1: Key Contributors and Approvers ············································37


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00, 14- Nov-2017
ISN/Protocol: 178-MA-3016
<14-Nov-2017>
Astellas
Page 4 of 38
I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (GPT)
ANCOVA
Analysis of Covariance
AST
Aspartate aminotransferase (GOT)
BP
Blood pressure
BPH
Benign prostatic hypertrophy
BUN
Blood urea nitrogen
CK
Creatinine kinase
CSR
Clinical Study Report
ECG
Electrocardiogram
FAS
Full Analysis Set
HUS
hours of undisturbed sleep
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IPSS
International Prostate Symptom Score
IRT
Interactive Response Technology
ISN
International study number
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measure
OAB
Overactive Bladder
OAB-q
Overactive Bladder questionnaire
OABSS
Overactive Bladder Symptom Score
PD
Protocol deviation
PK
Pharmacokinetic(s)
PPS
Per Protocol Set
PR
Pulse rate
PSA
Prostate-specific antigen
PVR
Post-void residual (volume)
Q1
1st Quartile, 25th Percentile
Q3
3rd Quartile, 75th Percentile
Qave
Average flow rate
Qmax
Maximum urine flow rate
QoL
Quality of Life
QTcF interval
QT interval, corrected for heart rate according to Fridericia's formula
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Standard deviation
TEAE
Treatment-emergent adverse event
TLF
Tables, Listings and Figures
Total HRQL score
Total Health-Related Quality of Life score
UFM
Uroflowmetry


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00, 14- Nov-2017
ISN/Protocol: 178-MA-3016
<14-Nov-2017>
Astellas
Page 5 of 38
Abbreviations
Description of abbreviations
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
List of Key Terms
Terms
Definition of terms
Adverse event
Any untoward medical occurrence in a subject administered a study 
drug, and which does not necessarily have a causal relationship to the 
study drug.
Baseline
Observed values/findings that are regarded as the observed starting 
point for comparison.  Visit 2 is the Baseline visit in this study.
Discontinuation
The act of an enrolled subject concluding study participation prior to 
completion of all protocol-required assessments.  Data from 
discontinued subjects are not necessarily excluded from the data 
analyses.
Endpoint
A variable that pertains to the trial objectives
Enroll
To register or enter into a clinical trial. NOTE: Once a subject has 
been enrolled, the clinical trial protocol applies to the subject. 
Investigational 
period
Period of time during which protocol objectives are observed, and 
when the test drug and comparative drug (sometimes without 
randomization) is given to subjects, and continues until the last 
assessment after completing administration of the test drug or 
comparative drug.
Randomization
The process of assigning study subjects to treatment or control 
groups, using an element of chance to determine treatment 
assignments, in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment 
in a trial.
Screen failure
A potential subject who did not meet one or more criteria required for 
participation in the trial.
Screening period
Period of time before the investigational period, from the time of 
informed consent at Visit 1 until just before the test drug or 
comparative drug is given to the subject at Visit 2. 
Study period
Period of time from the first site’s initiation date to the last site’s 
completion date.
Subject
An individual who participates in a clinical study, either as a recipient 
of the study drug or as a control.
Treatment period
For this study, from randomization at Visit 2 through Visit 5 (Week 
12/End of Treatment).
Variable
Any quantity that varies; any attribute, phenomenon, or event that can 
have different qualitative or quantitative values.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to unblinding.
This statistical analysis is coordinated by the responsible biostatistician of Astellas Pharma
Inc.. Any changes from the analyses planned in the SAP will be justified in the Clinical 
Study Report (CSR).


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2
FLOW CHART AND VISIT SCHEDULE
Figure 1
Study Design Flow Chart
Study Schematic Diagram
Treatment Period
(12 weeks)
Randomization
Single-blind
V3
V1
V2
V4
V5
Screening Period
(4 weeks)
Mirabegron 50 mg
plus Tamsulosin 0.2 mg
Double-blind
Placebo matched to Mirabegron 50 mg 
plus Tamsulosin 0.2 mg
4 
4 
4 
Placebo matched to 
Mirabegron 50 mg 
plus Tamsulosin 
0.2 mg


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Table 1: Schedule of Assessments
Screening/
Tamsulosin 
Screening
Treatment Period
Visit
1
2
3
4
5
Day
-28
1
29
57
85
Week
-4
0
4
8
12
Visit Windows
+/- 7d
-
+/- 7 d
+/- 7 d
+/- 7 d
Visit Windows (Study Days) a
-35 to -21
-
22 to 36
50 to 64
78 to 92
Informed Consent
X b
Inclusion/Exclusion Criteria
X
X
Medical History and OAB History
X
Demographics
X
Enter 4-week Tamsulosin Screening c
X
Enrollment
X
Randomization d
X
Physical Exam 
X
Weight and Height
X
Vital Signs (includes pulse and blood pressuree)
X
X
X
X
X
Serum PSA
X
Prostate volume
X
Serum chemistry f, hematology f, urinalysis
X
X d
X
12-Lead ECG (QTcF interval)
X
Ultrasonography or Bladder Scan (PVR)
X
X
X
X
X
Uroflowmetry g
X
X
X
Medication History and OAB Medication History
X
Concomitant Medications Assessment
X
X
X
X
X
Adverse Event Assessment
X
X
X
X
Dispense Study Drug 
X
X
X
X
Drug Accountability
X
X
X
X
X
Instruct Subject on 3-day Micturition Diary h
X
X
X
X
Subject Completes 3-day Micturition Diary 
X i
X i
X i
X i
OABSS
X
X
X
X
X
IPSS & IPSS (QoL)
X
X
X
X
X


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Screening/
Tamsulosin 
Screening
Treatment Period
Visit
1
2
3
4
5
Day
-28
1
29
57
85
Week
-4
0
4
8
12
Visit Windows
+/- 7d
-
+/- 7 d
+/- 7 d
+/- 7 d
Visit Windows (Study Days) a
-35 to -21
-
22 to 36
50 to 64
78 to 92
OAB-q
X
X
X
Review Micturition Diary j
X
X
X
X
Abbreviations: PSA=Prostate-specific antigen, ECG =electrocardiogram; IPSS = International Prostate Symptom Score; OAB = 
Overactive bladder; OAB-q = Overactive Bladder questionnaire; OABSS = Overactive Bladder Symptom Score; PVR = Post-void 
residual (volume); QoL = Quality of Life; UFM = uroflowmetry
a.
Visit windows/study days will be calculated based on Day 1 (Visit 2).
b.
If a drug for the treatment of BPH is to be changed to tamsulosin to enroll a subject in this clinical study, the change to tamsulosin 
should be done only after informed consent form signature and a new informed consent is to be obtained at Visit 1 (Screening).
c.
Subjects must take tamsulosin for at least 28 days before the Screening period.
d.
Randomization is to occur after confirming all eligibility criteria and after performing all other visit procedures at Visit 2.
e.
Measured during the patient diary period and at each visit (only at visit for discontinued subjects if there is no entry in the patient 
diary)
f.
Blood samples need not be under fasting conditions. 
g.
Any UFM results obtained within 28 days prior to the start of the Screening period may be used, with the subject’s consent, 
instead of the Visit 1 data.
h.
At the Tamsulosin Screening visit (Visit 1), all subjects will be provided a micturition diary that will be used to record the date and 
time of each of their micturitions, episodes of incontinence, urgency, and voiding volume. Voiding volumes will be collected at 
Visit 2 (Baseline) and Visit 5 (Week 12). Additionally, the diary will be used to record daily medication intake and self-


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measurement of blood pressure and pulse rate. Subjects will be instructed to begin completing the micturition diary 3 days prior to 
each in-office study visit, including Visit 2 (Baseline) and Visits 3 through 5 (Treatment Period), and to complete the diary for the
full 3 days.  
i.
For Visits 2, 3, 4, and 5, subjects should complete the micturition diary on the 3 days immediately prior to the study visit, but in 
any case, on consecutive days within 1 week prior to the study visit.
j.
Investigator, or designee, must review the micturition diary with the subject to ensure completion compliance and to discuss the 
data captured.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
The following objectives are investigated in male patients with overactive bladder (OAB) 
symptoms while taking the alpha blocker, tamsulosin, for benign prostatic hypertrophy 
(BPH). The hypothesis being tested is that mirabegron is superior to placebo in the 
treatment of OAB symptoms.
3.1.1
Primary Objective
To study the efficacy of mirabegron versus placebo in male patients with OAB symptoms 
while taking the alpha blocker, tamsulosin, for BPH.
3.1.2
Secondary Objective
To assess the safety and tolerability of mirabegron versus placebo in male patients with 
OAB symptoms while taking the alpha blocker, tamsulosin, for BPH.
3.1.3
Other Objectives
To assess patient-reported outcomes as measured by Symptom Bother, and Total Health-
Related Quality of Life scores as assessed by the Overactive Bladder questionnaire 
(OAB-q) and IPSS (QoL) of mirabegron versus placebo in male subjects with OAB 
symptoms who are taking the alpha blocker, tamsulosin, for BPH.
3.2
Study Design
This is a randomized, double-blind, placebo-controlled study of the efficacy, safety, and 
tolerability of treatment with mirabegron for OAB in male subjects at least 40 years of 
age who are taking tamsulosin for BPH.  Eligible subjects must have a history of (on 
average) at least 2 urgency episodes and 8 or more micturitions in a 24-hour period during 
the 3 days prior to the start of the Screening period.  
The study will consist of a 4-week single-blind Screening period followed by a 12-week 
double-blind Treatment period.  During the Screening period and beginning with Visit 1, 
all subjects will receive tamsulosin 0.2 mg along with mirabegron 50 mg matching 
placebo once daily after breakfast.  
At the conclusion of the 4-week tamsulosin Screening period, subjects will complete a 3-
day micturition diary just prior to Visit 2 (Baseline).  Subjects who meet entry criteria at 
the end of the tamsulosin Screening period will be randomized (at Visit 2) to receive 
either mirabegron 50 mg or matching placebo for 12 weeks of double-blind treatment, 
while continuing their treatment with tamsulosin 0.2 mg daily.
For randomization, key efficacy assessments, safety and tolerability assessments of 
mirabegron administered concomitantly with tamsulosin, refer to section 3.3, 6.1 and 6.2
respectively.
Individual subject participation in the study will be ~16 weeks, which includes the 4-week 
Screening period and the 12-week double-blind Treatment period.


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The study will be conducted in Japan (~50 centers) and Korea (~5 centers).  The target 
enrollment is 550 subjects, with 275 randomized to each treatment group.
3.3
Randomization
Subjects will be randomized 1:1 to receive mirabegron 50 mg or matching placebo once 
daily during the 12-week treatment period. The randomization will be stratified by site.
Randomization will be performed via Interactive Response Technology (IRT).  Prior to 
the initiation of the study treatment, the site staff will contact the IRT in order to 
determine the randomly assigned treatment for each subject.
4
SAMPLE SIZE
The sample size for this study was based on 248 subjects per treatment group (using the 
Full Analysis Set [FAS]) to provide 90% power to detect a 0.7 reduction in the mean 
number of micturitions/24 hours in the mirabegron group compared to the placebo group, 
at a two-sided alpha level of 0.05.  A standard deviation (SD) of 2.4 is assumed.  
Assumptions for the mean reduction and SD are based on data from previous studies.  If 
90% of the randomized subjects are evaluable for efficacy, 550 subjects should be 
randomized, with 275 subjects randomized to each treatment group.
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations 
in guidelines E3 and E9, the following analysis sets will be used for the analyses.
The final handling of the analysis sets will be decided with the decisions based on the 
opinions and advice of medical experts prior to breaking of the randomization code.
Demographics and other baseline characteristics will be summarized by treatment group 
for the Full Analysis Set, Per Protocol Set (PPS), and Safety Analysis Set (SAF).
The efficacy analysis will be conducted on the FAS, with the PPS as a supportive analysis.
All secondary efficacy analyses will be performed on the FAS.
The safety analysis will be performed on the SAF.
5.1
Full Analysis Set (FAS)
The FAS consists of all subjects who are randomized and receive at least 1 dose of 
double-blind study drug and have a Baseline micturition measurement and at least 1 post-
Baseline micturition measurement.
5.2
Per Protocol Set (PPS)
The PPS includes all subjects of the FAS who do not meet criteria for exclusion from PPS 
listed in section 5.2.1 of the SAP. 


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5.2.1
Reasons for Exclusion From PPS
Subjects in FAS who meet any of the following criteria will be excluded from PPS:
1. Those subjects who violated the inclusion criteria.
2. Those subjects who violated the exclusion criteria. 
3. Those subjects with drug compliance during the Screening period and Treatment 
period of less than 80%.
4. Those subjects who took the study drug for less than 42 days from the day 
following dispensing during the Treatment period.  However, subjects who 
discontinued the study for efficacy-related reasons, such as insufficient therapeutic 
effect, will be included in the PPS, even if the drug was taken for less than 42 
days.
5. Subjects without diary entries for at least 2 of the 3 consecutive days at Visit 2 and 
the last visit during the Treatment period.
6. Subjects who received any of the prohibited concomitant medications/therapies 
that may affect the evaluation of efficacy.
5.3
Safety Analysis Set (SAF)
The SAF consists of all subjects who received at least 1 dose of double-blind study 
medication.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint
The primary endpoint is the change from Baseline to End of Treatment in the mean 
number of micturitions in 24 hours, based on a 3-day micturition diary.
For each patient, the mean number of micturitions per 24 hours will be calculated by 
taking the sum of all marked episodes in the patient diary where the variable ‘Urinated’ is 
indicated, divided by the number of days on which episodes were marked in the column 
‘Urinated’.
A diary day will cover information from 6:00 AM to 5:59 AM the following morning, 
consequently both date and time of the episodes recorded need to be considered when 
assessing the number of days on which episodes were marked.
The mean number of micturitions/24 hours in the 3-day diary period before baseline 
(Visit 2) will be regarded as the baseline value.
6.1.2
Secondary Efficacy Endpoints
The secondary endpoints include the change from Baseline to post-baseline and End of 
Treatment in:
●
Mean number of micturitions/24 hours (except for End of Treatment visit)
Calculation is same as the primary endpoint.
●
Mean number of urgency episodes/24 hours


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Calculation is similar to ‘micturition’, but sum episodes in the diary where the 
variable ‘Urgency’ is indicated. The calculation of days is as per ‘micturition’. If 
there is no urgency episodes on all evaluable days in each visit, then the mean 
number of urgency episodes/24 hours is equal to zero. Only those subjects whose 
symptoms were confirmed at baseline (Visit 2) will be analysed, therefore if the 
mean number of urgency episodes per 24 hours is “0” at baseline, this subject is 
excluded from the analysis.
●
Mean number of urgency incontinence episodes/24 hours
Calculation is similar to ‘micturition’, but sum episodes in the diary where both the 
variables ‘Urgency’ and ‘Urinary incontinence’ are indicated. Only those subjects 
whose symptoms were confirmed at baseline (Visit 2) will be analysed.If there is no 
urgency incontinence episodes on all evaluable days in each visit, then the mean 
number of urgency incontinence episodes/24 hours is equal to zero. Therefore if the 
mean number of urgency incontinence episodes per 24 hours is “0” at baseline, this 
subject is excluded from the analysis.
●
Mean number of incontinence episodes/24 hours
Calculation is similar to ‘micturition’, but sum episodes in the diary where the 
variable ‘Urinary incontinence’ is indicated. Only those subjects whose symptoms 
were confirmed at baseline (Visit 2) will be analysed. If there is no incontinence 
episodes on all evaluable days in each visit, then the mean number of incontinence 
episodes/24 hours is equal to zero. Therefore if the mean number of incontinence 
episodes per 24 hours is “0” at baseline, this subject is excluded from the analysis.
●
Mean number of nocturia episodes
Calculation is similar to ‘micturition’, but sum episodes in the diary where the 
variable ‘Urinated’ is indicated during the night time excluding the same time 
recorded as the time of sleep onset, divided by the number of nights. If the interval 
between sleep onset time and wake up datetime is more than 24 hours, then the 
records during the interval will not be used as nocturia. 
Night time is the period between after sleep onset time and the wake-up time the 
following day (micturitions at the same time as the wake-up time will be excluded).
The diary must be completed for at least 2 consecutive days to allow assessment of 
night time frequency for at least 1 night.  Any data collected before the wake-up time 
on the first day of diary completion and after the sleep onset time on the third day 
cannot be included in the assessment of night time frequency.  Only those subjects 
whose symptoms were confirmed at baseline (Visit 2) will be analyzed.
If there is no nocturia episode on all evaluable night time in each visit, then the mean 
number of nocturia episodes/24 hours is equal to zero. Therefore if the mean number 
of nocturia episodes per 24 hours is “0” at baseline, this subject is excluded from the 
analysis.
●
Mean volume voided per micturition
Calculation is similar to ‘micturition’, but sum urinary volumes where the volume 
voided is > 0 and where ‘Urinary incontinence’ is not indicated, rather than count the 
episodes.  The denominator will be the number of micturitions where the volume 
voided is > 0 and where ‘urinary incontinence’ is not indicated. Only those subjects 
whose symptoms were confirmed at baseline (Visit 2) will be analysed.


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●
Total OABSS score 
For each patient, OABSS total score will be the sum total of the score of each item 
(Questions 1-4).
●
Subscale scores (daytime frequency, nighttime frequency, urgency and urgency 
incontinence) from OABSS score
For each patient, OABSS subscale scores will be the score of each item (Questions 1-
4).
●
Total IPSS score 
For each patient, total IPSS score will be the sum total of the score of each item 
(Questions 1-7).
●
Subscale scores (storage subscale, voiding subscale-1, voiding subscale-2 and quality 
of life item) and individual scores from IPSS score
For each patient, IPSS subscale scores will be calculated by following each formula.
Storage subscale is derived as sum of scores for questions 2, 4, and 7. Voiding 
subscale-1 is derived as sum of scores for questions 3, 5, and 6. Voiding subscale-2 is 
derived as sum of voiding subscale-1 and the score for question 1.
For each patient, Individual scores and IPSS QoL score will be the score of each item 
(Questions 1-7 and quality of life item).
●
Symptom Bother and Total Health-Related Quality of Life scores (Total HRQL 
scores), as assessed by OAB-q
For each patient, OAB-q score (Symptom Bother and Total HRQL score) will be 
calculated by following each formula.
Symptom Bother is derived as sum of scores for questions 1-8; lowest possible raw 
score: 8; highest possible raw score: 48; possible raw score range: 40.
Symptom Bother = (Actual raw score –  lowest possible raw score)
Possible raw score range
× 100
Higher Symptom Bother is indicative of greater symptom bother.
Total HRQL score is derived as sum of HRQL subscale scores (not individual items); 
lowest possible raw score: 25; highest possible raw score: 150; possible raw score 
range: 125.
Total HRQL score = (Highest possible raw score –  Actual raw score)
Possible raw score range
× 100
Higher total HRQL score is indicative of better HRQL.
For the subscale analyses, if < 50% of the scale items are missing, the scale should be 
retained with the mean scale score of the items present used to impute a score for the 
missing items. If >= 50% of the items are missing, no scale score should be 
calculated and the subscale score should be considered missing. If any subscale score
(refer to section 6.1.3 for detail) is missing, the HRQL Total score cannot be 
calculated.
Subjects should be instructed to complete the 3-day micturition diary on the 3 days 
leading up to the visit for Visit 2 (Day 1), Visit 3 (Day 29 ± 7 days), Visit 4 
(Day 57 ±7 days), and Visit 5 (Day 85 ±7 days).  If the subject is unable to fill out the 
diary on the 3 days prior to the visit, then the diary should be completed on any 3 days 
within the 7 days prior to the visit.


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Subjects will complete the OABSS and IPSS/IPSS (QoL) assessments at Visit 1 to Visit 
5.
Subjects will complete the OAB-q at Visit 1, Visit 2, and Visit 5.
6.1.3
Exploratory Efficacy Endpoints
The exploratory endpoints will include the change from Baseline to post baseline and End 
of Treatment in:
●
Hours of undisturbed sleep (HUS) 
For each patient, hours of undisturbed sleep (HUS) will be calculated by visit and 
night. Only those subjects whose symptoms were confirmed at baseline (Visit 2) will 
be analyzed, therefore if IPSS Q7 score is “0” at baseline, this subject is excluded 
from the analysis. 
HUS is calculated as time from sleep onset time to time of first micturition episode 
(the variable ‘Urinary incontinence’ or ‘Urgency’ is NOT indicated and after the time 
of sleep onset time) only if the diary completed for 3 consecutive days is available. 
On the other hand, for those subjects who have no micturition episode between after 
sleep onset time and wake up time, HUS is calculated as time from sleep onset time 
to wake up time.
If the interval between sleep onset time and wake up time is more than 24 hours, 
HUS will be calculated as follows:
HUS is calculated as time from sleep onset time to time of first micturition episode 
(the variable ‘Urinary incontinence’ or ‘Urgency’ is NOT indicated and after the time 
of sleep onset time) only if the diary completed for 3 consecutive days is available
and the time of first micturition episode is before AM.5:59 of the next day of sleep 
onset. On the other hand, for those subjects who have no micturition episode between 
after sleep onset time and AM.5:59 of the next day, HUS is null.
●
First nighttime voided volume
For each patient, urinary volume at the first nighttime (between after the time of sleep
onset and wake up time + 30 minutes) will be calculated. Only those subjects whose 
symptoms were confirmed at baseline (Visit 2) will be analysed.
If the interval between sleep onset time and wake up time is more than 24 hours, first 
nighttime voided volume will be calculated as follows:
For each patient, urinary volume at the first nighttime (after the time of sleep onset 
and before AM.5:59 of the next day) will be calculated. On the other hand, for those 
subjects who have no micturition episode between after sleep onset time and 
AM.5:59 of the next day, urinary volume at the first nighttime is null. Only those 
subjects whose symptoms were confirmed at baseline (Visit 2) will be analysed.
●
Subscale scores (coping, concern, sleep and social interaction) and individual scores
from OAB-q scores
For each patient, OAB-q subscales will be calculated similar to Total HRQL score. 
Coping is derived as sum of scores for questions 9, 11, 16, 21, 22, 26, 32, and 33. 
Concern is derived as sum of scores for questions 12, 13, 14, 19, 23, 25, and 29.
Sleep is derived as sum of scores for questions 10, 15, 17, 24, and 30. Social 
interaction is derived as sum of scores for questions 18, 20, 27, 28, and 31.


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●
Normalization rate of OABSS
For each patient, normalization according to OABSS score will be classified by 
following criteria.
Normal: OABSS total score <= 2 or the score of Questions 3 <= 1
Not-normal: OABSS total score >= 3 and the score of Questions 3 >= 2
●
Normalization rate of micturition diary (number of episodes of
micturition/urgency/urgency incontinence/incontinence/nocturia)
For each patient, normalization according to symptom derived from the patient diary
will be classified by following criteria.
For micturitions,
Normal: mean number of micturitions per 24 hours < 8
Not-normal: mean number of micturitions per 24 hours >= 8
For urgency episodes, incontinence episodes, urgency incontinence episodes and 
nocturia,
Normal: mean number of each symptom per 24 hours is equal to zero.
Not-normal: mean number of each symptom per 24 hours > 0
6.1.4
Other Efficacy Variables
Not available.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Incidence and severity of treatment emergent adverse events (TEAEs)
●
Laboratory parameters (serum chemistry, hematology and urinalysis)
●
Vital signs: sitting systolic and diastolic blood pressure and pulse rate (home based 
self-measurements and office measurements)
●
Post-void residual (PVR) urine volume
●
Maximum urine flow rate (Qmax)
TEAE is defined as an adverse event observed after starting administration of study drug. 
If the adverse event occurs on Day 1 and the onset check box is marked “Onset after first 
dose of study drug for the treatment period” or the onset check box is left blank, then the 
adverse event will be considered treatment emergent. If the adverse event occurs on Day 
1 and the onset check box is marked “Onset before first dose of study drug for the 
treatment period”, then the adverse event will not be considered treatment emergent. If a 
subject experiences an event both during the screening period and during the treatment
period, the event will be considered as TEAE only if it has worsened in severity (i.e. it is 
reported with a new start date). All adverse events collected that occur within 7 days after 
taking the last dose of study drug will also be counted as TEAE.
A drug-related TEAE is defined as any TEAE with at least a possible relationship as 
assessed by the investigator, with ‘not assessable’ or with missing assessment of the 
causal relationship to both or either one of Mirabegron/Placebo and Tamsulosin. 
6.3
Other Variables
The following variables will be derived for analysis:


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●
The duration of exposure in treatment period
For each subject, the Length of Time on study drug in treatment period will be 
calculated in days, using the following formula:
(‘Date of Last Study Drug Taken in Treatment period’# - ‘Date of First Study Drug 
Taken in Treatment period#) + 1
#: These dates can be taken from [Date of Study Drug Taken-page of the Case Report 
Form]
●
The duration of the primary diagnosis (unit: months)
Duration of the primary diagnosis (months) = 12 * (year of visit date of screening 
visit (Visit 1) – year of Diagnosis) + month of visit date of screening visit (Visit 1) –
month of Diagnosis.
If the month for diagnosis is missing, then the month will be imputed by January. As 
a result, if the duration of primary diagnosis is less than 1 month, then it will be 
assumed to be 1 month.
If the month and year for diagnosis is missing, then duration of the primary diagnosis 
is missing.
●
Percent overall compliance of the study drug (Mirabegron/Placebo) and Tamsulosin 
during treatment period
Overall compliance to the dosing schedule will be examined for subjects whose total 
tablet count of the study drug (Mirabegron/Placebo) and Tamsulosin is known. 
Number of tablets which should have been taken depends on the duration of exposure 
because they should be taken as 1 tablet once daily after breakfast. The following 
formula can be used for both study drug (Mirabegron/Placebo) and Tamsulosin:
[Total number of tablets consumed during treatment period]
------------------------------------------------------------------------- x 100
         [The duration of exposure in treatment period]
Where, total number of tablets consumed will be calculated as:
(total number of tablets dispensed) – (total number of tablets returned) – (total number of 
tablets lost).
●
Previous and concomitant medication
Previous medication is defined as medication with at least one dose taken before the date 
of the first dose of study drug in treatment period. 
Concomitant medication is defined as medication with at least one dose taken between the 
date of first dose (inclusive) and the date of last dose (inclusive) of study drug in 
treatment period.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
Assessment at Visit 2 (Day 1) will be treated as baseline for efficacy and safety analysis.


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The End of Treatment assessment is defined as the last post-Baseline assessment during 
the double-blind study period for which the primary efficacy data are available.
For continuous variables, descriptive statistics will include the number of subjects (n), 
mean, standard deviation, minimum, Q1 (25th percentile), median, Q3 (75th percentile) 
and maximum. Frequencies and percentages will be displayed for categorical data. 
Percentages by categories will be based on the number of subjects with no missing data, 
i.e. will add up to 100%.
Summaries based on FAS and PPS (e.g. disposition, baseline and efficacy data) will be 
presented by planned treatment group, unless specifically stated otherwise. Safety 
analysis and other summaries based on SAF will be presented by actual treatment 
received. 
All statistical comparisons will be made using two sided tests at the α=0.05 significance 
level unless specifically stated otherwise.  All null hypotheses will be of no treatment 
difference, all alternative hypotheses will be two-sided, unless specifically stated 
otherwise.
All data processing, summarization, and analyses will be performed using Windows 
SAS® Version 9.4. Specifications for table, figures, and data listing formats can be found 
in the Tables, Listings and Figures (TLF) specifications for this study.
For the definition of subgroups of interest please refer to section 7.8.
Total and subscale score of OABSS, IPSS and OAB-q are as follows:
Name of score
Subscale score
Calculation
Range
IPSS
(Question 1-7 and 
Quality Life Item)
Storage Subscale
Sum of Question 2,4 and 7
0-15
Voiding Subscale-1
Sum of Question 3, 5 and 6
0-15
Voiding Subscale-2
Sum of Question 1, 3, 5 and 6
0-20
Quality of Life Item
-
0-6
Total Index Score
Sum of Question 1 to 7
0-35
OABSS
(Question 1-4)
Daytime frequency
Question 1
0-2
Nighttime frequency
Question 2
0-3
Urgency
Question 3
0-5
Urgency incontinence
Question 4
0-5
Total Score
Sum of Question 1 to 4
0-15
OAB-q
(Question 1-33)
Symptom bother
Sum of Q1-8
0-100
Coping
Sum of Q9,11,16,21,22,26,32,33
0-100
Concern
Sum of Q12,13,14,19,23,25,29
0-100
Sleep
Sum of Q10,15,17,24,30
0-100
Social Interaction
Sum of Q18,20,27,28,31
0-100
Total Health-Related Quality of Life scores
Sum of OAB-q subscale scores 
(Coping, Concern, Sleep, Social 
Interaction)t
0-100
The coding dictionary ‘World Health Organization Drug Dictionary (WHO-DD)
Enhanced (December 1, 2015)’ and ATC classification will be used for previous and 
concomitant medication. And the coding dictionary ‘MedDRA (ver.18.1)’ will be used 
for name of disease (Adverse Event, medical history etc.).


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7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
●
Number of subjects with informed consent, discontinued before randomization and
randomized (overall only);
●
Number and percentage of subjects discontinued before screening period by primary 
reason (overall only);
●
Number and percentage of subjects discontinued in screening period by primary 
reason (overall only);
Screenig failure is all subjects who signed informed consent but discontinued before 
randomization.
●
Number and percentage of subjects randomized in each analysis set, by treatment 
group and overall;
●
Number and percentage of subjects who completed or discontinued the study, by 
primary reason for study discontinuation for randomized subjects and by treatment 
group; and
●
Number and percentage of subjects excluded from PPS by reason for exclusion
defined in section 5.2.1, by treatment group for FAS.
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations
(Unique to Korea)) will be assessed for all randomized subjects. The number and 
percentage of subjects meeting any criteria will be summarized for each criterion and 
overall, by treatment group and total as well as by study site. Subjects deviating from a 
criterion more than once will be counted once for the corresponding criterion. Any 
subjects who have more than one protocol deviation will be counted once in the overall 
summary. A data listing will be provided by site and subject.   
The protocol deviation (PD) criteria will be uniquely identified in the summary table and 
listing. The unique identifiers will be as follows:
PD1 - Screening examination was performed before informed consent.
PD2 - Did not obtain updated informed consent from.
PD3 - No efficacy data after administration
PD4 - Violate the inclusion Criteria or exclusion criteria assessed at Visit 1 
(Screening)
PD5 - Violate the inclusion Criteria or exclusion criteria assessed at Visit 2 
(Baseline)
PD6 - Drug compliance during the Screening period and Treatment period of less 
than 80%
PD7- Duration of fixed dose period administration was less than 42 days
PD8 - Lack of diary entries at Visit 2 or the last visit during the Treatment period


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PD9 - Receive of the prohibited concomitant medications/therapies
PD10 - Antihistamines, ephedrine hydrochloride, and methylephedrine 
hydrochloride for common cold, etc.
PD11-Lack of diary entries during go out
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by descriptive 
statistics by treatment group for the SAF, FAS and PPS.
Number and percentage of subjects in each country will be presented by treatment group 
for the SAF, FAS and PPS.
Descriptive statistics for age, duration of the primary diagnosis, body weight, body mass 
index (BMI), height, prostate volume, PSA and QT interval, corrected for heart rate 
according to Fridericia's formula (QTcF interval), IPSS (total/, QOL,), OABSS-total, 
OAB-q (Symptom Bother, total), Qmax, Qave, PVR at visit 1 will be presented.  Also, 
IPSS (total/, QOL,), OABSS-total, OAB-q (Symptom Bother, total), Qmax, Qave, PVR, 
Micturition diary(Micturitions, Urgency, Urgency Incontinence, Incontinence, Volume 
voided per Micturitons, Nocturia) at visit 2 will be presented. Frequency tabulations for 
sex, race, ethnicity, age group (defined in section 7.8, medical condition of primary 
diagnosis, status of urinary incontinence, duration of the primary diagnosis group (defined 
in section 7.8 ). This will be done for the SAF, FAS and PPS by treatment group.
Additionally, to detect the difference of distribution between treatment groups, 2-sample 
t-test will be used for numerical data and Fisher’s exact test will be used for categorical 
data (Two-sided significance level of 0.05 will be used as a measure).
Complication is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT), by treatment group for the SAF, FAS and PPS. The 
definition of complication is  all medical history that is ongoing at Visit 1.
7.2.4
Previous and Concomitant Medications
Previous and concomitant medications are coded with WHO-DD, and will be summarized 
by therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and 
preferred WHO name by treatment group for the SAF, FAS and PPS. 
As with previous medication, concomitant medication will be summarized for each 
treatment group by therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC
4th level) and preferred WHO name for the SAF, FAS and PPS. Subjects taking the same 
medication multiple times will be counted once per medication. A medication which can 
be classified into several chemical and/or therapeutic subgroups is presented in all
chemical and therapeutic subgroups.
If the start day of concomitant medications/therapy is missing, then the day will be 
imputed by 1st of the months. As a result, if the start day of concomitant 
medications/therapy is earlier than the first administration date of the study drug for 
treatment period, then the onset date will be re-imputed by the same date as the first 
administration date of the study drug for treatment period. If the end day of concomitant 
medications/therapy is missing, then the day will be imputed by last of the months. As a 
result, if the end date of concomitant medications/therapy is earlier than the first 


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administration date of the study drug for treatment period, the end date will be re-imputed 
by the same date as the first administration date of the study drug for treatment period.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for each treatment group 
for the SAF, FAS and PPS:
Duration of exposure in treatment period will be summarized in two ways.
●
Descriptive statistics will be presented by treatment group.
●
Exposure time will be categorized according to the following categories by treatment 
group:
○
less than 14 days
○
at least 14 days, less than 28 days 
○
at least 28 days, less than 56 days 
○
at least 56 days, less than 84 days
○
84 days or more
○
Unknown.
Counts and percentages of subjects in each of these categories will be summarized for 
each treatment group for the SAF, FAS and PPS.
7.3.2
Treatment Compliance
Overall compliance of the study drug (Mirabegron/Placebo) and Tamsulosin with the 
dosing schedule will be examined for subjects whose total study drug and Tamsulosin
count and first and last days of treatment are known for the SAF, FAS and PPS.
Percent overall compliance of the study drug and Tamsulosin during treatment period will 
be summarized in two ways for the SAF, FAS and PPS:
●
Descriptive statistics will be presented by treatment group.
●
Percent compliance will be categorized according to the following categories by 
treatment group:
○
less than 50%
○
at least 50%, less or equal to 80%
○
greater than 80%
○
Unknown.
7.4
Analysis of Efficacy 
Continuous variables will be summarized using descriptive statistics, including mean, 
standard deviation, minimum, Q1, median, Q3 and maximum.  Categorical variables will 
be described using absolute and relative frequency.
7.4.1
Analysis of Primary Endpoint(s)
7.4.1.1 Primary Analysis of Primary Endpoint
The primary efficacy endpoint, change from Baseline to End of Treatment in the mean 
number of micturitions per 24 hours, will be analyzed using an Analysis of Covariance 


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(ANCOVA), including treatment group and region as fixed factors and baseline as a 
covariate for the FAS.  Within the framework of the ANCOVA model, point estimates 
and two-sided 95% confidence intervals (95% CI) for the mean change from Baseline 
both within and between treatment groups (point estimate will be calculated as 
[Mirabegron + Tamsulosin] minus [PLACEBO + Tamsulosin]) will be calculated.  The 
two-sided significance level will be set at 5%. 
The SAS code used to implement ANCOVA will be similar to that shown below:
PROC GLM;
CLASS treatment region;
MODEL chg = treatment region base / SS3;
LSMEANS treatment / ALPHA=0.05 CL PDIFF=CONTROL("PLACEBO + Tamsulosin");
RUN;
Here, variables in the MODEL statement are:
●
chg: Change from baseline to End of Treatment in the mean number of micturitions per 24 hours
●
treatment: Treatment group (PLACEBO + Tamsulosin/Mirabegron + Tamsulosin)
●
region: Region (Japan/Korea)
●
base: Baseline mean number of micturitions per 24 hours
The hypotheses for the treatment group comparisons are as follows:
H0: The change from Baseline to End of Treatment in the mean number of micturitions 
over 24 hours is the same in subjects who received mirabegron compared to those 
who received placebo.
H1: The change from Baseline to End of Treatment in the mean number of micturitions 
over 24 hours is not the same in subjects who received mirabegron compared to those 
who received placebo.
The End of Treatment assessment will be analyzed.
Separately, ANCOVA including the interaction between treatment and other covariates
will be investigated in order to present information of significance of interactions.
The SAS code used to implement ANCOVA including the interaction will be similar to 
that shown below:
PROC GLM;
CLASS treatment region;
MODEL chg = treatment region base treatment*region treatment*base / SS3;
RUN;
Here, variables in the MODEL statement are same as those for ANCOVA not including 
the interaction.
7.4.1.2 Sensitivity Analysis of Primary Endpoint  
An analysis of the primary endpoint will be conducted on the PPS. The method used for 
this analysis will be identical to the primary analysis described in section 7.4.1.1.


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7.4.1.3 Subgroup Analysis of Primary Endpoint  
The analyses described in section 7.4.1.1 will be conducted by subgroups defined in 
section 7.8. The SAS code used to implement ANCOVA by subgroups will be similar to 
that shown below:
PROC GLM;
BY grouping variables;
CLASS treatment region;
MODEL chg = treatment region base / SS3;
LSMEANS treatment / ALPHA=0.05 CL PDIFF=CONTROL("PLACEBO + Tamsulosin");
RUN;
7.4.1.4 Secondary Analysis of Primary Endpoint  
The primary efficacy endpoint will also be analyzed using a Mixed Model Repeated 
Measure (MMRM). MMRM analysis will be conducted for change from baseline in the 
mean number of micturition episodes per 24 hours to post-baseline visits using the 
baseline the mean number of micturition episodes per 24 hours as a covariates, analysis 
visits and region as a fixed effect, subject as random effect and including interaction of 
[treatment group x visit] for FAS and PPS. For MMRM, Restricted Maximum Likelihood
(REML) approach will be used, KENWARD-ROGER approximation will be used to 
estimate of degree of freedom of denominator, and ‘Unstructured” will be assumed as 
structure of variance-covariance matrix. Though, when the calculation will not be 
converged, other covariance structures will be selected in the following order; 
“Unstructured Correlations”, “Heterogeneous Toeplitz”, “Heterogeneous First-Order 
Autoregressive”, “Toeplitz”, “First-Order Autoregressive”, “Compound Symmetry”, and 
“Variance Components” instead. Within the framework of MMRM, point estimates and 
two-sided 95% CIs for the mean change from Baseline both within and between treatment 
groups (point estimate will be calculated as [Mirabegron + Tamsulosin] minus 
[PLACEBO + Tamsulosin]) will be calculated. 
The SAS code used to implement MMRM will be similar to that shown below:
PROC MIXED method=REML;
CLASS treatment region visit usubjid;
MODEL chg = treatment region base visit treatment*visit / ddfm=KENWARDROGER;
REPEATED visit / type=UN subject=usubjid r;
LSMEANS treatment*visit / CL PDIFF=CONTROL("PLACEBO + Tamsulosin");
RUN;
Here, variables in the MODEL statement are:
●
chg: Change from baseline to End of Treatment in the mean number of micturitions per 24 hours
●
treatment: Treatment group (PLACEBO + Tamsulosin/Mirabegron + Tamsulosin)
●
region: Region (Japan/Korea)
●
base: Baseline mean number of micturitions per 24 hours
●
visit: Post-baseline visit (Week 4. Week 8, Week 12)
●
usubjid: Subject Identifier


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7.4.2
Analysis of Secondary Endpoints 
The secondary endpoints are actual value and the change from Baseline to post-baseline 
and End of Treatment in: 
●
Mean number of micturitions/24 hours (except for End of Treatment visit)
●
Mean number of urgency episodes/24 hours
●
Mean number of urgency incontinence episodes/24 hours
●
Mean number of incontinence episodes/24 hours
●
Mean number of nocturia episodes
●
Mean volume voided per micturition
●
Total OABSS score 
●
Subscale scores (daytime frequency, nighttime frequency, urgency and urgency 
incontinence) from OABSS score
●
Total IPSS score 
●
Subscale scores (storage subscale, voiding subscale and quality of life item) and
individual scores from IPSS score
●
Symptom Bother and total Health-Related QoL scores, as assessed by the OAB-q 
questionnaire.
For the changes in mean number of incontinence and urge incontinence episodes, the 
analysis will be based on those subjects who have at least 1 incontinence episode at 
Baseline.
For the change in the mean number of nocturia episodes, the analysis will be based on 
those subjects who had at least 1 nocturia episode at Baseline.
Concerning actual value and the change from baseline to post-baseline of the secondary 
endpoints, descriptive statistics will be calculated by treatment group at each visit and at 
the End of Treatment for FAS and PPS.
Mean (+/- SD) plot for actual value and change from baseline to post-baseline will be 
presented by treatment group for FAS. In addition, for mean number of micturitions/24 
hours, this plot will be presented by subgroups defined in section 7.4.4 for FAS.
Radar charts of the mean of actual value for OABSS and IPSS will be made to present
relationship between each question by treatment group for FAS.
For individual score from OABSS score and IPSS score, frequency tabulations of scores
will be presented for each treatment group at each visit and at the End of Treatment for 
FAS and PPS.
Except for the changes in mean number of micturitions, incontinence and urge 
incontinence episodes, change from Baseline to End of Treatment of these endpoints will 
be analyzed using an ANCOVA (refer to section 7.4.1.1 for detail) for FAS and PPS.
The changes from Baseline to End of Treatment in mean number of incontinence and 
urge incontinence episodes will be analyzed using a Stratified Rank Analysis of 
Covariance (RANCOVA), including the rank score for change from Baseline to End of 
Treatment stratified by region as the dependent variable, treatment group and region as 
fixed factors and the rank score for baseline stratified by region as a covariate for FAS 


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and PPS. The rank score is defined as fractional ranks by dividing each rank by the 
number of data + 1 and mid-ranks will be assigned for ties. 
The SAS code used to implement RANCOVA will be similar to that shown below:
PROC RANK out=rank TIES = MEAN NPLUS1;
BY region;
VAR chg base;
RANKS cr br;
RUN;
PROC GLM data=rank;
CLASS region;
BY region;
MODEL cr = br / SS3;
OUTPUT out = out residual = residual;
RUN;
PROC FREQ data = out;
TABLE region*treatment*residual / CMH2;
     RUN;
Here, variables in the MODEL statement are:
●
chg: Change from baseline to End of Treatment in the mean number of micturitions per 24 hours
●
base: Baseline mean number of micturitions per 24 hours stratified 
●
treatment: Treatment group (PLACEBO + Tamsulosin/Mirabegron + Tamsulosin)
●
region: Region (Japan/Korea)
●
cr: The rank of change from baseline to End of Treatment in the mean number of micturitions per 24 
hours by region
●
br: The rank score of baseline mean number of micturitions per 24 hours stratified by region
7.4.3
Analysis of Exploratory Endpoints 
The exploratory endpoints include actual value and the change from Baseline to post-
baseline and End of Treatment in:
●
HUS
●
First nighttime voided volume
●
Subscale scores (coping, concern, sleep, social interaction) and individual scores
from OAB-q
Concerning actual value and the change from baseline to post-baseline of these endpoints, 
descriptive statistics will be calculated by treatment group at each visit and at the End of 
Treatment for FAS.
Mean (+/- SD) plot for actual value and change from baseline to post-baseline will be 
presented for FAS.
For HUS, similar analysis will be done only for those subjects who have at least one 
micturition episode between sleep onset time and wake up time at baseline (e.x., IPSS Q7 
> 0) or/and post-baseline. Descriptive statistics for HUS will be derived as the average of 
2 consecutive nighttime diary. For example, if subject has only one night time episode in 
the 2 consecutive nighttime diary, average of HUS (time from sleep onset time to time of 


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first micturition episode) and HUS (time from sleep onset time to wake up time) will be
calculated.
Kaplan-Meier curves will also be used to estimate the distribution of HUS for FAS. 
Median duration will be estimated using the corresponding 50th percentile of Kaplan-
Meier estimates. A two-sided 95% confidence interval will be provided for this estimate.
The 25th and 75th percentiles of Kaplan-Meier estimates, and the range of HUS
(minimum, maximum) will be presented as well. The range will be determined including 
censored observations.
Conventions of censoring of HUS will be defined as; those subjects who have no 
micturition episode between sleep onset time and wake up time will be censored at wake 
up time. Also, similar analysis will be done treating them as subjects who have an event 
at the wake up time.
Radar charts of the mean of actual value for OAB-q will be made to present relationship 
between subscale scores by treatment group for FAS.
For individual score from OAB-q, frequency tabulations of scores will be presented for 
each treatment group at each visit and at the End of Treatment for FAS.
In addition, exploratory endpoints also include several normalization rates. The 
percentage of subjects normalized will be calculated excluding the subjects who were 
normalized at Baseline. The definition of normalization is as follows:
●
OABSS: 1 point or less on Question 3, or a total score of ≤2 points
●
Micturition episodes: mean number per 24 hours of <8
●
Urgency episodes: mean number per 24 hours of zero
●
Urgency incontinence episodes: mean number per 24 hours of zero
●
Incontinence episodes: mean number per 24 hours of zero
●
Nocturia episodes: mean number per 24 hours of zero
The number and percentage of subjects who achieve normalization at the each visit and at 
the End of Treatment will be summarized along with 2 sided 95% CI (calculated by 
Clopper-Pearson method) for FAS.
7.4.4
Subgroup Analysis of Efficacy Endpoints
All efficacy endpoints (for continuous variables) will be summarized using descriptive 
statistics, including mean, standard deviation, minimum, Q1, median, Q3 and maximum 
for each treatment groups by subgroups defined in section 7.8.
7.5
Analysis of Safety
All analysis of safety will be presented by treatment group for SAF, unless specified 
otherwise. 
7.5.1
Adverse Events
Following definitions of AE will be used for analysis.
As for definition of TEAE and drug-related adverse events, refer to section 6.2.


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“Adverse event leading to permanent discontinuation of study drug” are events selected
“DRUG WITHDRAWN” checkbox as both or either one of “Action Taken for Study 
Drug (Mirabegron/Placebo)” and “Action Taken for Study Drug (Tamsulosin)”.
“Death” is event checked “Death” checkbox as detail of serious adverse event.
If the onset day TEAE is missing, then the day will be imputed by 1st of the months. As a 
result, if the onset date of TEAE is earlier than the first administration date of the study 
drug for treatment period, then the onset date will be re-imputed by the same date as the 
first administration date of the study drug for treatment period. If the end date TEAE is 
missing, then the date will be imputed by last day of the giving months. And if, the month 
TEAE is missing, then the date will be imputed by 31DEC. As a result, if the end date of 
TEAE is earlier than the first administration date of the study drug for treatment period, 
then the onset date will be re-imputed by the same date as the first administration date of 
the study drug for treatment period. The imputed onset day and end day will be used for 
summary of AE with time interval (section 7.5.1.4).
7.5.1.1 Adverse events
An overview table will include the following details:
●
Number of TEAEs,
●
Number and percentage with two-sided 95% CI of subjects with TEAEs,
●
Number of drug related TEAEs (Mirabegron/Placebo, Tamsulosin, Both),
●
Number and percentage with two-sided 95% CI of subjects with causally drug related 
TEAEs (Mirabegron/Placebo, Tamsulosin, Both),
●
Number of serious TEAEs,
●
Number and percentage with two-sided 95% CI of subjects with serious TEAEs,
●
Number of serious drug related TEAEs (Mirabegron/Placebo, Tamsulosin, Both),
●
Number and percentage with two-sided 95% CI of subjects with serious drug related 
TEAEs (Mirabegron/Placebo, Tamsulosin, Both),
●
Number of TEAEs leading to permanent discontinuation of study drug
(Mirabegron/Placebo, Tamsulosin, Both),
●
Number and percentage with two-sided 95% CI of subjects with TEAEs leading to 
permanent discontinuation of study drug (Mirabegron/Placebo, Tamsulosin, Both), 
●
Number of drug related TEAEs leading to permanent discontinuation of study drug*
(Mirabegron/Placebo, Tamsulosin, Both),
●
Number and percentage with two-sided 95% CI of subjects with drug related TEAEs 
leading to permanent discontinuation of study drug (Mirabegron/Placebo, Tamsulosin, 
Both),
●
Number of serious TEAEs leading to permanent discontinuation of study drug
(Mirabegron/Placebo, Tamsulosin, Both),
●
Number and percentage with two-sided 95% CI of subjects with serious TEAEs 
leading to permanent discontinuation of study drug (Mirabegron/Placebo, Tamsulosin, 
Both),
●
Number of serious drug related TEAEs leading to permanent discontinuation of study 
drug (Mirabegron/Placebo, Tamsulosin, Both),


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●
Number and percentage with two-sided 95% CI of subjects with serious drug related 
TEAEs leading to permanent discontinuation of study drug (Mirabegron/Placebo, 
Tamsulosin, Both) and
●
Number of deaths.
*: Categorization of drug related TEAEs leading to permanent discontinuation of 
study drug (Mirabegron/Placebo, Tamsulosin, Both) will be defined as events 
matching to the category for both relationship to study drug and action taken for 
study drug at the same time.
The treatment groups will be compared using Fisher’s Exact test, with a two-sided 95% 
exact unconditional CI (point estimate will be calculated as [Mirabegron + Tamsulosin] 
minus [PLACEBO + Tamsulosin]) and 5% significance level.
7.5.1.2 Adverse events by SOC and/or PT
The coding dictionary for this study will be MedDRA (ver.18.1), which will be used to 
summarize AEs by SOC and PT.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group. Summaries will be provided for:
●
TEAEs,
●
drug related TEAEs (Mirabegron/Placebo, Tamsulosin, Both), 
●
serious TEAEs, 
●
drug related serious TEAEs (Mirabegron/Placebo, Tamsulosin, Both), 
●
TEAEs leading to permanent discontinuation of study drug (Mirabegron/Placebo, 
Tamsulosin, Both), 
●
drug related TEAEs leading to permanent discontinuation of study drug
(Mirabegron/Placebo, Tamsulosin, Both), 
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 2.0% 
in any treatment group, and 
●
Common TEAEs that equal to or exceed a threshold of 2.0% in any treatment group. 
The treatment groups will be compared using Fisher’s Exact test, with a two-sided 95% 
exact unconditional CI and 5% significance level.
7.5.1.3
Severity of AE
The number of TEAEs and the number and percentage of subjects with TEAEs, as 
classified by SOC and PT will also be summarized by severity. In the subject count, if a 
subject has multiple TEAEs with the same SOC or PT, but with differing severity, then 
the subject will be counted only once with the worst severity, however, if any of the 
severity values are missing then the subject will be counted only once with missing 
severity.  In the adverse event count, the adverse events will be presented in each category 
they were classified to. Drug related TEAEs (Mirabegron/Placebo, Tamsulosin, Both)
will be presented in a similar way.
7.5.1.4 Relationship of AE
The number of TEAEs and the number and percentage of subjects with TEAEs, as 
classified by SOC and PT will also be summarized by relationship to study drug
(Mirabegron/Placebo, Tamsulosin). In the subject count, if a subject has multiple TEAEs 


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with the same SOC or PT, but with differing relationship, then the subject will be counted 
only once with the highest degree of relationship.  In the adverse event count, the adverse 
events will be presented in each category they were classified to.
7.5.1.5 Onset/Prevalence/First Onset of AE (Time Intervals)
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized in the following categories for each treatment group by time interval.
●
Onset of AE: For each adverse event in a particular interval, a subject will be counted 
if there is an onset of a treatment-emergent adverse event regardless of onset in other 
intervals.
●
Prevalence of AE: For each adverse event in a particular interval, a subject will be 
counted if the adverse event started, continued, or stopped during that interval.
●
First Onset of AE: For each adverse event only the earliest onset will be counted if 
there is more than one onset of that adverse event.
Time intervals will be categorized according to the following categories:
○
less than 14 days;
○
at least 14 days, less than 28 days;
○
at least 28 days, less than 56 days;
○
at least 56 days, less than 84 days; and
○
84 days or more.
7.5.1.6 Subgroup Analysis of AE
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group by subgroups defined in section 7.8.
7.5.1.7 AEs Reported During Screening Period by SOC and/or PT
The number and percentage of subjects with AEs reported during screening period, as 
classified by SOC and PT will be summarized for each treatment group. Summaries will 
be provided for:
●
AEs,
●
serious AEs.
7.5.1.8 Severity of AEs Reported During Screening Period
The number of TEAEs and the number and percentage of subjects with AEs reported 
during screening period, as classified by SOC and PT will also be summarized by severity.
The method used for this analysis will be identical to the analysis described in section 
7.5.1.3.
7.5.1.9 AEs of Special Interest
Following AEs of special interest are defined:
●
Cardiovascular events
●
Blood pressure
●
Urinary retention


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The number of TEAEs of special interest and the number and percentage of subjects with 
TEAEs of special interest, as classified by SOC and PT will be summarized for each 
treatment group.
7.5.2
Clinical Laboratory Evaluation
The baseline visit is the last measurement taken prior to initial study drug administration. 
Quantitative clinical laboratory variables, i.e. hematology, biochemistry, and urinalysis 
will be summarized using descriptive statistics for each treatment group at each visit and 
at the End of Treatment. Additionally, a within-subject change will be calculated as the 
post-baseline measurement minus the baseline measurement and summarized in the same 
way.
Each laboratory result will be classified as low (L), normal (N), or high (H) at each visit 
according to the laboratory supplied reference ranges. The number and percentage of 
subjects below and above reference range will be summarized for each treatment group at 
each visit and at the End of Treatment. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit and at the End of Treatment. 
For hematology and biochemistry, shift tables of reference range changes from baseline to 
Week 12 and End of Treatment will be presented for each treatment group. For urinalysis 
(qualitative), shift table will also be presented for each treatment group in the same way.
For coagulation, only listing will be presented for each treatment group.
The following data will be presented graphically by treatment group: 
●
Laboratory test results using box plot,
●
Change from baseline in laboratory test results using box plot,
●
Qualitative laboratory test results using bar chart,
●
Shift scatter plot of maximum laboratory test results on treatment versus baseline,
●
Laboratory test results using spaghetti plot.
All laboratory parameter’s unit for analysis will be used Japan original unit. If there 
would be some gap between Korean unit and Japan unit, transpose to Japan original unit 
to use analysis.
7.5.2.1 Liver Enzymes and Total Bilirubin 
The following potentially clinically significant criteria for liver tests – defined as Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate 
Transaminase (AST) and their combination are defined. The subject’s highest value 
during the investigational period will be used. 
Parameter
Criteria
ALT
> 3xUpper limit of normal (ULN)
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN


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> 20xULN
ALT or AST
> 3xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN
ALT and/or AST AND Total Bilirubin(*)
(ALT and/or AST > 3xULN) and 
total bilirubin > 2xULN
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in 
liver enzyme and total bilirubin tests during the investigational period will be presented 
by treatment group.
7.5.3
Vital Signs
The baseline visit is the last measurement taken prior to initial study drug administration.  
Vital signs were measured during each visit at the clinical site. In addition, patients were 
required to measure vital signs for 3 days prior to the visit at home, both in the morning 
and in the afternoon.
7.5.3.1 Vital signs (at the clinical site)
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) at the clinical 
site will be summarized using descriptive statistics by treatment group and at each visit
and at the End of Treatment. Additionally, a within-subject change will be calculated per 
visit as the post-baseline measurement minus the baseline measurement and summarized 
by treatment group and at each visit and at the End of Treatment. 
Following data will be presented graphically by treatment group: 
●
Vital sign results using mean (+/- 95% CI) plot,
●
Change from baseline in vital sign results using mean (+/- 95% CI) plot,
●
Shift scatter plot of maximum vital sign results on treatment versus baseline.
7.5.3.2 Vital signs (at home)
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) at home will 
be summarized using descriptive statistics by treatment group and at each visit and at the 
End of Treatment. Additionally, a within-subject change will be calculated per visit as the 
post-baseline measurement minus the baseline measurement and summarized by 
treatment group and at each visit and at the End of Treatment. 
Following data will be presented graphically by treatment group: 
●
Vital sign results using mean (+/- 95% CI) plot,
●
Change from baseline in vital sign results using mean (+/- 95% CI) plot,
●
Shift scatter plot of maximum vital sign results on treatment versus baseline.
The value for using table and figure are the average of  results for 3 days prior to the visit 
at home, both waking up and bedtime. And the value for using listing is the average of  
results for 3 days prior to the visit at home by waking up and bedtime.
7.5.4
Pregnancies
A detailed listing of all pregnancies will be provided.


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7.5.5
Other Safety-Related Observations
The other safety endpoints are as follows: 
●
Post-void residual urine volume
●
Qmax
●
Average flow rate (Qave)
Concerning actual value and the change from baseline to post-baseline of the secondary 
endpoints, descriptive statistics will be calculated by treatment group at each visit and at 
the End of Treatment.
7.6
Analysis of PK
Not applicable to this study. 
7.7
Analysis of PD
Not applicable to this study. 
7.8
Subgroups of Interest 
All efficacy endpoint and TEAEs will be summarized by the treatment group for the 
subgroups defined on the basis of the categorized variables listed below:
Grouping variable
Subgroups
Region*
Japan
Korea
Age1
< 65 years
>=65 years
Age2
< 65 years
>=65 - < 75 years
>=75 years
BMI
< 25 kg/m2
>= 25 kg/m2
Duration of the Primary Diagnosis**
<12months
>=12 months
Unknown
Urgency Incontinence at Baseline
0
> 0
PVR
<Median
>=Median
Qmax
<15 ml/sec
>=15 ml/sec
*: For subgroup analysis for primary efficacy endpoint, “region” will be excluded from 
ANCOVA model. 
**: If the month for diagnosis is missing and year of visit date of screening visit (Visit 1) 
– year of Diagnosis <= 1, then excluded from the subgroup analyses. 
“Unknown” will be used only for demographic analysis, not used for subgroup analysis.
For more details refer to section 7.4.1.3, 7.4.4 and 7.5.1.


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7.9
Interim Analysis (and Early Discontinuation of the Clinical 
Study)
No formal interim analysis is planned.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Refer to the data specification document in which more details are provided. 
7.10.1
Missing Data
The final handling of missing data will be decided by the time of database lock, and will 
be based on the opinion and advice of a medical expert.
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start and stop dates of AEs and concomitant medication.
The imputed dates will be used to allocate the concomitant medication and AEs to a 
treatment group, in addition to determining whether an AE is/is not treatment emergent. 
Listings of the AEs and concomitant medications will present the actual partial dates; 
imputed dates will not be shown.
7.10.2
Outliers
The final handling of outliers will be decided by the time of database lock, and will be 
based on the opinion and advice of a medical expert.
7.10.3
Visit Windows
The day of prescription of the study drug for the treatment period is defined as Day 1, and 
the following day is defined as Day 2.  
As indicated in Section 7.10.2, the final handling of outliers will be decided by the time of 
database lock, and will be based on the opinion and advice of a medical expert.  However, 
the policy described below will be followed as a general rule:
If multiple observed values have been obtained within the same visit window for a 
subject, the value closest to the scheduled date will be used.  If there are similar 
deviations from the scheduled date, the value obtained on the later date will be used.  
Data obtained as early as possible within the allowable range for each visit and within a 
7-day period from the final dose will be used.
Micturition Diary:
The mean number of: micturition episodes per 24 hours, urgency episodes per 24 hours, 
urinary incontinence episodes per 24 hours, urgency incontinence episodes per 24 hours, 
as well as mean volume voided per micturition and mean number of nocturia episodes 
will be calculated on the basis of the micturition diary and handled as follows: 
The information in the diary (recorded within 3 days before each visit, in principle) 
measured and recorded in the time windows specified below will be used as the data for 
that time point.
Time Point
Scheduled Day
Acceptable Time Range


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Diary retrieved at Visit 2
1
Day -7 to Day 1 (AM 5:59)
Diary retrieved at Visit 3
29
Day 19 to Day 36 (AM 5:59)
Diary retrieved at Visit 4
57
Day 47 to Day 64 (AM 5:59)
Diary retrieved at Visit 5
85
Day 75 to Day 92 (AM 5:59)
Diary retrieved at the final evaluation in 
the Treatment period
The final diary must be completed within 7 days after 
the last dose of study drug.
If the subject cannot complete the diary during the 3 days immediately prior to the visit, the diary 
entries must be recorded for any 3 days within 7 days prior to the visit.
If for some reason, information cannot be recorded in the diary during the 3 days before a 
given visit, data will be assessed based on the diary entries recorded within 7 days before 
the visit and within the above-specified time windows.
OABSS, IPSS, IPSS (QoL), and OAB-q*
The information measured and recorded within the time windows specified below will be 
used as the data for that time point.
Time Point
Scheduled Day
Acceptable Time Range
Completed at Visit 1
-28
Day -35 to Day -21
Completed at Visit 2
1
-
Completed at Visit 3
29
Day 22 to Day 36
Completed at Visit 4
57
Day 50 to Day 64
Completed at Visit 5
85
Day 78 to Day 92
Questionnaires are to be completed at 
the final evaluation during the Treatment 
period.
Final diary must be completed within 7 days after the 
last dose of study drug.
*OAB-q not performed at Visit 3 and Visit 4.
Safety Assessments
The time windows for the analysis of residual urine volume, laboratory tests*, and 
measurement of blood pressure (BP) and pulse rate (PR) are described below:
Time Point for Evaluation
Scheduled Day
Acceptable Time Range
Visit 1
-28
Day -35 to Day -21
Visit 2
1
-
Visit 3
29
Day 22 to Day 36
Visit 4
57
Day 50 to Day 64
Visit 5
85
Day 78 to Day 92
Final 
evaluation 
during 
the 
Treatment period
Final evaluation must be performed within 7 days after the 
last dose of study drug.
* Performed only at Week -4, Week 0, and Week 12/early termination


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The time windows for the analysis of self-measurement of BP and PR are described 
below:
Time point
Scheduled day
Acceptable time range
Diary retrieved at Visit 2
1
Day -7 to Day -1
Diary retrieved at Visit 3
29
Day 19 to Day 35
Diary retrieved at Visit 4
57
Day 47 to Day 63
Diary retrieved at Visit 5
85
Day 75 to Day 91
The diary is to be retrieved at the final 
evaluation during the Treatment period.
The final diary must be completed within 7 days after the last 
dose of study drug.
8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
DD-MMM-2017
NA
Document finalized
9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)


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10
APPENDICES
10.1
Appendix 1: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
Contributors and Reviewers