A Phase 3, Double-blind, Randomized, Multicenter, Parallel Group, Placebo-controlled Sequential Dose Titration Study to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Pediatric Subjects From 5 to < 18 Years of Age With Overactive Bladder
Phase: PHASE3
Conditions: Overactive Bladder (OAB), Pharmacokinetics of Mirabegron
Sponsor: Astellas Pharma Global Development, Inc.

Sponsor: APGD 
ISN/Protocol: 178-CL-204 
EudraCT number 2016-001767-37 
- CONFIDENTIAL - 
11 Feb 2021 
Astellas 
Page 1 of 157 
Version 2.0 Incorporating Substantial Amendment 1 
A Phase 3, Double-blind, Randomized, Multicenter, Parallel Group, 
Placebo-controlled Sequential Dose Titration Study to Evaluate 
Efficacy, Safety and Pharmacokinetics of Mirabegron in Pediatric 
Subjects from 5 to < 18 Years of Age with Overactive Bladder 
Double-blind Phase 3 Study with Mirabegron and Placebo in Pediatric Subjects  
from 5 to < 18 Years of Age with Overactive Bladder (Dolphin Study) 
ISN/Protocol 178-CL-204 
Version 2.0 Incorporating Substantial Amendment 1 
[see Section 13] 
11 Feb 2021 
 
EudraCT 2016-001767-37 
Pediatric Investigational Plan EMEA-000597-PIP02-10-M07 
 
Sponsor: 
Astellas Pharma Global Development Inc. 
1 Astellas Way 
Northbrook, IL 60062, US 
 
 
 
 
Protocol History: 
Version 1.0 [29 Oct 2019] 
Version 1.1 Incorporating Nonsubstantial Amendment 1 [13Nov2019] 
 
 
The information contained in this document is supplied as a background for clinical investigations.  This document contains 
confidential information, which is the intellectual property of Astellas.  By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research subject; and (4) where disclosure of such information is made to a member of the investigator’s team 
who agrees to hold this information in confidence. 

Sponsor: APGD 
ISN/Protocol: 178-CL-204 
EudraCT number 2016-001767-37 
- CONFIDENTIAL - 
11 Feb 2021 
Astellas 
Page 2 of 157 
Version 2.0 Incorporating Substantial Amendment 1 
Table of Contents  
SIGNATURES ································
································
································
 8 
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ································
·····  11 
1 
PROTOCOL SUMMARY ································
································
·······  12 
1.1 
Synopsis ································
································
························
 12 
1.2 
Study Schema ································
································
··················
 21 
1.3 
Schedule of Assessments ································
································
·····  22 
1.3.1 
Sample Collection Schedule ································
···························
 25 
2 
INTRODUCTION ································
································
·················
 25 
2.1 
Background ································
································
····················
 25 
2.1.1 
Treatment of Overactive Bladder in Pediatric Population ··························
 25 
2.1.2 
Nonclinical and Clinical Data ································
··························
 26 
2.1.2.1 
Nonclinical Data ································
································
···  26 
2.1.2.2 
Clinical Data ································
································
·······  26 
2.1.3 
Summary of Key Safety Information for Investigational Product(s) ··············
 29 
2.2 
Study Rationale ································
································
················
 30 
2.3 
Risk-Benefit Assessment ································
································
·····  30 
3 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ································
··············
 32 
4 
STUDY DESIGN AND DOSE RATIONALE ································
················
 34 
4.1 
Study Design ································
································
···················
 34 
4.2 
Dose Rationale ································
································
················
 35 
4.3 
End of Study Definition ································
································
······  36 
5 
STUDY POPULATION ································
································
··········
 37 
5.1 
Inclusion Criteria ································
································
··············
 37 
5.2 
Exclusion Criteria ································
································
·············
 38 
5.3 
Restrictions During the Study ································
·······························
 40 
5.4 
Screen Failures ································
································
················
 40 
5.4.1 
Rescreen ································
································
··················
 40 
5.4.1.1 
Rescreen for Urinary Tract Infection or Constipation ·························
 40 
5.4.1.2 
Rescreen for Other Eligibility Criteria ································
··········
 40 
6 
INVESTIGATIONAL PRODUCT(S) AND OTHER STUDY TREATMENT(S) ····  41 
6.1 
Investigational Product(s) Administered and Other Study Treatment(s) ···············
 41 

Sponsor: APGD 
ISN/Protocol: 178-CL-204 
EudraCT number 2016-001767-37 
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11 Feb 2021 
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Version 2.0 Incorporating Substantial Amendment 1 
6.1.1 
Investigational Product(s) ································
······························
 41 
6.1.2 
Other Study Treatment(s) ································
······························
 43 
6.2 
Preparation/Handling/Storage/Accountability ································
·············
 44 
6.2.1 
Packaging and Labeling ································
································
 44 
6.2.2 
Handling, Storage and Accountability ································
················
 44 
6.3 
Randomization and Blinding ································
································
 44 
6.3.1 
Blinding Method ································
································
·········  44 
6.3.2 
Confirmation of the Indistinguishability of the Investigational Product ··········
 44 
6.3.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ································
································
··················
 45 
6.3.4 
Breaking the Treatment Code for Emergency ································
·······  45 
6.3.5 
Breaking the Treatment Code by the Sponsor ································
·······  45 
6.3.6 
Assignment and Allocation································
·····························
 45 
6.3.6.1 
Subject Number ································
································
····  45 
6.3.6.2 
Randomization Number ································
···························
 46 
6.3.6.3 
Subject Replacement ································
······························
 46 
6.4 
Investigational Product(s) and Other Study Treatment(s) Compliance ·················
 46 
6.4.1 
Investigational Product(s) ································
······························
 46 
6.4.2 
Other Study Treatment(s) ································
······························
 46 
6.5 
Previous and Concomitant Treatment (Medication and Nonmedication Therapy) ····  46 
6.6 
Dose Modification ································
································
············
 47 
6.7 
Criteria for Continuation of Treatment(s) ································
··················
 47 
7 
STUDY PROCEDURES AND ASSESSMENTS ································
············
 47 
7.1 
Efficacy Assessments ································
································
·········  48 
7.1.1 
Bladder Electronic Diary ································
·······························
 48 
7.2 
Safety Assessments ································
································
···········
 48 
7.2.1 
Adverse Events ································
································
··········
 48 
7.2.2 
Laboratory Assessments ································
································
 48 
7.2.3 
Vital Signs and Electrocardiograms ································
···················
 49 
7.2.3.1 
Clinic-measurement of Vital Signs and Electrocardiograms ·················
 49 
7.2.3.2 
Self-measurement of Vital Signs ································
················
 50 
7.2.4 
Physical Examination ································
································
···  50 
7.2.5 
Post Void Residual Volume Assessments ································
············
 50 
7.2.6 
Acceptability and Palatability Questionnaire ································
········  51 

Sponsor: APGD 
ISN/Protocol: 178-CL-204 
EudraCT number 2016-001767-37 
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Version 2.0 Incorporating Substantial Amendment 1 
7.2.7 
Order of Assessments ································
································
···  51 
7.3 
Adverse Events and Other Safety Aspects ································
·················
 51 
7.3.1 
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information ································
································
···············
 51 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ···············
 51 
7.3.3 
Follow-up of Adverse Events ································
··························
 51 
7.3.4 
Reporting of Serious Adverse Events ································
·················
 52 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ································
··········
 52 
7.3.6 
Adverse Events of Special Interest ································
····················
 52 
7.3.7 
Special Situations ································
································
········  53 
7.3.8 
Supply of New Information Affecting the Conduct of the Study ··················
 53 
7.3.9 
Urgent Safety Measures ································
································
 53 
7.3.10 
Reporting Urgent Safety Measures ································
····················
 53 
7.4 
Pharmacokinetics ································
································
··············
 54 
7.5 
Pharmacodynamics | Immunogenicity ································
······················
 54 
7.6 
Electronic Clinical Outcome Assessment ································
··················
 54 
7.7 
Other Assessments ································
································
············
 56 
7.8 
Total Amount of Blood ································
································
·······  56 
8 
DISCONTINUATION ································
································
············
 56 
8.1 
Discontinuation of Individual Subject(s) From Study Treatment(s) ····················
 56 
8.2 
Discontinuation of Individual Subject(s) From Study ································
····  57 
8.2.1 
Lost to Follow-up································
································
········  57 
8.3 
Discontinuation of the Study Site ································
···························
 57 
8.4 
Discontinuation of the Study································
································
· 57 
9 
STATISTICAL METHODOLOGY ································
···························
 58 
9.1 
Sample Size ································
································
····················
 58 
9.2 
Analysis Sets ································
································
···················
 59 
9.2.1 
Full Analysis Set ································
································
········  59 
9.2.2 
Per Protocol Set ································
································
··········
 59 
9.2.3 
Safety Analysis Set ································
································
······  59 
9.2.4 
Pharmacokinetics Analysis Set ································
························
 59 
9.2.5 
Pharmacodynamic Analysis Set ································
·······················
 59 
9.3 
Demographics and Baseline Characteristics ································
···············
 59 

Sponsor: APGD 
ISN/Protocol: 178-CL-204 
EudraCT number 2016-001767-37 
- CONFIDENTIAL - 
11 Feb 2021 
Astellas 
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Version 2.0 Incorporating Substantial Amendment 1 
9.3.1 
Demographics ································
································
············
 60 
9.3.2 
Subject Disposition ································
································
······  60 
9.3.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ································
································
··················
 60 
9.3.4 
Medical History ································
································
··········
 60 
9.3.5 
Investigational Product Exposure ································
·····················
 60 
9.4 
Analysis of Efficacy ································
································
··········
 61 
9.4.1 
Analysis of Primary Endpoint ································
·························
 61 
9.4.1.1 
Primary Analysis ································
································
···  61 
9.4.1.2 
Secondary Analysis ································
································
 61 
9.4.1.3 
Subgroup Analysis ································
································
· 62 
9.4.2 
Analysis of Secondary Endpoints ································
·····················
 62 
9.4.3 
Analysis of Exploratory Endpoints ································
····················
 62 
9.5 
Analysis of Safety ································
································
·············
 63 
9.5.1 
Adverse Events ································
································
··········
 63 
9.5.2 
Laboratory Assessments ································
································
 63 
9.5.3 
Vital Signs ································
································
················
 63 
9.5.4 
Physical Examination ································
································
···  64 
9.5.5 
Electrocardiogram ································
································
·······  64 
9.5.6 
Post Void Residual Volume ································
····························
 64 
9.5.7 
Acceptability and Palatability Questionnaire ································
········  64 
9.6 
Analysis of Pharmacokinetics ································
·······························
 64 
9.6.1 
Estimation of Pharmacokinetic Parameters ································
··········
 64 
9.7 
Analysis of Pharmacodynamics | Immunogenicity ································
········  64 
9.8 
Other Analyses ································
································
················
 65 
9.9 
Major Protocol Deviations ································
································
···  65 
9.10 
Interim Analysis (and Early Discontinuation of the Study) ······························
 65 
9.11 
Additional Conventions ································
································
······  65 
10 
OPERATIONAL CONSIDERATIONS ································
·······················
 65 
10.1 
Data Collection ································
································
················
 65 
10.2 
Demographics and Baseline Characteristics ································
···············
 66 
10.2.1 
Demographics ································
································
············
 66 
10.2.2 
Medical History ································
································
··········
 66 
10.2.3 
Diagnosis of the Target Disease, Severity and Duration of Disease ··············
 66 

Sponsor: APGD 
ISN/Protocol: 178-CL-204 
EudraCT number 2016-001767-37 
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Version 2.0 Incorporating Substantial Amendment 1 
10.3 
Major Protocol Deviations ································
································
···  66 
10.4 
Study Organization ································
································
············
 67 
10.4.1 
Data and Safety Monitoring Board ································
····················
 67 
10.4.2 
Independent Data Analysis Center ································
····················
 67 
10.4.3 
Other Study Organization ································
······························
 67 
11 
REFERENCES ································
································
····················
 68 
12 
APPENDICES ································
································
·····················
 69 
12.1 
Ethical, Regulatory and Study Oversight Considerations ································
 69 
12.1.1 
Ethical Conduct of the Study ································
···························
 69 
12.1.2 
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities ································
································
················
 69 
12.1.3 
Protocol Amendment and/or Revision ································
················
 69 
12.1.4 
Financial Disclosure ································
································
····  70 
12.1.5 
Informed Consent/Assent of Subjects ································
·················
 70 
12.1.5.1 
Subject Information and Consent/Assent ································
·······  70 
12.1.5.2 
Supply of New and Important Information Influencing the Subject’s 
Consent/Assent and Revision of the Written Information ····················
 71 
12.1.6 
Source Documents ································
································
······  72 
12.1.7 
Record Retention ································
································
········  72 
12.1.8 
Subject Confidentiality and Privacy ································
···················
 73 
12.1.9 
Arrangement for Use of Information and Publication of the Study ···············
 73 
12.1.10 
Insurance of Subjects and Others ································
······················
 74 
12.1.11 
Signatory Investigator for Clinical Study Report ································
····  74 
12.2 
Procedure for Study Quality Control ································
·······················
 74 
12.2.1 
Study Monitoring ································
································
········  74 
12.2.2 
Direct Access to Source Data/Documents ································
············
 74 
12.2.3 
Data Management ································
································
·······  74 
12.2.4 
Quality Assurance ································
································
·······  75 
12.3 
Contraception Requirements ································
································
· 76 
12.4 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up and Reporting ································
································
··············
 78 
12.4.1 
Definition of Adverse Events ································
··························
 78 
12.4.1.1 
Abnormal Laboratory Findings ································
··················
 78 
12.4.1.2 
Potential Cases of Drug-induced Liver Injury ································
··  78 
12.4.2 
Definition of Serious Adverse Events································
·················
 78 

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12.4.3 
Criteria for Causal Relationship to Investigational Product ························
 79 
12.4.4 
Criteria for Defining the Severity of an Adverse Event ····························
 80 
12.4.5 
Reporting Procedures for Serious Adverse Events ································
··  80 
12.4.6 
Reporting Procedures for Special Situations ································
·········  82 
12.4.6.1 
Pregnancy ································
································
···········
 82 
12.4.6.2 
Lack of Efficacy ································
································
···  82 
12.4.6.3 
Medication Error, Overdose and “Off-label Use” ·····························
 83 
12.4.6.4 
Misuse/Abuse ································
································
······  83 
12.4.6.5 
Occupational Exposure ································
···························
 83 
12.4.6.6 
(Suspicion of) Transmission of Infectious Agent ······························
 83 
12.4.6.7 
Suspected Drug-drug Interaction ································
················
 83 
12.5 
Liver Safety Monitoring and Assessment ································
··················
 84 
12.6 
List of Excluded Concomitant Medications································
················
 87 
12.7 
Laboratory Assessments ································
································
······  89 
12.8 
Acceptability and Palatability Questionnaire for Tablets································
· 90 
12.9 
Acceptability and Palatability Questionnaire for Oral Suspension ······················
 91 
12.10 
Centiles of Heart Rate for Normal Children from Birth to 18 Years of Age ···········
 93 
12.11 
Centers for Disease Control and Prevention Data Table of Stature for Age Chart 
for Males ································
································
·······················
 94 
12.12 
Centers for Disease Control and Prevention Data Table of Stature for Age Chart 
for Females ································
································
···················
 101 
12.13 
Clinical Study Continuity ································
································
··  108 
12.14 
List of Abbreviations and Definition of Key Study Terms ·····························
 114 
13 
ATTACHMENT 1: SUBSTANTIAL AMENDMENT 1 ································
· 117 
14 
COORDINATING INVESTIGATOR’S SIGNATURE ································
··  156 
15 
SPONSOR’S SIGNATURES ································
································
··  157 
 
 
 

Sponsor: APGD 
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SIGNATURES 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in 
[Section 15 Sponsor’s Signatures]. 
 
 

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2.  COORDINATING INVESTIGATOR’S SIGNATURE 
The coordinating investigator’s signature is located in [Section 13 Coordinating 
Investigator’s Signature]. 

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3.  INVESTIGATOR’S SIGNATURE 
A Phase 3, Double-blind, Randomized, Multicenter, Parallel Group, Placebo-controlled 
Sequential Dose Titration Study to Evaluate Efficacy, Safety and Pharmacokinetics of 
Mirabegron in Pediatric Subjects from 5 to < 18 Years of Age with Overactive Bladder 
ISN/Protocol 178-CL-204 
Version 2.0 Incorporating Substantial Amendment 1 
11 Feb 2021 
I have read all pages of this protocol for which Astellas is the sponsor.  I agree to conduct the 
study as outlined in the protocol and to comply with all the terms and conditions set out therein.  
I confirm that I will conduct the study in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) guidelines and applicable local regulations.  I will also ensure that 
subinvestigator(s) and other relevant members of my personnel have access to copies of this 
protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions 
of these documents. 
Principal Investigator: 
Signature: 
 
 
 
 
Date (DD Mmm YYYY) 
Printed Name: 
 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 

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CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL 
24-hour Contact for Serious 
Adverse Events 
 
See [Appendix 12.4.5 
Reporting Procedures for 
Serious Adverse Events] 
 
Please fax or email the serious adverse events/special situations 
worksheet to: 
Astellas Pharma Global Development Inc. 
US Pharmacovigilance 
North America fax number: +1-888-396-3750 
North America alternate fax number: +1-847-317-1241 
International fax number: +44-800-471-5263 
Email: safety-us@astellas.com 
Medical Monitor/Study 
Physician 
 
 
 
Medical Specialties Therapeutic Area, Tokyo 
Astellas Pharma Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku 
Tokyo 103-8411, Japan 
 
 
Clinical Research Contact(s) 
 
 
Astellas Pharma Global Development Inc. 
1 Astellas Way 
Northbrook, IL, 60062 
 
 
 
 
Astellas Pharma Global Development Inc. 
1 Astellas Way 
Northbrook, IL, 60062 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Date and Version of Protocol Synopsis: 
11 Feb 2021, Version 2.0 
Sponsor: 
Astellas Pharma Global Development Inc. (APGD) 
Protocol Number: 
178-CL-204 
Compound Name: 
YM178 (mirabegron) 
Phase of Development: 
Phase 3 
Title of Study: 
A Phase 3, Double-blind, Randomized, Multicenter, Parallel Group, Placebo-controlled Sequential Dose 
Titration Study to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Pediatric Subjects 
from 5 to < 18 Years of Age with Overactive Bladder 
Planned Study Period: 
From approximately 1Q2020 to 2Q2023 
Study Objective(s) and Endpoint(s): 
The primary, secondary and exploratory objectives and endpoints for this study are listed in the table 
below. 
Study Objectives and Endpoints 
Primary and secondary objectives and endpoints apply to children only; exploratory objectives and 
endpoints also apply to adolescents. 
Objectives 
Endpoints 
Primary 
● 
To evaluate the efficacy of mirabegron in children 
(5 to < 12 years of age) with OAB 
● 
Change from baseline at the end of the 12-week 
treatment period: 
○ 
Mean number of micturitions per 24 hours 
Secondary 
● 
To evaluate the efficacy of mirabegron in children 
(5 to < 12 years of age) with OAB 
● 
Change from baseline at the end of the 12-week 
treatment period: 
○ 
Mean volume voided per 24 hours 
○ 
Maximum volume voided 
○ 
Mean number of daytime incontinence 
episodes per 24 hours 
○ 
Mean number of nighttime incontinence 
episodes per 24 hours 
○ 
Mean number of daytime micturitions per 
24 hours 
● 
Number of dry (incontinence-free) days per 
7 days at the end of the 12-week treatment period 
● 
To evaluate the safety and tolerability of 
mirabegron in pediatric subjects with OAB 
● 
Nature, frequency and severity of AEs 
● 
Clinical laboratory tests (hematology, 
biochemistry and urinalysis) 
● 
Vital signs (blood pressure and pulse) 
● 
Routine 12-lead ECG 
● 
PVR volume 
● 
Acceptability and palatability questionnaire 
Table continued on next page 

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Objectives 
Endpoints 
Secondary continued 
● 
To evaluate the pharmacokinetics after multiple 
dose administration of mirabegron in pediatric 
subjects with OAB 
● 
Steady-state Cmax, AUCtau, Ctrough, Tmax, CL/F, 
and Vz/F.  Additional parameters may be 
calculated based on the population 
pharmacokinetic model used  
Exploratory 
● 
To evaluate the efficacy of mirabegron in 
pediatric subjects (5 to < 18 years) with OAB 
● 
Percentage of subjects with a reduction in 
daytime incontinence episodes (< 50% 
reduction [nonresponder], 50% [partial 
responder] and 100% [responder]) 
● 
Improvement from baseline in worst 
incontinence grading 
● 
Change from baseline at the end of the 12-week 
treatment period adjusted for fluid intake: 
○ 
Mean number of micturitions per 24 hours 
● 
Change from baseline at the end of the 12-week 
treatment period (adolescents only): 
○ 
Mean number of micturitions per 24 hours 
○ 
Mean number of daytime micturitions per 
24 hours 
○ 
Mean volume voided per 24 hours 
○ 
Mean number of incontinence episodes per 
24 hours 
● 
Number of dry (incontinence-free) days per 
7 days at the end of the 12-week treatment 
period (adolescents only) 
● 
Mean number of daytime grade 3 or 4 (PPIUS) 
urgency episodes per 24 hours (adolescents 
only) 
AE: adverse event; ECG: electrocardiogram; OAB: overactive bladder; PPIUS: patient perception of intensity of 
urgency scale; PVR: post void residual. 
Estimand 
The estimand of most clinical importance for this study is defined by the following 4 attributes: 
● 
Target population: all children who took at least 1 dose of the study drug, and in whom a nonmissing 
measurement for micturition frequency at baseline and after administration of the study drug is 
available 
● 
Outcome measurement: micturition frequency/day (24 hours) 
● 
Intercurrent events: 
1. 
Discontinuation from treatment (if week 12/EoT not obtained) 
2. 
AE urinary tract infection (UTI) (if occurred in week 12/EoT) 
3. 
Other muscarinic antagonists or botulinum toxin (if taken during the last 2 weeks prior to week 
12/EoT assessment); in all cases, a hypothetical strategy will be applied 
● 
Population-based summary: Change from baseline to week 12/EoT in micturition frequency/day 
(= primary endpoint, primary estimator), compared to placebo 
For this placebo-controlled study, this “de jure” estimand chosen is considered the appropriate choice.  As 
some effect is expected early in the study and with continued treatment could be expected to be 
maintained, it’s considered appropriate to impute for subjects with missing values at visit 7/week 12/EoT 
by their last recorded post baseline visit value prior to it.  This strategy also assumes that the responses 
after the intercurrent event would be same as for patients continuing on their respective treatment. 

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Planned Total Number of Study Sites and Location(s): 
Approximately 65 study sites 
Europe, Latin America, Africa, Middle East, Asia-Pacific and North America 
Study Population: 
Male and female pediatric subjects 5 to < 18 years of age with overactive bladder (OAB; as defined 
according to the International Children’s Continence Society [ICCS]) who have had received 4 weeks of 
urotherapy prior to randomization 
Number of Subjects to be Enrolled/Randomized: 
Approximately 368 children enrolled to achieve 184 children (5 to < 12 years of age) randomized and 
approximately 64 adolescents enrolled to achieve at least 32 adolescents (12 to < 18 years of age) 
randomized (at least 92 children and 16 adolescents must be randomized to mirabegron) 
Study Design Overview:  
This is a double-blind, randomized, multicenter, parallel group, placebo-controlled sequential dose 
titration study to evaluate efficacy, safety and pharmacokinetics of mirabegron in pediatric subjects with 
OAB.  Subjects will have to receive 4 weeks of urotherapy prior to randomization. 
The study consists of 3 periods with a total duration of 18 weeks. 
● 
Screening period/urotherapy (4 weeks): 
This period starts with visit 1/week -4 (screening) and ends with visit 3/week 0 (baseline).  After 
informed consent/assent has been obtained and immediately after eligibility has been confirmed at 
visit 1/week -4 (screening), subjects using prohibited medication will complete 1 week of washout 
(if applicable), while beginning 4 weeks of urotherapy. 
After a successful screening visit (visit 1/week -4 [screening]), all subjects will complete a 2-day 
bladder e-diary (weekend) to get acquainted with the bladder e-diary and the assessments.  
Completion of this bladder e-diary should start in the weekend prior to visit 2.  All subjects will also 
complete a 7-day bladder e-diary the week prior to the baseline visit.  The 7-day diary will consist of 
a 5-day weekday bladder e-diary and 2-day weekend e-diary. 
● 
Double-blind, placebo-controlled period (12 weeks): 
This period starts with the day after visit 3/week 0 (baseline) and ends with visit 7/week 12 (end of 
treatment [EoT]). 
At visit 3/week 0 (baseline) inclusion and exclusion criteria will be evaluated.  Subjects continuing 
urotherapy who still meet the OAB entry criteria at baseline will be randomized.  Subjects whose 
symptoms are not satisfactorily controlled with urotherapy and still fulfill the inclusion/exclusion 
criteria will enter the study.  These subjects will be randomized to receive mirabegron in pediatric 
equivalent dose 25 mg (PED25) or placebo using a 1:1 ratio.  Subjects with a body weight of ≥ 35 kg 
are to receive the tablet unless unable to swallow tablets and would be provided the oral suspension 
as an alternative.  Subjects with a body weight < 35 kg or those who cannot be dosed with the tablet 
will receive an oral suspension.  Daily investigational product (IP) administration will start on day 1 
(i.e., the day after this visit) and continue at this dose until visit 5/week 4 (i.e., for 4 weeks).  
Urotherapy will continue throughout the study treatment period until visit 7/week 12 (EoT). 
At visit 5/week 4, dose up-titration to mirabegron in pediatric equivalent dose 50 mg (PED50) will 
be performed unless the investigator determines that the subject is adequately treated for OAB at the 
PED25 dose or if there are safety concerns identified and considered associated with the use of 
PED25.  Dose down-titration from PED50 to PED25 can be done at any time thereafter for safety 
reasons. 
Subjects will start with the subsequent 7-day bladder e-diaries approximately 7 days prior to the 
indicated visit (or TC). 
Pharmacokinetic blood samples will be collected at visit 5/week 4 and visit 7/week 12 (EoT) as 
indicated in the Schedule of Assessments. 

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● 
Follow-up period (2 weeks): 
This period starts the day after visit 7/week 12 (EoT) and ends with visit 8/week 14 (end of study 
[EoS]).  The follow-up period is applicable to all subjects who have been randomized and received 
IP. 
At visit 7/week 12 (EoT), IP administration will be stopped and a safety observation period of 
2 weeks will start. 
An independent Data and Safety Monitoring Board (DSMB) will be established.  A separate charter will 
describe the responsibilities of the DSMB. 
The IP will not be provided after study completion without written approval from the sponsor. 
Inclusion/Exclusion Criteria: 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply: 
Inclusion at Visit 1/Week -4 (Screening) 
1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed 
consent/assent and privacy language as per national regulations (e.g., General Data Protection 
Regulations for European Union study sites) must be obtained from the subject and/or from the 
subject’s parent(s)/legal guardian(s) prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable); assent by the subject is obtained as required by local law. 
2. 
Subject has OAB defined according to the ICCS criteria. 
3. 
Subject is a male or female between 5 to < 18 years of age, at screening. 
4. 
Subject weighs at least 13 kg at screening. 
5. 
Subject is able to take the IP in accordance with the protocol. 
6. 
Subject agrees to drink an adequate fluid volume during urine collection weekends, as instructed by 
the investigator. 
7. 
Subject and subject’s parent(s)/legal guardian(s) agree that the subject will not participate in another 
interventional study while participating in the present study. 
8. 
Subject and subject’s parent(s)/legal guardian(s) are willing and able to comply with the study 
requirements and with the concomitant medication restrictions. 
9. 
Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at least 1 of 
the following conditions apply: 
a. 
Not a female of childbearing potential (see [Appendix 12.3 Contraception Requirements]). 
b. 
Female of childbearing potential who agrees to follow the contraceptive guidance (see 
[Appendix 12.3 Contraception Requirements]) from the time of informed consent/assent 
through at least 30 days after final IP administration. 
10. Female subject must agree not to breastfeed starting at screening and throughout the study period and 
for 30 days after final IP administration. 
11. Female subject must not donate ova starting at first dose of IP and throughout the study period and 
for 30 days after final IP administration. 
12. Male subject with female partner(s) of childbearing potential (including breastfeeding partner[s]) 
must agree to use contraception (see [Appendix 12.3 Contraception Requirements]) throughout the 
treatment period and for 30 days after final IP administration. 
13. Male subject must agree not to donate sperm during the treatment period and for 30 days after final 
IP administration. 
14. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the 
duration of the pregnancy throughout the study period and for 30 days after final IP administration. 
Additional Inclusion at Visit 3/Week 0 (Baseline) 
15. Subject must have a micturition frequency of at least 8 times (on average) per day, in the 7 days prior 
to visit 3/week 0 (baseline), as recorded in the bladder e-diary. 

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16. Subject must have at least 1 daytime incontinence episode (on average) per day, during the 7-day 
period before visit 3/baseline, as recorded in the bladder e-diary. 
17. Subject whose symptoms are not satisfactorily controlled with urotherapy and still fulfills the 
inclusion/exclusion criteria will enter the study. 
Exclusion Criteria 
Subject will be excluded from participation in this study if any of the following apply: 
Exclusion at Visit 1/Week -4 (Screening) 
1. 
Subject has extraordinary daytime only urinary frequency according to the ICCS definition. 
● 
This applies to a toilet-trained child who has the frequent need to void that is associated with 
small micturition volumes solely during the day. 
● 
The daytime voiding frequency is at least once per hour with an average voided volume of 
< 50% of expected bladder capacity (EBC) (typically 10% to 15%). 
● 
Incontinence is rare and nocturia is absent. 
2. 
Subject has an uroflow indicative of pathology other than OAB. 
3. 
Subject has monosymptomatic enuresis. 
4. 
Subject has dysfunctional voiding. 
5. 
Subject has bladder outlet obstruction, except if successfully treated. 
6. 
Subject has anatomical anomalies (surgically treated or untreated) that affect lower urinary tract 
function. 
7. 
Subject with hematuria on dipstick test.  In the case of hematuria on dipstick test in a female during 
menstruation, the test can be repeated before randomization (after the end of menstruation). 
8. 
Subject with diabetes insipidus. 
9. 
Subject has kidney or bladder stones. 
10. Subject has suffered from chronic UTI or has had more than 3 UTIs in the 2 months prior to 
visit 1/week -4 (screening). 
11. Criterion has been removed. 
12. Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well controlled, as 
defined by the 2017 American Academy of Pediatrics Clinical Practice Guidelines. 
13. Subject has QTcF > 440 msec on screening ECG, a risk of QT prolongation (e.g., hypokalemia, long 
QT syndrome [LQTS] or family history of LQTS or exercise-induced syncope) or is currently taking 
medication known to prolong the QT interval. 
14. Subject’s aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is ≥ 2 × upper limit 
of normal (ULN) or total bilirubin (TBL) is ≥ 1.5 × ULN according to age and sex (subjects with 
Gilbert’s syndrome are excepted from the bilirubin threshold). 
15. Subject has mild or moderate renal impairment (estimated glomerular filtration rate according to the 
modified Schwartz of < 60 mL/min per 1.73 m2). 
16. Subject has a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling 
urine) UTI.  Note: if the UTI is treated successfully (clinical recovery: confirmed by dipstick test and 
repeated dipstick test after 14 days [both should be negative]), the subject can be rescreened. 
17. Subject has a history or presence of any malignancy. 
18. Subject uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates with a narrow 
therapeutic index, sensitive P-glycoprotein (P-gp) substrates, or moderate or strong cytochrome 
CYP3A4/5 or P-gp inhibitors or inducers after the start of washout. 
19. Subject is using or has used prohibited prior and/or concomitant medication(s) [Appendix 12.6 List 
of Excluded Concomitant Medications] that cannot be discontinued. 
20. Subject has known or suspected hypersensitivity to mirabegron or any components of the 
formulations used. 
21. Subject has participated in another clinical study (and/or subject has received any investigational 

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therapy within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is 
longer) prior to visit 1/week -4 (screening). 
22. Subject received urinary catheterization within 2 weeks prior to screening. 
23. Subject has constipation as defined by the Rome IV criteria that cannot be successfully treated prior 
to study entry. 
24. Female subject who has been pregnant within 6 months prior to screening or breastfeeding within 
3 months prior to screening. 
25. Subject has any condition, which in the opinion of the investigator, makes the subject unsuitable for 
study participation. 
Additional Exclusion at Visit 3/Week 0 (Baseline) 
26. Subject has extraordinary daytime only urinary frequency according to the ICCS definition based on 
the bladder e-diary. 
27. Subject has monosymptomatic enuresis confirmed by the bladder e-diary. 
28. Subject has a maximum voided volume (morning volume excluded) > EBC for age ([age +1] × 30) 
in mL, based on the bladder e-diary. 
29. Subject has polyuria defined as voided urine volumes of > 40 mL/kg baseline body weight during 
24 hours or > 2.8 L urine for a child weighing ≥ 70 kg (ICCS definition) [Austin et al, 2014], based 
on bladder e-diary. 
30. Subject has PVR volume > 20 mL (lowest PVR volume result) as measured by ultrasonography. 
31. Subject suffers from a symptomatic (symptoms can include pain, fever, hematuria, new onset 
foul-smelling urine) UTI.  Note: if a symptomatic UTI is present, all visit 3/week 0 (baseline) 
assessments must be postponed until the UTI is successfully treated (clinical recovery: confirmed by 
dipstick test and repeated dipstick test after 14 days [both should be negative]), and the urotherapy 
should continue.  The postponed visit 3/week (baseline) should be within 14 days of the intended 
visit 3/week 0 (baseline). 
32. Subject with hematuria on dipstick test.  In the case of hematuria on dipstick test in a female during 
menstruation, the test can be repeated before randomization (after the end of menstruation). 
33. Subject has a pulse > 99th percentile for age. 
34. Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well controlled, as 
defined by the 2017 American Academy of Pediatrics Clinical Practice Guidelines. 
35. Any reason, in the opinion of the investigator, that makes the subject unsuitable for study 
participation. 
Investigational Product(s): 
Name/Use: 
Mirabegron tablets in 25 mg and 50 mg (test product) and matching placebo 
Mirabegron oral suspension containing 8 mg/mL (test product) and matching placebo 
Dose(s): 
Once daily dosing according to the table below. 

Sponsor: APGD 
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Body Weight-based Doses for Tablets or Suspension 
 
Body Weight Range† 
(kg) 
Oral Suspension Volume‡ 
(mL) 
Tablet Dose 
(mg) 
PED25 
13 to < 22 
3 
- 
22 to < 35 
4 
- 
≥ 35 
6 
25 
PED50 
13 to < 22 
6 
- 
22 to < 35 
8 
- 
≥ 35 
11 
50 
PED25: pediatric equivalent dose 25 mg; PED50: pediatric equivalent dose 50 mg 
† 
Subjects with a body weight ≥ 35 kg will receive the tablet.  Subjects with a body weight < 35 kg or those who 
cannot be dosed with the tablet will receive an oral suspension. 
‡ 
Oral suspension containing 8 mg/mL. 
The starting dose will be PED25 starting administration the day after visit 3/week 0 (baseline).  At 
visit 5/week 4, dose up-titration to PED50 will be performed unless the investigator determines that the 
subject is adequately treated for OAB at the PED25 dose or if there are safety concerns identified and 
considered associated with the use of PED25.  Dose down-titration from PED50 to PED25 can be done at 
any time thereafter for safety reasons. 
Mode(s) of Administration: 
IP will be administered orally, once daily in the morning around the same time of day and around time of 
food intake (i.e., within 1 hour before or after breakfast). 
Tablets will be administered with a sip of water (tablet should be taken as a whole and should not be 
chewed, divided or crushed).  Oral suspension will be administered via an oral syringe with a sip of water 
afterwards. 
Dose Modifications: 
Dose down-titration from PED50 to PED25 can be done at any time for safety reasons. 
Other Study Treatment(s): 
During the screening period, all subjects will receive 4 weeks of urotherapy.  At visit 3/week 0 (baseline), 
inclusion and exclusion criteria will be evaluated.  Subjects continuing urotherapy who still meet the 
OAB entry criteria at baseline will be randomized.  Urotherapy will continue throughout the study 
treatment period until visit 7/week 12 (EoT). 
Concomitant Treatment (Medication and Nonmedication Therapy) Restrictions or Requirements: 
Subjects are not allowed to use ongoing treatment with any of the following prohibited medications after 
the start of the washout: 
● 
Any medication, other than the IP, used for the treatment of OAB (including tricyclic 
antidepressants, 1st generation H1 antagonists and alpha blockers) 
● 
Any drugs that are sensitive CYP2D6 substrates with a narrow therapeutic index or sensitive 
P-glycoprotein substrates 
● 
Any medications known to prolong the QT interval  
● 
Any medication that is a moderate or strong cytochrome CYP3A4/5 or P-gp inhibitor or inducers 
including natural and herbal remedies 
● 
Intradetrusor botulinum toxin injections; except if given > 9 months prior screening and symptoms 
reappeared comparable to those before botulinum toxin injections 

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● 
Nonmedication therapies like urotherapy, chiropractic, physical therapy will also be collected on the 
nonmedication therapy case report form. 
○ 
The site will need to make special notes for those subjects who do not follow urotherapy for 7 
or more consecutive days in electronic case report forms. 
These treatments are prohibited from being started after the start of the washout period. All other 
concomitant treatment use will be reported. 
The use of previous and concomitant treatment within 30 days prior to signing the informed consent and 
throughout the study will be documented on the appropriate electronic case report form. 
Duration of Treatment: 
Once daily dosing for 12 weeks 
Treatment Discontinuation Criteria: 
Discontinuation of Individual Subject(s) From Study Treatment(s): 
A subject must discontinue study treatment for any of the following reasons: 
● 
Subject requests to stop treatment. 
● 
Any clinical adverse events, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued treatment is not in the best interest of the subject 
● 
If signs or symptoms of hypersensitivity to mirabegron are observed (e.g., anaphylactic reaction, 
erythema multiforme or exfoliative dermatitis). 
● 
ALT or AST > 8 × ULN. 
● 
ALT or AST > 5 × ULN for more than 2 weeks. 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or international normalized ratio (INR) > 1.5 (if INR 
testing is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or eosinophilia (> 5%). 
● 
Female subject becomes pregnant. 
● 
Prolongation of QT > QTcF > 440 msec and/or QT interval prolongation > 30 msec versus baseline. 
● 
Subject with (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mmHg. 
If a subject discontinues treatment prematurely, the subject will be encouraged to complete all scheduled 
visits to record all available information. 
Discontinuation of the Study: 
The independent data monitoring committee will review safety data periodically and provide a 
recommendation to the sponsor if the study should continue or be stopped due to safety concerns.  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 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.  The study may also be stopped as a result of the outcome of the 
interim analysis. 
Statistical Methods: 
Sample Size Justification: 
Efficacy of mirabegron in children will be based on both primary and secondary endpoints.  Given the 
clinical hurdle to demonstrate efficacy in a population challenging to recruit, an alpha-level of 10% 
would appear reasonable and justified.  In a study with propiverine in children, a difference in mean 
number of micturition episodes/24 hours of 0.8 between propiverine and placebo was observed, with a 
SD between 2.2 and 2.3.  Assuming at least similar efficacy of mirabegron, with a treatment effect of 
0.9 micturitions per day between mirabegron and placebo and a common SD of 2.3, a sample size of 
82 evaluable subjects (children) per treatment group is assumed per treatment group would provide a 

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power of 80%.  Under the assumption that after randomization about 10% of the subjects will not be 
evaluable for the analysis of the primary endpoint (i.e., not fulfilling the criteria for inclusion in full 
analysis set), at least 184 children (5 to < 12 years of age) must be randomized in order to have at least 
164 evaluable children for the analysis of the primary efficacy endpoint.  For adolescents, no formal 
sample size will be calculated, at least 32 adolescents (12 to < 18 years of age) must be randomized, 
yielding at least 16 adolescents on mirabegron.  Further assuming a 50% screen failure rate, 
approximately 368 children have to be enrolled to achieve 184 children (5 to < 12 years of age) 
randomized and approximately 64 adolescents will be enrolled to achieve at least 32 adolescents 
(12 to < 18 years of age) randomized (at least 92 children and 16 adolescents must be randomized to 
mirabegron).  Recruitment will continue until the minimum number to be randomized in both children 
and adolescents have been achieved. 
Efficacy: 
The primary analysis of the primary efficacy end-point in children (5 to < 12 years of age), change from 
baseline to visit 7/week 12 (EoT) in mean number of micturitions per 24 hours, will be analyzed using an 
analysis of covariance (ANCOVA).  The ANCOVA model will include treatment group, sex and 
geographical region as fixed effects and the mean number of micturitions per 24 hours at visit 3/week 0 
(baseline) as covariate. 
The secondary analysis will be a repeated measures ANCOVA.  This model will include treatment group, 
visit (week 4, 8, 12), sex, geographical region and the interaction between treatment group and visit as 
fixed effects and mean number of micturitions per 24 hours at baseline as covariate.  Mirabegron will be 
compared to placebo using a linear contrast within the repeated measures ANCOVA model, with 2-sided 
significance level of alpha = 0.1 and 90% CI. 
In addition to the parametric ANCOVA, a nonparametric ANCOVA will also be performed: (stratified) 
rank ANCOVA. 
Safety: 
Safety endpoints will be summarized using descriptive statistics.  Safety parameters such as vital signs 
will be summarized with respect to age- and sex-specific percentiles.  Clinical laboratory tests 
(hematology, biochemistry and urinalysis [urinalysis dipstick]) and electrocardiogram results will also be 
summarized. 
Pharmacokinetics: 
Pharmacokinetic parameters will be summarized using descriptive statistics. 
Pharmacodynamics | Immunogenicity: 
Not applicable. 
Interim Analyses: 
A blinded interim analysis will be performed after 50% of children planned to be randomized have had 
their week 12/EoT assessment.  The interim analysis will determine if the chance of a positive study with 
respect to the primary endpoint at the EoS is high enough to justify continuation of the study; otherwise, 
the study will be stopped for futility. 
 

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1.2 
Study Schema 
Figure 1 
Study Schema 
 
 
 
 
 
 
 
 
 
EoS: end of study; EoT: end of treatment; ICF: informed consent form; PED25: pediatric equivalent dose 25 mg; PED50: pediatric equivalent dose 50 mg 
 
Screening 
& 
Urotherapy (4 weeks) + 
Washout (1 week, if applicable) 
Mirabegron + Urotherapy 
(4 weeks PED25, 8 weeks PED50) 
Placebo + Urotherapy 
(4 weeks PED25, 8 weeks PED50) 
Safety Observation 
(2 weeks) 
ICF/Assent 
Signed 
EoS 
Randomization 
at Baseline 
EoT 
Screening Period/Urotherapy (4 weeks) 
Double-blind, Placebo-controlled Period (12 weeks) 
Follow-up Period (2 weeks) 

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1.3 
Schedule of Assessments 
Table 1 
Schedule of Assessments 
Schedule of Assessments 
Screening Period/Urotherapy 
(4 weeks) 
Double-blind Placebo-controlled Period 
(12 weeks) 
Follow-up Period 
(2 weeks) 
Visit 1 
Visit 2/TCa 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Week -4 
Screening 
Week -2 
Week 0 
Baseline 
Week 2 
TCa 
Week 4 
Week 8 
TCa 
Week 12 
(EoT)b 
Week 14 
(EoS)b,c 
Day -28 
(-3 days) 
Day -14 
(± 5 days) 
Day -1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days) 
Day 56 
(± 3 days) 
Day 84 
(± 3 days) 
Day 98 
(+ 3 days) 
Obtaining Informed Consent/Assent 
X 
 
 
 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
 
X 
 
 
 
 
 
Washout 
Xd 
 
 
 
 
 
 
 
Urotherapy 
X 
X 
X 
X 
X 
X 
X 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
Previous and Concomitant Medication 
X 
 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
X 
 
X 
 
Height and Body Weight 
X 
 
X 
 
 
 
X 
 
Uroflow 
X 
 
 
 
 
 
 
 
Dose Titratione 
 
 
 
 
X 
 
 
 
Dispense IPf 
 
 
X 
 
X 
 
 
 
Drug Accountability 
 
 
X 
 
X 
 
X 
 
Vital Signsg 
X 
 
X 
 
X 
 
X 
X 
SBPMh 
 
X 
X 
X 
X 
X 
X 
 
Routine 12-lead ECGg 
X 
 
X 
 
X 
 
X 
 
Clinical Laboratory Tests (Hematology and Biochemistry) 
X 
 
Xi 
 
X 
 
X 
Xi 
Clinical Laboratory Tests (Urinalysis) 
X 
 
Xi 
 
X 
 
X 
Xi 
Pregnancy Testj 
X 
 
X 
 
X 
 
X 
X 
PVR Volumek 
 
 
X 
 
X 
 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Bladder e-diarya,l 
 
X 
X 
X 
X 
X 
X 
 
Table continued on next page 

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Schedule of Assessments 
Screening Period/Urotherapy 
(4 weeks) 
Double-blind Placebo-controlled Period 
(12 weeks) 
Follow-up Period 
(2 weeks) 
Visit 1 
Visit 2/TCa 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Week -4 
Screening 
Week -2 
Week 0 
Baseline 
Week 2 
TCa 
Week 4 
Week 8 
TCa 
Week 12 
(EoT)b 
Week 14 
(EoS)b,c 
Day -28 
(-3 days) 
Day -14 
(± 5 days) 
Day -1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days) 
Day 56 
(± 3 days) 
Day 84 
(± 3 days) 
Day 98 
(+ 3 days) 
Acceptability and Palatability Questionnairem 
 
 
 
 
 
 
X 
 
Pharmacokineticsn 
 
 
 
 
X 
 
X 
 
AE: adverse event; ECG: electrocardiogram; e-diary: electronic diary; EoS: end of study; EoT: end of treatment; IP: investigational product; PED25: pediatric equivalent dose 25 mg; 
PED50: pediatric equivalent dose 50 mg; PVR: post void residual; SBPM: self blood pressure monitoring; TC: telephone call 
a. 
For the visits where a TC is indicated, there is no need for the subject to visit the clinic provided that the bladder e-diary data are reviewed by the investigator prior to the TC and 
discussed and confirmed with the subject or parent(s)/legal guardian(s) during the TC.  Urotherapy is also to be discussed and confirmed with the subject or parent(s)/legal 
guardian(s) during each TC. 
b. 
Subjects who withdraw early from the study after having received IP should complete both the EoT and EoS visits. 
c. 
The EoS visit (visit 8/week 14 [EoS]) should take place at least 14 days after the EoT visit (visit 7/week 12 [EoT]). 
d. 
Subjects using prohibited medication will complete 1 week of washout (if applicable), while beginning 4 weeks of urotherapy. 
e. 
Dose up-titration to PED50 to occur at visit 5/week 4 unless investigator determines OAB is adequately controlled.  Dose down-titration from PED50 to PED25 can be done at 
any time for safety reasons. 
f. 
Daily IP administration will start on day 1 (i.e., the day after visit 3/week 0 [baseline]). 
g. 
Blood pressure, pulse, body temperature and ECGs will all be measured in single measurements.  Subject to be in the sitting position (when possible, otherwise supine, but always 
in the same position for each procedure).  Subject should have been calm and without distress for at least 5 minutes.  Preferably, the right arm should be used to measure vital 
signs.  Body temperature will be measured with an ear thermometer.  Clinic measurements will be used to assess eligibility. 
h. 
SBPM will be measured once in the morning and evening during the 2-day weekend bladder e-diary collection period. SBPM measurements should start in the weekend prior to 
week -2 and be taken in the weekend prior to the indicated visit (or TC). SBPM will be measured on 2 consecutive days at 1 and 2 weeks after start of dosing with PED25 (day 1) 
and after up-titration to PED50, if not already covered by the scheduled SBPM.  Measurements will be taken in the sitting position (when possible, otherwise supine, but always 
in the same position).  Preferably, the right arm should be used.  Subject should have been calm and without distress for at least 5 minutes.  Morning measurement should be taken 
before IP intake and evening measurement should be taken prior to bedtime. 
i. 
Additional hematology, biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 3/week 0 (baseline) and visit 8/week 14 (EoS) only if an AE related to 
hematology, biochemistry or urinalysis parameters occurred since the previous visit or at the discretion of the investigator. 
j. 
Urine pregnancy test will be performed for females of childbearing potential at all on-site visits. 
Footnotes continued on next page 

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k. 
PVR volume will be assessed by ultrasonography at visit 3/week 0 (baseline), visit 5/week 4, visit 7/week 12 (EoT) and visit 8/week 14 (EoS).  For each subject, the same method 
should be used throughout the study.  The bladder should only be emptied when it was initially filled with preferably > 50% of the bladder capacity for age.  Every attempt should 
be made to measure PVR volume within a minute of voiding.  A PVR volume of ≤ 20 mL is sufficient and the assessment does not have to be repeated.  If the PVR volume is 
> 20 mL, the PVR volume assessment should be repeated (filled with preferably > 50% of the bladder capacity for age).  If the subject is unable to complete a second 
measurement, it is up to the investigator to judge whether it can be skipped (and write the reason in the case report form).  At visit 3/week 0 (baseline), the lowest PVR volume 
result measured should be used to evaluate the exclusion criterion.  In case the lowest PVR volume measured is > 20 mL at visit 3/week 0 (baseline), the subject should be 
excluded from the study. 
l. 
At the end of a successful screening visit (visit 1/week -4 [screening]), all subjects will be provided with a device to collect diary information. At the weekend prior to the week -2 
visit, the subject will complete the 2-day bladder e-diary to get acquainted with the data collection. The 2-day diary will be reviewed at the week -2 visit. If completion is 
successful, all subjects will start with the 7-day bladder e-diary completion approximately 7 days prior to the indicated visit (or TC). The bladder e-diary is used for a 7-day period 
to record micturition frequency and incontinence episodes; it also contains a 2-day weekend period to record additional volume measurements and vital signs. 
m. 
The acceptability and palatability questionnaire will be completed on one weekend day proceeding at visit 7/week 12 (EoT). 
n. 
There will be 2 pharmacokinetic sampling days at visit 5/week 4 and visit 7/week 12 (EoT).  Both pharmacokinetic sampling days will consist of collecting 1 predose (trough) 
sample.  On pharmacokinetic sampling days, dosing should occur in the clinic and breakfast should be eaten at the clinic within 1 hour before dosing. 
 

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1.3.1 
Sample Collection Schedule 
There will be 2 pharmacokinetic sampling days at visit 5/week 4 and visit 7/week 12 (EoT).  
Both pharmacokinetic sampling days will consist of collecting 1 predose (trough) sample.  
On pharmacokinetic sampling days, dosing should occur in the clinic and breakfast should be 
eaten at the clinic within 1 hour before dosing. 
Table 2 
Sample Collection Schedule 
Visit 
Time Point 
Collection Window 
Whole Blood 
Pharmacokinetics 
Visit 5/week 4  
Predose (trough) 
Approximately 24 hours after  
previous dose 
X 
Visit 7/week 12 
(EoT) 
Predose (trough) 
Approximately 24 hours after  
previous dose 
X 
EoT: end of treatment 
2 
INTRODUCTION 
2.1 
Background 
The present study is designed to evaluate efficacy, safety and pharmacokinetics of 
mirabegron in pediatric subjects with overactive bladder (OAB). 
The study is part of the sponsor’s clinical program for development of mirabegron for the 
treatment OAB in pediatric patients.  Current drug therapy for OAB consists of oral 
antimuscarinics such as oxybutynin.  Although the vast majority (approximately 90%) of 
patients can be treated successfully with this, development of alternative therapy is desirable 
because of insufficient efficacy and/or the side effects of available therapies. 
Mirabegron is a first-in-class, selective human beta 3-adrenergic receptor (AR) agonist, 
represents a class of drugs for treatment of OAB with a direct mechanism of action.  
Mirabegron activation of beta 3-AR in the human bladder results in a relaxation of the 
detrusor smooth muscle during the fill-void cycle without interfering with the voiding 
contraction. Mirabegron is currently available as 25 mg and 50 mg tablets.  An oral 
suspension is also being investigated for the treatment of OAB and neurogenic detrusor 
overactivity (NDO) in the pediatric population. 
The population for this pediatric clinical efficacy study (Study 178-CL-204) with mirabegron 
is pediatric patients with OAB. 
2.1.1 
Treatment of Overactive Bladder in Pediatric Population 
Classical treatment of OAB in pediatric patients consists of urotherapy followed by 
antimuscarinic therapy if the urotherapy is not sufficient.  Other therapies for OAB are also 
described. 

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Urotherapy 
Standard urotherapy includes information on and demystification of the voiding function and 
dysfunction, instruction on voiding habits (such as regular voiding, voiding posture), life 
style advice regarding fluid intake, prevention of constipation, recording of symptoms and 
voiding habits in bladder diaries and support via regular follow-up by a caregiver. 
Specific interventions include various forms of pelvic floor training (relaxation, contraction), 
behavioral modification, electrical stimulation, catherization and biofeedback (use of 
objective measures, e.g., uroflow or surface electromyography (EMG) to show children how 
far they relax their pelvic floor during voiding).  Urotherapy can also include elements of 
cognitive behavioral therapy [Nevéus et al, 2006]. 
Other Therapies for OAB 
Alternative drug therapy for OAB includes antimuscarinic therapy such as oxybutynin. 
Neuromodulation is also used in patients who do not respond adequately to drug therapy. 
2.1.2 
Nonclinical and Clinical Data 
Detailed information from nonclinical and clinical studies conducted with mirabegron can be 
found in the Investigator’s Brochure.  Nonclinical and clinical data are also summarized in 
the current locally-available product information for mirabegron. 
2.1.2.1 Nonclinical Data 
The standard nonclinical pharmacology studies as conducted for the use of mirabegron in 
adult patients with OAB are also relevant for its use in adolescent pediatric patients with 
OAB or NDO.  Primary nonclinical pharmacology data for mirabegron qualitatively but not 
quantitatively translates to human clinical use in OAB.  Other pharmacological effects such 
as the glucogenolytic effects of mirabegron in rodents did not translate to an effect in 
humans.  These differences relate to species differences in molecular biology of the beta 
3-AR, differences in receptor distribution, and differences in coupling to downstream effector 
mechanisms.  From these factors only receptor expression or receptor-effector coupling 
efficiency are likely to vary by age.  No detailed information is available on potential 
differences in expression for beta 3-AR in humans or animals during maturation.  The sparse 
data available [Derweesh et al, 2000] suggest that any changes in beta-adrenergic 
responsiveness in rat urinary bladder could be expected at older age rather than at infancy or 
adolescence. 
2.1.2.2 Clinical Data 
The main clinical aspects of mirabegron prolonged-release tablets in adults are described in 
the current locally-available product information for mirabegron. 
To support the doses and formulations (tablets and oral suspension) selected for this study, 
the pediatric development program for mirabegron includes 4 phase 1 studies [Table 3]. 

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Table 3 
Overview of Current Supporting Mirabegron Studies in the Pediatric 
Clinical Development Program for Neurogenic Detrusor Overactivity and 
Overactive Bladder 
Study Number 
Study Title 
Study Progress 
178-CL-201 
A phase 1, single dose, 4-period crossover study to assess the 
bioavailability of mirabegron oral suspension relative to the 
mirabegron prolonged-release tablet and to assess the effect of 
food on the pharmacokinetics of mirabegron oral suspension in 
healthy young male and female subjects 
Completed 
178-CL-202 
A multicentre, open-label, single ascending dose phase 1 study to 
evaluate the pharmacokinetics, safety and tolerability of 
mirabegron OCAS tablets in pediatric subjects from 5 to less than 
18 years of age with NDO or OAB 
Completed 
178-CL-203 
A multicentre, open-label, single dose, phase 1 study to evaluate 
the pharmacokinetics, safety and tolerability of mirabegron oral 
suspension in pediatric subjects from 3 to less than 12 years of age 
with NDO or OAB 
Completed 
178-CL-208 
A phase 1, single dose, 3-period crossover study to assess the 
bioavailability of an oral suspension of 8 mg/mL mirabegron 
relative to the oral suspension of 2 mg/mL mirabegron and to 
assess the effect of food on the pharmacokinetics of the oral 
suspension of 8 mg/mL mirabegron in healthy male and female 
adult subjects 
Completed 
178-CL-206A 
An open-label, baseline-controlled, multicenter, phase 3 dose-
titration study followed by a fixed dose observation period to 
evaluate efficacy, safety and pharmacokinetics of mirabegron in 
children and adolescents from 3 to less than 18 years of age with 
NDO on CIC 
Completed 
CIC: Clean Intermittent Catheterization; NDO: neurogenic detrusor overactivity; OAB: overactive bladder; 
OCAS: oral-controlled absorption system. 
The data from Studies 178-CL-201 and 178-CL-202 were used to support the use of tablets in 
pediatric subjects with a body weight of ≥ 35 kg in this study.  For those pediatric subjects 
that cannot be dosed with tablets because their body weight is < 35 kg or because they cannot 
swallow the tablets, an oral suspension with a strength of 2 mg/mL was developed.  The 
results of Studies 178-CL-201 and 178-CL-202 were used to support the use of the 2 mg/mL 
in Study 178-CL-203.  With the results of the Study 178-CL-203, it became apparent that 
with a strength of 2 mg/mL the volume of the doses the patients have to take every day would 
be too high (up to 44 mL).  To overcome this issue, an oral suspension of 8 mg/mL was 
developed.  To support the use of this 8 mg/mL mirabegron oral suspension in pediatric 
subjects, Study 178-CL-208 was conducted.  The study follows a single dose, 3 period, 
crossover design in healthy adult subjects.  Subjects received the following three treatments 
in random order: 1) 11 mL of 8 mg/mL oral suspension of mirabegron under fasted 
conditions, 2) 11 mL of 8 mg/mL oral suspension of mirabegron under fed conditions and 
3) 44 mL of 2 mg/mL oral suspension of mirabegron under fasted conditions. 
The primary objective of Study 178-CL-208 was to assess the relative bioavailability of the 
8 mg/mL oral suspension compared to the 2 mg/mL oral suspension under fasted conditions.  

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The results of Study 178-CL-208 show that the bioavailability of both strengths is 
comparable [Table 4]. 
Table 4 
Study 178-CL-208 Results: Relative Bioavailability of the Mirabegron 
8 mg/mL Oral Suspension Formulation versus 2 mg/mL Oral Suspension 
Formulation (Pharmacokinetics Analysis Set) 
Parameter 
(units) 
Geometric LS Mean for 
8 mg/mL Suspension 
Fasted 
(n = 24) 
Geometric LS Mean for 
2 mg/mL Oral Suspension 
Fasted 
(n = 23) 
Geometric LS 
Mean Ratio 
(%)† 
90% CI of 
Ratio (%)† 
AUCinf 
(ng•h/mL) 
253 
251 
100.6 
(90.9, 
111.3) 
AUClast 
(ng•h/mL) 
234 
232 
100.9 
(90.6, 
112.4) 
Cmax 
(ng/mL) 
12.1 
11.3 
106.7 
(84.2, 
135.2) 
LS: least squares 
The analysis was performed on logarithm-transformed pharmacokinetic parameters using a linear mixed model 
with treatment and investigational period as fixed effects and accounting for the longitudinal nature of the data 
by subject using a repeated statement.  The covariance matrix is structured by period. 
† 
The geometric LS mean ratios (and associated 90% CIs) were obtained by back-transforming (antilogging) 
the LS means of the treatment differences. 
This study demonstrated that 88 mg mirabegron administered as the 8 mg/mL oral 
suspension formulation was bioequivalent to 88 mg mirabegron administered as the 
2 mg/mL oral suspension formulation.  An effect of food in line with the literature data for 
50 mg mirabegron prolonged-release tablets was observed for the 8 mg/mL mirabegron oral 
suspension formulation. 
Study 178-CL-206A was a phase 3, 52-week, open-label, baseline-controlled, dose-titration 
multicenter study evaluating the efficacy and safety of mirabegron tablets and oral 
suspension (8 mg/mL) in 86 pediatric patients with NDO using clean intermittent 
catheterization (CIC), including 55 children aged 3 to < 12 years and 31 adolescents aged 
12 to < 18 years.  Patients received mirabegron tablets or oral suspension once daily for up to 
52 weeks, starting at pediatric equivalent dose 25 mg (PED25) and up-titrated to pediatric 
equivalent dose 50 mg (PED50). 
This study showed a statistically significant improvement that was present at week 4 and 
sustained throughout the efficacy treatment period.  Secondary and sensitivity analyses of the 
primary endpoint confirmed the primary analysis.  Mirabegron appeared to be safe and well 
tolerated by pediatric patients with NDO under the condition of Study 178-CL-206A. 
The detailed results of Studies 178-CL-201, 178-CL-202, 178-CL-203, 178-CL-208 and 
178-CL-206A are reported in the Investigator’s Brochure. 
The doses described in [Section 2.1.2.2 Clinical Data] suggest tablets for subjects with a 
body weight of ≥ 35 kg unless unable to swallow tablets and would be provided the oral 
suspension as an alternative, and the 8 mg/mL oral suspension for subjects with a body 
weight < 35 kg. 

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Safety and Tolerability 
In Study 178-CL-203 the safety and tolerability of the oral suspension when dosed in 
children was evaluated and it was concluded that it was safe and well tolerated. 
From the 9 subjects who completed the study (6 with NDO and 3 with OAB) 1 treatment 
emergent adverse event (TEAE) was reported: pyrexia on day 1 in an NDO subject.  The 
intensity was mild and was judged by the investigator not to be related to study drug.  No 
clinically significant electrocardiogram (ECG) abnormalities have been seen throughout the 
study, there were no QT interval using Fridericia’s correction formula (QTcF) values 
> 450 msec and no QT interval prolongation > 30 msec versus baseline was observed (mean 
of triplicates). 
A 24-hour continuous 12-lead ECG recording was recorded in all subjects on a reference day 
and on the dosing day.  The main objective of the continuous 12-lead ECG recording was to 
evaluate the effect of mirabegron on heart rate in a time-matched manner, taking into account 
the circadian rhythm.  A median increase in 24-hour heart rate of 5.1 bpm was observed.  
This was not considered as clinically relevant due to the multiple blood draws, the low 
number of subjects and the absence of a placebo treatment group. 
Some changes in laboratory values were observed, but they were not considered as clinically 
relevant. 
For Study 178-CL-208 single doses of 88 mg mirabegron oral suspension to adults were safe 
and well tolerated.  Eleven of 24 subjects reported 22 adverse events (AEs).  All except for 
2 events (1 headache moderate and 1 dysmenorrhea moderate) were mild.  Twenty AEs were 
considered not related; 2 were considered possibly related (dizziness, mild and orthostatic 
dizziness mild). 
For study 178-CL-206A mirabegron tablets and oral suspension (8 mg/mL) once daily for up 
to 52 weeks, starting at PED25 and up-titrated to PED50 was generally well tolerated by 
pediatric patients in the completed clinical study.  One of 86 (1.2%) patients (an adolescent) 
reported bradycardia.  Using Fleming et al [2011], 3 of 50 (6.0%) children and 2 of 
28 (7.1%) adolescents had potentially clinically relevant pulse rate readings during the study.  
Only 1 of 78 (1.3%) patients (a child) met the criteria for a TEAE of hypertension which was 
considered not related to the study drug by the investigator. 
There were no clinically significant vital signs, clinical laboratory value or 12-lead ECG 
findings.  Based on the mean visual analogue scale score for palatability, the suspension was 
acceptable in pediatric population and did not require further taste adjustment.  The oral 
suspension when dosed in children was considered to be safe and well tolerated. 
2.1.3 
Summary of Key Safety Information for Investigational Product(s) 
Mirabegron has not been approved or marketed for use in pediatric subjects. 
Detailed reference safety information (RSI) can be found in the Investigator’s Brochure for 
mirabegron. 

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Mirabegron has been approved in more than 81 countries worldwide.  In adults, the safety of 
mirabegron treatment has been well characterized in 5863 subjects (95% with OAB) in the 
phase 2/3 registration studies treated with mirabegron at doses ranging from 25 to 
200 mg once daily.  Identified risks include increased heart rate and tachycardia, 
hypersensitivity reactions, increased blood pressure and urinary retention.  Potential risks 
include QT prolongation, urinary tract infection (UTI), fetal disorders after exposure during 
pregnancy and events induced by concomitant treatment with cytochrome 
P450 2D6 (CYP2D6) substrates with a narrow therapeutic index.  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 adults. 
2.2 
Study Rationale 
OAB is recognized by the International Children’s Continence Society (ICCS) [Austin et al, 
2014], this study is intended to assess the effects of mirabegron in pediatric patients with 
OAB to understand its potential role in therapy.  This study (Study 178-CL-204) is part of the 
sponsor’s clinical program to develop mirabegron for OAB in pediatric subjects.  In the EU, 
the development of mirabegron for the indication of OAB is outlined in the pediatric 
investigational plan (PIP) for mirabegron and has been approved by the Pediatric Committee.  
This study is part of PIP commitment. 
2.3 
Risk-Benefit Assessment 
This study will be conducted as a double-blind, randomized, multicenter, parallel group, 
placebo-controlled sequential dose titration study in pediatric subjects from 5 to < 18 years of 
age with OAB. 
The study design and dose rationale are presented in [Section 4 Study Design and Dose 
Rationale]. 
Mirabegron tablets have been approved for the indication of OAB in adult subjects.  
Mirabegron oral suspension has been shown to be safe and well tolerated in 2 phase 1 studies 
in healthy adult subjects (Studies 178-CL-201 and 178-CL-208).  In the pediatric 
phase 1 studies executed thus far, mirabegron tablets and mirabegron oral suspension had an 
acceptable safety profile and were well tolerated.  Given the available data on mirabegron in 
the adult population and in the pediatric population to date, the risk-benefit attributes are well 
defined and can be managed through ongoing safety assessments throughout study conduct as 
defined in the Schedule of Assessments [Table 1]. 
The important identified and potential risks in adults are recognized as potential drug safety 
risks for this study (Study 178-CL-204).  These risks will be monitored on a regular basis and 
can be mitigated as follows: 
● 
The initial dose of mirabegron will be based on the subject’s body weight and is 
predicted to achieve plasma concentrations equivalent to the steady-state exposures 

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expected with 25 mg mirabegron administered once daily in adults (PED25).  This low 
dose is chosen considering possible beta-adrenergic side effects of mirabegron. 
● 
At visit 5/week 4 (i.e., after 4 weeks on PED25), dose up-titration to PED50 will be 
performed unless the investigator determines that the subject is adequately treated for 
OAB at the PED25 dose or if there are safety concerns identified and considered 
associated with the use of PED25.  Dose down-titration from PED50 to PED25 can be 
done at any time thereafter for safety reasons.  By striving to get an efficacious dose of 
mirabegron early after start of dosing, the risk for bladder and kidney damage is 
mitigated. 
● 
Potential fetal disorders after exposure during pregnancy is mitigated by the inclusion 
criteria 
● 
Hypersensitivity reactions (immediate or nonimmediate and cutaneous or noncutaneous) 
will be monitored by AE monitoring and will require discontinuation of study treatment 
● 
Potential UTI will be monitored by urinalysis at each visit in the clinic  
● 
Increased blood pressure will be monitored by at-home and clinic measurements and can 
be mitigated by dose titration 
● 
Increased heart rate and tachycardia will be monitored by at-home and clinic 
measurements and can be mitigated by dose titration 
● 
Potential QT prolongation will be monitored by ECG at each visit at the clinic and can 
be mitigated by dose titration 
● 
Potential events by concomitant treatment with CYP2D6 substrates with narrow 
therapeutic index is mitigated by excluding these medications 
For activation of thermogenesis in brown fat, weight loss will be monitored by regular body 
weight measurements and the potential activation of thermogenesis will be monitored by 
body temperature measurements. 
For both the tablet and the oral suspension formulation, all excipients are pharmaceutical 
grade materials and are considered safe for the intended pediatric population.  Their 
concentrations remain below the acceptable daily intake as set by the joint Food and 
Agriculture Organization (FAO) of the UN and the WHO (joint FAO/WHO Expert 
Committee on Food Additives, 2015). 
The protocol is designed to monitor safety and mitigate risk to the pediatric subject by 
optimizing the number of vital signs, ECG and post void residual (PVR) volume assessments, 
minimizing the number of blood draws (safety and pharmacokinetic sampling) and focusing 
the number of study visits. 
The use of population pharmacokinetics for the analysis of the pharmacokinetic profile of 
mirabegron allows reduction of the number of blood draws for pharmacokinetic analysis to 2.  
Butterfly needles can be used and are allowed to stay in place to reduce the number of 
punctures. 
The blood draws for clinical laboratory tests have been minimized to lessen subject burden 
while ensuring subject safety.  Additional hematology and biochemistry tests will be 
performed at visit 3/week 0 (baseline) and visit 8/week 14 (end of study [EoS]) only if an AE 

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related to hematology, biochemistry or urinalysis parameters occurred since the previous visit 
or at the discretion of the investigator. 
The assessments to be performed are routine assessments and generally do not pose any 
particular risk to the subjects.  Every effort will be made to reduce the anxiety felt by 
subjects, e.g., during a blood test, topical anesthetic will be offered at venipuncture to 
minimize distress of the subject. 
Subjects may experience AEs associated with the assessments performed during the study, 
such as local irritations due to ECG recording, and bleeding, hematoma as a result of blood 
collection, or the experience of transient stinging or burning during emptying or of the 
passing of a little blood as a result of the urodynamic investigation.  There is also a small risk 
of developing a bladder infection in relation to the urodynamic procedure. 
An independent Data and Safety Monitoring Board (DSMB) will be established 
[Section 10.4 Study Organization].  A separate charter will describe the responsibilities of the 
DSMB. 
3 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
The primary, secondary and exploratory objectives and endpoints for this study are listed in 
[Table 5]. Primary and secondary objectives and endpoints apply to children only; 
exploratory objectives and endpoints also apply to adolescents. 
Table 5 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
● 
To evaluate the efficacy of mirabegron in 
children (5 to < 12 years of age) with OAB 
● 
Change from baseline at the end of the 12-week 
treatment period: 
○ 
Mean number of micturitions per 24 hours 
Secondary 
● 
To evaluate the efficacy of mirabegron in 
children (5 to < 12 years of age) with OAB 
● 
Change from baseline at the end of the 12-week 
treatment period: 
○ 
Mean volume voided per 24 hours 
○ 
Maximum volume voided 
○ 
Mean number of daytime incontinence 
episodes per 24 hours 
○ 
Mean number of nighttime incontinence 
episodes per 24 hours 
○ 
Mean number of daytime micturitions per 
24 hours 
● 
Number of dry (incontinence-free) days per 
7 days at the end of the 12-week treatment period 
Table continued on next page 

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Objectives 
Endpoints 
● 
To evaluate the safety and tolerability of 
mirabegron in pediatric subjects with OAB 
● 
Nature, frequency and severity of AEs 
● 
Clinical laboratory tests (hematology, 
biochemistry and urinalysis) 
● 
Vital signs (blood pressure and pulse) 
● 
Routine 12-lead ECG 
● 
PVR volume 
● 
Acceptability and palatability questionnaire 
● 
To evaluate the pharmacokinetics after multiple 
dose administration of mirabegron in pediatric 
subjects with OAB 
● 
Steady-state Cmax, AUCtau, Ctrough, Tmax, CL/F and 
Vz/F.  Additional parameters may be calculated 
based on the population pharmacokinetic model 
used 
Exploratory 
● 
To evaluate the efficacy of mirabegron in 
pediatric subjects (5 to < 18 years) with OAB 
● 
Percentage of subjects with a reduction in daytime 
incontinence episodes (< 50% reduction 
[nonresponder], 50% [partial responder] and 
100% [responder]) 
● 
Improvement from baseline in worst incontinence 
grading 
● 
Change from baseline at the end of the 12-week 
treatment period adjusted for fluid intake: 
○ 
Mean number of micturitions per 24 hours 
● 
Change from baseline at the end of the 12-week 
treatment period (adolescents only): 
○ 
Mean number of micturitions per 24 hours 
○ 
Mean number of daytime micturitions per 
24 hours 
○ 
Mean volume voided per 24 hours 
○ 
Mean number of incontinence episodes per 
24 hours 
● 
Number of dry (incontinence-free) days per 
7 days at the end of the 12-week treatment period 
(adolescents only) 
● 
Mean number of daytime grade 3 or 4 (PPIUS) 
urgency episodes per 24 hours (adolescents only) 
AE: adverse event; ECG: electrocardiogram; OAB: overactive bladder; PPIUS: patient perception of intensity of 
urgency scale; PVR: post void residual. 
3.1 
Estimand 
The estimand of most clinical importance for this study is defined by the following 
4 attributes: 
● 
Target population: all children who took at least 1 dose of the study drug, and in whom a 
nonmissing measurement for micturition frequency at baseline and after administration 
of the study drug is available 
● 
Outcome measurement: micturition frequency/day (24 hours) 
● 
Intercurrent events: 
1. Discontinuation from treatment (if week 12/EoT not obtained) 
2. AE UTI (if occurred in week 12/EoT) 

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3. Other muscarinic antagonists or botulinum toxin see [Appendix 12.6 List of 
Excluded Concomitant Medications]) (if taken during the last 2 weeks prior to 
week 12/EoT assessment); in all cases, a hypothetical strategy will be applied 
● 
Population-based summary: Change from baseline to week 12/EoT in micturition 
frequency/day (= primary endpoint, primary estimator), compared to placebo 
For this placebo-controlled study, this “de jure” estimand chosen is considered the 
appropriate choice.  As some effect is expected early in the study and with continued 
treatment could be expected to be maintained, it’s considered appropriate to impute for 
subjects with missing values at visit 7/week 12/EoT by their last recorded post baseline visit 
value prior to it.  This strategy also assumes that the responses after the intercurrent event 
would be same as for patients continuing on their respective treatment. 
4 
STUDY DESIGN AND DOSE RATIONALE 
4.1 
Study Design 
This is a double-blind, randomized, multicenter, parallel group, placebo-controlled sequential 
dose titration study to evaluate efficacy, safety and pharmacokinetics of mirabegron in 
pediatric subjects with OAB.  Male and female pediatric subjects 5 to < 18 years of age with 
OAB; as defined according to the ICCS [Austin et al, 2014] who have had received 4 weeks 
of urotherapy prior to randomization. 
Planned total number of study sites includes approximately 65 study sites across Europe, 
Latin America, Africa, Middle East, Asia-Pacific and North America. 
The study consists of 3 periods with a total duration of 18 weeks. 
● 
Screening period/urotherapy (4 weeks): 
This period starts with visit 1/week -4 (screening) and ends with visit 3/week 0 (baseline).  
After informed consent/assent has been obtained and immediately after eligibility has 
been confirmed at visit 1/week -4 (screening), subjects using prohibited medication will 
complete 1 week of washout (if applicable), while beginning 4 weeks of urotherapy. 
After a successful screening visit (visit 1/week -4 [screening]), all subjects will need to 
complete a 2-day bladder e-diary (weekend) to get acquainted with the bladder e-diary 
and the assessments.  Completion of this bladder e-diary should start in the weekend 
prior to visit 2.  All subjects will also complete a 7-day bladder e-diary the week prior to 
the baseline visit.  The 7-day diary will consist of a 5-day weekday bladder e-diary and 
2-day weekend e-diary. 
● 
Double-blind, placebo-controlled period (12 weeks): 
This period starts with the day after visit 3/week 0 (baseline) and ends with 
visit 7/week 12 (EoT). 
At visit 3/week 0 (baseline), inclusion and exclusion criteria will be evaluated.  Subjects 
continuing urotherapy who still meet the OAB entry criteria at baseline will be 

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randomized.  Subjects whose symptoms are not satisfactorily controlled with urotherapy 
and still fulfill the inclusion/exclusion criteria will enter the study.  These subjects will 
be randomized to receive mirabegron in PED25 or placebo using a 1:1 ratio.  Subjects 
with a body weight of ≥ 35 kg are to receive the tablet unless unable to swallow tablets 
and would be provided the oral suspension as an alternative.  Subjects with a body 
weight < 35 kg or those who cannot be dosed with the tablet will receive an oral 
suspension.  Daily investigational product (IP) administration will start on day 1 (i.e., the 
day after this visit) and continue at this dose until visit 5/week 4 (i.e., for 4 weeks).  
Urotherapy will continue throughout the study treatment period until 
visit 7/week 12 (EoT). 
At visit 5/week 4, dose up-titration to mirabegron in PED50 will be performed unless the 
investigator determines that the subject is adequately treated for OAB at the PED25 dose 
or if there are safety concerns identified and considered associated with the use of 
PED25.  Dose down-titration from PED50 to PED25 can be done at any time thereafter 
for safety reasons. 
Subjects will start with the subsequent 7-day bladder e-diaries approximately 7 days 
prior to the indicated visit (or TC). 
Pharmacokinetic blood samples will be collected at visit 5/week 4 and 
visit 7/week 12 (EoT) as indicated in the Schedule of Assessments [Table 1]. 
● 
Follow-up period (2 weeks): 
This period starts the day after visit 7/week 12 (EoT) and ends with 
visit 8/week 14 (EoS).  The follow-up period is applicable to all subjects who have been 
randomized and received IP. 
At visit 7/week 12 (EoT), IP administration will be stopped and a safety observation 
period of 2 weeks will start. 
An independent DSMB will be established.  A separate charter will describe the 
responsibilities of the DSMB. 
A blinded interim analysis will be performed after 50% of children planned to be 
randomized have had their week 12/EoT assessment.  The interim analysis will 
determine if the chance of a positive study with respect to the primary endpoint at the 
EoS is high enough to justify continuation of the study; otherwise, the study will be 
stopped for futility. 
The IP will not be provided after study completion without written approval from the sponsor. 
4.2 
Dose Rationale 
The target exposures of 69 and 188 ng•h/mL for PED25 and PED50 were derived from the 
adult phase 3 program and are the mean steady-state area under plasma concentration-time 
curve over dosing interval (AUCtau) values following 25 and 50 mg prolonged-release tablets 
once daily in adults. 

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A population pharmacokinetic model was used to predict the pediatric equivalent dose for 
subjects in Study 178-CL-204.  In brief, this population pharmacokinetic model was 
developed on adult phase 3 data, and allometric (weight-based) scaling was added to all 
clearance and volume terms to allow for scaling of the pharmacokinetics to pediatric subjects.  
The model was validated on pediatric data in Study 178-CL-202 (single ascending-dose 
study) and was shown to appropriately predict the pharmacokinetics of mirabegron in 
pediatric subjects. 
Simulations were then performed to determine a body weight at which subjects would have 
steady-state exposures comparable to those in adults when dosed with 25 or 50 mg daily; this 
weight was determined to be ≥ 35 kg.  Based on prior experience obtained in an ongoing 
Astellas study in another program in patients with NDO (Study 905-CL-047) the average age 
at which children reach a body weight of 35 kg is approximately 11 years.  The dosing 
recommendation based on this modeling is in line with the literature [Momper et al, 2013] in 
which a meta-analysis of compounds submitted to the US FDA with a similar indication in 
adults and adolescents showed that in almost all cases, the adolescents required the same dose 
as the adults. 
Therefore, subjects with a body weight of ≥ 35 kg can be dosed with mirabegron tablets 
unless unable to swallow tablets and would be provided the oral suspension as an alternative.  
Subjects with a body weight < 35 kg cannot be dosed with the 25 and 50 mg tablets because 
that would exceed the target exposures.  Subjects with a body weight < 35 kg will therefore 
be dosed with mirabegron oral suspension. 
Mirabegron oral suspension (8 mg/mL) has been developed for use in the pediatric 
population.  The population pharmacokinetic model referred to above includes a formulation 
factor to account for the different (lower) relative bioavailability of the oral suspension 
compared to the tablet.  This factor has been used in simulations to predict the suspension 
doses and weight categories that would have a reasonable variance around the target 
exposures. 
For dosing with oral suspension, the weight range to be covered is from 13 kg (the 
approximate body weight of a 5-year-old child, according to the National Health and 
Nutrition Examination Survey database [McDowell et al, 2008]) to 35 kg (above which 
pediatric subjects could be dosed with the tablet formulation).  Subjects with a body weight 
< 13 kg will not be included in the study.  Suspension dosing for body weights ≥ 35 kg was 
also determined for cases in which a pediatric subject in that weight category who cannot be 
dosed with the tablets.  The simulation resulted in the 3 body weight categories that can be 
found in the dosing schedule (see [Table 7]). 
4.3 
End of Study Definition 
The study start is defined as the date the first subject and/or the subject’s parent(s)/legal 
guardian(s) sign(s) informed consent/assent.  End of the study is defined as the last visit or 
scheduled procedure shown in the Schedule of Assessments [Table 1] for the last subject in 
the study. 

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5 
STUDY POPULATION 
All screening assessments must be completed and reviewed to confirm the potential subject 
meets all eligibility criteria.  Prospective approval of protocol deviations to eligibility criteria 
(also known as protocol waivers or exemptions) is not permitted. 
5.1 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply: 
Inclusion at Visit 1/Week -4 (Screening) 
1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved 
written informed consent/assent and privacy language as per national regulations (e.g., 
General Data Protection Regulations for European Union study sites) must be obtained 
from the subject and/or from the subject’s parent(s)/legal guardian(s) prior to any 
study-related procedures (including withdrawal of prohibited medication, if applicable); 
assent by the subject is obtained as required by local law. 
2. Subject has OAB defined according to the ICCS criteria. 
3. Subject is a male or female between 5 to < 18 years of age, at screening. 
4. Subject weighs at least 13 kg at screening. 
5. Subject is able to take the IP in accordance with the protocol. 
6. Subject agrees to drink an adequate fluid volume during urine collection weekends, as 
instructed by the investigator. 
7. Subject and subject’s parent(s)/legal guardian(s) agree that the subject will not 
participate in another interventional study while participating in the present study. 
8. Subject and subject’s parent(s)/legal guardian(s) are willing and able to comply with the 
study requirements and with the concomitant medication restrictions. 
9. Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at 
least 1 of the following conditions apply: 
a. 
Not a female of childbearing potential (see [Appendix 12.3 Contraception 
Requirements]). 
b. 
Female of childbearing potential who agrees to follow the contraceptive guidance 
(see [Appendix 12.3 Contraception Requirements]) from the time of informed 
consent/assent through at least 30 days after final IP administration. 
10. Female subject must agree not to breastfeed starting at screening and throughout the 
study period and for 30 days after final IP administration. 
11. Female subject must not donate ova starting at first dose of IP and throughout the study 
period and for 30 days after final IP administration. 
12. Male subject with female partner(s) of childbearing potential (including breastfeeding 
partner[s]) must agree to use contraception (see [Appendix 12.3 Contraception 
Requirements]) throughout the treatment period and for 30 days after final IP 
administration. 
13. Male subject must agree not to donate sperm during the treatment period and for 30 days 
after final IP administration. 

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14. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom 
for the duration of the pregnancy throughout the study period and for 30 days after final 
IP administration. 
Additional Inclusion at Visit 3/Week 0 (Baseline) 
15. Subject must have a micturition frequency of at least 8 times (on average) per day, in the 
7 days prior to visit 3/week 0 (baseline), as recorded in the bladder e-diary. 
16. Subject must have at least 1 daytime incontinence episode (on average) per day, during 
the 7-day period before visit 3/baseline, as recorded in the bladder e-diary. 
17. Subject whose symptoms are not satisfactorily controlled with urotherapy and still 
fulfills the inclusion/exclusion criteria will enter the study. 
5.2 
Exclusion Criteria 
Subject will be excluded from participation in this study if any of the following apply: 
Exclusion at Visit 1/Week -4 (Screening) 
1. Subject has extraordinary daytime only urinary frequency according to the ICCS 
definition. 
● 
This applies to a toilet-trained child who has the frequent need to void that is 
associated with small micturition volumes solely during the day. 
● 
The daytime voiding frequency is at least once per hour with an average voided 
volume of < 50% of expected bladder capacity (EBC) (typically 10% to 15%). 
● 
Incontinence is rare and nocturia is absent. 
2. Subject has an uroflow indicative of pathology other than OAB. 
3. Subject has monosymptomatic enuresis. 
4. Subject has dysfunctional voiding. 
5. Subject has bladder outlet obstruction, except if successfully treated. 
6. Subject has anatomical anomalies (surgically treated or untreated) that affect lower 
urinary tract function. 
7. Subject with hematuria on dipstick test.  In the case of hematuria on dipstick test in a 
female during menstruation, the test can be repeated before randomization (after the end 
of menstruation). 
8. Subject with diabetes insipidus. 
9. Subject has kidney or bladder stones. 
10. Subject has suffered from chronic UTI or has had more than 3 UTIs in the 2 months prior 
to visit 1/week -4 (screening). 
11. Criterion has been removed. 
12. Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well 
controlled, as defined by the 2017 American Academy of Pediatrics Clinical Practice 
Guidelines. 
13. Subject has QTcF > 440 msec on screening ECG, a risk of QT prolongation (e.g., 
hypokalemia, long QT syndrome [LQTS] or family history of LQTS or exercise-induced 
syncope) or is currently taking medication known to prolong the QT interval. 

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14. Subject’s aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is 
≥ 2 × upper limit of normal (ULN) or total bilirubin (TBL) is ≥ 1.5 × ULN according to 
age and sex (subjects with Gilbert’s syndrome are excepted from the bilirubin threshold). 
15. Subject has mild or moderate renal impairment (estimated glomerular filtration rate 
according to the modified Schwartz of < 60 mL/min per 1.73 m2). 
16. Subject has a symptomatic (symptoms can include pain, fever, hematuria, new onset 
foul-smelling urine) UTI.  Note: if the UTI is treated successfully (clinical recovery: 
confirmed by dipstick test and repeated dipstick test after 14 days [both should be 
negative]), the subject can be rescreened. 
17. Subject has a history or presence of any malignancy. 
18. Subject uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates 
with a narrow therapeutic index, sensitive P-glycoprotein (P-gp) substrates, or moderate 
or strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers after the start of washout. 
19. Subject is using or has used prohibited prior and/or concomitant medication(s) 
[Appendix 12.6 List of Excluded Concomitant Medications] that cannot be discontinued. 
20. Subject has known or suspected hypersensitivity to mirabegron or any components of the 
formulations used. 
21. Subject has participated in another clinical study (and/or subject has received any 
investigational therapy within 30 days (or 5 half-lives of the drug, or the limit set by 
national law, whichever is longer) prior to visit 1/week -4 (screening). 
22. Subject received urinary catheterization within 2 weeks prior to screening. 
23. Subject has constipation as defined by the Rome IV criteria that cannot be successfully 
treated prior to study entry. 
24. Female subject who has been pregnant within 6 months prior to screening or 
breastfeeding within 3 months prior to screening. 
25. Subject has any condition, which in the opinion of the investigator, makes the subject 
unsuitable for study participation. 
Additional Exclusion at Visit 3/Week 0 (Baseline) 
26. Subject has extraordinary daytime only urinary frequency according to the ICCS 
definition based on the bladder e-diary. 
27. Subject has monosymptomatic enuresis confirmed by the bladder e-diary. 
28. Subject has a maximum voided volume (morning volume excluded) > EBC for age 
([age +1] × 30) in mL, based on the bladder e-diary. 
29. Subject has polyuria defined as voided urine volumes of > 40 mL/kg baseline body 
weight during 24 hours or > 2.8 L urine for a child weighing ≥ 70 kg (ICCS definition) 
[Austin et al, 2014], based on bladder e-diary. 
30. Subject has PVR volume > 20 mL (lowest PVR volume result) as measured by 
ultrasonography. 
31. Subject suffers from a symptomatic (symptoms can include pain, fever, hematuria, new 
onset foul-smelling urine) UTI.  Note: if a symptomatic UTI is present, all 
visit 3/week 0 (baseline) assessments must be postponed until the UTI is successfully 
treated (clinical recovery: confirmed by dipstick test and repeated dipstick test after 

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14 days [both should be negative]), and the urotherapy should continue.  The postponed 
visit 3/week 0 (baseline) should be within 14 days of the intended 
visit 3/week 0 (baseline). 
32. Subject with hematuria on dipstick test.  In the case of hematuria on dipstick test in a 
female during menstruation, the test can be repeated before randomization (after the end 
of menstruation). 
33. Subject has a pulse > 99th percentile for age. 
34. Subject has stage 2 hypertension or subject has stage 1 hypertension that is not well 
controlled, as defined by the 2017 American Academy of Pediatrics Clinical Practice 
Guidelines. 
35. Any reason, in the opinion of the investigator, that makes the subject unsuitable for study 
participation. 
5.3 
Restrictions During the Study 
Restrictions for foods and drinks are not applicable.  On visit days where a pharmacokinetic 
sample is planned in the clinic, dosing should occur in the clinic and breakfast should be 
eaten at the clinic within 1 hour before dosing.  
5.4 
Screen Failures 
A screen failure is defined as a potential subject who signed the informed consent form 
(ICF)/assent and/or whose parent(s)/legal guardian(s) signed the ICF/assent, but did not meet 
1 or more criteria required for participation in the study and was not enrolled. 
For screen failures, the demographic data, date of signing the ICF/assent, inclusion and exclusion 
criteria, AEs up to the time of screen failure and reason for screen failure will be collected in the 
electronic data source.  Rescreening is only allowed once for an individual subject. 
5.4.1 
Rescreen 
5.4.1.1 Rescreen for Urinary Tract Infection or Constipation 
In addition, if a subject has UTI/constipation at visit 3/week 0 (baseline), all visit 
3/week 0 (baseline) assessments must be postponed until the UTI/constipation is successfully 
treated (clinical recovery), and the urotherapy should continue.  Then the subject’s postponed 
visit 3/week 0 (baseline) assessments should be completed within 14 days of the intended 
visit 3/week 0 (baseline) or the subject will be documented as a screen failure and can be 
re-screened.  If the postponed visit 3/week 0 (baseline) is rescheduled within 14 days of the 
intended visit 3/week 0 (baseline) visit, then the subject's 7-day e-diary will be restarted with 
respect to the postponed visit 3/week 0 (baseline) visit. 
5.4.1.2 Rescreen for Other Eligibility Criteria 
Results of screening assessments that do not meet the parameters required by eligibility 
criteria (e.g., clinical laboratory tests, vital signs, physical examination, ECG, etc.) may be 
repeated once within the 4-week screening period without the need to register the subject as a 
screen failure.  If any exclusion criteria are met or more than 4 weeks elapse from the date of 
signing the ICF/assent, the subject must be documented as a screen failure.  In order to 

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rescreen a subject previously registered as a screen failure, a new ICF/assent must be signed 
and the subject will be entered into screening with a new subject identification number.  The 
old subject number will also be entered to link the subject’s data. 
6 
INVESTIGATIONAL PRODUCT(S) AND OTHER STUDY 
TREATMENT(S) 
6.1 
Investigational Product(s) Administered and Other Study 
Treatment(s) 
6.1.1 
Investigational Product(s) 
Mirabegron prolonged-release (or extended-release) tablets were approved in Japan in 2011, 
and to date have been approved in more than 81 countries worldwide; trade names include 
Betanis® [BETANIS® prescribing information, Jun 2012], Betmiga® [BETMIGA® 
prescribing information, Apr 2018] and Myrbetric® [MYRBETRIC® prescribing 
information, Jun 2012].  The approved indication is the treatment of OAB with symptoms of 
urge urinary incontinence, urgency and urinary frequency in adults. 
Mirabegron oral suspension has been developed as an appropriate formulation for 
weight-based dosing in smaller children. 

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Table 6 
Investigational Product(s) 
Name 
Mirabegron 
Matching Placebo 
Mirabegron 
Matching Placebo 
Use 
Test product 
Placebo 
Test product 
Placebo 
Dosage Formulation 
Tablet 
Tablet 
Oral suspension 
Oral suspension 
Physical Description 
Brown (25 mg) or yellow (50 mg) 
film-coated tablet 
Brown (25 mg) or yellow (50 mg) 
film-coated tablet 
Yellowish white granules 
reconstituted with water to 
prepare oral suspension 
Yellowish white granules 
reconstituted with water to 
prepare oral suspension 
Unit Dose Strength 
25 and 50 mg 
To match mirabegron 
8 mg/mL 
To match mirabegron 
Packaging and Labeling 
-35 tablets of Mirabegron 25 mg 
in a wallet 
-35 tablets of Mirabegron 50 mg 
and 7 tablets of Mirabegron 25 
mg in a wallet 
35 tablets of Mirabegron 25 mg 
placebo in a wallet 
-35 tablets of Mirabegron 50 mg 
placebo and 7 tablets of 
Mirabegron 25 mg placebo in a 
wallet 
1 bottle of Mirabegron 830 mg 
granules for oral suspension 
1 bottle of placebo Mirabegron 
830 mg granules for oral 
suspension 
Route of Administration 
Oral 
Oral 
Oral 
Oral 
Administration Instruction 
IP will be administered orally, once daily in the morning around the 
same time of day and around time of food intake (i.e., within 1 hour 
before or after breakfast).  Tablets will be administered with a sip of 
water (tablet should be taken as a whole and should not be chewed, 
divided or crushed). 
IP will be administered orally, once daily in the morning around the 
same time of day and around time of food intake (i.e., within 1 hour 
before or after breakfast).  Oral suspension will be administered via an 
oral syringe with a sip of water afterwards.  Detailed information on 
the preparation of the mirabegron oral suspension will be provided to 
the subject and subject’s parent(s)/legal guardian(s) in local language. 
IMP or Non-IMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by sponsor 
Provided centrally by sponsor 
Provided centrally by sponsor 
Provided centrally by sponsor 
IMP: investigational medicinal product; IP: investigational product 
 

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For detailed information on mirabegron prolonged-release tablets, please refer to the current 
locally-available product information for mirabegron. For detailed information on 
mirabegron granules for oral suspension, please refer to the Investigator’s Brochure and 
Investigational Medicinal Product Dossier. 
IP will be administered according to [Table 7]. 
Table 7 
Body Weight-based Doses for Tablets or Suspension 
 
Body Weight Range† 
(kg) 
Oral Suspension Volume‡ 
(mL) 
Tablet Dose 
(mg) 
PED25 
13 to < 22 
3 
- 
22 to < 35 
4 
- 
≥ 35 
6 
25 
PED50 
13 to < 22 
6 
- 
22 to < 35 
8 
- 
≥ 35 
11 
50 
PED25: pediatric equivalent dose 25 mg; PED50: pediatric equivalent dose 50 mg 
† 
Subjects with a body weight ≥ 35 kg will receive the tablet.  Subjects with a body weight< 35 kg or those 
who cannot be dosed with the tablet will receive an oral suspension. 
‡ 
Oral suspension containing 8 mg/mL. 
The starting dose will be PED25 starting administration the day after 
visit 3/week 0 (baseline).  At visit 5/week 4, dose up-titration to PED50 will be performed 
unless the investigator determines that the subject is adequately treated for OAB at the 
PED25 dose or if there are safety concerns identified and considered associated with the use 
of PED25.  Dose down-titration from PED50 to PED25 can be done at any time thereafter for 
safety reasons. 
6.1.2 
Other Study Treatment(s) 
During the screening period, all subjects will receive 4 weeks of urotherapy.  At 
visit 3/week 0 (baseline) inclusion and exclusion criteria will be evaluated.  Subjects 
continuing urotherapy who still meet the OAB entry criteria at baseline will be randomized.  
Urotherapy will continue throughout the study treatment period until visit 7/week 12 (EoT). 
Urotherapy is to be discussed and confirmed with the subject or parent(s)/legal guardian(s) 
during each visit (or TC) to ensure compliance. 
Standard urotherapy includes information on and demystification of the voiding function and 
dysfunction, instruction on voiding habits (such as regular voiding, voiding posture), life 
style advice regarding fluid intake, prevention of constipation, recording of symptoms and 
voiding habits in bladder diaries and support via regular follow-up by a caregiver. 
Specific interventions include various forms of pelvic floor training (relaxation, contraction), 
behavioral modification, electrical stimulation, catherization and biofeedback (use of 
objective measures, e.g., uroflow or EMG to show children how far they relax their pelvic 
floor during voiding).  Urotherapy can also include elements of cognitive behavioral therapy 
[Nevéus et al, 2006]. 

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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Packaging and Labeling 
All IP used in this study will be prepared, packaged and labeled under the responsibility of 
qualified personnel at Astellas Pharma Europe B.V. (APEB) or sponsor’s designee in 
accordance with APEB or sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) guidelines, and applicable local laws/regulations. 
Each IP package will bear a label conforming to regulatory guidelines, GMP and local laws 
and regulations that identifies the contents as an investigational drug. 
A qualified person of APEB or sponsor’s designee will perform the final release of the 
medication according to the requirements of the EU Directive 2003/94/EC annex 13. 
6.2.2 
Handling, Storage and Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and 
resolved before use of the IP. 
2. Only subjects enrolled in the study may receive IP and only authorized study site 
personnel (listed under delegation log) may supply or administer IP.  Only IP with 
appropriate expiry/retest dating may be dispensed. 
3. All IP must be stored in a secure, environmentally controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions and access must be 
limited to the investigator and authorized study site personnel. 
4. The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records). 
The site must return IP to the Sponsor or designee at the EoS or upon expiration.  If due to 
institutional policy or local law, used IP cannot be returned to the Sponsor or designee the IP 
may be destroyed according to local law. 
6.3 
Randomization and Blinding 
6.3.1 
Blinding Method 
This is a double-blind study.  Subjects will be randomized to receive mirabegron or placebo 
in a blinded manner such that neither the investigator, sponsor’s study management team, 
clinical personnel, nor the subject will know which IP is being administered.  The 
randomization number will be assigned based on information obtained from the interactive 
response technology (IRT) system. 
6.3.2 
Confirmation of the Indistinguishability of the Investigational Product 
The appearance of both the dosage form and packaging of mirabegron are identical to those 
of their matching placebo. 

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6.3.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking 
The randomization list and treatment assignment blind will be maintained by the IRT system. 
6.3.4 
Breaking the Treatment Code for Emergency 
The treatment code for each randomized subject will be obtained from the IRT system in the 
event of a medical emergency requiring knowledge of the treatment assigned to the subject.  
The IRT system will be programmed with blind-breaking instructions that can only be 
requested by the investigator or sub investigator(s) designated to have access to perform 
blind-breaking.  In case of a medical emergency, the investigator has the sole responsibility 
for determining if unblinding of the subject’s treatment assignment is warranted.  Subject 
safety must always be the first consideration in making such determination.  If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a subject’s treatment assignment unless this could 
delay emergency treatment for the subject. 
Prior to the initial IP shipment, the investigator must have confirmed ability to access 
code-break through the IRT system and must have a designated backup (e.g., redundant 
processes) to support emergency unblinding requirements. 
Prior to randomization, subjects should be provided with information that includes the study 
site emergency contact number and back-up contact number in case of a medical emergency.  
Any unblinding by the investigational personnel must be reported immediately to the sponsor 
and include an explanation of why the IP was unblinded.  If unblinding is associated with a 
serious adverse event (SAE), the investigator is to follow the instructions in 
[Appendix 12.4.5 Reporting Procedures for Serious Adverse Events]. 
Care will be taken to limit knowledge of the treatment assignment, in case this can affect the 
blinding of other subjects or future study assessment for the subject. 
6.3.5 
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 personnel who are responsible to break the codes for all SUSAR cases 
for reporting purposes. 
6.3.6 
Assignment and Allocation 
6.3.6.1 Subject Number 
Subjects will be assigned a subject number at study entry (i.e., signing the ICF/assent).  The 
subject numbers will be sequential and rising.  The subject number will comprise of 10 digits; 
5 digits for the site number (provided by the sponsor) and 5 digits for the consecutive subject 
number. 

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Subjects will be randomized to receive IP according to the randomization schedule obtained 
via the IRT system.  The study site personnel will dispense the treatment according to the 
IRT system’s assignment.  Specific procedures for randomization through the IRT system are 
contained in the study procedures manual. 
6.3.6.2 Randomization Number 
Subjects will be randomized in a 1:1 ratio to receive treatment according to the 
randomization schedule obtained via the IRT system.  The study site personnel will dispense 
the treatment according to the IRT system’s assignment.  Specific procedures for 
randomization through the IRT system are contained in the study procedures manual. 
6.3.6.3 Subject Replacement 
An enrolled subject who withdraws or discontinues before dosing or before randomization 
will be considered a screen failure.  Randomized subjects who withdraw or discontinue will 
not be replaced. 
6.4 
Investigational Product(s) and Other Study Treatment(s) 
Compliance 
6.4.1 
Investigational Product(s) 
Subject compliance with IP and other study treatment(s) will be assessed at each visit.  
Compliance will be assessed by counting or weighing returned IP at each clinic visit.  
Deviations from the prescribed dose regimen will be recorded in the electronic data source. 
If compliance less than 80%, the investigator or designee is to counsel the subject and/or the 
subject’s parent(s)/legal guardian(s) and ensure steps are taken to improve compliance. 
6.4.2 
Other Study Treatment(s) 
Subjects will have to receive 4 weeks of urotherapy prior to randomization and will continue 
urotherapy throughout the study.  Urotherapy is to be discussed and confirmed with the 
subject or parent(s)/legal guardian(s) during each TC to ensure subject compliance. 
Specific interventions include various forms of pelvic floor training (relaxation, contraction), 
behavioral modification, electrical stimulation, catherization and biofeedback (use of 
objective measures, e.g., uroflow or surface EMG to show children how far they relax their 
pelvic floor during voiding).  Urotherapy can also include elements of cognitive behavioral 
therapy [Nevéus et al, 2006]. 
6.5 
Previous and Concomitant Treatment (Medication and 
Nonmedication Therapy) 
Subjects are not allowed to use ongoing treatment with any of the following prohibited 
medications after the start of the washout: 
● Any medication, other than the IP, used for the treatment of OAB  (including tricyclic 
antidepressants, 1st generation H1 antagonists and alpha blockers) 

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● 
Any drugs that are sensitive CYP2D6 substrates with a narrow therapeutic index or 
sensitive P-gp substrates 
● 
Any medications known to prolong the QT interval  
● 
Any medication that is a moderate or strong cytochrome CYP3A4/5 or P-gp inhibitor or 
inducers including natural and herbal remedies  
● 
Intradetrusor botulinum toxin injections; except if given > 9 months prior screening and 
symptoms reappeared comparable to those before botulinum toxin injections 
● 
Nonmedication therapies like urotherapy, chiropractic, physical therapy will also be 
collected on the nonmedication therapy case report form (CRF). 
○ 
The site will need to make special notes for those subjects who do not follow 
urotherapy for 7 or more consecutive days in electronic case report forms (eCRFs). 
Please refer to [Appendix 12.6 List of Excluded Concomitant Medications] for drug classes 
or specific medications that are prohibited during participation in the study. These treatments 
are prohibited from being started after the start of the washout period. All other concomitant 
treatment use will be reported. 
The use of previous and concomitant treatment within 30 days prior to signing the informed 
consent and throughout the study will be documented on the appropriate eCRF. 
6.6 
Dose Modification 
At visit 5/week 4 (i.e., after 4 weeks on PED25), dose up-titration to PED50 will be 
performed unless the investigator determines that the subject is adequately treated for OAB at 
the PED25 dose or if there are safety concerns identified and considered associated with the 
use of PED25. 
At any time, down-titration from PED50 to PED25 can be performed if there is an AE 
possibly related to the drug that is considered bothersome by the subject or that leads to 
medical intervention (e.g., initiation of medication therapy to treat the AE).  Of note, PED25 
is the lowest dose to be used in this study. 
Criteria for discontinuation of individual subject(s) from study treatment are listed in 
[Section 8.1 Discontinuation of Individual Subject(s) from Study Treatment(s)]. 
6.7 
Criteria for Continuation of Treatment(s) 
Mirabegron (PED25/PED50) will not be made available after conclusion of the study to 
subjects who are still receiving and benefitting from study treatment in countries where the 
product does not have marketing approval and is not commercially available. 
7 
STUDY PROCEDURES AND ASSESSMENTS 
Refer to the Alternate Schedule of Assessments [Table 12] in [Appendix 12.13 Clinical Study 
Continuity] for acceptable alternate methods to assess safety and efficacy parameters in the 
event the study is interrupted due to a crisis (e.g., natural disaster, pandemic). 

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7.1 
Efficacy Assessments 
7.1.1 
Bladder Electronic Diary 
The bladder diary is part of the subject’s e-diary.  After a successful visit 1/screening, all 
subjects start with the completion of a 2-day weekend e-diary to get acquainted with the 
e-diary and the assessments.  Completion of this diary should start in the weekend prior to 
visit 2. 
The e-diary data is reviewed by the investigator or designee prior to the start of visit 2 and 
discussed and confirmed with the subject or the subject’s parent(s)/caregiver(s) during the 
(telephone) visit 2.  If the investigator is under the impression that the subject and/or the 
subject’s parent(s)/caregiver(s) can perform all the required assessments and are able to 
complete all required forms with credible data, completion is considered successful. 
If successful completion of the 2-day weekend e-diary is confirmed at visit 2, subjects will 
start with collection of the 7-day bladder e-diary approximately 7 days prior to 
visit 3/week 0 (baseline).  The 7-day bladder e-diary consists of a 5-day weekday bladder 
e-diary, which is used to collect micturition frequency and incontinence episodes; the 
remaining consists of the 2-day weekend diary. 
After successful randomization, subsequent bladder e-diaries will be completed by the 
subject or subject’s parent(s)/caregiver(s) in the week prior to visit 4/week 2, visit 5/week 4, 
visit 6/week 8 and visit 7/week 12.  Completion of 7-day bladder diaries should start 
approximately 7 days prior to the indicated visit (or telephone contact). 
7.2 
Safety Assessments 
7.2.1 
Adverse Events 
See [Section 7.3 Adverse Events and Other Safety Aspects] for information regarding AE 
collection and data handling. 
7.2.2 
Laboratory Assessments 
Blood samples for hematology and biochemistry and urine samples for urinalysis will be 
collected as indicated in the Schedule of Assessments [Table 1].  All clinical laboratory 
assessments will be performed at a central laboratory except for urinalysis dipsticks which 
will be conducted locally to support study eligibility or AEs.  A urine pregnancy test in 
female subjects of childbearing potential will be performed at all on-site visits.  A topical 
anesthetic cream or plaster must be offered at the point of venipuncture to minimize distress 
of the subject.  For sampling the arm opposite to the arm used for blood pressure 
measurements should be used (i.e., preferably the left arm).  Blood sampling should occur 
after vital signs and ECG measurements. 
Sample collection, handling and storage will be described in a laboratory manual.  All 
clinical laboratory test results, including ULNs used in exclusion and discontinuation criteria, 
will be compared to age appropriate norms. 

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Scheduled blood sampling will only be performed at screening (visit 1), week 4 (visit 5) and 
EoT (visit 7) to keep the burden to subjects at a minimum. Additional hematology, 
biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 3/week 0 
(baseline) and visit 8/week 14 (EoS) only if an AE related to hematology, biochemistry or 
urinalysis parameters occurred since the previous visit or at the discretion of the investigator.  
If any of the clinical laboratory tests results are outside the normal range at any scheduled 
time point during the study, the investigator may decide to repeat the test(s) on new samples.  
The clinical relevance of the abnormal results will be documented.  Clinically relevant 
changes will be recorded as AEs (see [Section 7.3 Adverse Events and Other Safety 
Aspects]). 
Refer to the Alternate Schedule of Assessments [Table 12] for acceptable alternate methods 
to assess safety and efficacy parameters in the event the study is interrupted due to a crisis 
(e.g., natural disaster, pandemic). 
7.2.3 
Vital Signs and Electrocardiograms 
7.2.3.1 Clinic-measurement of Vital Signs and Electrocardiograms 
Blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), pulse, and 
routine 12-lead ECG measurements will be taken as indicated in the Schedule of Assessments 
[Table 1]. 
The preferred method of measurement is via the auscultatory technique.  If this method is not 
available at the study site, measurements will be per standard clinic practices.  Single 
measurements of blood pressure, pulse, body temperature and ECGs will be measured in the 
sitting position (when possible, otherwise supine, but always in the same position).  Subject 
should have been calm and without distress for at least 5 minutes.  Preferably, the right arm 
should be used to measure vital signs.  Body temperature will be measured with an ear 
thermometer as per standard of care.  Clinic measurements will be used to assess eligibility. 
For ECGs, dates and times may be generated by the machine’s internal clock and are 
considered source data.  The results are to be interpreted by qualified personnel in real time 
for the management of the subjects’ clinical condition.  The principal investigator/designee 
will initial and date and provide his/her clinical interpretation on each report.  Any 
abnormalities must be evaluated in clinical context (based on subject’s medical history and 
concomitant medication) and the investigator should determine if it is clinically significant.  
The results (normal, abnormal not clinically significant, abnormal clinically significant) are 
to be recorded in the eCRFs. 
The original print-out and an electronic copy of all scheduled and unscheduled ECG tracings 
should be maintained on site as source data. 
Clinic measurements will be used to assess eligibility.  Clinically relevant adverse changes in 
vital signs and ECGs will be recorded as an AE (see [Appendix 12.4.1 Definition of Adverse 
Events]). 

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7.2.3.2 Self-measurement of Vital Signs 
Self-blood pressure monitoring (SBPM; SBP and DBP) will be measured as indicated in the 
Schedule of Assessments [Table 1] and whenever deemed necessary by the investigator. 
SBPM will be measured once in the morning and evening during the 2-day weekend bladder 
e-diary collection period.  Measurements will be taken in the sitting position (when possible, 
otherwise supine, but always in the same position).  Preferably, the right arm should be used.  
Subject should have been calm and without distress for at least 5 minutes.  Morning 
measurement should be taken before IP intake and evening measurement should be taken 
prior to bedtime. 
Devices for measuring blood pressure will be provided to subjects for home measurements.  
Detailed on-site training to use the SBPM device and a booklet with operating instructions in 
local language will be provided to the subject and the subject’s parent(s)/legal guardian(s).  
Results will be directly entered by the subject or subject’s parent(s)/legal guardian(s) in the 
e-diary (see [Section 10.1 Data Collection]). 
7.2.4 
Physical Examination 
Physical examination will be performed as indicated in the Schedule of Assessments 
[Table 1] and whenever there is a medical indication. 
The physical examination will be performed as described in the study site’s SOPs for 
physical examination. In this study, the physical examination will be done to evaluate general 
physical condition and encompasses standard, full physical examinations to assess general 
appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, 
musculoskeletal, neurologic status, mental status and lymphatic systems. 
New or worsening clinically significant physical examination findings after signing of ICF 
will be recorded as AEs if they meet the criteria in [Section 7.3 Adverse Events and Other 
Safety Aspects]. 
7.2.5 
Post Void Residual Volume Assessments 
PVR volume will be assessed by ultrasonography at visit 3/week 0 (baseline), visit 5/week 4, 
visit 7/week 12 (EoT) and visit 8/week 14 (EoS).  For each subject, the same method should 
be used throughout the study.  The bladder should only be emptied when it was initially filled 
with preferably > 50% of the bladder capacity for age.  Every attempt should be made to 
measure PVR volume within a minute of voiding.  A PVR volume of ≤ 20 mL is sufficient 
and the assessment does not have to be repeated.  If the PVR volume is > 20 mL, the PVR 
volume assessment should be repeated (filled with preferably > 50% of the bladder capacity 
for age).  If the subject is unable to complete a second measurement, it is up to the 
investigator to judge whether it can be skipped (and write the reason in the CRF).  At 
visit 3/week 0 (baseline), the lowest PVR volume result measured should be used to evaluate 
the exclusion criterion.  In case the lowest PVR volume measured is > 20 mL at 
visit 3/week 0 (baseline), the subject should be excluded from the study. 

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7.2.6 
Acceptability and Palatability Questionnaire 
The acceptability and palatability questionnaire will be completed as indicated in the 
Schedule of Assessments [Table 1].  For each IP formulation, a separate questionnaire is 
available [Appendix 12.8 Acceptability and Palatability Questionnaire for Tablets and 
Appendix 12.9 Acceptability and Palatability Questionnaire for Oral Suspension]. 
7.2.7 
Order of Assessments 
The following order should be followed when more than 1 assessment is required at a time 
point with blood sampling for pharmacokinetics/metabolic profiling being collected nearest 
to the scheduled time point: 
1. ECG 
2. Vital signs 
3. Blood collection 
7.3 
Adverse Events and Other Safety Aspects 
The definitions of an AE or SAE can be found in [Appendix 12.4 Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up or Reporting]. 
The investigator and medically qualified designee(s) are responsible for detecting, 
documenting and recording events that meet the definition of an AE or SAE. 
7.3.1 
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information 
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received IP.  AE collection begins after the signing of the ICF/assent and will be collected 
until 30 days after the final IP administration or when the subject is determined to be a screen 
failure. 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
The methods of recording, evaluating and assessing seriousness, causality and severity of 
AEs and SAEs are described in [Appendix 12.4 Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up or Reporting].  Care will be taken not to introduce bias 
when detecting AEs and/or SAEs.  Open-ended and nonleading verbal questioning of the 
subject is the preferred method to inquire about AE occurrences. 
An AE with a change in severity is recorded as a new AE. 
7.3.3 
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 by the investigator. 
If after the protocol-defined AE collection period (see [Section 7.3.1 Time Period for 
Collecting Adverse Event and Serious Adverse Event Information]), an AE progresses to an 

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SAE, or the investigator learns of any (S)AE (serious adverse event or adverse event) 
including death, where he/she considers there is reasonable possibility it is related to the IP or 
study participation, the investigator must promptly notify the sponsor. 
7.3.4 
Reporting of Serious Adverse Events 
Prompt notification by the investigator to the sponsor of an SAE is essential, so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
intervention under clinical investigation are met. 
In the case of an SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness). 
Procedures for reporting SAEs to the sponsor are described in [Appendix 12.4.5 Reporting 
Procedures for Serious Adverse Events]. 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Under this protocol, the following event(s) will not be considered as an SAE: 
● 
Disease progression: events including defined study endpoints that are clearly consistent 
with the expected pattern of progression of the underlying disease are not to be recorded 
as AEs.  These data will be captured as efficacy assessment data as outlined in 
[Section 7.1 Efficacy Assessments].  If there is any uncertainty as to whether an event is 
due to anticipated disease progression and/or if there is evidence suggesting a causal 
relationship between the IP and the event, it should be reported as an SAE.  All deaths up 
to 30 days after the final IP administration must be reported as an SAE, even if attributed 
to disease progression. 
● 
Preplanned and elective hospital/clinical procedures/interventions or procedures for 
diagnostic, therapeutic, or surgical procedures for a pre-existing condition that did not 
worsen during the course of the study.  These procedures are collected per the electronic 
data source’s completion guidelines. 
7.3.6 
Adverse Events of Special Interest 
Adverse Events of Special Interest include: 
● 
Increased blood pressure 
● 
Cardiac electrophysiology (including QTc prolongation) and cardiac arrhythmia 
(including increased heart rate, tachycardia, atrial fibrillation and palpitations) 
● 
Hypersensitivity reactions 
● 
Urinary retention 
● 
Hepatotoxicity 
● 
Seizure/syncope 
AEs (serious or nonserious) of special interest are to be collected via the SAE worksheet and 
reported within 24 hours as described in [Appendix 12.4.5 Reporting Procedures for Serious 
Adverse Events]. 

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7.3.7 
Special Situations 
Certain special situations observed in association with the IP, such as incorrect administration 
(e.g., wrong dose of IP or background therapy) are collected in the electronic data source, as 
protocol deviation per [Section 10.3 Major Protocol Deviations] or may require special 
reporting, as described below.  These special situations are not considered AEs, but do 
require to be communicated to Astellas as per the timelines defined below. 
If a special situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the special situation and captured as an AE in the electronic data source.  If 
the AE meets the definition of an SAE, the SAE is to be reported as described in 
[Appendix 12.4.5 Reporting Procedures for Serious Adverse Events] and the details of the 
associated special situation are to be included in the clinical description on the SAE 
worksheet. 
The special situations are: 
● 
Pregnancy 
● 
Medication error/overdose 
● 
Misuse/abuse 
● 
Occupational exposure 
● 
Suspected drug-drug interaction 
Instructions and procedures for reporting special situations are provided in [Appendix 12.4.6 
Reporting Procedures for Special Situations]. 
7.3.8 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that is necessary for conducting the study properly, 
the sponsor will inform all investigators involved in the study as well as the appropriate 
regulatory authorities.  Investigators should inform the IRB/IEC of such information when 
needed. 
The investigator will also inform the subjects, who will be required to sign an updated 
ICF/assent in order to continue in the study. 
7.3.9 
Urgent Safety Measures 
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities and IRB/IEC, where applicable, in order to protect 
subjects from any immediate hazard to their health and/or safety.  Either the investigator or 
the sponsor can initiate a USM.  The cause of a USM can be safety-, product- or 
procedure-related. 
7.3.10 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the study physician (within 
24 hours of awareness).  Full details of the potential USM are to be recorded in the subject’s 

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medical records.  The sponsor may request additional information related to the event to 
support their evaluation. 
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure the 
safety and welfare of the subjects.  These actions may include but are not limited to a change 
in study procedures or study treatment, halting further enrollment in the study, or stopping 
the study in its entirety.  The sponsor or sponsor’s designee will notify the relevant competent 
authorities and concerned ethics committee within the timelines required per current local 
regulations, and will inform the investigators, as required.  When required, investigators must 
notify their IRB/IEC within timelines set by regional regulations. 
7.4 
Pharmacokinetics 
Blood samples for the analysis of mirabegron in plasma will be collected as indicated in the 
Schedule of Assessments [Table 1] for the evaluation of pharmacokinetics. 
The actual date and time of each blood sample collection will be documented.  Sample 
collection, handling and storage will be described in the laboratory manual.  Bioanalysis of 
mirabegron will be performed using a validated method. 
A topical anesthetic cream or plaster must be offered at the point of venipuncture to minimize 
distress of the subject.  For sampling the arm opposite to the arm used for blood pressure 
measurements should be used (i.e., preferably the left arm).  Blood sampling should occur 
after vital signs and ECG measurements. 
The pharmacokinetic parameters that will be calculated as part of the secondary 
pharmacokinetic endpoint are steady-state Cmax, AUCtau, Ctrough, Tmax, CL/F and Vz/F. 
Additional parameters may be calculated based on the population pharmacokinetic model 
used. 
7.5 
Pharmacodynamics | Immunogenicity 
Not applicable. 
7.6 
Electronic Clinical Outcome Assessment 
For this study, it has been decided that there are justifiable scientific reasons (i.e., recall bias) 
to limit subject reported changes to changes reported by the subject to the site within 
1 business day of its entry, as changes outside of this window could potentially impact the 
data integrity of the study.  The data that will be under this rule are all subject/guardian/ 
parent-entered primary and secondary endpoints data.  However, the site/investigator can 
remove/inactivate any data that they determine to be in error at any time with source 
documentation to support the change including subject confirmation. Data will never be 
deleted from the electronic database by the electronic clinical outcome assessment (eCOA) 
service provider, but will be removed logically as per investigator’s request and approval. All 
data changes are audit trailed showing the original entries alongside all changes including 
who requested the change, why it was requested, who made the change and when it was 

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made. Audit trails are reviewed by the sponsor/clinical research organization (CRO) to ensure 
adherence to the protocol and appropriate source exists at site to substantiate the change.   
Subject bladder diaries, questionnaires and other data will be completed by the subject or the 
subject’s parent(s)/legal guardian(s)/caregiver(s) on an electronic device (e-diary).  The 
information on the electronic device will be automatically uploaded to a central website.  The 
investigator or site designee should review the diaries and questionnaire data on the website 
to ensure completion and protocol compliance before each planned visit of the subject (on 
site visit or TC) and discuss the results or retrain the subject and/or subject’s parent(s)/legal 
guardian(s)/caregiver(s), if applicable.  In case clinically relevant adverse changes are noticed 
during review of the e-diary, these will be recorded as an AE [Appendix 12.4.1 Definition of 
Adverse Events]. 
The bladder e-diary, questionnaire results and other data collected in the e-diary will be 
transferred electronically to the sponsor or designee at predefined intervals during the study.  
The vendor will provide the sponsor or designee with a complete and clean copy of the study 
data. The ownership of this data is with the investigator and subsequently any changes 
requested to these subject-reported or nonsubject reported data will be made using the 
vendor’s established process (e.g., a data clarification form to the vendor). The requested 
change must be supported by documented evidence at study site. 
For this study the following information will be collected and entered by the subject or 
subject’s parent(s)/legal guardian(s) in the e-diary (see [Sections 7.2.6 Acceptability and 
Palatability Questionnaire and 7.2.3.2 Self-measurement of Vital Signs] for detailed 
information per visit): 
● 
Bladder e-diary: 
○ 
Each day on weekend prior to week -2: volume measurements 
○ 
Each day for 7 days before visit 3/week 0: micturition frequency 
○ 
Each day for 7 days before visit 3/week 0: incontinence episodes 
○ 
On the 2-day weekend period: volume measurements 
● 
SBPM (blood pressure and pulse): 
○ 
Each day of the 2-day weekend period: twice per day 
○ 
On 2 consecutive weekend days at around 1 and 2 weeks after start of dosing with 
PED25 (day 1) and after up-titration to PED50, if not already covered by the 
scheduled SBPM 
● 
Acceptability and Palatability Questionnaire: 
○ 
On 1 weekend day preceding visit 7/week 12 (EoT) 
The investigator must guide the subject and subject’s parent(s)/legal guardian(s) to ensure 
that on the evening before and during the 2-day weekend period collection of volume, the 
subject’s fluid intake should be regulated (as per investigator guidance) to an appropriate 
level considering, e.g., age, sex and subject’s condition into account.  The intake must remain 
as consistent as possible on these volume collecting days throughout the entire study. 

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7.7 
Other Assessments 
Acceptability and palatability questionnaire will be completed on 1 weekend day preceding 
Visit 7/Week 12 (EoT).  For each formulation a separate questionnaire is available, please see 
Appendices 12.8 Acceptability and Palatability Questionnaire for Tablets and 
12.9 Acceptability and Palatability Questionnaire for Oral Suspension. 
Questionnaires are to be completed by the subject or the subject’s parent(s)/caregiver(s) in 
the local language and provided via the e-diary.  Results will be directly entered in the e-diary 
by the subject or subject’s parent(s)/caregiver(s). 
7.8 
Total Amount of Blood 
The total amount of blood for each subject will vary depending on the course of their disease, 
duration on treatment and central laboratory requirements.  At any time during the study, if 
any laboratory abnormalities are found for a subject, additional blood may be drawn for 
safety monitoring. 
The maximum blood volume to be collected within 24 hours is approximately 9.5 mL per 
subject on pharmacokinetic sampling days at visit 5/week 4 and visit 7/week 12 (EoT). 
The total blood volume to be collected will be as follows 
Table 8 
Total Blood Volume per Subject over the Entire Study Period 
Sample Type 
Number of Samples 
Sample Volume (mL) 
Total Volume (mL) 
Pharmacokinetics 
2 
5.0 
10.0 
Clinical Laboratory Tests† 
Biochemistry/hematology 
3 
4.5‡ 
13.5 
Total 
23.5 
† 
Additional hematology and biochemistry tests of approximately 4.5 mL total will be performed at 
visit 3/week 0 (baseline) and visit 8/week 14 (EoS) only if an adverse event related to hematology or 
biochemistry parameters occurred since the previous visit or at the discretion of the investigator.  The total 
amount of blood drawn from subjects who require additional hematology and biochemistry tests due to 
AEs could be up to 32.5 mL. 
‡ 
Volume does not take any unscheduled visits or repeat tests into account (e.g., follow up of adverse events). 
8 
DISCONTINUATION 
8.1 
Discontinuation of Individual Subject(s) From Study Treatment(s) 
A discontinuation from treatment is defined as a subject who is randomized and for whom 
study treatment is permanently discontinued for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to discontinue the participant from study treatment or to terminate a 
subject’s involvement in the study at any time if the subject’s clinical condition warrants it. 
The reason for discontinuation from study treatment must be documented in the subject’s 
medical records. 

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A subject must discontinue study treatment for any of the following reasons: 
● 
Subject requests to stop treatment. 
● 
Any clinical AEs, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued treatment is not in the best interest of the subject. 
● 
If signs or symptoms of hypersensitivity to mirabegron are observed (e.g., anaphylactic 
reaction, erythema multiforme or exfoliative dermatitis). 
● 
ALT or AST > 8 × ULN. 
● 
ALT or AST > 5 × ULN for more than 2 weeks. 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or international normalized ratio (INR) 
> 1.5 (if INR testing is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
● 
Female subject becomes pregnant. 
● 
Prolongation of QT > QTcF > 440 msec and/or QT interval prolongation > 30 msec 
versus baseline. 
● 
Subject with (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure  
≥ 100 mmHg. 
If a subject discontinues treatment prematurely, the subject will be encouraged to complete 
all scheduled visits to record all available information. 
8.2 
Discontinuation of Individual Subject(s) From Study 
All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specific follow-up procedures as outlined in the Schedule of 
Assessments [Table 1].  The subject will also be encouraged to attend all planned visits until 
the planned End of Study visit to provide data even if not on treatment anymore.  The only 
exception to this is when the subject specifically withdraws consent/assent for any further 
contact with him/her or persons previously authorized by the subject to provide this 
information. 
8.2.1 
Lost to Follow-up 
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data and 
retrieve IP. 
8.3 
Discontinuation of the Study Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor. 
8.4 
Discontinuation of the Study 
The DSMB will review safety data periodically and provide a recommendation to the sponsor 
if the study should continue or be stopped due to safety concerns.  The sponsor may terminate 
this study prematurely, either in its entirety or at any study site, for reasonable cause provided 

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that written notice is submitted in advance of the intended termination.  Advance notice is not 
required if the study is stopped due to safety 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.  The study may also be stopped as a result of the 
outcome of the interim analysis [Section 9.10 Interim Analysis and Early Discontinuation of 
the Study]. 
9 
STATISTICAL METHODOLOGY 
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 database hardlock.  Changes from the planned analyses planned in the final SAP that 
impact the statistical analyses will be justified in the clinical study report (CSR). 
In general, all data will be summarized with descriptive statistics frequency and percentage 
for categorical data.  Data will be summarized by age group, treatment group and visit unless 
otherwise stated.  
9.1 
Sample Size 
Efficacy of mirabegron in children will be based on both primary and secondary endpoints.  
Given the clinical hurdle to demonstrate efficacy in a population challenging to recruit, an 
alpha-level of 10% would appear reasonable and justified.  In a study with propiverine in 
children, Marschall-Kehrel (2009) showed a difference in mean number of micturition 
episodes/24 hours of 0.8 between propiverine and placebo, with a SD between 2.2 and 2.3.  
Assuming at least similar efficacy of mirabegron, with a treatment effect of 0.9 micturitions 
per day between mirabegron and placebo and a common SD of 2.3, a sample size of 
82 evaluable subjects (children) per treatment group is assumed per treatment group would 
provide a power of 80%. 
These assumptions, together with levels for Type-1 error and power were agreed upon with 
Pediatric Committee in the current Pediatric Investigation Plan. 
Under the assumption that after randomization about 10% of the subjects will not be 
evaluable for the analysis of the primary endpoint (i.e., not fulfilling the criteria for inclusion 
in full analysis set [FAS]), at least 184 children (5 to < 12 years of age) must be randomized 
in order to have at least 164 evaluable children for the analysis of the primary efficacy 
endpoint. 
For adolescents, no formal sample size will be calculated; at least 32 adolescents (12 to 
< 18 years of age) must be randomized, yielding at least 16 adolescents on mirabegron.  
Further assuming a 50% screen failure rate, approximately 368 children have to be enrolled 
to achieve 184 children (5 to < 12 years of age) randomized and approximately 
64 adolescents will be enrolled to achieve at least 32 adolescents (12 to < 18 years of age) 
randomized (at least 92 children and 16 adolescents must be randomized to mirabegron). 
Recruitment will continue until the minimum number to be randomized in both children and 
adolescents have been achieved. 

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9.2 
Analysis Sets 
Detailed criteria for analysis sets will be laid out in classification specifications and the 
allocation of subjects to analysis sets will be determined prior to database hardlock. 
9.2.1 
Full Analysis Set 
The FAS will consist of all subjects who are randomized and receive at least 1 dose of IP and 
have at least 1 post baseline measurement for mean number of micturitions per 24 hours.  The 
FAS will be analyzed by treatment arm as randomized (i.e., treatment arm based on 
randomization assignment).  This will be the primary analysis set for efficacy analyses.  
Selected demographic and baseline characteristics will also be summarized for the FAS. 
9.2.2 
Per Protocol Set 
The per protocol set (PPS) will consist of all subjects who are randomized and receive at least 
1 dose of IP and have at least 1 post baseline measurement for mean number of micturitions 
per 24 hours, and who do not meet criteria for PPS exclusion.  These criteria are to capture 
relevant nonadherence to the protocol and will be defined in the SAP.  Further criteria may be 
defined in the SAP.  The PPS will be a secondary analysis set for efficacy analyses. 
Selected demographic and baseline characteristics may also be summarized for the PPS. 
9.2.3 
Safety Analysis Set 
The safety analysis set (SAF) will consist of all subjects who took at least 1 dose of IP.  The 
safety set will be analyzed by treatment arm as treated (i.e., based on the treatment the subject 
actually received rather than the treatment to which the subject was randomized).  The SAF 
will be used for all summaries of demographic and baseline characteristics and all safety- and 
tolerability-related variables. 
9.2.4 
Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set (PKAS) will consist of all subjects who took at least 
1 dose of IP for whom sufficient plasma concentration data are available to facilitate 
derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the 
day before sampling.  Additional subjects may be excluded from the PKAS at the discretion 
of the pharmacokineticist.  Any formal definitions for exclusion of subjects or time points 
from the PKAS will be documented in the classification specifications and be determined at 
the classification meeting. 
9.2.5 
Pharmacodynamic Analysis Set 
Not applicable. 
9.3 
Demographics and Baseline Characteristics 
The summaries to be provided for demographics and baseline characteristics will be 
described here. 

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9.3.1 
Demographics 
The demographic summary will include age, sex, race, ethnicity, body weight, height, body 
mass index (BMI) (at screening) and EBC.  Baseline characteristics will include, among 
others, medical history, OAB diagnosis and history.  Selected demographic and baseline 
characteristics will be summarized at least for the SAF and FAS. 
Demographic data will be listed. 
9.3.2 
Subject Disposition 
The number and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented for all randomized subjects and for 
subjects in the SAF by age group, treatment group and overall.  Similar tables for screening 
disposition, investigational period disposition and follow-up disposition will also be 
presented for all enrolled subjects by age group and overall.  All disposition details and dates 
of first and last evaluations for each subject will be listed.  
9.3.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) 
Previous and concomitant medications will be coded with WHO-Drug Dictionary 
(WHO-DD), and will be summarized by therapeutic subgroup (Anatomical Therapeutic 
Chemical [ATC] Classification System 2nd level), chemical subgroup (ATC 4th level) and 
preferred WHO name for the SAF.  Subjects taking the same medication multiple times will 
be counted once per ATC level.  A medication which can be classified into several chemical 
and/or therapeutic subgroups will be presented in all chemical and therapeutic subgroups. 
A listing of previous and concomitant medications with ATC codes by WHO preferred name 
will be provided for all screened subjects. 
9.3.4 
Medical History 
Medical history will be coded in MedDRA and will be summarized by SOC and preferred 
term (PT) for the SAF.  Subjects will only be counted once per MedDRA level. 
Medical history for each subject will be listed. 
9.3.5 
Investigational Product Exposure 
Descriptive statistics for cumulative amount of the IP the subject was exposed to and average 
daily dose. 
Duration of exposure will be summarized in the following by descriptive statistics. 
Exposure time will be categorized according to the following categories for the treatment 
period: 
● 
< 14 days 
● 
At least 14 days, < 28 days 
● 
At least 28 days, < 56 days 
● 
At least 56 days 

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● 
Unknown 
All IP exposure data will be listed. 
9.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS and PPS, and interpretation of results from 
statistical tests in children (5 to < 12 years of age) will be based on the FAS.   
The PPS will be used to assess the robustness of the results from the statistical tests based on 
the FAS.  Efficacy analysis in adolescents will only be exploratory. 
9.4.1 
Analysis of Primary Endpoint 
9.4.1.1 Primary Analysis 
The primary estimator for the primary estimand as defined in [Section 3.1 Estimand] will be 
calculated according to the evaluation of the primary efficacy endpoint.  The primary efficacy 
endpoint change from baseline to week 12/EoT in mean micturitions per 24 hours (in 
children [5 to < 12 years of age]), will be analyzed using an analysis of covariance 
(ANCOVA).  The ANCOVA model will include treatment group, sex and geographical 
region as fixed effects and the mean number of micturitions per 24 hours at baseline as 
covariate.  This analysis will be performed and once with imputation of missing week 12 data 
using the last observation carried forward (LOCF) method. 
The hypothesis for comparisons is given as follows: 
H0: The adjusted mean change from baseline at week 12 in mean number of micturitions per 
24 hours for mirabegron and placebo are the same. 
H1: The adjusted mean change from baseline at week 12 in mean number of micturitions per 
24 hours for mirabegron and placebo are not the same. 
Statistical testing will be done at a 2-sided 0.1 significance level.  A 90% CI for the treatment 
difference (mirabegron – placebo) will be provided.  The primary analysis will use the FAS.  
The plausibility of the underlying assumption of missing at random for the primary estimator 
will be evaluated, and; therefore, the estimation of the treatment effect.  Sensitivity analyses 
under alternative assumptions for missing data mechanisms such as missing not at random to 
show robustness of the estimates will be further specified in the SAP. 
9.4.1.2 Secondary Analysis 
The same analysis of the primary endpoint as described in [Section 9.4.1.1 Primary Analysis] 
will be conducted using the PPS, and without imputation using FAS. 
The change from visit 3/week 0 (baseline) to visit 7/week 12 (EoT) in mean number of 
micturitions per 24 hours in children (5 to < 12 years of age) will be analyzed.  The primary 
analysis for the primary endpoint will be using a repeated measures ANCOVA model with 
treatment group, visits (week 4, 8 and 12), sex, geographical region and the interaction 
between treatment group and visit as fixed effects and mean number of micturitions per 
24 hours at baseline as covariate.  Mirabegron will be compared to placebo using a linear 

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contrast within the repeated measures ANCOVA model, with 2-sided significance level of 
alpha = 0.1 and 90% CI.  This analysis will be conducted using the FAS. 
In addition to the parametric ANCOVA, a nonparametric ANCOVA will also be performed: 
(stratified) rank ANCOVA.  This analysis will be conducted using the FAS. 
9.4.1.3 Subgroup Analysis  
For the primary efficacy endpoint, descriptive statistics (n, mean, 95% confidence interval 
around the mean, SD, minimum, median, maximum) will be calculated for mean change from 
baseline at each visit by sex, race, ethnicity, geographical region, formulation (tablets vs. oral 
suspension), prior OAB treatment and symptomatic UTI. 
9.4.2 
Analysis of Secondary Endpoints 
The same analysis (ANCOVA) as for the primary endpoint will be applied to change from 
baseline at the end of the 12-week treatment period in children (5 to < 12 years of age) for: 
● 
Mean volume voided per 24 hours 
● 
Maximum volume voided 
● 
Mean number of daytime incontinence episodes per 24 hours 
● 
Mean number of nighttime incontinence episodes per 24 hours 
● 
Mean number of daytime micturitions per 24 hours 
Change from baseline in the number of dry (incontinence free) days per 7 days at the end of 
the 12-week treatment period will be analyzed with a negative binomial regression model 
including treatment group, sex, geographical region as factors and the log baseline rate of 
number of dry days (e.g., the log of the number of dry days divided by number of diary days 
at baseline) as covariate. 
9.4.3 
Analysis of Exploratory Endpoints 
All efficacy endpoints for adolescents will be analyzed descriptively. 
Data of the following explorative endpoints will be summarized, separately, for pediatric 
subjects: 
● 
Percentage of subjects with a reduction in daytime incontinence episodes (< 50% 
reduction [nonresponder], 50% [partial responder] and 100% [responder]) 
● 
Improvement from baseline in worst incontinence grading 
● 
Change from baseline at the end of the 12-week treatment period adjusted for fluid 
intake: 
○ 
Mean number of micturitions per 24 hours 
● 
Change from baseline at the end of the 12-week treatment period (adolescents only): 
○ 
Mean number of micturitions per 24 hours 
○ 
Mean number of daytime micturitions per 24 hours 
○ 
Mean volume voided per 24 hours 
○ 
Mean number of incontinence episodes per 24 hours 

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● 
Number of dry (incontinence-free) days per 7 days at the end of the 12-week treatment 
period (adolescents only) 
Mean number of daytime grade 3 or 4 (Patient Perception of Intensity of Urgency Scale 
[PPIUS]) urgency episodes per 24 hours (adolescents only) will be summarized. 
Correlations between the primary endpoint and mean volume voided, as well as incontinence 
episodes, will be explored.   
Scatter plots will be presented to access the correlation between the primary end point, and 
mean volume voided and number of incontinence episodes at week 12. 
9.5 
Analysis of Safety 
Safety analysis will be conducted on the SAF and conducted separately for children, 
adolescents and overall.  Safety endpoints will be summarized using descriptive statistics. 
9.5.1 
Adverse Events 
AEs will be coded using MedDRA.  A TEAE is defined as an AE observed after starting 
administration of the IP and 30 days after the final administration of IP.  An IP-related TEAE 
is defined as any TEAE with a causal relationship assessed as “yes” by the investigator. 
The number and percentage of TEAEs, drug-related TEAEs, serious TEAEs, drug-related 
serious TEAEs, TEAEs leading to leading to withdrawal of treatment and drug-related 
TEAEs leading to leading to withdrawal of treatment will be summarized by SOC, preferred 
term, age group and treatment group.  The number and percentage of TEAEs by severity will 
also be summarized.  The worst severity will be summarized if the same AE is recorded more 
than once for a subject. 
AE data will be listed. 
9.5.2 
Laboratory Assessments 
For quantitative clinical laboratory measurements (hematology, biochemistry and urinalysis), 
descriptive statistics will be used to summarize results and change from baseline by treatment 
group and within treatment group and across age group. 
Shifts relative to normal ranges from baseline to each visit during the treatment period in 
clinical laboratory tests will be tabulated. 
Laboratory data will be listed. 
The laboratory parameters that will be assessed during the conduct of the study are listed in 
[Appendix 12.7 Laboratory Assessments]. 
In cases where laboratory evaluations are conducted locally, the values obtained will be 
adjusted to values obtained by the central laboratory. Details will be described in the SAP. 
9.5.3 
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and within treatment group and across age group.  For clinic 

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measurements Z-scores and percentiles for SBP and DBP will be calculated and summarized 
based on a comparison with age and height norms supplied by the Center for Disease Control 
and Prevention.  Details to calculate Z-scores and percentiles will be provided in the SAP. 
Z-scores and percentiles for pulse rate will be calculated and summarized based on a 
comparison with age norms based on Fleming [Fleming et al, 2011].  Details to calculate 
Z-scores and percentiles will be provided in the SAP. 
Vital signs data will be listed. 
9.5.4 
Physical Examination  
Abnormal findings/conditions identified during the physical examinations will be listed as 
part of the medical history for the screening visit, or as AEs at later visits. 
9.5.5 
Electrocardiogram 
The routine 12-lead ECG results will be summarized separately for children (5 to < 12 years 
of age) and adolescents (12 to < 18 years of age) by treatment group and visit. ECGs will be 
recorded prior to blood draw.  
9.5.6 
Post Void Residual Volume 
The PVR volume data and change from baseline data will be summarized by treatment group 
and within treatment group and across age. 
9.5.7 
Acceptability and Palatability Questionnaire 
Results from the acceptability and palatability questionnaire for tablets 
[Appendix 12.8 Acceptability and Palatability Questionnaire for Tablets] and for oral 
suspension [Appendix 12.9 Acceptability and Palatability Questionnaire for Oral Suspension] 
will be summarized at week 12/EoT by age group and treatment group. 
9.6 
Analysis of Pharmacokinetics 
Pharmacokinetic analysis will be conducted on the PKAS and conducted separately for 
children, adolescents and overall.  Descriptive statistics (n, mean, SD, minimum, median, 
maximum, coefficient of variation (CV), geometric mean and geometric CV) will be used to 
summarize plasma concentrations of mirabegron by visit and time point.  Further details will 
be specified in the SAP. 
9.6.1 
Estimation of Pharmacokinetic Parameters 
The plasma concentrations will be analyzed with nonlinear mixed effects modeling 
(population pharmacokinetics) using Non-Linear Mixed Effects Modeling (NONMEM) 
software (version 7.3 or higher, ICON Development Solutions, Ellicott City, MD, US) to 
estimate the pharmacokinetic parameters.  Results will be reported separately. 
9.7 
Analysis of Pharmacodynamics | Immunogenicity 
Not applicable. 

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9.8 
Other Analyses 
Not applicable. 
9.9 
Major Protocol Deviations 
Major protocol deviations as defined in [Section 10.3 Major Protocol Deviations] will be 
summarized for all randomized subjects by study site, treatment group and overall separately 
for children (5 to < 12 years of age) and adolescents (12 to < 18 years of age). 
Major protocol deviation data will be listed by study site and subject. 
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. 
9.10 
Interim Analysis (and Early Discontinuation of the Study) 
A blinded interim analysis will be performed after 50% of children planned to be randomized 
have had their week 12/EoT assessment.  The interim analysis will determine if the chance of 
a positive study with respect to the primary endpoint at the EoS is high enough to justify 
continuation of the study; otherwise, the study will be stopped for futility. 
Given the data at the interim analysis, the independent data analysis center (IDAC) will 
calculate the predictive probability of a positive study.  A positive study is defined as the 
final 1-sided p-value ≤ 0.05 when comparing Mirabegron vs. placebo in the primary efficacy 
analysis (in children [5 to < 12 years of age]).  If the predictive probability is ≤ 5% at this 
interim evaluation, the study will be recommended to stop for futility.  Otherwise, the study 
will continue. 
Detailed information on the decision rule of futility and simulations illustrating the operating 
characteristics of futility criterion will be presented in the SAP. 
9.11 
Additional Conventions 
Missing data for efficacy endpoints will be imputed as EoT values, details will be described 
in the SAP.  Handling of incomplete dates will also be described in the SAP. 
Geographical regions that do not enroll sufficient subjects to allow estimation of the 
geographical effect will be pooled for analyses by geographical region.  The pooling 
decisions will be made and documented prior to study hardlock. 
10 
OPERATIONAL CONSIDERATIONS 
10.1 
Data Collection 
The investigator or site designee will enter data collected using an electronic data capture 
system.  In the interest of collecting data in the most efficient manner, the investigator or 
designee should record data (including clinical laboratory values, if applicable) in the 
electronic case report form within 5 days after the subject’s visit. 

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The monitor should verify the data in the electronic case report forms with the source and 
confirm that there are no inconsistencies among them. 
Clinical laboratory tests are performed at central laboratory.  Central laboratory data will be 
transferred electronically to the sponsor or designee at predefined intervals during the study.  
The central laboratory will provide the sponsor or designee with a complete and clean copy 
of the data. 
Subject bladder e-diaries and questionnaires as described in [Section 7.6 Electronic Clinical 
Outcome Assessment] will be completed by the subject on an electronic device and the 
collected electronic data source will be hosted at the vendor. 
The investigator or designee will review the diaries and questionnaire data throughout the 
study to ensure completion and protocol compliance. 
10.2 
Demographics and Baseline Characteristics 
10.2.1 Demographics 
Demographics and baseline characteristics will be collected as indicated in the Schedule of 
Assessments [Table 1].  This will include age, sex, race, ethnicity, body weight and height. 
10.2.2 Medical History 
A complete medical history will be collected as indicated in the Schedule of Assessments 
[Table 1]. 
10.2.3 Diagnosis of the Target Disease, Severity and Duration of Disease  
A detailed OAB history for each subject will be collected at visit 1/screening.  This history 
includes the underlying condition, comorbidities associated with OAB and treatment history 
for OAB. 
10.3 
Major Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  All deviations from the protocol are to be 
recorded.  A protocol waiver is a documented prospective approval of a request from an 
investigator to deviate from the protocol.  Protocol waivers are strictly prohibited. 
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 
well-being 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 subjects. 
A major protocol deviation is 1 that may potentially impact the completeness, accuracy or 
reliability of data contributing to the primary endpoint or affect the rights, safety or well-
being of a subject.  Major protocol deviations will have additional reporting requirements. 
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified.  The sponsor will follow up with 

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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. 
The major protocol deviation criteria that will be summarized at the EoS are as follows:  
PD1 - Entered into the study even though the subject did not satisfy entry criteria 
PD2 - Developed withdrawal criteria during the study and was not withdrawn 
PD3 - Received wrong treatment or incorrect dose 
PD4 - Received excluded concomitant treatment 
The investigator will also assure that deviations meeting IRB/IEC and appropriate regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation and 
communications to the IRB/IEC and appropriate regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File. 
10.4 
Study Organization 
10.4.1 Data and Safety Monitoring Board 
A DSMB will be implemented to act in an advisory capacity to the sponsor to monitor 
participant safety and data quality. 
Subject safety overviews will be prepared by the IDAC and will be reviewed on a regular 
basis by the DSMB, who will advise the sponsor on appropriate steps to protect study 
participants, which may include the early termination of the study. 
A separate charter will describe the responsibilities, remit and timing of DSMB meetings. 
10.4.2 Independent Data Analysis Center 
An IDAC for this study will serve the 2 purposes: (1) to generate periodic safety overviews 
for the DSMB and (2) to calculate the futility analysis. The statistical member of the DSMB 
may also serve as the IDAC statistician, as described in the DSMB charter. A SAP describing 
the details of the periodic safety review of outputs will be developed with input from the 
DSMB members. 
10.4.3 Other Study Organization 
Not applicable. 

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11 
REFERENCES 
Austin PF, Bauer SB, Bower W, Chase J, Franco I, Hoebeke P, et al.  The standardization of 
terminology of lower urinary tract function in children and adolescents: update report from the 
Standardization Committee of the International Children’s Continence Society.  J. Urol.  
2014;191:1863-5. 
BETANIS® (prescribing information).  Northbrook, Illinois: Astellas Pharma US, Inc.; Jun 2012. 
BETMIGA® (prescribing information).  Northbrook, Illinois: Astellas Pharma US, Inc.; Apr 2018. 
Derweesh IH, Wheeler MA, Weiss RM.  Alterations in G-proteins and β-adrenergic responsive 
adenylyl cyclase in rat urinary bladder during aging.  J Pharmacol Exp Therap.  
2000;294:969-74. 
Drossman DA, Hasler WL.  Rome IV functional gastrointestinal disorders: disorders of gut-brain 
interaction.  Gastroenterology.  2016;150:1257-61.  Available at: 
https://www.gastrojournal.org/article/S0016-5085(16)30048-8/fulltext. Accessed 21 Jun 2019. 
Fleming S, Thompson M, Stevens R, Heneghan C, Plüddemann A, Maconochie I, et al.  Normal 
ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic 
review of observational studies.  Lancet.  2011;377:1011-18. 
Flynn JT, Kaelbar DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al.  Clinical practice 
guideline for screening and management of high blood pressure in children and adolescents.  
Pediatrics.  2017;140(3):e20171904. 
Investigator’s Brochure Mirabegron (YM178), Astellas. 
Marschall-Kehrel D, Feustel C, Persson de Geeter C, Stehr M, Radmayr C, Sillén U, et al.  Treatment 
with propiverine in children suffering from nonneurogenic overactive bladder and urinary 
incontinence: results of a randomized placebo-controlled phase 3 clinical trial.  Eur Urol.  
2009;55:729-36. 
McDowell MA, Fryar CD, Ogden CL, Flegal KM.  Anthropometric reference data for children and 
adults: United States, 2003–2006.  Natl Health Stat Report.  2008;22(10):1-48. 
Momper JD, Mulugeta Y, Green DJ, Karesh A, Krudys KM, Sachs HC, et al.  Adolescent Dosing and 
Labeling Since the Food and Drug Administration Amendments Act of 2007.  JAMA Pediatr.  
2013;167:926-932. 
MYRBETRIQ® (prescribing information).  Northbrook, Illinois: Astellas Pharma US, Inc.; Jun 2012. 
Nevéus T, von Gontard A, Hoebeke P et al.  The standardization of terminology of lower urinary tract 
function in children and adolescents: report from the standardisation committee of the 
international children’s continence society.  J Urol. 2006; 176; 314 – 324. 
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al.  New Equations to 
Estimate GFR in Children with CKD.  J Am Soc Nephrol.  2009;20:629-37. 
Temple R.  Hy’s law: predicting serious hepatotoxicity.  Pharmacoepidemiol Drug Saf.  
2006;15:241-3. 

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12 
APPENDICES 
12.1 
Ethical, Regulatory and Study Oversight Considerations 
12.1.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing study conduct and the ethical principles that have their 
origin in the Declaration of Helsinki. 
12.1.2 Institutional Review Board/Independent Ethics Committee/Competent 
Authorities 
GCP requires that the protocol, any protocol amendments, Investigator’s Brochure, 
ICF/assent and all other forms of subject information related to the study (e.g., 
advertisements used to recruit subjects) and any other necessary documents be reviewed by 
an IRB/IEC.  The IRB/IEC will review the ethical, scientific and medical appropriateness of 
the study before it is conducted.  IRB/IEC approval of the protocol, ICF/assent and subject 
information and/or advertising, as relevant, will be obtained prior to initiation of any study-
specific procedures. 
Any substantial amendments to the protocol will require competent authority and IRB/IEC 
approval before implementation, except for changes necessary to eliminate an immediate 
hazard to subjects. 
The investigator will be responsible for the following: 
● 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies and procedures established by 
the IRB/IEC 
● 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
● 
Providing oversight of the conduct of the study at the study site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, EU Regulation No. 536/2014 for 
studies (if applicable), and all other applicable local regulations 
12.1.3 Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or nonsubstantial amendments.  
Depending on the nature of the amendment, either IRB/IEC or competent authority approval 
or notification may be required.  The changes will become effective only after the approval of 
the sponsor, investigator, IRB/IEC and appropriate regulatory authorities. 
Amendments to this protocol must be signed by the sponsor and investigator.  Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented.  
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations. 

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If there are changes to the ICF/assent, written verification of IRB/IEC approval must be 
forwarded to the sponsor.  An approved copy of the new ICF/assent must also be forwarded 
to the sponsor. 
12.1.4  Financial Disclosure 
Investigators and subinvestigator(s) will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
12.1.5 Informed Consent/Assent of Subjects 
12.1.5.1 Subject Information and Consent/Assent 
For this pediatric study in subjects aged 5 to < 18 years of age, in addition to information 
sheets and consent forms/assent for subjects (according to applicable local regulations), 
parent/legal guardian information sheets and consent forms/assent will also be prepared. 
The investigator or his/her representative will explain the nature of the study to the subject 
and his/her parent(s)/legal guardian(s) and answer all questions regarding this study.  Prior to 
any study-related screening procedures being performed on the subject, the ICF/assent will be 
reviewed, signed and dated by the subject or his/her parent(s)/legal guardian(s), the person 
who administered the ICF/assent and any other signatories according to local requirements.  
A copy of the signed ICF/assent 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 the ICF/assent was signed prior to any study-related procedures 
and that the subject received a signed copy of the ICF/assent. 
The following general rules apply but these may vary by local regulations for pediatric 
studies: 
● 
The investigator/subinvestigator(s) is responsible for explaining the nature and purpose 
of the study as well as other study-related matters to subjects and their parent(s)/legal 
guardian(s), using the written information, and for obtaining the child’s assent and the 
parent(s)’/guardian(s)’ full understanding and written consent/assent to participate in the 
study of their own free will. 
● 
In cases where there might be an explicit wish of a minor or an incapacitated adult, who 
is capable of forming an opinion and assessing this information, to refuse to participate 
or to be withdrawn from the clinical study at any time, this will have to be considered by 
the investigator, even if consent/assent is given by the parent(s)/legal guardian(s).  Every 
effort should be made to understand and respect differences of opinion between the 
subject and their parent(s)/legal guardian(s).  Strong and definitive objections from the 
child should be respected. 
● 
The investigator or other responsible personnel who provided explanations (including 
collaborators who gave supportive information, if applicable) and the subject and 

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parent(s)/legal guardian(s) should sign and date the written information, or write down 
his/her name, and date the form. 
● 
Informed consent/assent must be obtained prior to any study-related procedures 
(including discontinuation of prohibited medication, if applicable).  Consent/assent 
should be obtained from the subject and his/her parent(s)/legal guardian(s), before start 
of pre-investigational period.  Consent/assent will be obtained per local regulations. 
● 
The investigator or other responsible personnel must give a copy of the signed 
consent/assent form to the subject and parent(s)/legal guardian(s) and store the original 
appropriately in accordance with the rules at the study site concerned. 
● 
The investigator or other responsible personnel should note the following when obtaining 
consent/assent from subjects and parent(s)/legal guardian(s): 
○ 
No subject may be subjected to undue influence, such as compulsory enrollment into 
a study. 
○ 
The language and expressions used in the written information should be as plain and 
understandable as possible.  Subjects and their parent(s)/legal guardian(s) should be 
given the opportunity to ask questions and receive satisfactory answers to the 
inquiry and should have adequate time to decide whether or not to participate in the 
study.  Written information should not contain any language or contents that causes 
the subject to waive or appears to waive any legal rights, or that releases/mitigates or 
appears to release/mitigate the study site, the investigator/subinvestigator(s), 
collaborators, or the sponsor from liability for negligence. 
The signed ICFs/assents will be retained by the investigator and made available (for review 
only) to the study monitor, auditor and appropriate regulatory authorities and other applicable 
individuals upon request. 
12.1.5.2 Supply of New and Important Information Influencing the Subject’s 
Consent/Assent and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject verbally 
whenever new information becomes available that may be relevant to the subject’s 
consent/assent or may influence the subject’s willingness to continue participating in the 
study (e.g., report of serious adverse drug reaction).  The communication must be 
documented in the subject’s medical records and whether the subject is willing to remain 
in the study or not must be confirmed and documented. 
2. The investigator must update the subject’s ICF/assent and submit it for approval to the 
IRB/IEC.  The investigator or his/her representative must obtain written informed 
consent/assent from the subject on all updated ICFs/assents throughout their participation 
in the study.  The investigator or his/her designee must reconsent subjects with the 
updated ICF/assent even if relevant information was provided verbally.  The investigator 
or his/her representative who obtained the written informed consent/assent and the 
subject should sign and date the ICF/assent.  A copy of the signed ICF/assent will be 
given to the subject and the original will be placed in the subject’s medical record.  An 
entry must be made in the subject’s records documenting the reconsent process. 

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12.1.6 Source Documents 
1. Source data must be available at the study site to document the existence of the subjects 
and to substantiate the integrity of study data collected.  Source data must include the 
original documents relating to the study, as well as the medical treatment and medical 
history of the subject. 
2. The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
3. The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are handwritten on 
paper or entered electronically.  If source data are created (first entered), modified, 
maintained, achieved, retrieved or transmitted electronically via computerized systems 
(and/or other kind of electronic devices) as part of regulated study activities, such 
systems must be compliant with all applicable laws and regulations governing use of 
electronic records and/or electronic signatures.  Such systems may include, but are not 
limited to, electronic medical/health records, protocol-related assessments, AE tracking, 
electronic clinical outcome assessment eCOA and/or drug accountability. 
4. Paper records from electronic systems used in place of electronic format must be 
certified copies.  A certified copy must be an exact copy and must have all the same 
attributes and information as the original.  Certified copies must include signature and 
date of the individual completing the certification.  Certified copies must be a complete 
and chronological set of study records (including notes, attachments, and audit trail 
information, if applicable).  All printed records must be kept in the subject file and be 
available for archiving. 
5. Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH 
GCP and all applicable regulatory requirements. 
12.1.7 Record Retention 
The investigator will archive all study data (e.g., subject identification code list, source data 
electronic data source and investigator’s file) and relevant correspondence.  These documents 
are to be kept on file for the appropriate term determined by local regulation.  The sponsor 
will notify the study site/investigator if the European Medicines Agency (EMA) is approved 
or if the IND/investigational medicinal product dossier is discontinued.  The investigator 
agrees to obtain the sponsor’s agreement prior to disposal, moving or transferring of any 
study-related records.  The sponsor will archive and retain all documents pertaining to the 
study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subject’s 
medical records and/or study progress notes. 
The documents of the efficacy and safety evaluation committee (minutes and SOPs and 
others) and the judgment committee outside the study sites (minutes and SOPs and others) 
shall be retained by the sponsor. 

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12.1.8 Subject Confidentiality and Privacy 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the subject provides written 
consent/assent or approval.  Additional medical information may be given only after approval 
of the subject to the investigator or to other appropriate medical personnel responsible for the 
subject’s well-being. 
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the study without justifiable reasons. 
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to a subject’s privacy due to direct access to source 
documents, or from other sources, they may not disclose the content to third parties. 
The sponsor affirms the subject’s right to protection against invasion of privacy.  Only a 
subject identification number will identify subject data retrieved by the sponsor.  However, 
the sponsor requires the investigator to permit the sponsor, sponsor’s representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study. 
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and privacy laws in the US.  If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then the sponsor shall serve as the controller of 
such data, as defined by the EU Data Protection Directive (DPD), and investigator and/or 
third party shall act only under the instructions of the sponsor in regard to personal data.  If 
the sponsor is not based in the EEA, the sponsor must appoint a third party to act as its local 
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the DPD. 
12.1.9 Arrangement for Use of Information and Publication of the Study 
Information concerning the test product, patent applications, processes, unpublished scientific 
data, the Investigator’s Brochure and other pertinent information is confidential and remains 
the property of the sponsor.  Details should be disclosed only to the persons involved in the 
approval or conduct of the study.  The investigator may use this information for the purpose 
of the study only.  It is understood by the investigator that the sponsor will use the 
information obtained during the study in connection with the development of the 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 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 study agreement. 

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12.1.10 Insurance of Subjects and Others 
The sponsor has covered this study by means of an insurance of the study according to 
national requirements.  The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
investigator’s file. 
12.1.11 Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final CSR that 
forms part of a marketing authorization application, be signed by the representative for the 
coordinating investigator(s) or the principal investigator(s).  The representative for the 
coordinating investigator(s) or the principal investigator(s) will have the responsibility to 
review the final study results to confirm to the best of his/her knowledge it accurately 
describes the conduct and results of the study.  The representative for the coordinating 
investigator(s) or the principal investigator(s) will be selected from the participating 
investigators by the sponsor prior to database hardlock. 
12.2 
Procedure for Study Quality Control 
12.2.1 Study Monitoring 
The sponsor is responsible for monitoring the study to ensure that the rights, safety and well-
being of subjects are protected, the study is properly conducted in adherence to the current 
protocol and GCP.  The sponsor is responsible for assigning the study monitor(s) to this study 
for proper monitoring.  They will monitor the study in accordance with planned monitoring 
procedures. 
12.2.2 Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the sponsor, as 
well as inspections from the IRB/IEC and appropriate regulatory authorities.  In these 
instances, they must provide all study-related records including source documents when they 
are requested by the sponsor monitors and auditors, the CRO, the IRB/IEC or appropriate 
regulatory authorities.  The confidentiality of the subject’s identity shall be well protected 
consistent with local and national regulations when the source documents are subject to direct 
access. 
12.2.3 Data Management 
Data management will be coordinated by the Data Science department or designee of the 
sponsor in accordance with the SOPs for data management.  All study-specific processes and 
definitions will be documented by data management.  Electronic data source completion will 
be described in the electronic data source instructions.  Coding of medical terms and 
medications will be performed using MedDRA and the WHO Drug Dictionary, respectively.  
Data management is accountable for eCOA. 

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12.2.4 Quality Assurance 
The sponsor is implementing and maintaining quality assurance (QA) and quality control 
(QC) systems with written SOPs to ensure that studies are conducted and data are generated, 
documented, recorded, and reported in compliance with the protocol, GCP and applicable 
regulatory requirement(s).  Where applicable, the QA and QC systems and written SOPs of 
the CRO will be applied. 
The sponsor or sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities.  The audit may include on-site review of regulatory documents, CRFs and source 
documents.  Direct access to these documents will be required by the auditors. 
To support quality around subject safety and reliability of study results, quality tolerance 
limits (QTLs) are defined and monitored.  QTLs represent the acceptable variation of study 
data, taking into consideration the current state of medical and statistical knowledge about the 
variables to be analyzed as well as the statistical design of the study.  It is a level, point, or 
value associated with a parameter that should trigger an evaluation if a deviation is detected 
to determine if there is a possible systematic issue (i.e., a trend has occurred).  The QTLs 
defined for this study are provided below. 
Table 9 
Quality Tolerance Limit 
QTL #: Name and Parameter 
Definition 
Parameter Justification 
Subject ePRO diary completion: 
Proportion (%) of randomized 
subjects who provide the number of 
micturitions in 7 days of ePRO diary 
data at week 4, week 8 and week 12. 
Proportion (%) of randomized 
subject with missing number 
of micturitions in 7 days of 
diary data at week 4, week 8 
and week 12. 
If subject diaries are not completed 
accurately or are discrepant with 
source data, there is a risk of 
inaccurate data which may impact 
primary endpoint. 
Subject ePRO diary completion: 
Proportion (%) of randomized 
subjects who provide urine volume 
voided data over 2 days of ePRO 
diary data at week 4, week 8 and 
week 12. 
Proportion (%) of randomized 
subjects with missing urine 
volume voided data over 
2 days of diary data at week 4, 
week 8 and week 12. 
If subject diaries are not completed 
accurately or are discrepant with 
source data, there is a risk of 
inaccurate data which may impact 
secondary endpoints. 
Subject ePRO diary completion: 
Proportion (%) of randomized 
subjects who provide number of dry 
days and number of wet days for 
7 days of ePRO diary data at week 4, 
week 8 and week 12. 
Proportion (%) of randomized 
subjects with missing number 
of dry days and number of wet 
days for 7 days of diary data at 
week 4, week 8 and week 12. 
If subject diaries are not completed 
accurately or are discrepant with 
source data, there is a risk of 
inaccurate data which may impact 
secondary endpoints. 
Subject ePRO diary completion:  
Proportion (%) of randomized 
subjects with missing acceptability 
and palatability questionnaire at 
week 12. 
Proportion (%) of randomized 
subjects with missing 
acceptability and palatability 
questionnaire at week 12. 
A high number of missing 
acceptability and palatability 
questionnaire will have a negative 
impact on the interpretation of the 
secondary endpoints. 
Pharmacokinetic sample results:  
Proportion (%) missing week 4 and 
week 12 pharmacokinetic sample 
results. 
Proportion (%) of overall 
planned sampling time points 
with a missing result due to 
any reason, such as missed 
collection, lost or mishandled. 
A high number of missing 
pharmacokinetic sample results can 
have a negative impact on 
interpretation of secondary endpoints. 
ePRO: electronic patient-reported outcome; QTL: quality tolerance limit 
QTL Management Activities: 
For control of risks associated with QTLs, refer to the Study Monitoring Plan. 

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12.3 
Contraception Requirements 
Contraception for Pediatric Male Subjects of Reproductive Potential 
Male children/adolescents in the following categories are not considered of reproductive 
potential: 
1. 
Tanner stage 1 development 
2. 
Documented surgically sterile  
Documentation from the site personnel’s review of the male subject’s medical records, 
medical exam and medical history interview is necessary.  
Contraception guidance for male children/adolescents of reproductive potential: 
● 
Male children/adolescents of reproductive potential (Tanner Stage 2 and above) 
receiving non-genotoxic agents should use a condom during treatment and for 3 weeks + 
5 × half-life of drug after last dose.  
● 
Male children/adolescents of reproductive potential receiving genotoxic agents should 
use a condom during treatment and for 90 days + 5 × half-life of drug after last dose. 
● 
Male participants should inform their female partners that they are participating in a 
clinical trial and effective methods of contraception should be used.  
● 
Female partners of male subjects who have not undergone bilateral orchiectomy should 
consider use of highly effective methods of contraception until the end of relevant 
systemic exposure, as defined above.  
Contraception for Pediatric Female Subjects of Childbearing Potential 
Female children/adolescents in the following categories are not considered of 
childbearing potential: 
1. Pre-menarchal  
2. Documented surgically sterile (hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy) 
Documentation from the site personnel’s review of the female subject’s medical records, 
medical exam and medical history interview is necessary. 
Contraception guidance for female children/adolescents of childbearing potential: 
● 
Female children/adolescents of childbearing potential receiving non-genotoxic agents 
should use highly effective contraception during treatment and for 30 days after last 
dose. 
● 
Female children/adolescents of childbearing potential receiving genotoxic agents should 
use contraception during treatment and for 180 days + 5 × half-life of drug after last 
dose. 
● 
Pregnancy testing for female children/adolescents of childbearing potential 
o At all on-site visits and 30 days after end of relevant systemic exposure 

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One of the highly effective methods of contraception listed below is required at the time of 
informed consent and until the end of relevant systemic exposure as defined above. 
Highly Effective Birth Control Methods-failure rate < 1%/year 
1. Combined estrogen and progestogen containing hormonal contraception  
a. Oral 
b. Intravaginal 
c. Transdermal-Patch 
d. Injectable-Cyclofem, Mesigyna 
e. Intrauterine device 
f. Intrauterine hormone-releasing system 
2. Progestogen-only hormonal contraception  
a. Oral 
b. Injectable-DMPA-IM or -SC 
c. Implantable-Norplant 
3. Bilateral tubal occlusion 
4. Vasectomized male partner 
5. True abstinence* 
*True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. Sexual abstinence is considered a 
highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. It is not necessary to use any other 
method of contraception when complete abstinence is elected. 
Birth control methods considered unacceptable: 
1. Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
2. Withdrawal (coitus interruptus) 
3. Spermicides only 
4. Lactational amenorrhea 
 

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12.4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
12.4.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject administered an IP, and which does 
not necessarily have to have a causal relationship with this treatment.  An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of IP whether 
or not considered related to the IP. 
12.4.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g., hematology, biochemistry or urinalysis dipstick) or 
other safety assessment (e.g., vital signs, physical examination, ECGs or radiographic scans), 
including those that worsen from baseline should be considered to be reported as an (S)AE. 
Any abnormal laboratory finding or other abnormal safety assessment, which is associated 
with the underlying disease or with concomitant medication, will not be considered an AE 
unless judged by the investigator to be more severe than expected for the subject’s condition 
or not associated with the known side effects of the concomitant medication. Additionally, 
minor laboratory deviations or fluctuations outside of normal ranges of preexisting disease(s) 
or condition(s) present or detected at the start of the study that do not worsen and/or that are 
not reproducible with re-testing will not to be considered an AE. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE.  Any abnormal test result that is determined to be 
an error does not require reporting as an AE. 
12.4.1.2 Potential Cases of Drug-induced Liver Injury 
Refer to [Appendix 12.5 Liver Safety Monitoring and Assessment] for detailed instructions 
on drug induced liver injury.  Abnormal values in AST and/or ALT concurrent or with 
abnormal elevations in TBL that meet the criteria outlined in [Appendix 12.5 Liver Safety 
Monitoring and Assessment], in the absence of other causes of liver injury, are considered 
potential cases of drug-induced liver injury (potential Hy’s Law cases) and are always to be 
considered important medical events and reported per [Appendix 12.4.5 Reporting 
Procedures for Serious Adverse Events].  
12.4.2 Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or sponsor, the event: 
● 
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) 

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● 
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 (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE) 
● 
Other medically important events (defined in paragraph below) 
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 1 of the other outcomes listed in the definition 
above.  These events, including those that may result in disability/incapacity, usually are 
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. 
12.4.3 Criteria for Causal Relationship to Investigational Product 
A medically qualified investigator is obligated to assess the relationship between IP and each 
occurrence of each (S)AE.  This investigator will use medical judgment as well as the 
reference safety information [Section 2.1.3 Summary of Key Safety Information for 
Investigational Product(s)] to determine the relationship.  The causality assessment is 1 of the 
criteria used when determining regulatory reporting requirements. 
The investigator is requested to provide an explanation for the causality assessment for each 
(S)AE and must document in the medical notes that he/she has reviewed the (S)AE and has 
provided an assessment of causality. 
Following a review of the relevant data, the causal relationship between the IP and each 
(S)AE will be assessed by answering “yes” or “no” to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the IP?” 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the IP (rather than a relationship cannot be ruled out) 
or if there is evidence to reasonably deny a causal relationship: 
● 
Has the subject been administered IP? 
● 
Plausibility (i.e., could the event have been caused by the suspect drug? Consider 
biologic and/or pharmacologic mechanism, half-life, literature evidence, drug class, 
preclinical and study data, etc.) 
● 
Dechallenge/dose reduction/rechallenge: 
○ 
Dechallenge: did the (S)AE resolve or improve after only stopping the dose of the 
suspect drug without any treatment? 
○ 
Dose reduction: did the (S)AE resolve or improve after reducing the dose of the 
suspect drug? 

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○ 
Rechallenge: did the (S)AE reoccur if the suspected drug was reintroduced after 
having been stopped? 
● 
Laboratory or other test results: a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the IP (e.g., based on values pre-, during and 
post-treatment) 
● 
Available alternative explanations independent of IP exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc., and strength of the 
alternative explanation 
● 
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible 
temporal relationship between exposure to the IP and (S)AE onset and/or resolution will 
be provided.  Did the (S)AE occur in a reasonable temporal relationship to the 
administration of the IP? 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor.  However, it is very important that 
the investigator always assesses causality for every event before the initial transmission of the 
SAE data to the sponsor.  With limited or insufficient information about the event to make an 
informed medical judgment and in absence of any indication or evidence to establish a causal 
relationship, a causality assessment of “no” is to be considered.  In such instance, the 
investigator is expected to obtain additional information regarding the event as soon as 
possible and to re-evaluate the causality upon receipt of additional information.  The 
medically qualified investigator may revise his/her assessment of causality in light of new 
information regarding the SAE and shall send an SAE follow-up report and update the 
electronic data source with the new information and updated causality assessment. 
12.4.4 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 
12.4.5 Reporting Procedures for Serious Adverse Events 
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by fax or email immediately 
(within 24 hours of awareness). 
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
delegation of authority log).  Signature confirms accuracy and completeness of the SAE data 
as well as the investigator causality assessment including the explanation for the causality 
assessment. 
If the SAE is associated with emergency unblinding by the investigator as outlined in 
[Section 6.3.4 Breaking the Treatment Code for Emergency], this is to be recorded on the 

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SAE worksheet.  On the SAE worksheet, the investigator is to include when unblinding took 
place in association with the SAE. 
For contact details, see [Contact Details of sponsor's Key Personnel].  Fax or email the 
SAE/special situations worksheet to: 
Astellas Pharma Global Development Inc. 
US Pharmacovigilance 
North America fax number: +1-888-396-3750 
North America alternate fax number: +1-847-317-1241 
International fax number: +44 800 471 5263 
Email: safety-us@astellas.com 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor/study physician or their designee [Contact Details of Sponsor’s 
Key Personnel]. 
Follow-up information for the event should be sent promptly (as soon as available but no 
longer than within 7 days of the initial notification). 
Full details of the SAE should be recorded on the medical records, SAE/special situation 
worksheet and on the electronic data source. 
The following minimum information is required: 
● 
International study number/study number 
● 
Subject number, sex and age 
● 
Date of report 
● 
Description of the SAE (event and seriousness criteria) 
● 
Causal relationship to the IP (including reason) 
● 
Blinded regimen 
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality, and 
expectedness of the events (e.g., SUSAR reporting) according to current local/regional 
regulatory requirements.  The sponsor or sponsor’s designee will submit expedited safety 
reports to competent authorities and concerned ethics committee per current local regulations 
and will inform the investigators of such regulatory reports as required.  Investigators must 
submit safety reports as required by their IRB/IEC within timelines set by regional 
regulations (e.g., EMA, FDA) where required.  Documentation of the submission to and 
receipt by the IRB/ IEC of expedited safety reports should be retained by the study site.  In 
the US, FDA expedited IND reporting guidelines will be followed. 
The sponsor will notify all investigators responsible for ongoing clinical studies with the test 
product of all SUSARs, which require submission per local requirements IRB/IEC. 
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor. 

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The investigator may contact the sponsor’s medical monitor/study physician for any other 
problem related to the rights, safety or well-being of the subject. 
12.4.6 Reporting Procedures for Special Situations 
12.4.6.1 Pregnancy 
If a female subject becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Appendix 12.4.5 Reporting Procedures for Serious Adverse 
Events] using the SAE worksheet as a special situation and in the electronic data source. 
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing and report the information to the sponsor according to the 
timelines in [Appendix 12.4.5 Reporting Procedures for Serious Adverse Events] using the 
SAE worksheet as a special situation. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data, etc., should be included in this 
information. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
subject as an AE in the electronic data source or SAE per [Appendix 12.4.5 Reporting 
Procedures for Serious Adverse Events].  For (S)AEs experienced by a female partner of a 
male subject, (S)AEs are to be reported via the SAE worksheet. 
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below: 
● 
“Spontaneous abortion” includes miscarriage, abortion and missed abortion 
● 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the IP 
● 
If an infant die more than 1 month after the birth, it is to be reported if a relationship 
between the death and intrauterine exposure to the IP is judged as “possible” by the 
investigator 
● 
Congenital anomaly (including anomaly in miscarried fetus) 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination or other 
means as appropriate.  (S)AEs experienced by the newborn/infant should be reported via the 
pregnancy reporting form.  Generally, follow up will be no longer than 6 to 8 weeks 
following the estimated delivery date. 
12.4.6.2 Lack of Efficacy  
Not applicable. 

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12.4.6.3 Medication Error, Overdose and “Off-label Use” 
If a medication error (defined as an unintended failure in the treatment process that leads to, 
or has the potential to lead to, harm to the subject), overdose or “off-label use” (i.e., use 
outside of what is stated in the protocol) is suspected, refer to [Section 10.3 Major Protocol 
Deviations].  Any associated (S)AEs are to be reported in the electronic data source.  If the 
AE meets the definition of an SAE, the SAE is also to be reported as described in 
[Appendix 12.4.5 Reporting Procedures for Serious Adverse Events] together with the details 
of the medication error, overdose and/or “off-label use.” 
In the event of suspected overdose, refer to the approved package insert, summary of product 
characteristics, or local product information supplied by the manufacturer for each IP. 
12.4.6.4 Misuse/Abuse 
Definition of misuse: Situations where the IP is/are intentionally and inappropriately used not 
in accordance with the intended use as defined in the protocol. 
Definition of abuse: Persistent or sporadic, intentional excessive use of medicinal products 
which is accompanied by harmful physical or psychological effects. 
If misuse or abuse of the IP is suspected, the investigator must forward the special situation 
worksheet to the sponsor by fax or email immediately (within 24 hours of awareness).  Any 
associated (S)AEs are to be reported in the electronic data source.  If the AE meets the 
definition of an SAE, the SAE is also to be reported as described in [Appendix 12.4.5 
Reporting Procedures for Serious Adverse Events] together with details of the misuse or 
abuse of the IP. 
12.4.6.5 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the subject) to the IP occurs, the investigator must forward 
the special situation worksheet to the sponsor by fax or email immediately (within 24 hours 
of awareness).  Any associated (S)AEs occurring to the individual associated with or 
resulting from the special situation are to be reported on the special situations worksheet. 
12.4.6.6 (Suspicion of) Transmission of Infectious Agent 
Not applicable. 
12.4.6.7 Suspected Drug-drug Interaction 
If a drug-drug interaction associated with the IP is suspected, the investigator must forward 
the special situation worksheet to the sponsor by fax or email immediately (within 24 hours 
of awareness).  Any associated (S)AEs are to be reported in the electronic data source.  If the 
AE meets the definition of an SAE, the SAE is also to be reported as described in 
[Appendix 12.4.5 Reporting Procedures for Serious Adverse Events] together with details of 
the suspected drug-drug interaction. 

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12.5 
Liver Safety Monitoring and Assessment 
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver 
injury during the course of the study.  It should be noted that this section does not specify the 
EoS analyses of liver enzymes.  The EoS liver enzymes analyses will be described in the SAP.  
Any subject enrolled in a study with active drug therapy and reveals an increase of serum 
aminotransferases (AT) to > 3 × ULN or bilirubin > 2 × ULN should undergo detailed testing 
for liver enzymes (including at least alkaline phosphatase [ALP], ALT, AST and TBL).  
Testing should be repeated within 72 hours of notification of the test results.  For studies for 
which a central laboratory is used, alerts will be generated by the central laboratory regarding 
moderate and severe liver abnormality to inform the investigator and study team.  Subjects 
should be asked if they have any symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN is as 
shown below. 
Table 10 
Moderate and Severe Liver Abnormalities 
 
ALT or AST 
 
TBL 
Moderate 
> 3 × ULN 
or 
> 2 × ULN 
Severe 
> 3 × ULN 
and† 
> 2 × ULN 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; ULN: upper limit of 
normal 
† 
Samples taken simultaneously or within maximum 24 hours. 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and† and TBL > 2 × ULN or international normalized ratio 
(INR) > 1.5 (if INR testing is applicable/evaluated) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
† 
Samples taken simultaneously or within a maximum of 24 hours. 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and clinical laboratory tests.  The study site personnel are to complete 
the liver abnormality case report form (LA-CRF).  Subjects with confirmed abnormal liver 
function testing should be followed as described below. 

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Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly, 
and then weekly or less if abnormalities stabilize or the IP has been discontinued and the 
subject is asymptomatic. 
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE.  The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to IP are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new-onset diseases are to be recorded as “AEs” within the electronic data source.  
Illnesses and conditions such as hypotensive events and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted.  Nonalcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic and/or diabetic subjects and may be 
associated with fluctuating AT levels.  The investigator should ensure that the medical 
history form captures any illness that predates study enrollment that may be relevant in 
assessing hepatic function. 
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets.  Medications are to be entered in the electronic data source.  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: 
○ 
Acute viral hepatitis (A, B, C, D, E or other infectious agents) 
○ 
Ultrasound or other imaging to assess biliary tract disease 
○ 
Other clinical laboratory tests, including INR and direct bilirubin 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Treatment Discontinuation 
In the absence of an explanation for increased liver function tests, such as viral hepatitis, 
preexisting or acute liver disease, or exposure to other agents associated with liver injury, the 
subject may be discontinued from study treatment.  The investigator may determine that it is 
not in the subject’s best interest to continue study treatment.  Discontinuation of study 
treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and† TBL > 2 × ULN or INR > 1.5) (if INR testing is 
applicable/evaluated) 

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● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
† 
Samples taken simultaneously or within a maximum of 24 hours. 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued. 
Hy’s Law definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant). 
The 2 “requirements” for Hy’s Law are:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in AT elevations > 3 × ULN (“2 × ULN elevations are too common in treated 
and untreated subjects to be discriminating”). 
2. Cases of increased TBL (at least 2 × ULN) with concurrent AT elevations at least 
3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) 
or Gilbert’s syndrome [Temple, 2006]. 
FDA Guidance for Industry titled, “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control 
drug or placebo. 
2. Among subjects showing such AT elevations, often with ATs much greater than 
3 × ULN, 1 or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 
References 
Temple R.  Hy’s Law: Predicting Serious Hepatotoxicity.  Pharmacoepidemiol Drug Saf.  
2006; 15:241-3. 

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12.7 
Laboratory Assessments 
Laboratory tests will be performed according to the schedule of assessments and sent to a 
central laboratory for analysis. 
Table 11 
Clinical Laboratory Tests 
Panel/Assessments 
Parameters to be Analyzed 
Hematology 
Hematocrit 
Hemoglobin 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Platelets 
Red blood cell count 
White blood cell count 
White blood cell count differential 
Biochemistry 
Albumin  
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Corrected serum calcium 
Creatinine 
Creatinine kinase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Serum hCG for female subjects 
Sodium 
Total bilirubin (total and direct) 
Total protein 
Urinalysis 
Leukocyte esterase 
Nitrites 
pH 
Protein 
Red blood cells 
hCG: human chorionic gonadotropin 

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12.10 Centiles of Heart Rate for Normal Children from Birth to 18 Years of Age 
 
 

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12.11 Centers for Disease Control and Prevention Data Table of Stature 
for Age Chart for Males 
 

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12.12 Centers for Disease Control and Prevention Data Table of Stature 
for Age Chart for Females 
 

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12.13 Clinical Study Continuity 
 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during any crisis (e.g., natural disaster, pandemic).    
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during any crisis. The site is expected to follow the 
protocol and associated Schedule of Assessments [Table 1] unless the site principal 
investigator discusses the need with the Astellas medical monitor to implement the alternate 
measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study required assessments and 
procedures if study activities are unable to be performed as described in [Section 7 Study 
Procedures and Assessments] due to a crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this Appendix 
will be required to provide informed consent, which explicitly informs them of the nature of 
and rationale for these changes, and gain their agreement to continue participation in the 
study prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the principal investigator or designee will obtain oral 
agreement from the subject followed by written documentation as soon as is feasible. A 
separate addendum to the study informed consent will be provided to document the 
participant’s consent of the changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 
• Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
• Site facilities have been closed for clinical study conduct  
• Site has been restricted to treating patients with conditions outside of the scope of the 
study 
• Site personnel have temporarily relocated the conduct of the study to a location that place 
a burden on the participant with respect to time and travel 

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• Participant(s) have temporarily relocated from the current study site to an alternate study 
site to avoid placing a burden on the participant with respect to travel 
• Participant(s) have temporarily relocated from their home location and the new distances 
from the site would cause undue burden with respect to time and travel 
• Participant has risk factors for which traveling to the site poses an additional risk to the 
participant’s health and safety 
Adherence to the original protocol as reflected in the Schedule of Assessments [Table 1] is 
expected, where plausible, in the case of a crisis. The alternate measures as noted in 
[Table 12] below are only permissible in the event of a crisis, and after discussing the need 
with the Astellas medical monitor to implement the alternate measures. This is to allow for 
continuity of receiving IP and maintaining critical safety and efficacy assessments for 
patients participating in the study at a time of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, the site 
should document in the participant’s source document the justification for implementing the 
alternate measure and the actual alternate measures that were implemented, along with the 
corresponding time point(s). 

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Table 12 
 Alternate Schedule of Assessments in Response to a Crisis 
Critical Assessments 
Alternate Approach(es) 
Double-blind Placebo-controlled Period 
(12 weeks) 
Follow-up Period 
(2 weeks) 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Week 0 
Baseline 
Week 2 
TCa 
Week 4 
Week 8 
TCa 
Week 12 
(EoT)b 
Week 14 
(EoS)b,c 
Day -1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days) 
Day 56 
(± 3 days) 
Day 84 
(± 3 days) 
Day 98 
(+ 3 days) 
Previous and Concomitant Medication 
Remote/Virtual/Telemedicine Visits 
allowed. Please refer to protocol schedule of 
assessments. 
X 
X 
X 
X 
X 
X 
Physical Examination 
The exam can be done at a local clinic and 
the results submitted to PI. 
 
 
X 
 
X 
 
Height and Body Weight 
Can be obtained at a local clinic or at home 
X 
 
 
 
X 
 
Dose Titrationd 
Courier service directly to subject.  Titration 
to occur based on PI’s evaluation via phone.  
For tablets: subject to take spare 25 mg 
tablets until 50 mg wallet is delivered via 
courier.  
 
 
X 
 
 
 
Dispense IPe 
Courier service directly to subject  
X 
 
X 
 
 
 
Drug Accountability 
Used product can be shipped back to site via 
courier. 
X 
 
 
 
X 
 
Vital Signsf 
Can be performed at a local clinic and 
results submitted to PI for evaluation  
OR  
Blood pressure and pulse collected via 
SBPM and temperature collected at home 
and reported to site (respiration rate 
missing).  
X 
 
X 
 
X 
X 
SBPMg 
Will be sent to subject’s home address 
X 
X 
X 
X 
X 
 
Table continued on next page 

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Critical Assessments 
Alternate Approach(es) 
Double-blind Placebo-controlled Period 
(12 weeks) 
Follow-up Period 
(2 weeks) 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Week 0 
Baseline 
Week 2 
TCa 
Week 4 
Week 8 
TCa 
Week 12 
(EoT)b 
Week 14 
(EoS)b,c 
Day -1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days) 
Day 56 
(± 3 days) 
Day 84 
(± 3 days) 
Day 98 
(+ 3 days) 
Routine 12-lead ECGf 
ECG testing can be completed at local 
clinic. 
X 
 
X 
 
X 
 
Clinical Laboratory Tests (Hematology and 
Biochemistry)h 
Visit collection of samples at local facility 
acceptable if results can be made available 
to investigative site. 
Xi 
 
X 
 
X 
Xi 
Clinical Laboratory Tests (Urinalysis)h 
Visit collection of samples at local facility 
acceptable if results can be made available 
to investigative site. 
Xi 
 
X 
 
X 
Xi 
Pregnancy Testi 
Visit collection of samples at local facility 
acceptable if results can be made available 
to investigative site. 
X 
 
X 
 
X 
X 
AEs 
Remote/Virtual/Telemedicine Visits 
allowed. Please refer to protocol schedule of 
assessments. 
X 
X 
X 
X 
X 
X 
Bladder e-diary 
Will be sent to subject’s home address 
X 
X 
X 
X 
X 
 
Acceptability and Palatability Questionnairej 
To be performed remotely via e-diary. 
 
 
 
 
X 
 
Pharmacokineticsk 
Astellas Medical Monitor to assess. Not 
allowed at an alternate clinical due to 
special sample handling. 
 
 
X 
 
X 
 
AE: adverse event; ECG: electrocardiogram; e-diary: electronic diary; EoS: end of study; EoT: end of treatment; IP: investigational product; OAB: overactive bladder; 
PED25: pediatric equivalent dose 25 mg; PED50: pediatric equivalent dose 50 mg; PI: principal investigator; SBPM: self blood pressure monitoring; TC: telephone call 
Footnotes continued on next page 

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a. 
For the visits where a TC is indicated, there is no need for the subject to visit the clinic provided that the bladder e-diary data are reviewed by the investigator prior to the TC and 
discussed and confirmed with the subject or parent(s)/legal guardian(s) during the TC.  Urotherapy is also to be discussed and confirmed with the subject or parent(s)/legal 
guardian(s) during each TC as indicated in Table 1. 
b. Subjects who withdraw early from the study after having received IP should complete both the EoT and EoS visits. 
c. 
The EoS visit (visit 8/week 14 [EoS]) should take place at least 14 days after the EoT visit (visit 7/week 12 [EoT]). 
d. Dose up-titration to PED50 to occur at visit 5/week 4 unless investigator determines OAB is adequately controlled.  Dose down-titration from PED50 to PED25 can be done at any 
time for safety reasons. 
e. 
Daily IP administration will start on day 1 (i.e., the day after visit 3/week 0 [baseline]). 
f. 
Blood pressure, pulse, body temperature and ECGs will all be measured in single measurements.  Subject to be in the sitting position (when possible, otherwise supine, but always 
in the same position for each procedure).  Subject should have been calm and without distress for at least 5 minutes.  Preferably, the right arm should be used to measure vital 
signs.  Body temperature will be measured with an ear thermometer.  Clinic measurements will be used to assess eligibility. 
g. SBPM will be measured once in the morning and evening during the 2-day weekend bladder e-diary collection period. SBPM measurements should start in the weekend prior to 
week -2 and be taken in the weekend prior to the indicated visit (or TC). SBPM will be measured on 2 consecutive days at 1 and 2 weeks after start of dosing with PED25 (day 1) 
and after up-titration to PED50, if not already covered by the scheduled SBPM.  Measurements will be taken in the sitting position (when possible, otherwise supine, but always in 
the same position).  Preferably, the right arm should be used.  Subject should have been calm and without distress for at least 5 minutes.  Morning measurement should be taken 
before IP intake and evening measurement should be taken prior to bedtime. 
h. Additional hematology, biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 3/week 0 (baseline) and visit 8/week 14 (EoS) only if an AE related to 
hematology, biochemistry or urinalysis parameters occurred since the previous visit or at the discretion of the investigator. 
i. 
Urine pregnancy test will be performed for females of childbearing potential at all on-site visits. 
j. 
The acceptability and palatability questionnaire will be completed on one weekend day preceding at visit 7/week 12 (EoT). 
k. There will be 2 pharmacokinetic sampling days at visit 5/week 4 and visit 7/week 12 (EoT).  Both pharmacokinetic sampling days will consist of collecting 1 predose (trough) 
sample.  On pharmacokinetic sampling days, dosing should occur in the clinic and breakfast should be eaten at the clinic within 1 hour before dosing.

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INVESTIGATIONAL PRODUCT SUPPLY 
If any of the conditions outlined above in the Participant Procedures Assessment are met, if 
the following mitigating strategy will be employed, as needed, to ensure continuity of IP 
supply to the participants:   
● 
Increase stock of IP on site to reduce number of shipments required, if site space will 
allow. 
● 
Direct-to-subject shipments of IP from the site to the subject’s home. 
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study may have 
been affected by a crisis and to accommodate data collection resulting from alternate 
measures implemented to manage the conduct of the study and participant safety.  
• Critical assessments for safety and efficacy based on study endpoints to be identified 
as missing or altered (performed virtually, at alternative locations, out of window, or 
other modifications) due to the crisis.  

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12.14 List of Abbreviations and Definition of Key Study Terms 
List of Abbreviations 
Abbreviation 
Description  
APEB 
Astellas Pharma Europe B.V. 
APGD 
Astellas Pharma Global Development Inc. 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AR 
adrenergic receptor 
AST 
aspartate aminotransferase 
AT 
aminotransferases 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
AUC24 
area under the concentration-time curve from time zero to 24 hours 
AUCtau 
area under concentration-time curve over dosing interval 
AUCinf 
area under the concentration-time curve from the time of dosing extrapolated to 
time infinity 
AUClast 
area under the concentration-time curve from the time of dosing to the last 
measurable concentration 
BMI 
body mass index 
Cmax 
maximum drug concentration 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CV 
coefficient of variation 
CY 
cytochrome 
DBP 
diastolic blood pressure 
DPD 
Data Protection Directive 
DSMB 
Data and Safety Monitoring Board 
EBC 
expected bladder capacity 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
e-diary 
electronic diary 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EMG 
electromyography 
EoS 
end of study 
EoT 
end of treatment 
FAO 
Food and Agricultural Organization 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
hCG 
human chorionic gonadotropin 
ICCS 
International Children’s Continence Society 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 

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Abbreviation 
Description  
IDAC 
independent data analysis center 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISN 
international study number 
LA-CRF 
liver abnormality case report form 
LOCF 
last observation carried forward 
LQTS 
long QT syndrome 
LS 
least squares 
NDO 
neurogenic detrusor overactivity 
NONMEM 
non-linear mixed effects modeling 
OAB 
overactive bladder 
OCAS 
oral-controlled absorption system 
PED 
pediatric equivalent dose 
P-gp 
P-glycoprotein 
PIP 
pediatric investigational plan 
PKAS 
pharmacokinetic analysis set 
PPIUS 
Patient perception of intensity of urgency scale 
PPS 
per protocol set 
PVR 
post void residual 
QA 
quality assurance 
QC 
quality control 
QTL 
quality tolerance limit 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SBPM 
self-blood pressure measurement 
SOP 
standard operating procedure 
SUSAR 
serious unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TBL 
total bilirubin 
TC 
telephone call 
USM 
urgent safety measure 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
WHO-DD 
WHO-Drug Dictionary 

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

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13 
ATTACHMENT 1: SUBSTANTIAL AMENDMENT 1 
I.  The purpose of this amendment is: 
Substantial Changes 
1. Update Schedule of Assessments 
DESCRIPTION OF CHANGE: 
The schedule of assessments is updated with the following changes: 
• Physical examination is added to visit 5 (week 4). 
• Height and body weight measurement is added to visit 7 (week 12). 
• Clinical Laboratory Tests (Hematology and Biochemistry) footnote is removed from 
visit 5 (week 4) 
• Self-blood pressure measurement (SBPM) is added visit 2 (week -2) and removed 
from visit 8 (week 14). 
• Pregnancy tests are added to visit 3 (week 0), visit 5 (week 4) and visit 7 (week 12). 
• Additional text is added to footnote h to explain that the SBPM should be done 
during the weekend preceding the study visit. 
• Footnote i is revised to remove visit 5 (week 4).  
• Footnote j is revised to clarify that urine pregnancy tests will be performed for 
females of childbearing potential at all on-site visits. 
 
RATIONALE: 
This is a combination of regulatory commitments to include additional pregnancy testing and 
laboratory testing, as well as fixing some errors for clarification. 
Footnote i was removed from the Clinical Laboratory Tests at visit 5 (week 4), because this 
visit is now required. 
 
2. Update Subject Weight Range 
DESCRIPTION OF CHANGE: 
The minimum weight of subjects is changed from 11 kg to 13 kg. This is updated in the dose 
rationale and Inclusion Criterion #4. 
 
RATIONALE: 
This study should only include children and adolescents from 5 years to 18 years; therefore, 
the lower weight limit was revised. 
 
3. Delete Exclusion Criterion #11 
DESCRIPTION OF CHANGE: 
A criterion (#11) that subjects must have a pulse of > 99th percentile for age at Screening is 
deleted. 
 

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RATIONALE: 
This criterion is the same as exclusion criterion #33 because the criterion was originally 
checked at screening and baseline. The criterion itself still applies to subjects, but is only 
needed at baseline. 
 
4. Update Exclusion Criterion #13 
DESCRIPTION OF CHANGE: 
Text is added to allow the option that the subject is currently taking medication known to 
prolong the QT interval. 
 
RATIONALE: 
This revision is made for consistency with Table 21 in the Investigator’s Brochure. 
 
5. Update Exclusion Criterion #18 
DESCRIPTION OF CHANGE: 
The criterion is updated to exclude subjects who use moderate or strong cytochrome 
CYP3A4/5 or P-gp inhibitors or inducers. 
 
RATIONALE: 
This revision is made per a Regulatory request. 
 
Nonsubstantial Changes 
1. Update Key Sponsor Personnel 
DESCRIPTION OF CHANGE:  
Contact details for medical monitor are updated. 
 
RATIONALE: 
Contact details of medical monitor are updated based on changes to study personnel. 
 
2. Update Compound Name 
DESCRIPTION OF CHANGE:  
The compound name has been updated to YM178 (from ED178). 
 
RATIONALE: 
This revision is made to correct an error. ED178 is the project name for pediatric. 
 

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3. Update Planned Study Period 
DESCRIPTION OF CHANGE:  
The planned completion date is extended to 2Q2023 (from 3Q2022). 
 
RATIONALE: 
This revision is made based on current enrollment projections. 
 
4. Update Background  
DESCRIPTION OF CHANGE: 
Text regarding mirabegron mechanism of action is added to the Background section. 
 
RATIONALE: 
This revision is made for consistency with the current Mirabegron Investigator’s Brochure. 
 
5. Updated Total Number and Location of Study Sites 
DESCRIPTION OF CHANGE: 
The number of planned study sites is increased to 65 (from 50) and North America is added 
as a study site location. 
 
RATIONALE: 
The planned number of study sites is increased to account for the current number of 
approved sites. The revision to study location is made to correct an error. During 
development of the statistical analysis plan, it was noted that North America was not listed in 
the protocol. 
 
6. Update Study Objectives and Endpoints 
DESCRIPTION OF CHANGE: 
Text is added to note that primary and secondary objectives and endpoints apply to children 
only; exploratory objectives and endpoints also apply to adolescents. Subject age is added to 
the exploratory objective. Mean number of micturitions per 24 hours is added as an 
exploratory endpoint. 
 
RATIONALE: 
These revisions are made for clarification. To ensure mean micturitions is analyzed for 
adolescents. The mean number of micturitions endpoint is added ensure mean micturitions is 
analyzed for adolescents. 
 
7. Clarify Exclusion Criterion #19 
DESCRIPTION OF CHANGE: 
The criterion is updated to add the text ‘and cannot be discontinued.’ 

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RATIONALE: 
This revision is made to for clarification. If the prohibited medication can be discontinued, 
the subject may be enrolled in the study. 
 
8. Clarify Reference for Investigational Products (IP) 
DESCRIPTION OF CHANGE: 
Section 6.1.1 is updated to clarify that detailed information on mirabegron granules for oral 
suspension is located in the Investigator’s Brochure and Investigational Medicinal Product 
Dossier. 
 
RATIONALE: 
The original protocol stated where to locate additional information for tablets only, so text is 
added on where to find additional information for the granules.   
 
9. Update Subject Compliance 
DESCRIPTION OF CHANGE: 
Weighing is added a method for assessing compliance of subject compliance with IP. 
 
RATIONALE: 
This revision is made for clarification. Tablets will be counted and granules for oral 
suspension will be weighed. 
 
10. Expand Urotherapy Information in Section 6.4.2 
DESCRIPTION OF CHANGE: 
Additional information about urotherapy is added to Section 6.4.2. 
 
RATIONALE: 
This revision is made for clarification. 
 
11. Update Concomitant Medications 
DESCRIPTION OF CHANGE: 
Medications that prolong the QT interval, and medications that are moderate or strong 
cytochrome CYP3A4/5 or P-gp inhibitors, are added to the list of prohibited concomitant 
medications. Examples of medications used for the treatment of overactive bladder are 
added. 
 

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RATIONALE: 
In accordance with Section 6.5.3 of the Investigator’s Brochure, these medications are added 
on the list of concomitant medications excluded from the protocol. 
 
12. Update Description of Physical Examination 
DESCRIPTION OF CHANGE: 
Additional details of the physical examination are added to Section 7.2.4. 
 
RATIONALE: 
This revision is made for clarification. 
 
13. Update Total Amount of Blood 
DESCRIPTION OF CHANGE: 
The number of clinical laboratory samples and total blood volume are updated. 
 
RATIONALE: 
This revision is made since visit 5 (week 4) is now mandatory.  The blood volumes are 
updated to account for the clinical laboratory tests at this visit. 
 
14. Define Pharmacokinetic Parameters 
DESCRIPTION OF CHANGE: 
The pharmacokinetic parameters that will be calculated as part of the secondary 
pharmacokinetic endpoint are defined. 
 
RATIONALE: 
The specific pharmacokinetic parameters to be calculated were not previously defined. 
 
15. Clarify Electronic Clinical Outcome Assessments 
DESCRIPTION OF CHANGE: 
Section 7.6, Electronic Clinical Outcome Assessment, is updated to provide additional 
information about the integrity of the data. Additional text from the latest Global Protocol 
Format (GPF) is added. 
 
RATIONALE: 
These revisions are made to describe how the integrity of the data is ensured, especially the 
data subjects enter into electronic forms. 
 

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16. Update Subject Discontinuation Criteria 
DESCRIPTION OF CHANGE: 
The following criteria are added as reasons that a subject may be discontinued from study 
treatment: 
• Pregnancy 
• Prolongation of QT > QTcF > 440 msec and/or QT interval prolongation > 30 msec 
• Systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mmHg 
Follow-up for prolongation of QT intervals is added to Section 9.5.5. 
 
RATIONALE: 
These revisions are made due to regulatory agency feedback/request. 
 
17. Update Rationale for Sample Size 
DESCRIPTION OF CHANGE: 
Text is added to state that the assumptions about sample size, in addition to the levels for 
Type-1 error and power, were agreed upon with Pediatric Committee in the current Pediatric 
Investigation Plan. 
 
RATIONALE: 
This revision is made for clarification of assumptions. 
 
18. Clarify Local Laboratory Evaluations 
DESCRIPTION OF CHANGE: 
Text is added to clarify that when local laboratory evaluations are conducted, the values 
obtained will be adjusted to values obtained by the central laboratory. A reference is made to 
the statistical analysis plan. 
 
RATIONALE: 
This revision is made to indicate how the local lab values will be analyzed when the 
modified schedule of assessments is utilized. 
 
19. Add Section for Independent Data Analysis Center (IDAC) 
DESCRIPTION OF CHANGE: 
A new section is added to Section 10, Operational Considerations, to describe the purpose of 
the IDAC and its members. 
 
RATIONALE: 
This revision is made to clarify the role of the IDAC and the interactions between the IDAC 
and the Data and Safety Monitoring Board. 
 

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20. Update Source Documents 
DESCRIPTION OF CHANGE: 
Appendix 12.1.6, Source Documents, is updated with compulsory text from the latest GPF. 
 
RATIONALE: 
This revision is made to align the study protocol with the current GPF and to add additional 
information for ensuring integrity of data. 
 
21. Remove Source Data Verification 
DESCRIPTION OF CHANGE: 
Information about source data verification is removed from Section 10.1, Data Collection 
and 12.2.1, Study Monitoring. Information about source data review is added to Appendix 
12.1.6, Source Documents. 
 
RATIONALE: 
This revision is made to comply with the European guidelines published by the European 
Commission regarding the remote source data verification during the COVID-19 pandemic. 
 
22. Update Contraception Requirements 
DESCRIPTION OF CHANGE: 
Appendix 12.3 is updated with standard text from the latest GPF in regards to contraception 
requirements for pediatric subjects. 
 
RATIONALE: 
This revision is made to align the study protocol with the current GPF and to provide 
pediatric-specific contraception requirements. 
 
23. Clarify Abnormal Laboratory Findings 
DESCRIPTION OF CHANGE: 
Updates are made to Appendix 12.4.1.1 to clarify abnormal laboratory findings and the 
process for reporting them. 
 
RATIONALE: 
This revision is made in accordance to the Agency’s comment on laboratory values, 
 
24. Update List of Excluded Concomitant Medications 
DESCRIPTION OF CHANGE: 
The List of Excluded Concomitant Medications in Appendix 12.6 is updated to include 
moderate and strong CYP3A4 inhibitors and inducers, and P-gp inhibitors and inducers 
 

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RATIONALE: 
This revision is made to incorporate the moderate and strong cytochrome CYP3A4/5 and 
P-gp inhibitors and inducers that are added to Exclusion Criterion #18. 
 
25. Add Appendix for Clinical Study Continuity 
DESCRIPTION OF CHANGE: 
A Clinical Study Continuity appendix is added to the protocol. This appendix contains 
procedures for continuity of care during a crisis. An alternative schedule of assessments is 
provided. A reference to this appendix is added to Section 7. 
 
RATIONALE: 
This appendix is added to provide acceptable alternate methods to assess safety and efficacy 
parameters in the event the clinical study is interrupted at the country, state, site or 
participant level during any crisis (e.g., natural disaster or pandemic). 
 
26. Minor Administrative-type Changes 
DESCRIPTION OF CHANGE:  
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol); change ‘woman of childbearing potential’ to ‘female of 
childbearing potential;=’ revise wording of Inclusion Criterion #13 from ‘must not donate’ to 
‘must agree not to donate;’ remove ‘Draft’ from ‘Draft Results’ in title of Table 4; add “or 
designee” as a reviewer for e-diary data in Section 7.1.1; and remove ‘WOCBP’ from the 
List of Abbreviations.    
 
RATIONALE: 
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures. 
 

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II.  Amendment Summary of Changes: 
IIA. Substantial Changes 
1 Protocol Summary 
1.3 Schedule of Assessments 
WAS: 
Schedule of Assessments 
Screening Period/Urotherapy 
(4 weeks) 
Double-blind Placebo-controlled Period 
(12 weeks) 
Follow-up Period 
(2 weeks) 
Visit 1 
Visit 2/TCa 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Week -4 
Screening 
Week -2 
Week 0 
Baseline 
Week 2 
TCa 
Week 4 
Week 8 
TCa 
Week 12 
(EoT)b 
Week 14 
(EoS)b,c 
Day -28 
(-3 days) 
Day -14 
(± 5 days) 
Day -1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days) 
Day 56 
(± 3 days) 
Day 84 
(± 3 days) 
Day 98 
(+ 3 days) 
Physical Examination 
X 
 
 
 
 
 
X 
 
Height and Body Weight 
X 
 
X 
 
 
 
 
 
Clinical Laboratory Tests (Hematology and Biochemistry) 
X 
 
Xi 
 
Xi 
 
X 
Xi 
Clinical Laboratory Tests (Urinalysis) 
X 
 
Xi 
 
X 
 
X 
Xi 
SBPMh 
 
 
X 
X 
X 
X 
X 
X 
Pregnancy Testj 
X 
 
 
 
 
 
 
X 
Bladder e-diarya,l 
X 
X 
X 
X 
X 
X 
X 
 
h. SBPM will be measured once in the morning and evening during the 2 day weekend bladder e-diary collection period. SBPM will be measured on 2 consecutive days at 1 and 2 
weeks after start of dosing with PED25 (day 1) and after up-titration to PED50, if not already covered by the scheduled SBPM.  Measurements will be taken in the sitting position 
(when possible, otherwise supine, but always in the same position).  Preferably, the right arm should be used.  Subject should have been calm and without distress for at least 5 
minutes.  Morning measurement should be taken before IP intake and evening measurement should be taken prior to bedtime. 
i. Additional hematology, biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 3/week 0 (baseline), visit 5/week 4 and visit 8/week 14 (EoS) only if an AE 
related to hematology, biochemistry or urinalysis parameters occurred since the previous visit or at the discretion of the investigator. 
j. Serum pregnancy test at screening and EoS (visit 8/week 14). 
l. After a successful screening visit (visit 1/week -4 [screening]), all subjects will start with the completion of a 2-day bladder e-diary to get acquainted with the bladder e-diary and 
the assessments.  Completion of this bladder e-diary should start in the weekend prior to week -2.  Subjects will start with the 7-day bladder e diaries, approximately 7 days prior to 
the indicated visit (or TC).  The bladder e-diary is used for a 7-day period to record micturition frequency and incontinence episodes; it also contains a 2-day weekend period to 
record additional volume measurements and vital signs. 
 

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IS AMENDED TO: 
Schedule of Assessments 
Screening Period/Urotherapy 
(4 weeks) 
Double-blind Placebo-controlled Period 
(12 weeks) 
Follow-up Period 
(2 weeks) 
Visit 1 
Visit 2/TCa 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Week -4 
Screening 
Week -2 
Week 0 
Baseline 
Week 2 
TCa 
Week 4 
Week 8 
TCa 
Week 12 
(EoT)b 
Week 14 
(EoS)b,c 
Day -28 
(-3 days) 
Day -14 
(± 5 days) 
Day -1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days) 
Day 56 
(± 3 days) 
Day 84 
(± 3 days) 
Day 98 
(+ 3 days) 
Physical Examination 
X 
 
 
 
X 
 
X 
 
Height and Body Weight 
X 
 
X 
 
 
 
X 
 
Clinical Laboratory Tests (Hematology and Biochemistry) 
X 
 
Xi 
 
Xi 
 
X 
Xi 
Clinical Laboratory Tests (Urinalysis) 
X 
 
Xi 
 
X 
 
X 
Xi 
SBPMh 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testj 
X 
 
X 
 
X 
 
X 
X 
Bladder e-diarya,l 
X 
X 
X 
X 
X 
X 
X 
 
h. SBPM will be measured once in the morning and evening during the 2 day weekend bladder e-diary collection period. SBPM measurements should start in the weekend prior to 
week -2 and be taken in the weekend prior to the indicated visit (or TC). SBPM will be measured on 2 consecutive days at 1 and 2 weeks after start of dosing with PED25 (day 
1) and after up-titration to PED50, if not already covered by the scheduled SBPM.  Measurements will be taken in the sitting position (when possible, otherwise supine, but always 
in the same position).  Preferably, the right arm should be used.  Subject should have been calm and without distress for at least 5 minutes.  Morning measurement should be taken 
before IP intake and evening measurement should be taken prior to bedtime. 
i. Additional hematology, biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 3/week 0 (baseline), visit 5/week 4 and visit 8/week 14 (EoS) only if an AE 
related to hematology, biochemistry or urinalysis parameters occurred since the previous visit or at the discretion of the investigator. 
j. UrineSerum pregnancy test will be performed for females of childbearing potential at screening and EoS (visit 8/week 14) all on-site visits. 
l. At the end ofAfter a successful screening visit (visit 1/week -4 [screening]), all subjects will be provided with a device to collect diary information. At start with the completion 
of a 2 day bladder e diary to get acquainted with the bladder e diary and the assessments.  Completion of this bladder e diary should start in the weekend prior to the week -2 visit, 
the subject will complete the 2-day bladder e-diary to get acquainted with the data collection. The 2-day diary will be reviewed at the week -2 visit. If completion is 
successful, all.  Ssubjects will start with the 7-day bladder e-diaryies completion, approximately 7 days prior to the indicated visit (or TC).  The bladder e-diary is used for a 7-day 
period to record micturition frequency and incontinence episodes; it also contains a 2-day weekend period to record additional volume measurements and vital signs. 

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1 Protocol Summary and 5 Study Population 
5.1 Inclusion Criterion #4 
WAS: 
Subject weighs at least 11 kg at screening. 
 
IS AMENDED TO: 
Subject weighs at least 1311 kg at screening. 
 
1 Protocol Summary and 5 Study Population 
5.1 Exclusion Criterion #11 
WAS: 
Subject has a pulse > 99th percentile for age 
 
IS AMENDED TO: 
Subject has a pulse > 99th percentile for ageCriterion has been removed. 
 
1 Protocol Summary and 5 Study Population 
5.1 Exclusion Criterion #13 
WAS: 
Subject has QTcF > 440 msec on screening ECG or a risk of QT prolongation (e.g., 
hypokalemia, long QT syndrome [LQTS] or family history of LQTS or exercise-induced 
syncope). 
 
IS AMENDED TO: 
Subject has QTcF > 440 msec on screening ECG, or a risk of QT prolongation (e.g., 
hypokalemia, long QT syndrome [LQTS] or family history of LQTS or exercise-induced 
syncope) or is currently taking medication known to prolong the QT interval. 
 
1 Protocol Summary and 5 Study Population 
5.1 Exclusion Criterion #18 
WAS: 
Subject uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates with a 
narrow therapeutic index or sensitive P-glycoprotein (P-gp) substrates after the start of 
washout. 
 
IS AMENDED TO: 
Subject uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates with a 
narrow therapeutic index, or sensitive P-glycoprotein (P-gp) substrates, or moderate or 
strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers after the start of washout. 
 
 

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IIB. Nonsubstantial Changes 
Contact Details of Sponsor’s Key Personnel 
 
WAS: 
Medical Monitor/Study 
Physician 
 
 
Medical and Development 
Astellas Pharma Global Development Inc. 
1 Astellas Way 
Northbrook, IL, 60062 
 
 
 
 
IS AMENDED TO: 
Medical Monitor/Study 
Physician 
 
 
 
 
Medical Specialties Therapeutic Area, Tokyo 
Astellas Pharma Global Development Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku 1 Astellas Way 
Tokyo 103-8411, JapanNorthbrook, IL, 60062 
 
 
 
 
2 Introduction 
2.1 Background 
ADDED: 
Mirabegron activation of beta 3-AR in the human bladder results in a relaxation of the 
detrusor smooth muscle during the fill-void cycle without interfering with the voiding 
contraction. 
 
2 Introduction 
2.1.2.2 Clinical Data (Table 4) 
WAS: 
The data from Studies 178 CL 201 and 178 CL 202 were used to support the use of tablets in 
pediatric subjects with a body weight of ≥ 35 kg in this study.  For those pediatric subjects 
that cannot be dosed with tablets because their body weight is < 35 kg or because they cannot 
be dosed with tablets, an oral suspension with a strength of 2 mg/mL was developed.   
Study 178-CL-208 Draft Results: Relative Bioavailability of the Mirabegron 8 mg/mL Oral 
PPD
PPD
PPD
PPD

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Suspension Formulation Versus 2 mg/mL Oral Suspension Formulation (Pharmacokinetics 
Analysis Set) 
The doses described in [Section 2.1.2.2 Clinical Data] suggest tablets for subjects with a 
body weight of ≥ 35 kg unless unable to swallow tablets and would be provided the oral 
suspension as an alternative, and the 8 mg/mL oral suspension for subjects with a body 
weight < 35 kg or those who cannot be dosed with the tablets. 
 
IS AMENDED TO: 
The data from Studies 178 CL 201 and 178 CL 202 were used to support the use of tablets in 
pediatric subjects with a body weight of ≥ 35 kg in this study.  For those pediatric subjects 
that cannot be dosed with tablets because their body weight is < 35 kg or because they cannot 
be dosed withswallow the tablets, an oral suspension with a strength of 2 mg/mL was 
developed.   
Study 178-CL-208 Draft Results: Relative Bioavailability of the Mirabegron 8 mg/mL Oral 
Suspension Formulation Versus 2 mg/mL Oral Suspension Formulation (Pharmacokinetics 
Analysis Set) 
The doses described in [Section 2.1.2.2 Clinical Data] suggest tablets for subjects with a 
body weight of ≥ 35 kg unless unable to swallow tablets and would be provided the oral 
suspension as an alternative, and the 8 mg/mL oral suspension for subjects with a body 
weight < 35 kg or those who cannot be dosed with the tablets. 
 
2 Introduction 
2.3 Risk-Benefit Assessment 
WAS: 
• Potential UTI will be monitored by urinalysis at each visit in the clinic and will require 
discontinuation of study treatment 
The blood draws for clinical laboratory tests have been minimized to lessen subject burden 
while ensuring subject safety.  Additional hematology and biochemistry tests will be 
performed at visit 3/week 0 (baseline), visit 5/week 4 and visit 8/week 14 (end of study 
[EoS]) only if an AE related to hematology, biochemistry or urinalysis parameters occurred 
since the previous visit or at the discretion of the investigator. 
 
IS AMENDED TO: 
• Potential UTI will be monitored by urinalysis at each visit in the clinic and will require 
discontinuation of study treatment 
The blood draws for clinical laboratory tests have been minimized to lessen subject burden 
while ensuring subject safety.  Additional hematology and biochemistry tests will be 
performed at visit 3/week 0 (baseline), visit 5/week 4 and visit 8/week 14 (end of study 
[EoS]) only if an AE related to hematology, biochemistry or urinalysis parameters occurred 
since the previous visit or at the discretion of the investigator. 
 

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1 Protocol Summary and 3 Study Objectives and Endpoints 
1.1 Synopsis 
WAS: 
Secondary continued 
● 
To evaluate the pharmacokinetics after multiple 
dose administration of mirabegron in pediatric 
subjects with OAB 
● 
Appropriate pharmacokinetic parameters will be 
calculated based on the population 
pharmacokinetic model used 
Exploratory 
● 
To evaluate the efficacy of mirabegron in 
pediatric subjects with OAB 
● 
Percentage of subjects with a reduction in 
daytime incontinence episodes (< 50% 
reduction [nonresponder], 50% [partial 
responder] and 100% [responder]) 
● 
Improvement from baseline in worst 
incontinence grading 
● 
Change from baseline at the end of the 12-week 
treatment period adjusted for fluid intake: 
○ 
Mean number of micturitions per 24 hours 
● 
Change from baseline at the end of the 12-week 
treatment period (adolescents only): 
○ 
Mean number of daytime micturitions per 
24 hours 
○ 
Mean volume voided per 24 hours 
○ 
Mean number of incontinence episodes per 
24 hours 
● 
Number of dry (incontinence-free) days per 
7 days at the end of the 12-week treatment 
period (adolescents only) 
● 
Mean number of daytime grade 3 or 4 (PPIUS) 
urgency episodes per 24 hours (adolescents 
only) 
 
IS AMENDED TO: 
Primary and secondary objectives and endpoints apply to children only; exploratory 
objectives and endpoints also apply to adolescents. 
Secondary continued 
● 
To evaluate the pharmacokinetics after 
multiple dose administration of mirabegron in 
pediatric subjects with OAB 
● 
Steady-state Cmax, AUCtau, Ctrough, Tmax, CL/F and 
Vz/F.  Additional parameters may be calculated 
based on the population pharmacokinetic model 
used Appropriate pharmacokinetic parameters will 
be calculated based on the population 
pharmacokinetic model used 
Exploratory 
● 
To evaluate the efficacy of mirabegron in 
pediatric subjects (5 to < 18 years) with OAB 
● 
Percentage of subjects with a reduction in daytime 
incontinence episodes (< 50% reduction 
[nonresponder], 50% [partial responder] and 100% 
[responder])  
● 
Improvement from baseline in worst incontinence 
grading 
● 
Change from baseline at the end of the 12-week 
treatment period adjusted for fluid intake: 

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○ 
Mean number of micturitions per 24 hours 
● 
Change from baseline at the end of the 12-week 
treatment period (adolescents only): 
○ 
Mean number of micturitions per 24 hours 
○ 
Mean number of daytime micturitions per 
24 hours 
○ 
Mean volume voided per 24 hours 
○ 
Mean number of incontinence episodes per 
24 hours 
● 
Number of dry (incontinence-free) days per 7 days at 
the end of the 12-week treatment period (adolescents 
only) 
● 
Mean number of daytime grade 3 or 4 (PPIUS) 
urgency episodes per 24 hours (adolescents only) 
 
1 Protocol Summary and 4 Study Design and Dose Rationale 
4.1 Study Design 
WAS: 
Planned total number of study sites include approximately 50 study sites across Europe, 
Latin America, Africa, Middle East, and Asia-Pacific and North America. 
 
IS AMENDED TO: 
Planned total number of study sites includes approximately 6550 study sites across Europe, 
Latin America, Africa, Middle East, and Asia-Pacific and North America 
 
4 Study Design and Dose Rationale 
4.2 Dose Rationale 
WAS: 
For dosing with oral suspension, the weight range to be covered is from 11 kg (the 
approximate body weight of a 3 year old child, according to the National Health and 
Nutrition Examination Survey database [McDowell et al, 2008]) to 35 kg (above which 
pediatric subjects could be dosed with the tablet formulation).  Subjects with a body weight < 
11 kg will not be included in the study.   
 
IS AMENDED TO: 
For dosing with oral suspension, the weight range to be covered is from 1311 kg (the 
approximate body weight of a 53-year old child, according to the National Health and 
Nutrition Examination Survey database [McDowell et al, 2008]) to 35 kg (above which 
pediatric subjects could be dosed with the tablet formulation).  Subjects with a body weight < 
1311 kg will not be included in the study.   
 
1 Protocol Summary and 5 Study Population 
5.1 Inclusion Criterion #9 
WAS: 

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Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at 
least 1 of the following conditions apply: 
c. 
Not a woman of childbearing potential (WOCBP) (see [Appendix 12.3 Contraception 
Requirements]). 
d. 
WOCBP who agrees to follow the contraceptive guidance (see [Appendix 12.3 
Contraception Requirements]) from the time of informed consent/assent through at least 
30 days after final IP administration. 
 
IS AMENDED TO: 
Female subject is not pregnant (see [Appendix 12.3 Contraception Requirements]) and at 
least 1 of the following conditions apply: 
a. Not a womanfemale of childbearing potential (WOCBP) (see [Appendix 12.3 
Contraception Requirements]). 
b. 
Female of childbearing potentialWOCBP who agrees to follow the contraceptive 
guidance (see [Appendix 12.3 Contraception Requirements]) from the time of informed 
consent/assent through at least 30 days after final IP administration. 
 
1 Protocol Summary and 5 Study Population 
5.1 Inclusion Criterion #13 
WAS: 
Male subject must not donate sperm during the treatment period and for 30 days after final IP 
administration. 
 
IS AMENDED TO: 
Male subject must agree not to donate sperm during the treatment period and for 30 days 
after final IP administration. 
 
1 Protocol Summary and 5 Study Population 
5.1 Exclusion Criterion #19 
WAS: 
Subject is using or has used prohibited prior and/or concomitant medication(s) [Appendix 
12.6 List of Excluded Concomitant Medications]. 
 
IS AMENDED TO: 
Subject is using or has used prohibited prior and/or concomitant medication(s) [Appendix 
12.6 List of Excluded Concomitant Medications] that cannot be discontinued. 
 
1 Protocol Summary and 6 Investigational Product(s) and Other Study Treatment(s) 
1.1 Synopsis, 6.1.1 Investigational Product(s) 
WAS: 
For detailed information on mirabegron prolonged release tablets and mirabegron granules 
for oral suspension, please refer to the current locally-available product information for 
mirabegron. 

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Table 7 
Body Weight-based Doses for Tablets or Suspension 
 
Body Weight Range† 
(kg) 
Oral Suspension Volume‡ 
(mL) 
Tablet Dose 
(mg) 
PED25 
11 to < 22 
3 
- 
22 to < 35 
4 
- 
≥ 35‡ 
6 
25 
PED50 
11 to < 22 
6 
- 
22 to < 35 
8 
- 
≥ 35‡ 
11 
50 
 
IS AMENDED TO: 
For detailed information on mirabegron prolonged release tablets and mirabegron granules 
for oral suspension, please refer to the current locally-available product information for 
mirabegron. For detailed information on mirabegron granules for oral suspension, 
please refer to the Investigator’s Brochure and Investigational Medicinal Product 
Dossier. 
Table 7 
Body Weight-based Doses for Tablets or Suspension 
 
Body Weight Range† 
(kg) 
Oral Suspension Volume‡ 
(mL) 
Tablet Dose 
(mg) 
PED25 
1311 to < 22 
3 
- 
22 to < 35 
4 
- 
≥ 35‡ 
6 
25 
PED50 
1311 to < 22 
6 
- 
22 to < 35 
8 
- 
≥ 35‡ 
11 
50 
 
6 Investigational Product(s) and Other Study Treatment(s) 
6.1.2 Other Study Treatment(s) 
WAS: 
Urotherapy is to be discussed and confirmed with the subject or parent(s)/legal guardian(s) 
during each TC to ensure compliance. 
 
IS AMENDED TO: 
Urotherapy is to be discussed and confirmed with the subject or parent(s)/legal guardian(s) 
during each visit (or TC) to ensure compliance. 
 
6 Investigational Product(s) and Other Study Treatment(s) 
6.4.1 Investigational Product(s) 
WAS: 
Subject compliance with IP and other study treatment(s) will be assessed at each visit.  
Compliance will be assessed by counting returned IP at each clinic visit.   
 

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IS AMENDED TO: 
Subject compliance with IP and other study treatment(s) will be assessed at each visit.  
Compliance will be assessed by counting or weighing returned IP at each clinic visit.   
 
6 Investigational Product(s) and Other Study Treatment(s) 
6.4.2 Other Study Treatment(s) 
ADDED: 
Specific interventions include various forms of pelvic floor training (relaxation, 
contraction), behavioral modification, electrical stimulation, catherization and 
biofeedback (use of objective measures, e.g., uroflow or surface EMG to show children 
how far they relax their pelvic floor during voiding).  Urotherapy can also include 
elements of cognitive behavioral therapy [Nevéus et al, 2006]. 
 
1 Protocol Summary and 6 Investigational Product(s) and Other Study Treatment(s) 
1.1 Synopsis, Treatment Discontinuation Criteria, 6.5 Previous and Concomitant Treatment 
(Medication and Nonmedication Therapy) 
WAS: 
Subjects are not allowed to use ongoing treatment with any of the following prohibited 
medications after the start of the washout: 
● Any medication, other than the IP, used for the treatment of OAB   
 
IS AMENDED TO: 
Subjects are not allowed to use ongoing treatment with any of the following prohibited 
medications after the start of the washout: 
● Any medication, other than the IP, used for the treatment of OAB  (including tricyclic 
antidepressants, 1st generation H1 antagonists and alpha blockers) 
● Any medications known to prolong the QT interval  
● Any medication that is a moderate or strong cytochrome CYP3A4/5 or P-gp 
inhibitor or inducers including natural and herbal remedies 
These treatments are prohibited from being started after the start of the washout 
period. All other concomitant treatment use will be reported. 
The use of previous and concomitant treatment within 30 days prior to signing the 
informed consent and throughout the study will be documented on the appropriate 
eCRF. 
 
7 Study Procedures and Assessments 
 
ADDED: 
Refer to the Alternate Schedule of Assessments [Table 12] in [Appendix 12.13 Clinical 
Study Continuity] for acceptable alternate methods to assess safety and efficacy 

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parameters in the event the study is interrupted due to a crisis (e.g., natural disaster, 
pandemic). 
 
7 Study Procedures and Assessments 
7.1.1 Bladder Electronic-Diary 
WAS: 
The e-diary data is reviewed by the investigator prior to the start of visit 2 and discussed and 
confirmed with the subject or the subject’s parent(s)/caregiver(s) during the (telephone) visit 
2.   
 
IS AMENDED TO: 
The e-diary data is reviewed by the investigator or designee prior to the start of visit 2 and 
discussed and confirmed with the subject or the subject’s parent(s)/caregiver(s) during the 
(telephone) visit 2.   
 
7 Study Procedures and Assessments 
7.2.2 Laboratory Assessments 
WAS: 
Pregnancy test in female subjects will be performed in serum at screening and visit 8/week 
14 (EoS).   
Additional hematology, biochemistry and urinalysis (urinalysis dipstick) tests will be 
performed at visit 3/week 0 (baseline), visit 5/week 4 and visit 8/week 14 (EoS) only if an 
AE related to hematology, biochemistry or urinalysis parameters occurred since the previous 
visit or at the discretion of the investigator.   
 
IS AMENDED TO: 
A urine Ppregnancy test in female subjects of childbearing potential will be performed in 
serum at screening and visit 8/week 14 (EoS) all on-site visits.   
Scheduled blood sampling will only be performed at screening (visit 1), week 4 (visit 5) 
and EoT (visit 7) to keep the burden to subjects at a minimum. Additional hematology, 
biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 3/week 0 
(baseline), visit 5/week 4 and visit 8/week 14 (EoS) only if an AE related to hematology, 
biochemistry or urinalysis parameters occurred since the previous visit or at the discretion of 
the investigator. 
Refer to the Alternate Schedule of Assessments [Table 12] for acceptable alternate 
methods to assess safety and efficacy parameters in the event the study is interrupted 
due to a crisis (e.g., natural disaster, pandemic). 
 
7 Study Procedures and Assessments 
7.2.3.1 Clinic-measurement of Vital Signs and Electrocardiograms 
WAS: 

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Body temperature will be measured with an ear thermometer.  Clinic measurements will be 
used to assess eligibility. 
 
IS AMENDED TO: 
Body temperature will be measured with an ear thermometer as per standard of care.  
Clinic measurements will be used to assess eligibility. 
 
7 Study Procedures and Assessments 
7.2.4 Physical Examination 
ADDED: 
In this study, the physical examination will be done to evaluate general physical 
condition and encompasses standard, full physical examinations to assess general 
appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, 
abdomen, musculoskeletal, neurologic status, mental status and lymphatic systems. 
 
7 Study Procedures and Assessments 
7.4 Pharmacokinetics 
WAS: 
Blood samples for the analysis of ED178/mirabegron and ethanol in plasma will be collected 
as indicated in the Schedule of Assessments [Table 1] for the evaluation of 
pharmacokinetics. 
 
IS AMENDED TO: 
Blood samples for the analysis of ED178/mirabegron and ethanol in plasma will be collected 
as indicated in the Schedule of Assessments [Table 1] for the evaluation of 
pharmacokinetics. 
The pharmacokinetic parameters that will be calculated as part of the secondary 
pharmacokinetic endpoint are steady-state Cmax, AUCtau, Ctrough, Tmax, CL/F and Vz/F. 
Additional parameters may be calculated based on the population pharmacokinetic 
model used. 
 
7 Study Procedures and Assessments 
7.6 Electronic Clinical Outcome Assessment 
WAS: 
For this study, it has been decided that there are justifiable scientific reasons (i.e., recall bias) 
to limit subject reported changes to changes reported by the subject to the site within 1 
business day of its entry, as changes outside of this window could potentially impact the data 
integrity of the study.  The data that will be under this rule are: all subject/guardian/parent 
entered, primary and secondary endpoints data.  However, the site/investigator can 
remove/inactivate any data that they determine to be in error at any time. 
Subject bladder diaries, questionnaires and other data completed by the subject or the 

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subject’s parent(s)/legal guardian(s) will be entered on an electronic device (e-diary).  The 
information on the electronic device will be automatically uploaded to a central website.  The 
investigator or site designee should review the diaries and questionnaire data on the website 
for correct completion before each planned visit of the subject (on site visit or TC) and 
discuss the results or retrain the subject and/or subject’s parent(s)/legal guardian(s) if 
applicable.  In case clinically relevant adverse changes are noticed during review of the e 
diary, these will be recorded as an AE [Appendix 12.4.1 Definition of Adverse Events]. 
The bladder e-diary, questionnaire results and other data collected in the e-diary will be 
transferred electronically to sponsor or designee at predefined intervals during the study.  
The vendor will provide sponsor or designee with a complete and clean copy of the data.  
 
IS AMENDED TO: 
For this study, it has been decided that there are justifiable scientific reasons (i.e., recall bias) 
to limit subject reported changes to changes reported by the subject to the site within 1 
business day of its entry, as changes outside of this window could potentially impact the data 
integrity of the study.  The data that will be under this rule are: all subject/guardian/parent- 
entered, primary and secondary endpoints data.  However, the site/investigator can 
remove/inactivate any data that they determine to be in error at any time with source 
documentation to support the change including subject confirmation. Data will never 
be deleted from the electronic database by the electronic clinical outcome assessment 
(eCOA) service provider, but will be removed logically as per investigator’s request and 
approval. All data changes are audit trailed showing the original entries alongside all 
changes including who requested the change, why it was requested, who made the 
change and when it was made. Audit trails are reviewed by the sponsor/clinical 
research organization (CRO) to ensure adherence to the protocol and appropriate 
source exists at site to substantiate the change. 
Subject bladder diaries, questionnaires and other data will be completed by the subject or the 
subject’s parent(s)/legal guardian(s)/caregiver(s) will be entered on an electronic device (e-
diary).  The information on the electronic device will be automatically uploaded to a central 
website.  The investigator or site designee should review the diaries and questionnaire data 
on the website for correctto ensure completion and protocol compliance before each 
planned visit of the subject (on site visit or TC) and discuss the results or retrain the subject 
and/or subject’s parent(s)/legal guardian(s)/caregiver(s), if applicable.  In case clinically 
relevant adverse changes are noticed during review of the e diary, these will be recorded as 
an AE [Appendix 12.4.1 Definition of Adverse Events]. 
The bladder e-diary, questionnaire results and other data collected in the e-diary will be 
transferred electronically to the sponsor or designee at predefined intervals during the study.  
The vendor will provide the sponsor or designee with a complete and clean copy of the 
study data. The ownership of this data is with the investigator and subsequently any 
changes requested to these subject-reported or nonsubject reported data will be made 
using the vendor’s established process (e.g., a data clarification form to the vendor). 
The requested change must be supported by documented evidence at study site. 
 

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7 Study Procedures and Assessments 
7.8 Total Amount of Blood (Table 8) 
WAS: 
Sample Type 
Number of Samples 
Sample Volume (mL) 
Total Volume (mL) 
Pharmacokinetics 
2 
5.0 
10.0 
Clinical Laboratory Tests† 
Biochemistry/hematology 
2 
4.5§‡ 
9.0 
Total 
19.0 
† Additional hematology and biochemistry tests of approximately 4.5 mL total will be performed at 
visit 3/week 0 (baseline), visit 5/week 4 and visit 8/week 14 (EoS) only if an adverse event related to 
hematology or biochemistry parameters occurred since the previous visit or at the discretion of the 
investigator.   
‡ Includes pregnancy test in female subjects who experienced menarche (if blood is drawn); no additional blood 
is required.  Volume does not take any unscheduled visits or repeat tests into account (e.g., follow up of 
adverse events). 
 
IS AMENDED TO: 
Sample Type 
Number of Samples 
Sample Volume (mL) 
Total Volume (mL) 
Pharmacokinetics 
2 
5.0 
10.0 
Clinical Laboratory Tests† 
Biochemistry/hematology 
32 
4.5§‡ 
13.59.0 
Total 
23.519.0 
† Additional hematology and biochemistry tests of approximately 4.5 mL total will be performed at 
visit 3/week 0 (baseline), visit 5/wee 4 and visit 8/week 14 (EoS) only if an adverse event related to 
hematology or biochemistry parameters occurred since the previous visit or at the discretion of the 
investigator.   
‡ Includes pregnancy test in female subjects who experienced menarche (if blood is drawn); no additional blood 
is required.  Volume does not take any unscheduled visits or repeat tests into account (e.g., follow up of 
adverse events). 
 
8 Discontinuation 
8.1 Discontinuation of Individual Subject(s) From Study Treatment(s) 
ADDED: 
A discontinuation from treatment is defined as a subject who is randomized and for 
whom study treatment is permanently discontinued for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason 
and at any time without giving reason for doing so and without penalty or prejudice. 
The investigator is also free to discontinue the participant from study treatment or to 
terminate a subject’s involvement in the study at any time if the subject’s clinical 
condition warrants it. 
… 
The reason for discontinuation from study treatment must be documented in the 
subject’s medical records. 
● Female subject becomes pregnant. 

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● Prolongation of QT > QTcF > 440 msec and/or QT interval prolongation > 30 msec 
versus baseline. 
● Subject with (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 
mmHg. 
 
9 Statistical Methodology 
9.1 Sample Size 
ADDED: 
These assumptions, together with levels for Type-1 error and power were agreed upon 
with Pediatric Committee in the current Pediatric Investigation Plan 
 
9 Statistical Methodology 
9.4.1.3 Subgroup Analysis 
WAS: 
For the primary efficacy endpoint, descriptive statistics (n, mean, 95% confidence interval 
around the mean, SD, minimum, median, maximum) will be calculated for mean change 
from baseline at each visit by sex, race, ethnicity, geographical region, formulation (tablets 
vs. oral suspension) and prior OAB treatment, with and without LOCF. 
 
IS AMENDED TO: 
For the primary efficacy endpoint, descriptive statistics (n, mean, 95% confidence interval 
around the mean, SD, minimum, median, maximum) will be calculated for mean change 
from baseline at each visit by sex, race, ethnicity, geographical region, formulation (tablets 
vs. oral suspension), and prior OAB treatment, with and without LOCF and symptomatic 
UTI. 
 
9 Statistical Methodology 
9.4.3 Analysis of Exploratory Endpoints 
ADDED: 
o Mean number of micturitions per 24 hours 
 
9 Statistical Methodology 
9.5.2 Laboratory Assessments 
ADDED: 
In cases where laboratory evaluations are conducted locally, the values obtained will be 
adjusted to values obtained by the central laboratory. Details will be described in the 
SAP. 
 

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9 Statistical Methodology 
9.5.5 Electrocardiogram 
ADDED: 
ECGs will be recorded prior to blood draw. 
 
9 Statistical Methodology 
9.6.1 Estimation of Pharmacokinetic Parameters 
WAS: 
The plasma concentrations will be analyzed with nonlinear mixed effects modeling 
(population pharmacokinetics) using Non-Linear Mixed Effects Modeling software (version 
7.3 or higher, ICON Development Solutions, Ellicott City, MD, US) to estimate the 
pharmacokinetic parameters.  Results will be reported separately. 
 
IS AMENDED TO: 
The plasma concentrations will be analyzed with nonlinear mixed effects modeling 
(population pharmacokinetics) using Non-Linear Mixed Effects Modeling (NONMEM) 
software (version 7.3 or higher, ICON Development Solutions, Ellicott City, MD, US) to 
estimate the pharmacokinetic parameters.  Results will be reported separately. 
 
10 Operational Considerations 
10.1 Data Collection 
DELETED: 
The investigator or site designee is responsible to ensure that all data in the electronic case 
report forms and queries are accurate and complete and that all entries are verifiable with the 
source.  These documents should be appropriately maintained by the study site. 
The e diary and questionnaire data will be transferred electronically to the sponsor or 
designee at predefined intervals during the study.  The vendor will provide the investigator 
with a complete and clean copy of the study site’s data and will provide the sponsor or 
designee with a complete and clean copy of the study data.  The ownership of this data is 
with the investigator and subsequently any changes requested to these subject reported data 
will be made using a data clarification form to the vendor.  The requested change must be 
supported by documented evidence at study site. 
 
10 Operational Considerations 
 
ADDED: 

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10.4.2 Independent Data Analysis Center 
An IDAC for this study will serve the 2 purposes: (1) to generate periodic safety 
overviews for the DSMB and (2) to calculate the futility analysis. The statistical 
member of the DSMB may also serve as the IDAC statistician, as described in the 
DSMB charter. A SAP describing the details of the periodic safety review or outputs 
will be developed with input from the DSMB members. 
 
11 References 
 
WAS: 
Investigator’s Brochure Mirabegron (ED178), Astellas. 
 
IS AMENDED TO 
Investigator’s Brochure Mirabegron (YMED178), Astellas. 
 
12 Appendices 
12.1.6 Source Documents 
ADDED: 
3. The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
5. Study monitors will perform ongoing source data review to confirm that the safety 
and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP and all applicable regulatory requirements. 
 
12 Appendices 
12.2.1 Study Monitoring 
WAS: 
The sponsor is responsible for monitoring the study to ensure that the rights, safety and well-
being of subjects are protected, the study is properly conducted in adherence to the current 
protocol and GCP and the study data reported by the investigator/subinvestigator(s) are 
accurate, complete and verifiable with the source.   
 
IS AMENDED TO 
The sponsor is responsible for monitoring the study to ensure that the rights, safety and well-
being of subjects are protected, the study is properly conducted in adherence to the current 
protocol and GCP and the study data reported by the investigator/subinvestigator(s) are 
accurate, complete and verifiable with the source.   
 

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12 Appendices 
12.3 Contraception Requirements 
WAS: 
WOCBP who are eligible for participation in the study, including those who choose complete 
abstinence, must have pregnancy tests as specified in the Schedule of Assessments.  
Pregnancy test results must confirm that the subject is not pregnant. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS 
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile. 
Females in the following categories are not considered WOCBP 
● 
Premenarchal 
● 
Premenopausal with 1 of the following (i.e., permanently sterile): 
○ 
Documented hysterectomy 
○ 
Documented bilateral salpingectomy 
○ 
Documented bilateral oophorectomy 
Documentation of any of these categories can come from the study site personnel’s review of 
the female subject’s medical records, medical examination or medical history interview. 
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILDBEARING 
POTENTIAL 
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use 1 of the highly effective methods of contraception listed below from the time of 
signing the ICF/assent and until the end of relevant systemic exposure, defined as 30 days 
after the final IP administration.a 
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b: 
● 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
○ 
Oral 
○ 
Intravaginal 
○ 
Transdermal 
● 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
○ 
Oral 
○ 
Injectable 
○ 
Implantable 
● 
Other combined (estrogen- and progesterone-containing) methods 
○ 
Vaginal ring 
○ 
Injectable 
○ 
Implantable 

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○ 
Intrauterine hormone-releasing system or intrauterine device 
● 
Bilateral tubal occlusion 
● 
Vasectomized partner 
● 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed.  If not, an additional highly effective method of contraception should be 
used. 
● 
Sexual abstinence 
● 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the test 
product.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the subject.  It is not 
necessary to use any other method of contraception when complete abstinence is elected. 
aLocal laws and regulations may require use of alternative and/or additional contraception methods. 
bTypical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. 
CONTRACEPTION GUIDANCE FOR MALE SUBJECTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL 
Male subjects with female partners of childbearing potential are eligible for participation in 
the study if they agree to the following during treatment and until the end of relevant 
systemic exposure defined as 30 days after final drug administration.a 
● 
Inform any and all partner(s) of their participation in a clinical drug study and the need 
to comply with contraception instructions as directed by the investigator 
● 
Use a condom 
● 
Female partners of male subjects who have not undergone a vasectomy with the absence 
of sperm confirmed or a bilateral orchiectomy should consider use of effective methods 
of contraception 
aLocal laws and regulations may require use of alternative and/or additional contraception methods. 
 
IS AMENDED TO: 
Contraception for Pediatric Male Subjects of Reproductive Potential 
Male children/adolescents in the following categories are not considered of reproductive 
potential: 
1. 
Tanner stage 1 development 
2. 
Documented surgically sterile  
Documentation from the site personnel’s review of the male subject’s medical records, 
medical exam and medical history interview is necessary.  
Contraception guidance for male children/adolescents of reproductive potential: 
● 
Male children/adolescents of reproductive potential (Tanner Stage 2 and above) 

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receiving non-genotoxic agents should use a condom during treatment and for 3 
weeks + 5 × half-life of drug after last dose.  
● 
Male children/adolescents of reproductive potential receiving genotoxic agents 
should use a condom during treatment and for 90 days + 5 × half-life of drug after 
last dose. 
● 
Male participants should inform their female partners that they are participating 
in a clinical trial and effective methods of contraception should be used.  
● 
Female partners of male subjects who have not undergone bilateral orchiectomy 
should consider use of highly effective methods of contraception until the end of 
relevant systemic exposure, as defined above.  
Contraception for Pediatric Female Subjects of Childbearing Potential 
Female children/adolescents in the following categories are not considered of 
childbearing potential: 
1. Pre-menarchal  
2. Documented surgically sterile (hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy) 
Documentation from the site personnel’s review of the female subject’s medical 
records, medical exam and medical history interview is necessary. 
Contraception guidance for female children/adolescents of childbearing potential: 
● 
Female children/adolescents of childbearing potential receiving non-genotoxic 
agents should use highly effective contraception during treatment and for 30 days 
after last dose. 
● 
Female children/adolescents of childbearing potential receiving genotoxic agents 
should use contraception during treatment and for 180 days + 5 × half-life of drug 
after last dose. 
● 
Pregnancy testing for female children/adolescents of childbearing potential 
o At all on-site visits and  30 days after end of relevant systemic exposure 
One of the highly effective methods of contraception listed below is required at the time 
of informed consent and until the end of relevant systemic exposure as defined above. 
Highly Effective Birth Control Methods-failure rate < 1%/year 
1. Combined estrogen and progestogen containing hormonal contraception  
a. Oral 
b. Intravaginal 
c. Transdermal-Patch 
d. Injectable-Cyclofem, Mesigyna 
e. Intrauterine device 
f. Intrauterine hormone-releasing system 
2. Progestogen-only hormonal contraception  
d. Oral 

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e. Injectable-DMPA-IM or -SC 
f. Implantable-Norplant 
3. Bilateral tubal occlusion 
4. Vasectomized male partner 
5. True abstinence* 
*True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Sexual 
abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. 
It is not necessary to use any other method of contraception when complete abstinence 
is elected. 
Birth control methods considered unacceptable: 
1. Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
2. Withdrawal (coitus interruptus) 
3. Spermicides only 
4. Lactational amenorrhea 
 
WOCBP who are eligible for participation in the study, including those who choose complete 
abstinence, must have pregnancy tests as specified in the Schedule of Assessments.  
Pregnancy test results must confirm that the subject is not pregnant. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS 
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile. 
Females in the following categories are not considered WOCBP 
● 
Premenarchal 
● 
Premenopausal with 1 of the following (i.e., permanently sterile): 
○ 
Documented hysterectomy 
○ 
Documented bilateral salpingectomy 
○ 
Documented bilateral oophorectomy 
Documentation of any of these categories can come from the study site personnel’s review of 
the female subject’s medical records, medical examination or medical history interview. 
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILDBEARING 
POTENTIAL 
Female subjects of childbearing potential are eligible for participation in the study if they 
agree to use 1 of the highly effective methods of contraception listed below from the time of 
signing the ICF/assent and until the end of relevant systemic exposure, defined as 30 days 

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after the final IP administration.a 
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly)b: 
● 
Combined (estrogen  and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
○ 
Oral 
○ 
Intravaginal 
○ 
Transdermal 
● 
Progestogen only hormonal contraception associated with inhibition of ovulation 
○ 
Oral 
○ 
Injectable 
○ 
Implantable 
● 
Other combined (estrogen  and progesterone containing) methods 
○ 
Vaginal ring 
○ 
Injectable 
○ 
Implantable 
○ 
Intrauterine hormone releasing system or intrauterine device 
● 
Bilateral tubal occlusion 
● 
Vasectomized partner 
● 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed.  If not, an additional highly effective method of contraception should be 
used. 
● 
Sexual abstinence 
● 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the test 
product.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the subject.  It is not 
necessary to use any other method of contraception when complete abstinence is elected. 
aLocal laws and regulations may require use of alternative and/or additional contraception methods. 
bTypical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. 
CONTRACEPTION GUIDANCE FOR MALE SUBJECTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL 
Male subjects with female partners of childbearing potential are eligible for participation in 
the study if they agree to the following during treatment and until the end of relevant 
systemic exposure defined as 30 days after final drug administration.a 
● 
Inform any and all partner(s) of their participation in a clinical drug study and the need 
to comply with contraception instructions as directed by the investigator 
● 
Use a condom 
● 
Female partners of male subjects who have not undergone a vasectomy with the absence 

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The purpose of this appendix is to provide acceptable alternate methods to assess safety 
and efficacy parameters, as appropriate, in the event the clinical study is interrupted at 
the country, state, site or participant level during any crisis (e.g., natural disaster, 
pandemic).    
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in 
the clinical study setting is paramount during any crisis. The site is expected to follow 
the protocol and associated Schedule of Assessments [Table 1] unless the site principal 
investigator discusses the need with the Astellas medical monitor to implement the 
alternate measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity 
and to provide acceptable alternate methods to complete the study required 
assessments and procedures if study activities are unable to be performed as described 
in [Section 7 Study Procedures and Assessments] due to a crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this 
Appendix will be required to provide informed consent, which explicitly informs them 
of the nature of and rationale for these changes, and gain their agreement to continue 
participation in the study prior to the implementation of any of these changes. In the 
event the urgency of implementing the alternate measures does not allow for the 
participant to provide written consent prior to implementation, the principal 
investigator or designee will obtain oral agreement from the subject followed by written 
documentation as soon as is feasible. A separate addendum to the study informed 
consent will be provided to document the participant’s consent of the changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 
● Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
● Site facilities have been closed for clinical study conduct  
● Site has been restricted to treating patients with conditions outside of the scope of 
the study 
● Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel 
● Participant(s) have temporarily relocated from the current study site to an alternate 
study site to avoid placing a burden on the participant with respect to travel 
● Participant(s) have temporarily relocated from their home location and the new 
distances from the site would cause undue burden with respect to time and travel 

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● Participant has risk factors for which traveling to the site poses an additional risk to 
the participant’s health and safety 
Adherence to the original protocol as reflected in the Schedule of Assessments [Table 1] 
is expected, where plausible, in the case of a crisis. The alternate measures as noted in 
[Table 12] below are only permissible in the event of a crisis, and after discussing the 
need with the Astellas medical monitor to implement the alternate measures. This is to 
allow for continuity of receiving IP and maintaining critical safety and efficacy 
assessments for patients participating in the study at a time of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, 
the site should document in the participant’s source document the justification for 
implementing the alternate measure and the actual alternate measures that were 
implemented, along with the corresponding time point(s). 
 

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12 Appendices 
 
ADDED: 
Table 12  Alternate Schedule of Assessments in Response to a Crisis 
Critical Assessments 
Alternate Approach(es) 
Double-blind Placebo-controlled Period 
(12 weeks) 
Follow-up Period 
(2 weeks) 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Week 0 
Baseline 
Week 2 
TCa 
Week 4 
Week 8 
TCa 
Week 12 
(EoT)b 
Week 14 
(EoS)b,c 
Day -1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days) 
Day 56 
(± 3 days) 
Day 84 
(± 3 days) 
Day 98 
(+ 3 days) 
Previous and Concomitant Medication 
Remote/Virtual/Telemedicine Visits 
allowed. Please refer to protocol schedule 
of assessments. 
X 
X 
X 
X 
X 
X 
Physical Examination 
The exam can be done at a local clinic 
and the results submitted to PI. 
 
 
X 
 
X 
 
Height and Body Weight 
Can be obtained at a local clinic or at 
home 
X 
 
 
 
X 
 
Dose Titrationd 
Courier service directly to subject.  
Titration to occur based on PI’s 
evaluation via phone.    
For tablets: subject to take spare 25 mg 
tablets until 50 mg wallet is delivered via 
courier.  
 
 
X 
 
 
 
Dispense IPe 
Courier service directly to subject  
X 
 
X 
 
 
 
Drug Accountability 
Used product can be shipped back to site 
via courier. 
X 
 
 
 
X 
 
Vital Signsf 
Can be performed at a local clinic and 
results submitted to PI for evaluation  
OR  
Blood pressure and pulse collected via 
X 
 
X 
 
X 
X 

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SBPM and temperature collected at 
home and reported to site (respiration 
rate missing).  
SBPMg 
Will be sent to subject’s home address 
X 
X 
X 
X 
X 
 
Routine 12-lead ECGf 
ECG testing can be completed at local 
clinic. 
X 
 
X 
 
X 
 
Clinical Laboratory Tests (Hematology and 
Biochemistry)h 
Visit collection of samples at local facility 
acceptable if results can be made 
available to investigative site. 
Xi 
 
X 
 
X 
Xi 
Clinical Laboratory Tests (Urinalysis)h 
Visit collection of samples at local facility 
acceptable if results can be made 
available to investigative site. 
Xi 
 
X 
 
X 
Xi 
Pregnancy Testi 
Visit collection of samples at local facility 
acceptable if results can be made 
available to investigative site. 
X 
 
X 
 
X 
X 
AEs 
Remote/Virtual/Telemedicine Visits 
allowed. Please refer to protocol schedule 
of assessments. 
X 
X 
X 
X 
X 
X 
Bladder e-diary 
Will be sent to subject’s home address 
X 
X 
X 
X 
X 
 
Acceptability and Palatability Questionnairej 
To be performed remotely via e-diary. 
 
 
 
 
X 
 
Pharmacokineticsk 
Astellas Medical Monitor to assess. Not 
allowed at an alternate clinical due to 
special sample handling. 
 
 
X 
 
X 
 
AE: adverse event; ECG: electrocardiogram; e-diary: electronic diary; EoS: end of study; EoT: end of treatment; IP: investigational product; OAB: overactive bladder; 
PED25: pediatric equivalent dose 25 mg; PED50: pediatric equivalent dose 50 mg; PI: principal investigator; SBPM: self blood pressure monitoring; TC: telephone call 
a. For the visits where a TC is indicated, there is no need for the subject to visit the clinic provided that the bladder e-diary data are reviewed by the investigator prior to 
the TC and discussed and confirmed with the subject or parent(s)/legal guardian(s) during the TC.  Urotherapy is also to be discussed and confirmed with the subject or 
parent(s)/legal guardian(s) during each TC as indicated in Table 1. 
b. Subjects who withdraw early from the study after having received IP should complete both the EoT and EoS visits. 
c. 
The EoS visit (visit 8/week 14 [EoS]) should take place at least 14 days after the EoT visit (visit 7/week 12 [EoT]). 
d. Dose up-titration to PED50 to occur at visit 5/week 4 unless investigator determines OAB is adequately controlled.  Dose down-titration from PED50 to PED25 can be 
done at any time for safety reasons. 

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e. 
Daily IP administration will start on day 1 (i.e., the day after visit 3/week 0 [baseline]). 
f. 
Blood pressure, pulse, body temperature and ECGs will all be measured in single measurements.  Subject to be in the sitting position (when possible, otherwise supine, 
but always in the same position for each procedure).  Subject should have been calm and without distress for at least 5 minutes.  Preferably, the right arm should be 
used to measure vital signs.  Body temperature will be measured with an ear thermometer.  Clinic measurements will be used to assess eligibility. 
g. SBPM will be measured once in the morning and evening during the 2-day weekend bladder e-diary collection period. SBPM measurements should start in the weekend 
prior to week -2 and be taken in the weekend prior to the indicated visit (or TC). SBPM will be measured on 2 consecutive days at 1 and 2 weeks after start of dosing 
with PED25 (day 1) and after up-titration to PED50, if not already covered by the scheduled SBPM.  Measurements will be taken in the sitting position (when possible, 
otherwise supine, but always in the same position).  Preferably, the right arm should be used.  Subject should have been calm and without distress for at least 5 minutes.  
Morning measurement should be taken before IP intake and evening measurement should be taken prior to bedtime. 
h. Additional hematology, biochemistry and urinalysis (urinalysis dipstick) tests will be performed at visit 3/week 0 (baseline) and visit 8/week 14 (EoS) only if an AE 
related to hematology, biochemistry or urinalysis parameters occurred since the previous visit or at the discretion of the investigator. 
i. 
Urine pregnancy test will be performed for females of childbearing potential at all on-site visits. 
j. 
The acceptability and palatability questionnaire will be completed on one weekend day preceding at visit 7/week 12 (EoT). 
k. There will be 2 pharmacokinetic sampling days at visit 5/week 4 and visit 7/week 12 (EoT).  Both pharmacokinetic sampling days will consist of collecting 1 predose 
(trough) sample.  On pharmacokinetic sampling days, dosing should occur in the clinic and breakfast should be eaten at the clinic within 1 hour before dosing. 
 
INVESTIGATIONAL PRODUCT SUPPLY 
If any of the conditions outlined above in the Participant Procedures Assessment are met, if the following mitigating strategy will be employed, 
as needed, to ensure continuity of IP supply to the participants:   
● 
Increase stock of IP on site to reduce number of shipments required, if site space will allow. 
● 
Direct-to-subject shipments of IP from the site to the subject’s home. 
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study may have been affected by a crisis and to accommodate 
data collection resulting from alternate measures implemented to manage the conduct of the study and participant safety.  
• Critical assessments for safety and efficacy based on study endpoints to be identified as missing or altered (performed virtually, at 
alternative locations, out of window, or other modifications) due to the crisis.  

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12 Appendices 
12.4 List of Abbreviations and Definition of Key Study Terms 
WAS: 
WOCBP 
Woman of childbearing potential 
 
IS AMENDED TO: 
NONMEM 
non-linear mixed effects modeling 
WOCBP 
Woman of childbearing potential 
 
12 Appendices 
12.4 List of Abbreviations and Definition of Key Study Terms 
WAS: 
Intervention 
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study (e.g., 
health-related quality of life, efficacy, safety and pharmacoeconomics). 
 
IS AMENDED TO: 
Intervention 
The drug, device, therapy or process under investigation in a study that is 
believed to have an effect on outcomes of interest in a study (e.g., 
health-related quality of life, efficacy, safety and 
pharmacokineticseconomics). 
 
 

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14 
COORDINATING INVESTIGATOR’S SIGNATURE 
A Phase 3, Double-blind, Randomized, Multicenter, Parallel Group, Placebo-controlled 
Sequential Dose Titration Study to Evaluate Efficacy, Safety and Pharmacokinetics of 
Mirabegron in Pediatric Subjects from 5 to < 18 Years of Age with Overactive Bladder 
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I have read all pages of this protocol for which Astellas is the sponsor.  I agree that it contains 
all the information required to conduct this study. 
Coordinating Investigator: 
Signature: 
 
 
 
 
Date (DD Mmm YYYY) 
Printed Name:  
  
 
Address: 
 
 
 
 
 
 
 
 
 

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15 
SPONSOR’S SIGNATURES 
(Electronic signatures are attached at the end of the document.) 
 
 
Medical and 
Development 
 
 
 
 
 
Data Science 
 
PPD
PPD