Clinical trial NCT04641975
Conditions: Overactive Bladder (OAB) Pharmacokinetics of Mirabegron
Keywords: Pediatrics mirabegron
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2021-03-15; Completion date: 2023-07-24
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy of mirabegron in children (5 to \< 12 years of age) with OAB.

This study will also evaluated the safety and tolerability of mirabegron in pediatric participants with OAB and evaluated the pharmacokinetics after multiple dose administration of mirabegron in pediatric participants with OAB.

Detailed description:
The study consisted of 3 periods (Screening period/urotherapy (4 weeks); Double-blind, placebo-controlled period (12 weeks); Follow-up period (2 weeks)) for a total duration of 18 weeks.

Arms: arm 1: Participants aged 5 to \< 12 years received initial dose of 25 milligram (mg) of mirabegron orally once daily based on weight (pediatric equivalent dose of 25 mg \[PED25\]) on day 1. Participants with a body weight ≥ 35 kilogram (kg) received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the pediatric equivalent dose of 50 mg \[PED50\] based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12. arm 2: Participants aged 5 to \< 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12. arm 3: Participants aged 12 to \< 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12. arm 4: Participants aged 12 to \< 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight\< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.
Interventions: intervention 1: Mirabegron intervention 2: Placebo
Intervention descriptions: intervention 1: Oral/ Oral Suspension: Participants with a body weight of ≥ 35 kg are to receive the tablet form of IP unless unable to swallow tablets and will be provided the oral suspension as an alternative. Participants with a body weight \< 35 kg or those who cannot be dosed with the tablet will receive oral suspension. intervention 2: Oral/ Oral Suspension

Protocol documents:
Prot_000.pdf: 
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 
Astellas 
Page 3 of 157 
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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11 Feb 2021 
Astellas 
Page 4 of 157 
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 
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11 Feb 2021 
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Page 5 of 157 
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 
- CONFIDENTIAL - 
11 Feb 2021 
Astellas 
Page 6 of 157 
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


Sponsor: APGD 
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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. 


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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 
ISN/Protocol 178-CL-204 
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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

SAP_001.pdf: 
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SAP Final Version 3.0 
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23-MAR-2023 
Astellas 
Page 1 of 85 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Final Version 3.0 dated 23-MAR-2023 
 
 
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: 178-CL-204 
 
EudraCT number: 2016-001767-37 
 
 
 
 
Astellas Pharma Global Development Inc. (APGD) 
 
1 Astellas Way 
Northbrook, IL 60062, US  
 
 
 
This document contains confidential information which is the intellectual property of Astellas. By accepting or reviewing 
this document, you agree to hold this information in confidence and not copy or disclose it to others or use it for 
unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) where 
disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of such information 
is made to a member of the investigator’s team who agrees to hold this information in confidence. 


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Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 6 
1 
INTRODUCTION ································
································
··················
 9 
2 
STUDY OBJECTIVE(S) AND DESIGN ································
·······················
 9 
2.1 
Study Objectives ································
································
···············
 9 
2.1.1 
Estimand ································
································
··················
 11 
2.2 
Study Design ································
································
···················
 11 
2.3 
Randomization ································
································
·················
 13 
3 
SAMPLE SIZE································
································
·····················
 14 
4 
ANALYSIS SETS ································
································
·················
 15 
4.1 
All Screened Set ································
································
···············
 15 
4.2 
All Randomized Set ································
································
···········
 15 
4.3 
Full Analysis Set ································
································
··············
 15 
4.4 
Safety Analysis Set ································
································
···········
 15 
4.5 
Per Protocol Set ································
································
···············
 15 
4.5.1 
Reasons for Exclusion from Per Protocol Set ································
········  16 
4.6 
Pharmacokinetics Analysis Set ································
······························
 17 
4.7 
Pharmacodynamic Analysis Set ································
·····························
 17 
5 
EFFICACY AND SAFETY ENDPOINTS ································
···················
 18 
5.1 
Primary Efficacy Endpoint ································
································
···  19 
5.2 
Secondary Efficacy Endpoints ································
·······························
 20 
5.2.1 
Mean Volume Voided per 24 hours ································
···················
 21 
5.2.2 
Maximum Volume Voided ································
·····························
 21 
5.2.3 
Mean Number of Daytime Incontinence Episodes per 24 hours ···················
 21 
5.2.4 
Mean Number of Daytime Micturitions per 24 hours ·······························
 22 
5.2.5 
Number of Dry (incontinence free) Days per 7 Days at the End of the 12-
weeks Treatment Period ································
································
 22 
5.3 
Exploratory Endpoints ································
································
········  23 
5.3.1 
Percentage of Subjects With a Reduction in Daytime Incontinence 
Episodes (< 50% reduction [non-responder], 50% [partial responder] and 
100% [responder]) ································
································
·······  23 
5.3.2 
Improvement from Baseline in Worst Incontinence Grading ······················
 24 
5.3.3 
Mean Volume Voided as a Percentage of Expected Bladder Capacity ···········
 24 
5.3.4 
Mean Number of Micturitions per 24 hours, Adjusted for Fluid Intake ··········
 25 
5.3.5 
Mean Number of Micturitions per 24 hours (adolescents only) ···················
 26 


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5.3.6 
Mean Volume Voided per 24 hours (adolescents only) ·····························
 26 
5.3.7 
Maximum Volume Voided (adolescents only) ································
······  26 
5.3.8 
Mean Number of Incontinence Episodes per 24 hours (adolescents) ·············
 26 
5.3.9 
Mean Number of Daytime Micturitions per 24 hours (adolescents only) ········  26 
5.3.10 
Number of Dry (incontinence-free) Days per 7 Days at the End of the 12-
weeks Treatment Period (adolescents only) ································
··········
 26 
5.3.11 
Mean Number of Daytime Grade 3 or 4 (PPIUS) Urgency Episodes per 
24 hours (adolescents only) ································
····························
 26 
5.4 
Safety Endpoints ································
································
··············
 27 
5.4.1 
Adverse Events ································
································
··········
 27 
5.4.2 
Vital Signs ································
································
················
 28 
5.4.3 
Clinical Laboratory Variables ································
··························
 30 
5.4.4 
Physical Examination ································
································
···  32 
5.4.5 
12 Lead ECGs ································
································
···········
 32 
5.4.6 
Post Void Residual Volume ································
····························
 32 
5.4.7 
Acceptability and Palatability Questionnaires ································
·······  33 
5.5 
Other Endpoints ································
································
···············
 33 
5.5.1 
Exposure to Study Drug ································
································
 33 
5.5.2 
Compliance to Study Drug ································
·····························
 35 
6 
STATISTICAL METHODOLOGY ································
···························
 39 
6.1 
General Considerations ································
································
·······  39 
6.2 
Study Population ································
································
··············
 39 
6.2.1 
Disposition of Subjects ································
································
· 39 
6.2.2 
Protocol Deviations ································
································
·····  40 
6.2.3 
Demographic and Other Baseline Characteristics ································
···  40 
6.2.4 
Previous and Concomitant Medications ································
··············
 41 
6.3 
Study Drug Exposure and Compliance ································
·····················
 41 
6.3.1 
Exposure ································
································
··················
 41 
6.3.2 
Treatment Compliance ································
································
··  42 
6.4 
Analysis of Efficacy ································
································
··········
 42 
6.4.1 
Analysis of Primary Efficacy Endpoint ································
···············
 42 
6.4.2 
Analysis of Secondary Efficacy Endpoints ································
···········
 47 
6.4.3 
Analysis of Exploratory Endpoints ································
····················
 47 
6.5 
Analysis of Safety ································
································
·············
 48 
6.5.1 
Adverse Events ································
································
··········
 48 


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6.5.2 
Clinical Laboratory Evaluation ································
························
 49 
6.5.3 
Vital Signs ································
································
················
 51 
6.5.4 
Electrocardiograms ································
································
······  54 
6.5.5 
Pregnancies ································
································
···············
 55 
6.5.6 
Other Safety-Related Assessments ································
····················
 55 
6.5.7 
Subgroups of Interest for Safety ································
·······················
 56 
6.6 
Analysis of Pharmacokinetics ································
·······························
 56 
6.6.1 
Statistical Analysis ································
································
······  57 
6.7 
Analysis of Pharmacodynamics ································
·····························
 57 
6.8 
Other Analyses ································
································
················
 57 
6.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 57 
6.9.1 
Data Sources ································
································
·············
 59 
6.9.2 
Data Cut-off and Data Extraction ································
·····················
 59 
6.9.3 
Report Generation ································
································
·······  59 
6.10 
Additional Conventions ································
································
······  60 
6.10.1 
Analysis Windows ································
································
······  60 
6.10.2 
Imputation Rules for Incomplete Dates ································
···············
 62 
6.10.3 
Outliers ································
································
···················
 64 
7 
REVISION AND RATIONALE ································
································
 65 
7.1 
List of Changes in SAP Version 2.0 from Version 1.0 ································
···  65 
7.2 
List of Changes in SAP Version 3.0 from Version 2.0 ································
···  66 
8 
REFERENCES ································
································
····················
 69 
9 
APPENDICES ································
································
·····················
 70 
9.1 
Example of SAS Code for Nonparametric ANCOVA ································
····  70 
9.2 
AEs of Interest not covered by Standard MedDRA SMQs latest Version ·············
 71 
9.3 
2017 American Academy of Pediatric Clinical Practice Guidelines ····················
 72 
9.4 
Futility Analysis Simulation Report ································
························
 74 
9.5 
Derivation of Formula to Calculate Bayesian Predictive Probability ···················
 78 
9.6 
Interim Analysis Report Template ································
··························
 83 
9.7 
Key Contributors ································
································
··············
 84 
9.8 
Author and Approver Signatures ································
····························
 85 
 
 


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List of In-text Tables 
Table 1 
Study Objectives and Endpoints ································
······························
 9 
Table 2 
Standardized MedDRA Queries ································
·····························
 28 
Table 3 
Coefficients for Conversion of Blood Pressure to Percentiles ···························
 30 
Table 4 
Percentiles for Resting Pulse Rate in Relation to Age and Gender ·····················
 30 
Table 5 
Laboratory Assessments ································
································
······  31 
Table 6 
Number of Bottles to be Dispensed at each Visit ································
·········  36 
Table 7 
Body Weight-based Doses for Tablets or Suspension ································
····  37 
Table 8 
Definitions of Blood Pressure Categories and Stages································
·····  52 
Table 9 
Sample Collection Schedule ································
································
· 57 
Table 10 
Visit Windows for Efficacy and Safety Parameters ································
·······  60 
 
List of In-text Figures 
Figure 1 
Study Schema ································
································
··················
 12 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations  
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
APGD 
Astellas Pharma Global Development 
ASCM 
Analysis Set Classification Meeting  
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Intervals 
CRF 
Case Report Form 
CS 
Classification Specifications 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DSMB 
Data Safety Monitoring Board 
EBC 
Expected Bladder Capacity 
ECG 
Electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
GCMSL 
Global Clinical Modeling & Simulation Lead 
GD 
Global Development 
H 
High 
HTN 
Hypertension 
ICCS 
International Children’s Continence Society 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDAC 
Independent Data Analysis Center 
IP 
Investigational Product 
IRT 
Interactive Response Technology 
L 
Low 
LS 
Least Squares 
LLN  
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
ms 
Millisecond 
N 
Normal 
OAB 
Overactive Bladder 
PD 
Pharmacodynamic 


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


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List of Key Terms 
Terms 
Definition of terms 
Baseline  
Observed values/findings which are considered to be the starting point for 
comparison.   
Discontinuation 
The act of concluding participation in a trial by an enrolled subject, prior to 
completion of all protocol required elements.   
Note: subject discontinuation does not necessarily imply exclusion of subject 
data from analysis that was collected prior to discontinuation. 
Enroll 
To register or enter into a clinical trial, i.e., signing the informed consent form 
(ICF).  Once a subject has been enrolled, the clinical trial protocol applies to 
the subject.   
EoT result 
End of treatment result is based on the last available result which is obtained 
earlier or on the same date as the treatment stop date. 
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the study drug is given to a subject.  This period continues until the last 
assessment after completing the last dose of the study drug. 
Pediatric 
equivalent dose 
(PEDx) 
Weight-range based doses predicted to achieve plasma concentrations 
equivalent to steady state exposures expected with “x” mg mirabegron 
administered once daily in adults. 
Postinvestigational 
period 
Period of time after the last assessment of the protocol.  Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening 
A process of active consideration of potential subjects for a trial. 
Screening period 
Period of time before entering the investigational period, usually from the 
time the subject signed informed consent until just before the first dose of the 
study drug is given to a subject.   
Screening failure 
Screened subject who did not fulfill protocol inclusion and/or exclusion 
criteria, or decided not to participate anymore (withdrew consent) prior to 
first dose of study drug. 
Source data 
All information in original records or certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records, certified copies). 
Source documents 
Original documents, data, and records including source data. 
Steady state 
When the amount of drug intake is equilibrium with the rate of drug 
elimination. 
Note: for mirabegron steady state is considered to be reached after 10 days of 
daily dosing. 
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Subject 
An individual in the population of interest who participates in a clinical trial 
as recipient of the investigational product. 
Treatment 
emergent adverse 
event 
An adverse event observed after starting administration of the study drug. 
Trough sample 
Pharmacokinetic sample taken just prior to the next dose of study medication. 
 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes procedures for 
executing the statistical analysis to fulfil the objectives of the study.  
The final SAP will be approved prior to database hard lock and unblinding the subject 
treatment assignments.  If needed, revisions to the approved SAP may be made prior to 
database hard lock.  Revisions will be version controlled. 
Changes from the planned analyses in the final SAP that impact the statistical analyses will 
be documented in the Clinical Study Report (CSR).  
Prior to database hard lock, a final review of data and Tables Listings and Figures (TLFs) 
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification.  If required, consequences for the statistical analysis 
will be discussed and documented.  A meeting to determine analysis set classifications may 
also be held prior to database hard lock. 
Pharmacokinetic (PK) analyses will be described in a separate data analysis plan (PKDAP) 
which will be finalized prior to the analysis commencement and will be reported separately. 
2 
STUDY OBJECTIVE(S) AND DESIGN 
2.1 
Study Objectives 
The primary, secondary and exploratory objectives and endpoints for this study are listed in 
the table below.  Primary and secondary objectives and endpoints apply to children only; 
exploratory objectives and endpoints also apply to adolescents. 
Table 1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
● 
To evaluate the efficacy of mirabegron in 
children (5 to < 12 years of age) with 
Overactive Bladder (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 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.   
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 
● 
Mean number of micturitions per 24 hours, adjusted 
for fluid intake: 
o 
Number of micturitions per 24 hours that would 
be required at week 12/EoT to void the same 
total volume as voided at baseline 
o 
Difference in mean number of micturitions per 
24 hours adjusted for fluid intake compared to 
the expected mean number 
● 
Mean volume voided per micturition as a percentage 
of expected bladder capacity 
● Categorized mean volume voided per micturition as a 
percentage of expected bladder capacity (results and 
changes from baseline). 
● 
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 
○ Maximum volume voided 
● 
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. 
 


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2.1.1 
Estimand 
The estimand of most clinical importance for this study is defined by the following four 
attributes: 
● Target population: all children who took at least 1 dose of the study drug, and in whom a 
non-missing 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 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 is 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 
those patients continuing on their respective treatment. 
2.2 
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 International Children’s Continence Society (ICCS) will 
receive 4 weeks of urotherapy prior to randomization. 
Planned total number of study sites included approximately 65 study sites across Europe, 
Latin America, Africa, Middle East, Asia-Pacific and North America.  




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o 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 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. 
o Subjects will start with the subsequent 7-day bladder e-diaries approximately 7 days 
prior to the indicated visit (or TC). 
o 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 in protocol 
● 
Follow-up period (2 weeks): 
o 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. 
o At visit 7/week 12 (EoT), IP administration will be stopped and a safety observation 
period of 2 weeks will start. 
Details of the schedule of clinical assessments are available in the protocol. 
An independent DSMB will be established.  A separate charter will describe the 
responsibilities of the DSMB. 
A comparative interim analysis will be performed after 50% of children planned to be 
randomized have had their visit 7/week 12/EoT assessment.  The interim analysis will 
determine if the chance of a positive study with respect to the primary endpoint at the end of 
the study/Final Analysis is high enough to justify continuation of the study; otherwise, the 
study will be stopped for futility. For details see Section 6.9. 
2.3 
Randomization 
Subjects will be entered into the interactive response technology (IRT) system at screening 
and assigned a subject number.  At Visit 3 (baseline) randomization will be performed via the 
IRT system and treatment assigned in a 1:1 ratio to mirabegron or placebo.  Prior to the 
initiation of the study treatment, on day 1, the site staff will contact the IRT system in order 
to determine the randomly assigned treatment.  Subjects will be stratified by age category: 
5 – <12 years and 12 – <18 years of age. 
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. 
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. 
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. 


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3 
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 standard deviation (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 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 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 in both children and adolescents has 
been achieved. 
 
 


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4 
ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
The determination of whether subjects are included or excluded from the safety and efficacy 
analysis sets will be made prior to database hard-lock for the primary report and prior to 
unblinding.  
4.1 
All Screened Set 
The All Screened Set consists of all subjects for whom a valid informed consent/assent is 
available, as per applicable local law. 
Consent/assent should be obtained from the subject and his/her parent(s)/legal guardian(s), 
before start of pre-investigational period.  Up to three signatures might be available from the 
informed consent/assent.  For calculations using the date of informed consent/assent the last 
available date will be used. 
The All Screened Set will be used to summarize disposition of subjects who were screened. 
4.2 
All Randomized Set 
The All Randomized Set consists of all randomized subjects, i.e. all those subjects with a 
randomization number. 
The All Randomized Set will be used to summarize disposition of subjects who were 
randomized to treatment. 
4.3 
Full Analysis Set 
The Full Analysis Set (FAS) consists of 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. 
4.4 
Safety Analysis Set 
The Safety Analysis Set (SAF) consists of all subjects who took at least 1 dose of IP.  The 
safety set will be analyzed by treatment arm as treated (i.e., based on the treatment the 
subject actually received rather than the treatment to which the subject was randomized). 
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety- and tolerability-related variables.  
4.5 
Per Protocol Set 
The Per Protocol Set (PPS) consists 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 listed in Section 4.5.1 of this 


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SAP.  Final judgments on exclusion of subjects from the PPS are to be made prior to data 
base hard lock and will be documented in the Classification Specification document.  
The PPS will be used for sensitivity analyses of the efficacy data.  Selected demographic and 
baseline characteristics may also be summarized for the PPS. 
4.5.1 
Reasons for Exclusion from Per Protocol Set 
A subject may be excluded from the PPS if there has been a deviation from the protocol 
sufficient to affect the assessment of the efficacy of the study drug. Such deviations may 
include (but are not limited to) ineligible subjects being enrolled in the study, interventions 
performed that were prohibited by protocol, or when subjects did not adhere adequately to 
the study treatment or outcome assessments.  
There will be no partial exclusion (e.g., of particular timepoints only) of a subject from the 
PPS; all of a subject’s data will be excluded.  
Some reasons for exclusion of a subject from the PPS are given below: however the decision 
on whether a particular protocol deviation (see Section 6.2.2) requires the exclusion of a 
subject will be confirmed at the Analysis Set Classification Meeting (ASCM) with all reasons 
for the decision documented in the meeting minutes.  
Eligibility Deviations 
The inclusion and exclusion criteria for the study are detailed in Sections 5.1 and 5.2 of the 
protocol. These are all assessed at Screening (Visit 1) and selected criteria are also assessed 
at baseline (Visit 3). 
A subject will be excluded from the PPS if: 
● 
Any of inclusion criteria 2 and 15 are not met 
● 
Any of exclusion criteria 2, 4, 8, 10 and 28 are met 
Violations of other inclusion and exclusion criteria may also result in exclusion of the PPS if 
it is considered that there is a risk that the violation affects the assessment of the efficacy of 
the study drug.  All such violations will be considered on an individual basis at the ASCM. 
Prohibited and restricted medications and non-drug therapies 
A subject will be excluded from the PPS if they received prohibited medications or non-drug 
therapies. These include, but are not limited to, the following (see Table 12.6 in protocol for a 
more complete list): 
● 
Anti-muscarinics (including tricyclic and tetracyclic antidepressants), desmopressin, 
alpha-blockers and prescribed or OTC drugs that are potent CYP3A4 inhibitors (e.g., 
ketoconazole). They have to be stopped at screening (Visit 1) as soon as informed 
consent/assent has been obtained and eligibility has been confirmed and are 
prohibited during the study 
● 
A history of intravesical treatment with botulinum toxin within 9 months prior to 
screening (Visit 1) and intravesical administration of botulinum toxin during the 
study is prohibited 


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● 
A history of electrostimulation or bladder training within 2 weeks prior to screening 
(Visit 1) and at any time during the study (outside of study related urotherapy) is 
prohibited. 
Administration of restricted medications will be assessed during medical review to determine 
if the usage has fallen outside the protocol restrictions and if there is a risk that baseline or 
endpoint measurements may be affected. A list of restricted medications is given in 
Appendix 12.6 of the protocol. 
Compliance to study medication 
A subject will be excluded from the PPS for any of the following reasons based on 
compliance to the study medication (see Section 5.5.2 for details on the calculation of the 
compliance rate between study visits and over the whole double-blind study period): 
● 
Subject took double-blind study medication for less than 70 days. 
● 
Compliance with the double-blind study medication during the entire double-blind 
treatment period is less than 70%. 
● 
Compliance with the double-blind study medication has been assessed as being less 
than 80% between visit 6/week 8 and visit 7/week 12/EoT. 
All evidence and reasons for determining a violation based on compliance to the study 
medication will be documented in the minutes of the ASCM. 
Error in study drug administration 
A subject will be excluded from the PPS if they were dispensed incorrectly allocated study 
medication at any time during the double-blind treatment period. 
4.6 
Pharmacokinetics Analysis Set 
The Pharmacokinetic Analysis Set (PKAS) will consist of all subjects who took at least 
1 dose of IP and contributed at least one pharmacokinetic sample in which the date and time 
of the sample and prior dose are known.  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. 
Since the actual bioanalytical results may only become available after the data review 
meeting, additional data points may be excluded at the time of pharmacokinetic analysis at 
the discretion of the GCMSL.  These data points will be documented in the modeling report. 
The PKAS is used for all tables and graphical summaries of the PK data. 
4.7 
Pharmacodynamic Analysis Set 
Not applicable. 
 
 


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5 
EFFICACY AND SAFETY ENDPOINTS  
Data for the efficacy endpoints will be recorded on an e-diary.  This e-diary consists of a:  
● 
5-day Weekday Diary (bladder diary, Monday – Friday), which is used for a 
5-day period to record micturition frequency and incontinence episodes, and 
● 
2-day Weekend Episodic Diary (Saturday and Sunday), which is used to record 
micturition frequency, incontinence episodes, (pee) volume measurements, and 
worst leakage severity. 
A valid diary day for: 
● 
“Volumes” 
In the 2-day Weekend Episodic Diary, is any e-diary day for which at least one 
“Pee Volume” greater than 0 mL is recorded with complete date and time. 
● 
“Micturitions”  
o In 2-day Weekend Episodic Diary, is any diary day for which at least once “Pee 
Volume” greater than 0 is recorded.  
o In 5-day Week Diary, is any diary day for which the response to the question 
“Number of times using the toilet during the day/night” is not missing. 
● 
“Incontinence episodes” 
o In 2-day Weekend Episodic Diary, is any diary day for which at least: 
▪ One micturition (“Pee Volume” >0) and 
▪ One “Leakage“ or “Pee in toilet and Leakage” are recorded. 
o In 5-day Week Diary, is any diary day for which: 
▪ The response to the question “How was your day/night” is not missing. 
A valid diary for an analysis visit is a diary with at least 4 valid diary days within that 
analysis visit window.  If for more than 7 days the diary is filled in prior to a visit, only the 
last 7 days prior to that visit will be used for calculation of the efficacy endpoints.  
The number of valid diary days: Count of the valid diary days during the 7-day diary period. 
Days of visits to the clinic will not be counted as valid diary days. 
In the event that in the 2-day Weekend Episodic Diary there are two entries with the same 
collection date and time but with different times of entry on the device, the last entry (time) 
will be used for analysis. 
For several of the secondary efficacy endpoints, diary data will be classified as either 
“daytime” or “nighttime”, where “daytime” is considered to mean “between waking up in the 
morning and going to sleep later the same day or next day” and “nighttime” means “between 
going to sleep on a day and waking up on the same or next day”.  
Whether an entry into the 5-day Week Diary is done during daytime or nighttime is captured 
on this diary.  


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For entries into the 2-day Weekend Episodic Diary, “daytime” and “nighttime” will be 
derived from the time the subject went to sleep and the time the subject awakened.  These 
times are entered on this diary by the subject.  
The go-to-bed time for Sunday is not captured in the diary.  In order to distinguish between 
daytime and nighttime on Sunday the go-to-sleep time will be imputed as occurring a short 
time after the second (evening) SBPM was performed: time of second SBPM plus 1 hour.  If 
there is no time entered in the diary for the evening SBPM, then the go-to-sleep time will be 
imputed as 23:59 (on Sunday). 
5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to week 12/EoT in mean number 
of micturitions per 24 hours in children (5 to <12 years of age).   
Number of micturitions per 24 hours is calculated from: 
● 
The response to the questions “Number of times using the toilet during the 
night” and “Number of times using the toilet during the day” on the 5-day 
Week Diary,  
and  
● 
The number of times a “Pee in toilet” or a “Pee in toilet and leakage” was 
entered into the 2-day Weekend Episodic Diary. 
For a weekend day: 
● 
The daytime micturitions will be derived from the number of times a “Pee in 
Toilet” or a “Pee in Toilet and Leakage” was entered into the 2-day Weekend 
Episodic Diary between the time the subject woke up (exclusive) and went to 
sleep (inclusive). 
● 
The nighttime micturitions will be derived from the number of times a “Pee in 
Toilet” or a “Pee in Toilet and Leakage” was entered into the 2-day Weekend 
Episodic Diary between the time the subject went to sleep (exclusive) and woke 
up (inclusive). 
The total number of micturitions per weekend day is equal to the total number of times, in the 
diary, an amount of pee was recorded during daytime and nighttime for that day. 
For each subject, the mean number of micturitions at Visit x (x=4, 5, 6, 7), using all available 
(non-missing) number of micturitions per 24 hours for the valid days in the diary (at least 4 
and maximally 7), will be calculated as: 
Sum of the number of micturitions (per 24 hours) over the valid diary days prior to Visit x
Number of valid diary days
 
Note: 
● 
If for a week day (Monday – Friday): 
o the number of daytime micturitions is missing but the number of nighttime 
micturitions is not missing then the number of micturitions for that day is considered 
to be the number of micturitions during the nighttime. 


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o the number of nighttime micturitions is missing but the number of daytime 
micturitions is not missing then the number of micturitions for that day is considered 
to be the number of micturitions during the daytime.  
o both daytime and nighttime micturitions are missing then the number of micturitions 
for that day is considered missing.  
● 
If for a weekend day (Saturday – Sunday): 
o No pee volume is recorded for Saturday or for Sunday then the number of 
micturitions is missing for Saturday or Sunday, respectively. 
o No pee volume is recorded for Saturday and for Sunday then the number of 
micturitions is missing for both days. 
If the wake-up time is the same as the time of micturition, then the micturition will be 
counted as a nighttime micturition.  
Note: the first micturition occurring at or after the time of wake-up is considered a nighttime 
micturition. 
A micturition episode is counted as micturition regardless of whether volume voided was 
recorded or not. 
A micturition will also be counted if the subject assessed an episode as both micturition and 
incontinence (leakage). 
If data of more than 7 days prior to a visit is available, only the last 7 days prior to the visit 
will be used for the analysis. 
The baseline will be defined by the micturitions results obtained from the diary 7 days prior 
to visit 3/week 0 (baseline).   
The visit 7/week 12/EoT visit will be defined as the subject’s value at week 12 or in case of 
missing week 12 data, the last available result post-baseline.   
Subjects without baseline or any post-baseline value will not be included in the change from 
baseline calculation although they will be included in the summary for either baseline or any 
post-baseline visit whichever timepoint the data is available. 
Change from baseline to visit 7/week 12/EoT is defined as:  
Result at visit 7/week 12/EoT  –  Result at baseline (visit 3/week 0). 
5.2 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints, as derived from the e-diary, are the change from 
baseline to the end of the 12-week treatment period in children (5 to <12 years of age) in: 
● 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 


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For all above secondary efficacy endpoints the value calculated from the e-diary period 
7 days before visit 3/week 0/baseline will be regarded as the baseline value. 
5.2.1 
Mean Volume Voided per 24 hours 
Mean volume voided is derived from “Pee Volume” of the 2-day Weekend Episodic Diary. 
For each subject, the mean volume voided per day will be calculated as the sum of the 
volumes voided on that (valid diary) day divided by the number of times a volume was 
recorded on that day in the 2-day Weekend Episodic Diary.   
The mean volume voided at Visit x (x=4, 5, 6, and 7) will be calculated as the mean value of 
the mean volumes voided on each of the two days  
If volumes are recorded on 1 single (valid) day of the 2-day Weekend Episodic Diary, then 
the mean volume will be the sum of all available volumes of that day divided by the number 
of times a volume was recorded. 
If no volumes are recorded on either (valid) measuring day, then the mean volume will be 
missing. 
5.2.2 
Maximum Volume Voided 
Maximum volume voided data will be derived from “Pee Volume” of the 2-day Weekend 
Episodic Diary. 
For each subject, the maximum volume voided at Visit x (x=4, 5, 6, and 7) is the largest 
(non-zero) volume recorded over both of the 2 (valid) measuring days in the diary.  If 
volumes are recorded on 1 single (valid) day of the weekend diary, then the maximum 
volume voided per day is calculated as the largest of all available (non-zero) voided volumes 
recorded on that day. 
If no volumes are recorded on either (valid) measuring day, then maximum volume voided 
will be missing. 
5.2.3 
Mean Number of Daytime Incontinence Episodes per 24 hours 
For a week day the number of Incontinence Episodes per 24 hours will be derived from 
“Number of Leakages During the Day” and “Number of Leakages During the Night” of the 
5-day Week Diary.  Incontinence episodes on measuring days will be classified as daytime or 
nighttime episodes as entered in the 5-day Week Diary. 
For a weekend day the number of incontinence episodes will be derived from the times a 
“Leakage” or a “Pee in Toilet and Leakage” was entered into the 2-day Weekend Episodic 
Diary.  Whether an Incontinence Episode was during daytime or nighttime will be based on 
the time-points the subject went to sleep and woke-up. 
For each subject, the mean number of incontinence episodes per day/night (during the 
day/night) at Visit x (x=4, 5, 6, and 7) will be calculated using all available (non-missing) 
number of incontinence episodes for the valid diary days in the 5-day Week Diary and in the 
2-day Weekend Episodic Diary for daytime in the 7-day period before the visit:  
Mean No. of Daytime Incontinence Episodes at Visit x = 


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              Total number of ”Daytime Leakage Counts"  over the Valid Diary Days prior to Visit x
Number of Valid Diary Days
 
 
5.2.4 
Mean Number of Daytime Micturitions per 24 hours 
For a week day the daytime micturitions will be derived from “Number of Times using the 
Toilet During the Day” was entered into the 5-day Week Diary. 
For a weekend day the daytime micturitions will be derived from the number of times a “Pee 
in Toilet” or a “Pee in Toilet and Leakage” was entered into the 2-day Weekend Episodic 
Diary between the time the subject woke-up (exclusive) and went to sleep (inclusive).  
However, the first micturition occurring at or after the time of wake-up it is considered a 
nighttime micturition, see Section 5.1. 
The total number of micturitions per weekend day is equal to the total number of times, in the 
diary, an amount of pee was recorded during daytime for that day. 
For each subject, the mean number of daytime micturitions at Visit x (x=4, 5, 6, and 7) in the 
week before the visit will be calculated as: 
Sum of the Number of Daytime Micturitions (per day) over the Valid Diary Days prior to Visit x
Number of Valid Diary Days
 
 
5.2.5 
Number of Dry (incontinence free) Days per 7 Days at the End of the 12-weeks 
Treatment Period 
For a week day a “Dry (incontinence free) Day” is defined as a day where the response is 
“Dry” to the question “How was your Day” and to “How was your Night”.  
Let Ddry be the number of valid diary days where the response to both questions was “Dry”. 
Let Dwet be the number of valid diary days where the response to one of the two questions or 
to both questions was “Wet”. 
For a weekend day a “Dry (incontinence free) Day” is defined as a day where no “Leakage” 
and no “Pee in toilet and leakage” are reported. A “Wet (incontinence) Day” is defined as a 
day where a “Leakage” or a “Pee in toilet and leakage” is reported. 
If (𝐷𝑑𝑟𝑦+ 𝐷𝑤𝑒𝑡) > 3, then the number of dry days per 7 days at Visit 7 will be calculated for 
a subject as: 
𝐷𝑑𝑟𝑦
(𝐷𝑑𝑟𝑦+𝐷𝑤𝑒𝑡) × 7,   otherwise its value is missing. 


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5.3 
Exploratory Endpoints 
The following exploratory endpoints, as derived from data collected in the e-diary, are:  
1. Percentage of subjects with a reduction in daytime incontinence episodes 
2. Improvement from baseline in worst incontinence grading 
3. Mean number of micturitions per 24 hours adjusted for fluid intake 
4. Mean volume voided peer micturition as a percentage of EBC 
5. Categorized mean volume voided per micturitions a percentage of EBC 
6. Mean number of micturitions per 24 hours (adolescents only) 
7. Mean number of daytime micturitions per 24 hours (adolescents only) 
8. Mean volume voided per 24 hours (adolescents only) 
9. Maximum volume voided (adolescents only) 
10. Mean number of incontinence episodes per 24 hours (adolescents only) 
11. Number of dry (incontinence-free) days per 7 days (adolescents only) 
12. Mean number of daytime grade 3 or 4 (PPIUS) urgency episodes per 24 hours 
(adolescents only) 
5.3.1 
Percentage of Subjects With a Reduction in Daytime Incontinence Episodes 
(< 50% reduction [non-responder], 50% [partial responder] and 100% 
[responder]) 
Number of daytime incontinence episodes per 24 hours will be derived from: 
● 
“Number of leakages during the day” entered into the 5-day Weekday Diary, 
and  
● 
number of times “Leakage” or “Pee in toilet and leakage” was entered into the 
2-day Weekend Episodic Diary between awake time and sleep time. 
For each subject, the percent change from baseline to a Visit x (x=4, 5, 6 and 7) in the 
number of daytime incontinence episodes will be calculated as follows: 
Rx = No. Daytime Incontinence Episodes at Visit x −No. Daytime Incontinence Episodes at Baseline
No. Daytime Incontinence Episodes at Baseline
 
× 100%, 
where the number of daytime incontinence episodes at Visit x is equal to the sum of the 
number of incontinence episodes recorded over the 7-day period prior to Visit x.  Same 
calculation for baseline.  
If the number of daytime incontinence episodes at baseline is equal to zero, a constant equal 
to 0.5 will be added to the baseline number of leakages to allow denominator calculation. 
If the number of daytime incontinence episodes at baseline and/or at a post-baseline visit is 
missing then the response category in respect to incontinence will be missing. 


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Definition of responder: 
● 
Complete responder will be defined as a subject with a 100% improvement 
from baseline (i.e. RX= -100%). 
● 
Partial responder will be defined as a subject with a percent improvement from 
baseline ≥50% and <100% (i.e. -100% < RX ≤ -50%). 
● 
Non-responder will be defined as a subject with an improvement from baseline 
<50% or a worsening from baseline (i.e. RX > -50%). 
5.3.2 
Improvement from Baseline in Worst Incontinence Grading 
Worst Incontinence Grading is derived from: 
● 
The response to “Worst Leakage during the Day” and “Worst Leakage during 
the Night” from the 5-day Week Diary, and is equal to the worst outcome from 
both daytime and nighttime responses during a diary day.  
● 
The responses to “Worst Leakage Severity” every time it is reported in the 
2-day Weekend Episodic Diary. The worst response to the questions given 
during a diary day will be used for analysis. 
Possible outcomes are: Dry; Slightly Wet; Moderately Wet; and Fully Wet. 
Dry will be derived from the question on the 5-day Week Diary: “How was your day/night”, 
and from the 2-day Episodic Weekend Diary if no leakages are reported during a diary day. 
For each subject and visit the worst incontinence grade will be determined as the worst 
grading over the valid diary days preceding the study visit. 
Improvement: 
For Visit x (x=3, 4, 5, 6 and 7) the average over the valid week and weekend diary days will 
be calculated from the score of what was the worst leakage during the day”, i.e., 0 - Dry, 
1 - Slightly Wet; 2 - Moderately Wet; and 3 - Fully Wet: 
Worst Incontinence Grade at Visit x = 
Sum of Worst Incontinence Gradings over the Valid Diary Days prior to Visit x
Number of Valid Diary Days
 
For each subject, improvement at Visit x if:  
   Worst Incontinence Grade (Visit x) - Worst Incontinence Grade (Visit 3 [Baseline]) < 0. 
5.3.3 
Mean Volume Voided as a Percentage of Expected Bladder Capacity 
To calibrate the mean volume voided with bladder size, the ratio of mean volume voided to 
the subject’s EBC (= [age+1] × 30 in mL for children and 400 mL for adolescents) will be 
calculated at baseline and post-baseline study visits and expressed as a percentage.  These 
ratios will be summarized together with the change from baseline by age group and overall. 
The following variables will be summarized, for each age group and overall, by treatment 
group at each visit using number and percentage of subjects in the following categories: 
● 
Ratio of mean volume voided to EBC (%): ≤50%, >50% to ≤75%, >75% to ≤100%, 
>100% 


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● 
Change from baseline in ratio of mean volume voided to EBC (%): <0%, 0% to <15%, 
15% to <30%, ≥30% 
5.3.4 
Mean Number of Micturitions per 24 hours, Adjusted for Fluid Intake 
For this endpoint the voided volumes will be taken as surrogate for the fluid intake. 
In Sender Herschorn et al., (2017) page 56 Materials and Methods, the following subdivision 
is presented of the number of micturitions at a visit, say visit x. 
Number of Micturitions at Visit x (x= 4, 5, 6, and 7) =  
Total Volume Voided (Visit x) / Mean Volume Voided (Visit x) = 
[Total Volume Voided (Baseline) + ΔTotal Volume Voided]/Mean Volume Voided (Visit x) = 
Total Volume Voided(Baseline) / Mean Volume Voided(Visit x) +   
ΔTotal Volume Voided / Mean Volume Voided(Visit x), 
where Δ is the difference in total volume voided between Visit x and Baseline 
[=Total Volume Voided (Visit x) – Total Volume Voided (Baseline)]. 
This can be viewed as a partition of Number of Micturitions at Visit x into 2 parts as follows:  
● 
Total Volume Voided (Baseline) / Mean Volume Voided (Visit x) is the number of 
micturitions per 24 hours that would be required at Visit x to void the total daily volume, 
if this total volume remains unchanged from baseline, that is, if treatment did not affect 
subjects’ fluid intake. 
● 
ΔTotal Volume Voided / Mean Volume Voided(Visit x) is the additional number of 
micturitions per 24 hours (vs baseline) required to void the extra fluid intake.   
For each subject, the Mean Change in Number of Micturitions per 24 hours at Visit x (x= 4, 
5, 6, and 7), adjusted for fluid intake will be calculated as:  
 Total Volume Voided at Visit x − Total Volume Voided at Baseline
Mean Volume Voided per Micturition at Visit x
 
 
Example:  
A subject voided the following volumes: 
• At baseline, 
Saturday: 200 ml, 200 ml, 200 ml, 200 ml and 200 ml, and  
Sunday:   200 ml, 200 ml, 200 ml and 200 ml 
• At visit x, 
Saturday: 250 ml, 250 ml, 250 ml and 250 ml, and   
Sunday:   250 ml, 250 ml and 250 ml  
This results in: 
Total Volumes Voided per 24 hours at baseline and at visit x are 900 ml and 875 ml, 
respectively.  Mean Volume Voided per 24 hours at visit x is 250 ml, 


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Total Volume Voided (baseline) / Mean Volume Voided (visit x) = 900 ml / 250 ml = 3.6, 
which means that 3.6 micturitions per 24 hours would be required at visit x to void the same 
total volume as voided at baseline (3.6 x 250 = 900 ml). This is the expected mean number of 
micturitions per 24 hours at visit x. 
Mean number of micturitions at baseline and at visit x are 4.5 and 3.5, respectively.  Mean 
difference in the number of micturitions per 24 hours adjusted for fluid intake compared to 
expected mean number of micturitions per 24 hours at visit x is (875-900)/250 = -0.1. 
5.3.5 
Mean Number of Micturitions per 24 hours (adolescents only) 
See Section 5.1. 
5.3.6 
Mean Volume Voided per 24 hours (adolescents only) 
See Section 5.2.1. 
5.3.7 
Maximum Volume Voided (adolescents only) 
See Section 5.2.2. 
5.3.8 
Mean Number of Incontinence Episodes per 24 hours (adolescents) 
See Section 5.2.3. 
5.3.9 
Mean Number of Daytime Micturitions per 24 hours (adolescents only) 
See Section 5.2.4. 
5.3.10 Number of Dry (incontinence-free) Days per 7 Days at the End of the 12-weeks 
Treatment Period (adolescents only) 
See Section 5.2.5. 
5.3.11 Mean Number of Daytime Grade 3 or 4 (PPIUS) Urgency Episodes per 
24 hours (adolescents only) 
Result is obtained from “PPIUS-Urgency of the Micturition” from 2-day Weekend Episodic 
Diary. 
Scoring PPIUS scale: 
● 
Grade 0: No urgency – I felt no need to empty my bladder, but did so for other 
reasons 
● 
Grade 1: Mild urgency – I could postpone voiding as long as necessary, without 
fear of wetting myself 
● 
Grade 2: Moderate urgency – I could postpone voiding for a short while, 
without fear of wetting myself 
● 
Grade 3: Severe urgency – I could not postpone voiding, but had to rush to the 
toilet in order not to wet myself 
● 
Grade 4: Urge incontinence – I leaked before reaching the toilet 
Let N34 equal the number of times that an adolescent subject recorded a grade 3 or 4 urgency 
on a diary day.  If there are no grade 3 or 4 urgency episodes on a valid diary day, then N34 
equals 0. 


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For each subject, the mean number of grade 3 or 4 urgency episodes per 24 hours, at Visit x 
(x=4, 5, 6, and 7), is the mean of N34 over the valid diary days of the 2-day Weekend 
Episodic Diary.  
5.4 
Safety Endpoints 
Safety will be assessed by evaluation of the following variables: 
● 
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, 
and relationship to study drug) 
● 
Clinical laboratory variables (hematology, biochemistry including liver 
enzymes and total bilirubin, and urinalysis) 
● 
Vital signs (systolic and diastolic blood pressure and pulse rate) 
● 
12-lead electrocardiogram (ECG) 
● 
Post Void Residual (PVR) Volume 
● 
Acceptability and palatability questionnaires 
5.4.1 
Adverse Events 
AEs will be coded using MedDRA.  A TEAE is defined as an AE observed after starting 
administration of the IP until 30 days after the final administration of IP.   
If the adverse event occurs on Day 1 and the onset check box on the (AE) eCRF is marked 
“Onset after first dose of study drug” or the onset check box is left blank, then the adverse 
event will be considered treatment emergent.  If the adverse event occurs on Day 1 and the 
onset check box is marked “Onset before first dose of study drug”, then the adverse event 
will not be considered treatment emergent.  If a subject experiences an event both during the 
pre-investigational period and during the investigational period, the event will be considered 
as TEAE only if it has worsened in severity (i.e., it is reported with a new start date). 
A drug-related TEAE is defined as any TEAE with at least a possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.  
An AE designated as serious by either the investigator or determined by Important Medical 
Event process will be summarized as an SAE. However, if the event is on IME list but 
medical monitor agrees with investigator that event is not SAE, then event can be 
downgraded. 
Common TEAEs are defined as preferred terms (PTs) that have been reported by at least 5% 
of the subjects in any of the treatment groups. 
When an AE start or stop date is missing, the date will be imputed using the rules in 
Section 6.10.2.2. 
Adverse Events of Special Interest  
Adverse Events of Special Interest include: 
● 
Abnormal cardiac electrophysiology (including QTc prolongation), cardiac 
arrhythmia, and other cardiovascular adverse events 


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● 
Increased blood pressure as assessed through vital signs monitoring 
● 
Hypersensitivity reactions 
● 
Urinary retention 
● 
Abnormal nervous system events: seizure, syncope, headache and dizziness 
AEs of interest will be identified using all Preferred Terms (PT) from Standardized MedDRA 
queries (SMQ), see Table 2, or sponsor-defined list of search terms, see Appendix 9.2.   
Note: Most recent MedDRA version in which the AEs are coded will be used.  
Table 2 
Standardized MedDRA Queries  
CV - Increased blood pressure 
Hypertension SMQ – Narrow search 
CV - QT prolongation  
Torsade de pointes/QT prolongation SMQ – 
Broad search 
CV - cardiac arrhythmia, cardiovascular adverse 
events  
Arrhythmia related investigations signs and 
symptoms SMQ – Broad search,  
Supraventricular tachyarrhythmias (SMQ) – 
Broad search,  
Tachyarrhythmia terms nonspecific (SMQ) – 
Narrow search,  
Ventricular tachyarrhythmias (SMQ) -narrow 
search plus ventricular tachycardia 
Hypersensitivity reactions  
Hypersensitivity SMQ – Narrow search 
Seizure 
Lower Level Term 10039906 
Syncope 
Syncope SMQ – Narrow search (also included 
as part of the CV - Increased heart rate, 
tachycardia, atrial fibrillation, and palpitations) 
PT 10042772 
Headache 
Headache PT 10019211 
Dizziness 
Dizziness PT 10013573 
 
5.4.2 
Vital Signs 
5.4.2.1 Clinical Measurement of Vital Signs 
Single blood pressure, pulse and body temperature measurements will be performed at 
visit 1/screening, visit 3/baseline, visit 5/week 4, visit 7/week 12 (EoT), and visit 8/week 14 
(EoS).  Clinic measurements of vital signs at visit 1/screening and visit 3/baseline will be 
used to assess eligibility. 
The preferred method of blood pressure 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 pulse and body temperature will be measured in the sitting position 
(when possible, otherwise supine, but always in the same position).   
For subjects enrolled under: 
• Protocol version 1 and 2, one single blood pressure measurement will be taken. 


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• Protocol version 3 or higher (if applicable), at least two blood pressure measurements will 
be taken separated by 5 minutes and the average of these measurements will be the 
documented blood pressure. 
5.4.2.2 Self-Measurement of Vital Signs 
Self-blood pressure monitoring (SBPM; SBP and DBP) will be measured at visit 2/week 2, 
visit 3/baseline, visit 4/week 2, visit 5/week 4, visit 6/week 8, and visit 7/week 12 (EoT) and 
whenever deemed necessary by the investigator. 
SBPM will be measured once in the morning and evening during the 2-day Weekend 
Episodic 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.  Morning measurement should be taken before IP intake and evening measurement 
should be taken prior to bedtime. 
5.4.2.3 Conversion of Blood Pressure to Percentiles 
Both the systolic and diastolic blood pressure site measurements will additionally be 
converted to percentiles specific to the age (years), sex and height (cm) of the subject using 
the following steps [NIH, 2005]: 
● The height of a subject is measured at screening and baseline.  Height at baseline will 
be used.  
● Let Z = the z-score (i.e. the number of standard deviations above or below the mean) 
of the height (cm) of the subject at the study visit relative to healthy subjects of the 
same age and gender using CDC growth charts [CDC, 2000]. The SAS code to 
calculate this is located on the Centers for Disease Control (CDC) and Prevention 
website: https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. 
● Let BP = the blood pressure (mmHg) that is being converted (either systolic or 
diastolic) and Y=the age of the child in years. 
● Taking the coefficients from the appropriate column in Table 3 below, compute ZBP, 
the Z-score for the blood pressure: 










−
−
−
−
=


=
=
4
1
4
1
)
10
(
j
k
k
k
j
j
BP
Z
Y
BP
Z
 
● If (.) is the area under the standard normal curve to the left of Z, calculate P, the 
gender, age and height specific percentile of the blood pressure as P=(ZBP)*100%. 
● The exact age at a visit will be calculated as: 
𝐴𝑔𝑒= (𝐷𝑉−𝐷𝐵+ 1)
365.25
 
where Dv is the visit date and DB is the subject’s date of birth.  When the exact age at a 
visit is missing and cannot be calculated because of a missing date of birth, but where the 


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age entered at screening is known only to be Y years (an integer), the percentile will be 
calculated for age=Y+0.5. 
Table 3 
Coefficients for Conversion of Blood Pressure to Percentiles 
 
 
 
Systolic BP 
Diastolic BP 
Variable 
 
Symbol 
Male 
Female 
Male 
Female 
Intercept 
 
Α 
102.19768 
102.01027 
61.01217 
60.50510 
Age 
(Age-10) 
β1 
1.82416 
1.94397 
0.68314 
1.01301 
 
(Age-10)2 
β2 
0.12776 
0.00598 
-0.09835 
0.01157 
 
(Age-10)3 
β3 
0.00249 
-0.00789 
0.01711 
0.00424 
 
(Age-10)4 
β4 
-0.00135 
-0.00059 
0.00045 
-0.00137 
Height 
Z 
1 
2.73157 
2.03526 
1.46993 
1.16641 
Z-Score 
Z2 
2 
-0.19618 
0.02534 
-0.07849 
0.12795 
 
Z3 
3 
-0.04659 
-0.01884 
-0.03144 
-0.03869 
 
Z4 
4 
0.00947 
0.00121 
0.00967 
-0.00079 
Standard Deviation 
 
10.7128 
10.4855 
11.6032 
10.9573 
 
5.4.2.4 Pulse Rate in Relation to Age 
Resting pulse rate will be compared to age-related norms [Fleming et al., 2011] according to 
the percentiles shown in Table 4. 
Table 4 
Percentiles for Resting Pulse Rate in Relation to Age and Gender 
Age 
Percentile 
1st 
10th 
25th 
50th 
75th 
90th 
99th 
4-6y 
65 
81 
89 
98 
108 
117 
131 
6-8y 
59 
74 
82 
91 
101 
111 
123 
8-12y 
52 
67 
75 
84 
93 
103 
115 
12-15y 
47 
62 
69 
78 
87 
96 
108 
15-18y 
43 
58 
65 
73 
83 
92 
104 
Source: web appendix to the Fleming et al article (web table 5) 
Each value of pulse rate will be categorized as either being above the age-specific 99th 
percentile or below the 1st percentile. 
5.4.2.5 Body Temperature 
Body Temperature will be compared to a reference range of 35.4 to 37.7 degrees Celsius 
[Kliegman et al, 2007]. 
5.4.3 
Clinical Laboratory Variables 
Hematology, biochemistry and urinalysis assessments will be taken at visit 1/week -4 
(screening), visit 5/week 4, and visit 7/week 12 (EoT).  Additional hematology, biochemistry 
and urinalysis 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. 


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All clinical laboratory assessments will be performed at a central laboratory or at a local 
laboratory if results can be made available to the investigative site (see protocol, 
Appendix 12.23, Table 11), except for urine pregnancy testing and urinalysis (urinalysis 
dipstick), which will be performed at a local laboratory.  Pregnancy test in females of child 
bearing potential will be performed in serum at screening, at baseline, visit 5/week 4, visit 
7/week 12 (EoT), and visit 8/week 14 (EoS). 
Additional hematology, biochemistry and urinalysis (UA 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.  If any of the clinical laboratory tests results are outside the 
normal range at any scheduled time point during the study, the investigator may decide to 
repeat the test(s) on new samples.  The clinical relevance of the abnormal results will be 
documented.  Clinically relevant changes will be recorded as AEs (see Section 7.3 of 
protocol: Adverse Events and Other Safety Aspects). 
The laboratory parameters that will be assessed during the conduct of the study are listed in 
Table 5. 
Table 5 
Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Platelets 
Red blood cell count 
White blood cell count 
White blood cell count differential 
Albumin  
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Corrected serum calcium 
Creatinine 
Creatinine kinase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Serum hCG for female subjects 
Sodium 
Total bilirubin (total and direct) 
Total protein 
Leukocyte esterase 
Nitrites 
pH 
Protein 
Red blood cells 
hCG: human chorionic gonadotropin 
The value of each hematology and biochemistry parameter will be compared to its normal 
range and classified as High, Low or Normal.  Urinalysis parameters will be similarly 
classified as either Normal or Abnormal. 


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When calculating changes or shifts in a result from baseline, the value from visit 1 will be 
used as baseline.  If the visit 1 value is missing, the latest pre-baseline value will be used (i.e., 
from Visit 1 or any unscheduled visit conducted between visit 1 and 3). 
5.4.4 
Physical Examination 
Physical examinations will be performed at visit 1/week -4 (screening), visit 5/week 4, and 
visit 7/week 12 (EoT) and will include assessments of the main body systems. 
The physical examination will be performed per clinic standards and clinically significant 
findings at screening will be recorded as part of the subject’s medical history.  Clinically 
significant findings discovered after visit 1/screening will be recorded as an AE. 
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 of protocol: Adverse Events 
and Other Safety Aspects. 
5.4.5 
12 Lead ECGs 
A 12-lead ECG will be performed as single measurement at visit 1/screening, visit 3/baseline, 
visit 5/week 4, and visit 7/week 12 (EoT).  ECG traces will be evaluated by the investigator 
who will give an overall interpretation and may leave a qualifying comment in the eCRF.  
The overall interpretation will be recorded as:  
● 
Normal, or 
● 
Abnormal - not clinically significant, or 
● 
Abnormal - clinically significant 
 
As well as the overall interpretation, the following ECG variables will be supplied by the 
central laboratory: PR Interval (msec), RR Interval (msec), QRS Duration (msec), QTcF 
interval (msec) and Heart Rate (HR) (beats/min). 
5.4.6 
Post Void Residual Volume 
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 within a minute of voiding.   
A PVR of ≤ 20 mL (protocol version 1 and 2) is sufficient and the assessment does not have 
to be repeated.  If the PVR is > 20 mL (Protocol version 1 and 2), the PVR assessment should 
be repeated (filled with preferably > 50% of the bladder capacity for age).  If the subject is 
unable to complete a second measurement, it is up to the investigator to judge whether it can 
be skipped.  At visit 3/week 0 (baseline), the lowest PVR result measured should be used to 
evaluate the exclusion criterion.  In case the lowest PVR measured is > 20 mL (Protocol 
version 1 and 2) at visit 3/week 0 (baseline), the subject should be excluded from the study. 


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For subjects enrolled under protocol version 3.0 or higher (if applicable) the PVR volume 
should be 30 mL instead of 20 mL. 
5.4.7 
Acceptability and Palatability Questionnaires 
The acceptability and palatability questionnaire will be completed at the end of treatment 
period.  For each IP formulation, a separate questionnaire is available, see [Protocol 
Appendix 12.8 (Acceptability and Palatability Questionnaire for Tablets) and Appendix 12.9 
(Acceptability and Palatability Questionnaire for Oral Suspension)]. 
5.4.7.1 Acceptability for Tablets  
Subjects will evaluate the taste of the study medication ticking one of the following 
categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) and “Really 
Good” (4). 
Subjects will evaluate the swallow of the study medication ticking one of the following 
categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) 
and “Really Easy” (4). 
Taste and swallow acceptability will be summarized as categorical variables. 
5.4.7.2 Acceptability for Oral Suspension 
Subjects will evaluate the taste of the study medication ticking one of the following 
categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) and “Really 
Good” (4). 
Subjects will evaluate the smell of the study medication ticking one of the following 
categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) and “Really 
Good” (4). 
Subjects will evaluate the consumption of the study medication ticking one of the following 
categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) 
and “Really Easy” (4). 
Subjects will evaluate the preparation of the study medication ticking one of the following 
categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) 
and “Really Easy” (4). 
Taste, smell, consumption and preparation acceptability will be summarized as categorical 
variables. 
5.5 
Other Endpoints 
5.5.1 
Exposure to Study Drug 
The duration of exposure to each dose of study drug (PED25 and PED50) by visit and for the 
whole period will be calculated using the following information that is recorded in the eCRF: 
● 
Overall start date and stop date of the study medication. 


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The first dose of study drug is to be administered on Day 1, the day after the baseline visit 
(visit 3). The initial dose will be PED25 for all subjects. The last dose of treatment is to be 
taken in the morning of visit 7/week 12/EoT. 
● 
Start date and new dose of study drug at each titration step. 
At visit 5/week 4 the dose may be up-titrated, or may remain the same. 
Dose down-titration from PED50 to PED25 can be done at any time thereafter for safety 
reasons. 
● 
Start date and new dose of study drug after each unscheduled dose change. 
● 
At any time during the treatment period, the subject may have an unscheduled 
dose interruption or reduction. At each unscheduled change in dose, the (new) 
dose, start date and reason are recorded.  
In addition, the return date of study medication is assumed to be the date of clinical visit. 
In all cases where there is a dose change, either because of dose titration or an unscheduled 
dose interruption, reduction or increase, the last dose of the medication at the old level will be 
assumed to be the day before the given date of first dose at the new level.  In this way, the 
subject’s dosing history can be reduced to a series of unbroken intervals within each of 
which, the dose level is constant.  From these, the subject’s exposure at each dose can be 
calculated. 
To illustrate, consider a subject with the following dose information on the eCRF: 
● 
The dates of the very first and very last dose of the study medication given at 
D1=1st July 2019, Dlast=24th September 2019. 
● 
Up-titration to PED50 at Visit 5. The first dose at the new level is given at 
D2=29th July 2019. 
● 
Study drug interrupted at an unscheduled visit. The date of last dose at the 
PED50 level is given at D3=1st August 2019. 
● 
Study drug re-started at PED25 at an unscheduled visit. The first dose at the 
new level is given at D4=5th August 2019. 
● 
Remains at PED25 till Visit 6 (D5=25th August 2019). Up-titration to PED50 
at Visit 6. First dose at the new level is given at D6=26thAugust 2019. 
From these dates we calculate the following: 
● 
The duration of exposure to the treatment can be calculated as 
ETOT=Dlast-D1+1-(D4-D3-1) =83 days. 
● 
Between Visits 3 and 5, the subject is on PED25. The last dose at PED25 is 
given on D2-1, the day before the subject has the first dose at the new level 
PED50. The exposure at PED25 between Visits 3 and 5 is, therefore, (D2-1)-
D1+1=28 days 
● 
Between Visits 5 and 6, the study drug is temporarily suspended and then 
restarted. The subject will be considered to be exposed to the PED50 dose from 


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D2 until D3, i.e.  
D3-D2+1=4 days.  
● 
For the calculation of the exposure, suspension of the study drug is not ignored. 
The dose will be considered interrupted between D3+1 to D4-1, i.e. (D4-1) - 
(D3+1) + 1 = 3 days. 
● 
The study drug is at PED25 from D4 to D6-1, the date of the last dose prior to 
Visit 6, i.e. (D6-1)-D4+1=21 days. 
● 
Subject is on PED50 from D6 to Dlast, a total of Dlast-D6+1=30 days. 
● 
The total exposure at PED50 is EPED50=34 days, at PED25 is EPED25=49 
days 
● 
The total exposure between Visits 3 and 5 is E1=28 days, between Visits 5 and 
6 is E2=25 days, and between Visits 6 and 7 is E3 = 30 days. 
5.5.2 
Compliance to Study Drug 
Tablet compliance 
Compliance will be calculated according to the number of tablets of study medication 
dispensed, the number of wallets used and the duration of exposure between the applicable 
visits and overall. 
Each wallet of study medication contains 35 tablets of 25 mg at visit 3/week 0, and 35 tablets 
of 50 mg and 7 tablets of 25 mg at visit 5/week 4.  Subjects will receive an adequate number 
of wallets of both PED25 and PED50 as follows: 
● 
At visit 3, 1 wallet containing 35 tablets of 25 mg will be dispensed 
● 
At visit 5, wallets containing 35 tablets of 25 mg, or wallets containing 35 tablets of 
50 mg and 7 tablets of 25 mg will be dispensed  
The total number of tablets used between Visits i and j (i<j) is calculated as: 
Nused = Total number of tablets dispensed at Visit i - Total number of tablets returned at Visit j 
When a kit is not returned it will be assumed that all the medication from this kit was not 
used. 
When a kit is returned late, it will be assumed that the medication was used during the study 
period that it was dispensed for, e.g. all the medication used from a kit dispensed at Visit 3 
and returned at Visit 5 will be assumed to have been used between Visits 3 and 5. 
The amount of expected study drug intake depends on the number of days of study drug 
treatment and the number of prescribed daily tablets.  Since subjects are supposed to take 
1 tablet per day, the total number of expected tablets to be used between Visits i and j is 
calculated as follows: 
Nprescribed = (Number of Exposure Days between Visit_i and Visit_j) x 1 tablet, 
where Number of Exposure Days is calculated as: (Return date – Dispense date) + 1. 
Between Visits i and j the compliance to study medication will be calculated as follows: 


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Compliance = (Nused / Nprescribed) x 100%. 
To illustrate, at Visit 3 a subject was dispensed 1 wallet with 35 tables of 25 mg.  The date of 
first dose was 1st July 2019.  When the subject returned at Visit 5 (28th July 2019), the wallet 
contained 10 tablets. 
Nused = (35-10) = 25 tablets 
Number of exposure days = (28Jul2019 – 01Jul2019) + 1day = 28 days,  
Hence, Nprescribed = 28 tablets 
Compliance between Visits 3 and 5 = (25/28) x 100% = 89.3%. 
For the whole study period, the total amount of study drug used (TOTNused) is equal to the 
sum of the values of Nused at each applicable visit.  Similarly, the total amount of study drug 
prescribed (TOTNprescribed) is equal to the sum of the values of Nprescribed at each applicable 
visit.  Using these total values, the subject’s compliance over the whole study period can be 
calculated as 100% x (TOTNused / TOTNprescribed). 
Suspension Compliance 
Compliance for suspension will be calculated according to: 
● 
Number of bottles dispensed at each visit (Table 6);  
● 
Weight of the bottles returned to the site; and  
● 
Duration of exposure between the applicable visits and overall. 
Table 6 
Number of Bottles to be Dispensed at each Visit 
 
Body Weight Range (kg) 
Visit 3/Week 0 
Visit 5/Week 4 
PED25 
13 to < 22 
1 
2‡ 
22 to < 35 
2 
3‡ 
≥ 35 
2 
4‡ 
PED50 
13 to < 22 
- 
4 
22 to < 35 
- 
5 
≥ 35 
- 
7 
PED25: pediatric equivalent dose 25 mg; PED50: pediatric equivalent dose 50 mg 
Each kit of study medication contains a bottle with mirabegron granules.  After filling the 
bottle containing the granules with 100 mL drinking water, the weight of the bottle with 
content will have a standard weight.  
The total weight of the suspension/water and seal safes will not be weighed prior to 
dispensation but will be provided to the site and the IRT system will auto populate the weight 
of the IP prior to dispensation. 
Each used bottle will be weighed upon return from the subject.  Bottles that have been 
reconstituted and used will be weighed and the weight entered into the IRT drug 
accountability system.  For returned bottles that are unused the initial starting weight will be 
utilized as a standard across all sites. 


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Doses are calculated weight-based, see Table 7. The body weight at Visit 3/baseline 
determines the weight range for the starting dose (PED25) and the up-titration dose (PED50) 
to be used. 
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. 
At each dispensing visit, subjects will receive an adequate number of kits of both PED25 and 
PED50 following the same procedure as descripted above for tablets. 
The total dose of suspension used between Visits i and Visit j (i<j) is calculated as: 
Wused = Total weight of bottles dispensed at Visit i - Total weight of bottles returned at Visit j, 
and taking into account the suspension strength of 8 mg/mL. 
where:  
● Total weight dispensed = Number of kits dispensed at the Visit i x bottle standard 
weight; and  
● Total weight returned = Sum of the unused amount of study medication in each kit 
returned at Visit j. 
When a kit is not returned it will be assumed that all the medication from this kit was not 
used. 
When a kit is returned late, it will be assumed that the medication was used during the study 
period that it was dispensed for, e.g. all the medication used from a kit dispensed at Visit 3 
and returned at Visit 5 will be assumed to have been used between Visits 3 and 5. 
The amount of expected study drug intake depends on the number of days of study drug 
treatment and the number of prescribed daily suspension pouches.  Since subjects are 
supposed to administer 1 dose per day, the total amount of expected suspension to be used 
between Visit i and Visit j is calculated as follows: 
Wprescribed = Duration in days between Visit i and Visit j times the subject’s specific dose, see 
Table 7. 
The weight of the subject’s specific dose is determined by using a conversion factor of 1 mL 
corresponds to 1.0216 g. 


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The compliance to study medication between Visits i and j will be calculated as follows: 
Compliance = (Wused / Wprescribed) x 100%. 
To illustrate, a subject, who weighted 25 kg and with dose level PED25, was dispensed with 
5 kits at Visit 3.  The date of first dose was 1st July 2019.  When the subject returned at 
Visit 4 (31th July 2019), 3 kits were not used and the weight of the 2 used kits was: 32 and 
124 g. As an example, the bottle standard weight will be 137 g. 
Compliance calculation: 
1. Total amount of reconstituted study drug administered was resolved in (137-32) +  
(137-124) = 118 g of suspension, which is equal to 118/1.0216 mL = 115.5 mL. 
2. Given that the solution strength is 8 mg/mL this means that in total 115.5 mL x 8 mg/mL 
= 924 mg of study drug was administered to the subject. 
3. Duration was 31 days (= 31 July – 1 July +1), hence expected amount of study drug to be 
administered is 31 x 4 mL  = 124 mL (based on the weight of the subject the suspension 
volume is 4 mL, see Table 7).  This results in 124 mL x 8 mg/mL = 992 mg of study 
drug. 
4. Compliance between Visits 3 and 4 = (924/992) x 100% = 93.15%. 
For the whole study period, the total amount of study drug used (TOTWused) is equal to the 
sum of the values of Wused at each applicable visit.  Similarly, the total amount of study drug 
prescribed (TOTWprescribed) is equal to the sum of the values of Wprescribed at each applicable 
visit.  Using these total values, the subject’s compliance over the whole study period can be 
calculated as (TOTWused/TOTWprescribed) x 100%. 
 
 


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6 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
Efficacy data will be summarized for each age group (children [5 to <12 years of age] and 
adolescents [12 to <18 years of age]) by treatment group and visit, and safety data will be 
summarized for each age group and overall, by treatment group and visit, unless otherwise 
specified. 
In general, continuous data will be summarized descriptively including the number of 
subjects (n), mean, standard deviation (SD), median, minimum and maximum.  Categorical 
data will be summarized by frequencies and percentages.  Percentages by categories will be 
based on the number of subjects with no missing data, i.e. the percentages for the 
non-missing categories will add up to 100%. 
All statistical comparisons will be conducted using 2-sided tests at the 10% significance level 
unless stated otherwise.  All null hypotheses will be of no treatment difference, all alternative 
hypotheses will be two-sided, unless specifically stated otherwise. 
All data summarization and analyses will be performed using SAS® Version 9.4 or higher on 
Red Hat Enterprise Linux.  Specifications for table, figure, and data listing formats can be 
found in the TLF specifications. 
6.2 
Study Population 
6.2.1 
Disposition of Subjects 
The following subject data will be presented, for each of the two age categories, separately, 
and overall: 
● 
Number of subjects with informed consent, discontinued before randomization, 
randomized (overall only) (All Screened Set) 
● 
Number and percentage of subjects randomized in each analysis set, by 
treatment group and overall (All Randomized Set) 
● 
Number and percentage of subjects completed and discontinued screening, by 
primary reason for treatment discontinuation (including COVID-19 reasons) for 
randomized subjects (overall only) (All Screened Set) 
● 
Number and percentage of subjects completed and discontinued treatment, by 
primary reason for treatment discontinuation (including COVID-19 reasons) for 
randomized subjects, by treatment group and overall (All Randomized Set) 
● 
Number and percentage of subjects completed and discontinued the follow-up 
period, by primary reason for post-study period discontinuation (including 
COVID-19 reasons) for randomized subjects and by treatment group and 
overall (All Randomized Set)  
● 
Number and percentage of subjects excluded from PPS by reason for exclusion 
defined in Section 4.5.1, by treatment group and overall (FAS) 
● 
Number and percentages of subjects per protocol version (All Screened Set). 


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A listing of inclusion and exclusion criteria, listing of first and last evaluations as well as a 
listing of subjects who were excluded from at least 1 analysis set will be provided for the All 
Randomized Set. 
6.2.2 
Protocol Deviations  
The number and percentage of subjects with the following protocol deviation criteria will be 
summarized for each criterion and overall, for each age group and overall, by treatment group 
and total as well as by investigative site. Subjects deviating from a criterion more than once 
will be counted once for the corresponding criterion. 
The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria 
PD2 - Developed withdrawal criteria during the study and was not withdrawn 
PD3 - Received wrong treatment or incorrect dose 
PD4 - Received excluded concomitant treatment 
PD5 - Clinical study procedure conducted prior to signing the initial consent form 
PD6 - Events not reported within the expected turnaround time per regulatory reporting 
requirements 
PD7 - Missed safety or efficacy assessments related to primary or key secondary 
endpoints 
6.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by descriptive statistics. 
Summaries will be presented, for each age group and overall, by treatment group.  
Descriptive statistics for age, height (at baseline), weight (at baseline), BMI (at baseline, 
calculated as: weight (kg)/(height(cm)/100)2), and EBC (=[age+1] × 30 in mL for children 
and 400 mL for adolescents) will be presented as well as frequency tabulations for sex, 
ethnicity, and race.   
Note: for calculation of EBC the age of the subject in years [no decimals] will be used. 
Summaries for height and weight with respect to age- and sex-specific percentiles  will be 
provided.  This will be done using SAS code and dataset stored on the Centers for Disease 
Control (CDC) and Prevention website: 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. 
These summaries will be produced for the SAF, FAS and PPS.  
Number and percentage of subjects randomized to treatment in each region, country and site 
will be presented, for each age group and overall, by treatment group for the SAF. 
Geographical regions are defined as follows: 
● 
Europe: Belgium, Denmark, France, Germany, Italy, the Netherlands, Norway, 
Poland, Russian Federation, Serbia, Spain, Turkey, Ukraine, United Kingdom  
● 
Asia and Pacific (APAC): Korea (Republic of), Malaysia, Philippines 


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● 
North America: United States, Canada and Mexico 
● 
Southern Hemisphere: South Africa 
The final list of participating/enrolling countries might be updated after end of recruitment 
when the list becomes final.  If sites in additional countries will be opened due to changes in 
recruitment strategy, these countries will be allocated respectively and reported in the CSR. 
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) as well as by PT alone, for each age group and overall by 
treatment group for the SAF.  
Demographic data and other baseline characteristics will be provided in listing format by 
country, site and subject for the All Screened Set. 
6.2.4 
Previous and Concomitant Medications 
Previous and concomitant medications are coded with WHO-DD, and will be summarized by 
therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred 
WHO name, for each age group and overall, by treatment group for the SAF.  
Subjects taking the same medication multiple times will be counted once per medication and 
investigational period.  A medication which can be classified into several chemical and/or 
therapeutic subgroups is presented in all chemical and therapeutic subgroups. 
Previous medications are defined as medications that patients started and ended prior to first 
administration of study medication.  Concomitant medications are defined as any medications 
that subjects took after the first dose of study medication and through Follow-up period 
(EoS).  Medications that started prior to first administration of study drug and continued 
while study drug was given will be counted in both previous and concomitant medications. 
Previous and concomitant medication data as well as non-medication therapy data will be 
provided in listing format by country, site and subject for the All Screened Set. 
6.3 
Study Drug Exposure and Compliance  
6.3.1 
Exposure 
The following information on drug exposure will be presented, for each age group and 
overall category, by treatment group for the SAF: 
● 
Descriptive statistics for cumulative amount of the drug to which the subject was 
exposed; and 
● 
Number and percent of subjects with dose increases, decreases or interruptions. 
Duration of exposure will be summarized in two ways. 
● 
Descriptive statistics will be presented by age category and treatment group. 
● 
Exposure time will be categorized according to the following categories by age 
category and treatment group: 
○ less than 14 days 
○ at least 14 days, less than 28 days  
○ at least 28 days, less than 56 days  


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○ 56 days or more 
○ Unknown. 
Counts and percentages of subjects in each of these categories will be summarized, for each 
age group and overall, by treatment group for the SAF. 
Exposure details will be provided in listing format by country, site and subject for the All 
Randomized Set.  
6.3.2 
Treatment Compliance 
Overall compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known. 
Percent overall compliance will be summarized in two ways for the SAF: 
● 
Descriptive statistics will be presented, for each age group and overall, by treatment 
group. 
● 
Percent compliance will be categorized according to the following categories, for 
each age group and overall, by treatment group: 
○ less than 70% 
○ at least 70%, less than 80% 
○ at least 80%, less than 120% 
○ at least 120%, less than 130% 
○ greater or equal than 130% 
○ Unknown. 
Treatment compliance details, including all data relevant to the calculation, will be listed by 
country, site and subject for the All Randomized Set. 
6.4 
Analysis of Efficacy  
Efficacy analysis of the data from children (5 to <12 years of age) will be conducted on the 
FAS and PPS, and interpretation of results from statistical tests 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 (12 to <18 years of age) will only be exploratory, and will be 
conducted on the FAS. 
No multiplicity adjustment will be necessary in this study. 
Efficacy data will be summarized for each age group by treatment and visit (week 2, 4, 8 and 
12/EoT) unless otherwise specified.  Efficacy data will be provided in listing format by 
country, site and subject for the All Randomized Set.  
6.4.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline to week 12/EoT in mean micturitions 
per 24 hours in children (5 to <12 years of age). 


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6.4.1.1 Primary Analysis for Primary Efficacy Endpoint 
The primary estimator for the primary estimand as defined in Section [2.1.1 Estimand] will 
be calculated according to the evaluation of the primary efficacy endpoint.  The primary 
efficacy endpoint will be analyzed using 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 with imputation of missing visit 7/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 visit 7/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 visit 7/week 12 in mean number of 
micturitions per 24 hours for mirabegron and placebo are not the same. 
Statistical testing will be done 2-sided at a 10% 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. 
The ANCOVA model results will be presented with least squares (LS) means and two-sided 
90% confidence intervals (CIs) for mean changes from baseline within each treatment group.  
Differences in LS means between mirabegron versus placebo will be derived and presented 
together with two-sided 90% CIs.  T-statistics corresponding to the Type III sums of squares 
for the differences in the LS means will be used to obtain p-values for the comparisons. 
Model fitting will be visually assessed.  A scatter plot of residuals versus predicted values, 
along with histogram and normal probability plots will be produced. 
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. 
6.4.1.2 Graphical Summary of Data from Primary Efficacy Endpoint 
Mean number of micturitions per 24 hours at each visit and change from baseline in mean 
number of micturitions per 24 hours (without LOCF) will be plotted for FAS: mean (90% CI) 
values will be presented for each treatment group and visit. 
6.4.1.3 Sensitivity Analysis for Primary Efficacy Endpoint 
The following sensitivity analyses of the primary efficacy endpoint will be produced.  
6.4.1.3.1 
Analysis with LOCF for PPS 
The same analysis as described in Section 6.4.1.1 will be repeated for PPS (with imputation 
of missing data, LOCF).  


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6.4.1.3.2 
Analysis without LOCF 
The same analysis as described in Section 6.4.1.1 will be repeated for both FAS and PPS, 
both without imputing for missing data.  
6.4.1.3.3 
Analysis using Repeated Measures ANCOVA 
The primary endpoint will also be analyzed using a repeated measurements analysis of 
covariance (ANCOVA) model with treatment group, visit (week 2, 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.  
An appropriate covariance structure will be selected for the within subject repeated 
measurements.  An unstructured correlation pattern will be used to estimate the variance-
covariance of the within-subject repeated measures at first instance.  Parameters will be 
estimated using Restricted Maximum Likelihood with the Newton-Raphson algorithm and 
using the Kenward-Roger method for calculating the denominator degrees of freedom.  If 
there is a convergence problem due to the unstructured covariance matrix, the unstructured 
covariance matrix will be replaced by the compound symmetry covariance matrix.  
Mirabegron will be compared to placebo using a linear contrast within the repeated 
measurements ANCOVA model, with 2-sided significance level of alpha = 0.1 and 90% CI.   
This analysis will be conducted on the FAS and will serve as a sensitivity analysis to the 
LOCF method used in the primary model to assess the robustness of the findings.   
Model fitting will be visually assessed.  A scatter plot of residuals versus predicted values, 
along with histogram and normal probability plots will be produced. 
6.4.1.3.4 
Nonparametric Analysis 
A nonparametric ANCOVA on rank-transformed data (changes from baseline) will be 
performed (stratified rank ANCOVA) (with LOCF).  Statistical hypothesis testing (p-values) 
will be performed: the p-value of the treatment difference will be assessed using a rank 
ANCOVA stratified by region. 
Ranks within each geographical region will be derived across the two treatment groups for 
the baseline value and the change from baseline value.  
Then separate linear regression models for each geographical region will be performed with 
response variable ranked change from baseline value and dependent variables sex and ranked 
baseline value. 
Finally, the stratified mean value test, using the values of the residuals from the regression 
analysis as scores and geographical region and sex as stratum, compares the two treatment 
groups using the Cochran-Mantel-Haenszel (CMH) statistics. 
Appendix 9.1 present an example of the SAS® code to perform this analysis. 


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In addition, a (nonparametric) estimate for the difference between placebo and mirabegron, 
with associated (asymptotic) 90% CI, according to Hodges-Lehmann and Moses, will be 
presented. 
These analyses will be conducted on the FAS.  
6.4.1.3.5 
Sensitivity Analysis for the Primary Estimand 
Two analyses of the primary endpoint will be performed where missing data will be imputed 
using multiple imputation obtained from the procedure MI from SAS®. 
The imputation process will be broken up into a sequence of multiple imputation steps using 
PROC MI.  Two different sensitivity analyses will be performed by following either steps 1, 
2a, 3, and 4 (missing not at random), or steps 1, 2b, 3, and 4 (missing at random): 
Step 1: Subjects who have missing values for intermediate visits, the missing data will be 
imputed using the Monte Carlo Markov Chain (MCMC) methodology, as available 
in PROC MI and option MCMC.  The results of this procedure will be stored in a 
dataset.  This dataset now contains a so-called monotone missing data pattern (i.e., 
for a subject with missing data, all values are missing after a certain time-point). 
It is assumed here that subjects with missing data follow the same model as other 
subjects in their respective treatment arm that have complete data.  It can be said 
that this is a reasonable assumption for this partial imputation process because 
subjects tend to miss intermediate visits due to scheduling conflicts or other reasons 
unrelated to their medical condition under study. 
Step 2a: sequentially for one time-point data will be imputed for missing values: first for 
week 2 -> week 4 -> week 8 and finally for week 12. 
Missing data will be multiple imputed under a missing not at random assumption: 
borrow information from placebo arm subjects.  When imputing missing values for 
week t (t = 2, 4, 8, 12), the input dataset will include data from all placebo subjects 
and only data from those subjects from the mirabegron arm that have missing values 
at week t (Go to step 3.). 
Step 2b: sequentially for one time-point data will be imputed for missing values: first for 
week 2 -> week 4 -> week 8 and finally for week 12. 
Missing data will be multiple imputed under a missing at random assumption: 
borrow information from patients in the same treatment arm.  When imputing 
missing values for week t (t = 2, 4, 8, 12), the input dataset will include data from all 
subjects and only data from those subjects from the placebo and mirabegron arm 
that have missing values at week t. 
Step 3: Perform ANCOVA on each of the imputed datasets at week 12. 
Step 4: Results from ANCOVA analysis on the imputed datasets will be combined to derive 
an overall result by using PROC MIANALYZE. 
These analyses will be conducted for the FAS. 


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6.4.1.4 Summary by Subject and Caregiver 
In this study the eDiary contains an entry to capture whether the caregiver or the subject 
entered the data.   
To investigate whether there is a difference in scoring the micturitions by the caregiver or the 
subject the mean number of micturitions per 24 hours will be calculated for each of them 
separately.  This will be done as follows: for each (valid diary) day, the number of 
micturitions entered in the eDiary will be calculated for the subject and the caregiver, 
separately.  Next, for each visit, the mean number of micturitions will be calculated for the 
caregiver and subject (see Section 5.1). 
Presented will be the results for each age group and overall by treatment, visit and 
caregiver/subject.   
Note 1: a diary for a caregiver is valid for an analysis visit when at least 2 valid diary days 
are available. Same for subject. 
Note 2: in the event that 2 or more caregivers enter data in the eDiary of a subject these data 
will be reported as coming from 1 caregiver. 
6.4.1.5 Subgroup Analysis for Primary Efficacy Endpoint 
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, using LOCF. 
The following interactions will be investigated, separately:  
● 
treatment group by sex;  
● 
treatment group by geographical region;  
● 
treatment group by formulation;   
● 
treatment group by prior OAB treatment; and 
● 
treatment group by symptomatic UTI (yes/no) 
Note: symptomatic UTI is yes when it is reported as an AE during the trial, 
irrespective when it occurs.  
To investigate the first two interactions, separately, data of the primary efficacy endpoint will 
be analyzed using an ANCOVA model with treatment group, sex and geographical region as 
fixed effects, the mean number of micturitions per 24 hours at baseline as covariate and 
including the, above mentioned, interaction term that is investigated. 
To investigate the last three interactions, separately, data of the primary efficacy endpoint 
will be analyzed using an ANCOVA model with treatment group, sex, geographical region 
and either formulation, prior OAB treatment, or symptomatic UTI (yes/no) as fixed effects, 
the mean number of micturitions per 24 hours at baseline as covariate and including the, 
above mentioned, interaction term that is investigated. 


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6.4.2 
Analysis of Secondary Efficacy Endpoints 
Descriptive statistics (n, mean, SD, minimum, median, maximum) and the same primary 
efficacy 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 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 ratio of dry days and number of diary days at 
baseline) as covariate. 
Data of these secondary efficacy endpoints will be analyzed both without imputation and 
with imputation using the LOCF method, for the FAS. 
The same analysis detailed in Section 6.4.1.3 will be performed for all the secondary efficacy 
endpoints on the FAS as sensitivity analysis. 
6.4.3 
Analysis of Exploratory Endpoints 
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 [non-responder], 50% [partial responder] and 100% [responder]) 
● 
Improvement from baseline in worst incontinence grading.  Average over 7 days will be 
calculated of the score of “What was your worst leakage during the day”: 1 - Slightly 
Wet; 2 - Moderately Wet; and 3 - Fully Wet 
● 
Mean number of micturitions per 24 hours, adjusted for fluid intake: 
o 
Number of micturitions per 24 hours that would be required at week 12/EoT to void 
the same total volume as voided at baseline 
o 
Difference in mean number of micturitions per 24 hours adjusted for fluid intake 
compared to the expected mean number 
● 
Mean volume voided per micturition as a percentage of expected bladder capacity 
● 
Categorized mean volume voided per micturition as a percentage of expected bladder 
capacity (results and changes from baseline). 
Efficacy endpoints for adolescents will be analyzed descriptively. 
● 
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 


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○ Maximum volume voided 
○ 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 on Patient Perception of Intensity of Urgency Scale 
(PPIUS) urgency episodes per 24 hours (adolescents only) will be summarized by 
treatment group and visit. 
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 
visit 7/week 12. 
6.5 
Analysis of Safety 
Safety analysis will be conducted on the SAF and conducted separately for children, 
adolescents and overall.  Safety endpoints will be summarized, for each age group and 
overall, by treatment group and visit, if applicable.  Presented will be descriptive statistics. 
6.5.1 
Adverse Events 
Summaries and listings of SAEs and Serious TEAEs include SAEs upgraded by the sponsor 
based on review of the Sponsor’s list of Always Serious terms or upgraded according to the 
Important Medical Event process, if any upgrade was done. 
The coding dictionary for this study will be MedDRA.  It will be used to summarize AEs by 
SOC and PT. 
An overview table will include the following details:  
● Number of TEAEs 
● Number and percentage of subjects with TEAEs 
● Number of drug related TEAEs 
● Number and percentage of subjects with drug related TEAEs 
● Number of serious TEAEs 
● Number and percentage of subjects with serious TEAEs 
● Number of serious drug related TEAEs 
● Number and percentage of subjects with serious drug related TEAEs 
● Number of TEAEs leading to permanent discontinuation of study drug 
● Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug 
● Number of drug-related TEAEs leading to permanent discontinuation of study drug 
● Number and percentage of subjects with drug-related TEAEs leading to permanent 
discontinuation of study drug 
● Number of TEAEs leading to death 
● Number and percentage of subjects with TEAEs leading to death 
● Number of drug-related TEAEs leading the death 


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● Number and percentage of subjects with TEAEs leading to death 
● Number and percentage of subjects who died. 
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by age group and overall for each treatment group.  Summaries will be provided 
for: 
● TEAEs 
● Drug related TEAEs  
● Serious TEAEs  
● Drug related serious TEAEs  
● TEAEs leading to permanent discontinuation of study drug  
● Drug related TEAEs leading to permanent discontinuation of study drug  
● Common (>=5% in Any Treatment Group) TEAEs Excluding SAEs  
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized by age group and overall for each treatment group. 
The number of TEAEs and the number and percentage of subjects with TEAEs, as classified 
by SOC and PT will also be summarized by severity and by relationship to study drug.  In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity or relationship, then the subject will be counted only once with the worst severity 
and highest degree of relationship, however, if any of the severity or relationship values are 
missing then the subject will be counted only once with missing severity or relationship.  In 
the adverse event count, the adverse events will be presented in each category they were 
classified to.  Drug related TEAEs will be presented in a similar way by severity only. 
Adverse events of interest will be tabulated by PT. 
AEs will be provided in listing format by country, site and subject for the SAF. 
6.5.2 
Clinical Laboratory Evaluation 
The baseline value will be the last non-missing value taken on or prior to first dose of study 
drug. 
Quantitative clinical laboratory variables, i.e., hematology, biochemistry, and urinalysis will 
be summarized using mean, standard deviation, median, minimum and maximum, for each 
age group and overall, by treatment group and visit.  
Summary of laboratory values will be presented for visit 1, 3, 5, 7 and 8 (EoS)], and for EoT 
values. 
Additionally, a within-subject change will be calculated as the post-baseline measurement 
minus the baseline measurement and summarized in the same way. Each laboratory result 
will be classified as low (L), normal (N), or high (H) at each visit according to the laboratory 
supplied reference ranges.  
The number and percentage of subjects below and above reference range will be summarized, 
for each age group and overall, by treatment group and visit.  


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Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented, for each age group and overall, by treatment group and visit. 
Shifts from baseline to week 4, week 12 and EoT will be summarized by two types of shift 
tables: 
● 
Shift tables of reference range (low, normal, high) changes from baseline to 
week 12 and to EoT, and 
● 
Summary shifts of reference range changes from baseline to week 4, week12 
and EoT. 
These shifts are categorized as: 
o “Shift to Low”: shift from normal or high to low 
o “Shift to High”: shift from normal or low to high 
o “Categorized Increase”: shift from low to normal or from normal to high 
o “Categorized No Change”: value stays in the same reference range 
o “Categorized Decrease”: shift from high to normal or from normal to low. 
All clinical laboratory data collected during the study and variables derived from it will be 
listed using SAF. 
6.5.2.1 Central and Local Laboratory Data 
In this study laboratory data may come from a central laboratory or a local laboratory, see 
Table 12 of the protocol. 
For summarizing the data of a laboratory parameter the data from the local laboratory will be 
transformed.  First all data from the parameter assessed in the local laboratory will be 
transformed into SI units.  Next local laboratory data will be transformed according to the 
transformation formula below.  Let x be the value of the laboratory parameter from the local 
laboratory, ULNL the upper limit of the normal range of the local laboratory, and ULNC the 
upper limit of the normal range of central laboratory then the transformed value (t) from the 
local laboratory is: 
𝑡= 𝑥.
𝑈𝐿𝑁𝐶
𝑈𝐿𝑁𝐿 
(Scale normalization, Karvanen et al.) 
This value t will be used for reporting laboratory values.  
The results from the local laboratory will be used to determine whether a result is outside the 
normal range.  
6.5.2.2 Liver Safety Assessment 
The liver safety assessments will be summarized by the categories below based on the 
measurements from Alkaline Phosphatase (ALP), Alanine Transaminase (ALT), total 
bilirubin, Aspartate Transaminase (AST) and their combination.  These parameters will be 
based on measurements from a central laboratory. 


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The subject’s highest value during the investigational period will be used.  
● 
ALT >3xULN, >5xULN, >10xULN, >20xULN 
● 
AST >3xULN, >5xULN, >10xULN, >20xULN 
● 
ALT or AST >3xULN, >5xULN, >10xULN, >20xULN 
● 
ALP >1.5xULN 
● 
Total Bilirubin >2xULN 
● 
(ALT or AST >3xULN) and Total Bilirubin >2xULN 
● 
(ALT or AST >3xULN) and ALP <2xULN and Total Bilirubin >2xULN 
The last 2 criteria where 2 or more parameters are evaluated will be with the measurements 
on the same day or up to 1 day apart (Samples to be taken simultaneously or within a 
maximum of 24 hours).  
The denominator for each criterion will be the number of subjects who have at least one 
value during the investigational period.  The number and percentage of subjects meeting the 
criteria during the investigational period will be summarized, within and across age group by 
treatment group. 
A scatter plot of Peak AST or ALT data vs. Peak Total Bilirubin data will be presented for 
mirabegron subjects.  Data will be presented as fractions of the ULN.  In this scatter plot the 
area for Hy’s Law will be presented, where ALT or AST >3xULN and Total bilirubin 
> 2xULN (ALT, ALT and Total Bilirubin from same blood sample or within a maximum of 
24 hours).  The area for hyperbilirubinemia (ALT and AST <3xULN and Total bilirubin 
>2xULN), Temple’s corollary (ALT or AST >3xULN and Total bilirubin < 2xULN) will 
also be presented in this scatter plot. 
Laboratory data will be provided in listing format by country, site and subject for the SAF. 
6.5.3 
Vital Signs 
The baseline value will be the last non-missing value taken on or prior to first dose of study 
drug. 
In addition to the presentation by age groups 5 to < 12 years of age, 12 to < 18 years of age 
and overall, vital signs will also be presented for age groups 5 to < 8 years of age and 8 to 
< 12 years of age. 
6.5.3.1 Clinical Measurements 
Values and changes from baseline for vital signs (SBP, DBP, pulse rate and measurement for 
temperature) and percentiles of SBP, DBP and Pulse Rate compared to age and height norms 
(see Appendix 9.3 for Blood Pressures and Table 4 for Pulse Rate) will be listed and 
summarized, for each age group and overall, by treatment group and visit using mean, 
standard deviation, median, minimum and maximum. Summary of vital signs will be 
presented for each visit [visit 1, 3, 5, 7 and 8 (EoS)], and for EoT values. 


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2017 American Academy of Pediatric Clinical Practice Guidelines 
For each scheduled post-baseline visit, shift tables from baseline to each post-baseline visit 
will be presented with respect to the changes from normal blood pressure to elevated blood 
pressure; stage 1 HTN, or stage 2 HTN, see Table 8. For the cut-off points (90th, and 95th 
percentiles) see 2017 American Academy of Pediatric Clinical Practice Guidelines.  
Table 8 
Definitions of Blood Pressure Categories and Stages  
Children Aged 1–<13 years 
Adolescents Aged ≥13 years 
Normal BP: <90th percentile  
Normal BP: <120/<80 mm Hg 
(SBP < 120 mmHg and DBP < 80 mmHg) 
Elevated BP: ≥90th percentile to <95th percentile or 
120/80 mmHg to <95th percentile (whichever is 
lower) 
Elevated BP: 120/<80 to 129/<80 mmHg 
(120 ≤ SBP ≤ 129 mmHg and DBP ≤ 80 mmHg) 
Stage 1 HTN: ≥95th percentile to <95th percentile + 
12 mmHg, or 130/80 to 139/89 mmHg (whichever is 
lower) 
Stage 1 HTN: 130/80 to 139/89 mmHg 
(130 ≤ SBP ≤ 139 mmHg or 80 ≤ DBP ≤ 89 mmHg) 
Stage 2 HTN: ≥95th percentile + 12 mmHg, or 
≥140/90 mmHg (whichever is lower) 
Stage 2 HTN: ≥140/90 mmHg 
(SBP ≥ 140 or DBP ≥ 90 mmHg) 
Table obtained from: 2017 American Academy of Pediatric Clinical Practice Guidelines, Table 3 
Note: the age classification into children and adolescents in the Clinical Practice Guidelines (2017) differs 
from the definition used in the protocol 
Summaries will be presented for SBP and DBP separately, for each age group and overall, by 
treatment group.  See further details in Section 5.4.2.3: Conversion of Blood Pressure to 
Percentiles. 
In addition, PR measurements will be compared to age-related norms [Fleming et al, 2011] 
according to the percentiles shown in Table 4.  Each PR value will be categorized as either 
below the 1st percentile, between the 1st and 99th percentile (limits included) or above the 99th 
percentile.  For each scheduled post-baseline visit, shift tables from baseline to each 
post-baseline visit will be presented with respect to the changes from PR to below the 1st 
percentile and above the 99th percentile. 
Summaries will be presented, for each age group and overall, by treatment group for the 
number of subjects with PR values below and above the normal range, the normal range is 
defined as: 1st – 99th percentile. 
Potentially Clinically Relevant (PCR) criteria 
PCR criteria for SBP will be identified using the following criteria and cut-points: 
● Hypertension SMQ [20000147] (narrow search), or 
● 2017 American Academy of Pediatric Clinical Practice Guidelines: 
o For subjects aged 5 - <13 years: any SBP above the 95th percentile +12 mmHg or  
BP≥ 140/90 mmHg at a post baseline visit, and  
for subjects aged ≥13 years: BP ≥140/90 mmHg at a post-baseline visit, 
or 


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o Change in category from baseline (Normal or elevated BP or Stage 1 HTN) to 
post-baseline (Stage 1 HTN or Stage 2 HTN). 
PCR criteria for DBP will be identified using the following criteria and cut-points: 
● Hypertension SMQ [20000147] (narrow search), or 
● 2017 American Academy of Pediatric Clinical Practice Guidelines: 
o For subjects aged 5 - <13 years: any DBP above the 95th percentile + 12 mmHg or 
BP≥ 140/90 mmHg at a post baseline visit, and  
for subjects aged ≥13 years: BP ≥140/90 mmHg at a post-baseline visit, 
or 
o Change in category from baseline (Normal or elevated BP or Stage 1 HTN) to post-
baseline (Stage 1 HTN or Stage 2 HTN). 
Using these criteria, a high and low flag will be created to indicate if values meet these 
conditions (i.e., SBP/DBP PCR values) or not (i.e., non-SBP/DBP PCR values). 
For PR, the below criterion will be used to identify a PCR increase: 
● PR above 99th percentile compared to age-related norms PR [Fleming et al, 2011] and 
≥15 bpm change from baseline. 
PCR for SBP, DBP and PR will be summarized, for each age group and overall, by treatment 
group. 
Data obtained from the clinical measurements (SBP. DBP and PR) will be provided in listing 
format by country, site and subject for the SAF. 
6.5.3.2 Self-Measurements 
Similarly to the clinic vital signs measurements (Section 6.5.3.1), values and changes from 
baseline for self vital signs measurements (SBP, DBP, pulse rate) and percentiles of 
self-measurements SBP and DBP compared to age and gender norms will be listed and 
summarized at each visit using mean, standard deviation, median, minimum and maximum. 
The number and percentage of subjects outside reference ranges will be shown. 
For the purpose of the analyses, the average self-measurement vital signs will be calculated 
using all values from the 2-days diary collection for the regular measurements. If all 
measurements are missing, then the average will be missing.  Extra measurements will be 
listed only. 
For shifts from baseline to each post-baseline visit the categories used for presentation were 
obtained from the 2017 (American Academy of Pediatric) Clinical Practice Guidelines. 
For each scheduled post-baseline visit, shift tables from baseline to each post-baseline visit 
will be presented. Categories are: normal blood pressure; elevated blood pressure; stage 1 
HTN, and stage 2 HTN, see Table 8.  For the cut-off points (90th, and 95th percentiles) see 
2017 American Academy of Pediatric Clinical Practice Guidelines.  


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Potentially Clinically Relevant (PCR) criteria 
PCR criteria for SBP will be identified using the following criteria and cut-points: 
● Hypertension SMQ [20000147] (narrow search), or 
● 2017 Clinical Practice Guidelines: 
o For subjects aged 5 - <13 years: Any SBP above the 95th percentile +12 mmHg or 
BP≥ 140/90 mmHg at a post baseline visit, and  
for subjects aged ≥13 years: BP ≥140/90 mmHg at a post-baseline visit, 
or 
o Change in category from baseline (Normal or elevated BP or Stage 1 HTN) to post-
baseline (Stage 1 HTN or Stage 2 HTN). 
PCR criteria for DBP will be identified using the following criteria and cut-points: 
● Hypertension SMQ [20000147] (narrow search), or 
● 2017 Clinical Practice Guidelines: 
o For subjects aged 5 - <13 years: Any DBP above the 95th percentile +12 mmHg or 
BP≥ 140/90 mmHg at a post baseline visit, and  
for subjects aged ≥13 years: BP ≥140/90 mmHg at a post-baseline visit, 
or 
o Change in category from baseline (Normal or elevated BP or Stage 1 HTN) to post-
baseline (Stage 1 HTN or Stage 2 HTN). 
Using these criteria, a high and low flag will be created to indicate if values meet these 
conditions (i.e., SBP/DBP PCR values) or not (i.e., non-SBP/DBP PCR values). 
PR measurements will be compared to age-related norms [Fleming et al, 2011] according to 
the percentiles shown in Table 4.  For each scheduled post-baseline visit, shift tables from 
baseline to each post-baseline visit will be presented with respect to the changes from PR to 
below the 1st percentile and above the 99th percentile. 
For PR, the below criterion will be used to identify a PCR increase: 
● PR above 99th percentile compared to age-related norms PR [Fleming et al, 2011] and 
≥15 bpm change from baseline. 
Tables for potentially clinically relevant vital signs will be produced using the same criteria 
described in Section 6.5.3.1.  
Data obtained from the self-measurements (SBP. DBP and PR) will be provided in listing 
format by country, site and subject for the SAF. 
6.5.4 
Electrocardiograms 
ECG variables will be summarized using mean, standard deviation, median, minimum, and 
maximum, for each age group and overall, by treatment group and visit, including changes 
from baseline.  Summary of ECG data will be presented for visits 1, 3, 5, 7, and for EoT 
values.   


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Number and percent of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by investigator for the 12 lead ECG will be 
tabulated, for each age group and overall, by treatment group and visit.  
Shift tables will be presented for changes from baseline at each visit including local 
interpretation categories.  Shift tables will also be presented as above from baseline to worst 
post-baseline value during the treatment period.  
The corrected QT interval (i.e. QTcF) will be summarized for each visit showing the number 
and percentage of subjects in each of the following categories: 
For the children category: 
● 
440 ms 
For the male adolescents category: 
● 
450 ms 
● 
500 ms 
For the female adolescents category: 
● 
480 ms 
● 
500 ms 
Note that these categories are cumulative in that subjects satisfying criterion for more 
extreme category will also be counted in each applicable less extreme category. 
The corrected QT interval (i.e., QTcF) will also be summarized, for each age group and 
overall, by treatment group and visit showing the frequencies of subjects with the following 
changes from baseline: <0, ≥0 and <30, ≥30 and <60, and ≥ 60 ms. 
Number and percent of subjects with 12 lead ECG abnormalities as well as number and 
percent of subjects whose 12 lead ECG reading changed from normal at baseline to abnormal 
will be tabulated, for each age group and overall, by treatment group and visit.  
ECG data will be provided in listing format by country, site and subject for the SAF. 
6.5.5 
Pregnancies 
A detailed listing of all pregnancies will be provided if any occur using All Screened Set. 
6.5.6 
Other Safety-Related Assessments 
6.5.6.1 Post Void Residual Volume 
PVR will be summarized, for each age group and overall, by treatment group and visit using 
mean, standard deviation, median, minimum, and maximum at each treatment visit, including 
changes from baseline.  In case of 2 measurements at the same visit, the lowest (instead of 
mean) PVR volume will be used for the calculations. 
Summary of PVR data will be presented for visits 3, 5, 7 and 8 (EoS), and for EoT values.   
To calibrate PVR with bladder size, the ratio of PVR to the child’s Expected Bladder 
Capacity (EBC, =[age+1] × 30 in mL for children and 400 mL for adolescents) will also be 


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calculated at baseline and post-baseline study visits and expressed as a percentage.  These 
ratios will be summarized together with the change from baseline by age group and overall. 
The following variables will be summarized, for each age group and overall, by treatment 
group at each visit (and also for the maximum recorded post-baseline value of PVR) using 
number and percentage of subjects in the following categories: 
● 
PVR: 0 to <20 mL, 20 to <50 mL, ≥50 mL 
● 
Change from baseline in PVR: <0 mL, 0 to <20 mL, 20 to <50 mL, ≥50 mL 
● 
Ratio of PVR to EBC (%): 0% to <20%, 20% to <40%, ≥40% 
● 
Change from baseline in ratio of PVR to EBC (%): <0%, 0% to <20%, 20% to <40%, 
≥40% 
PVR data will be provided in listing format by country, site and subject for the SAF. 
6.5.6.2 Body Weight and Height 
Body weight, height and BMI will be summarized, for each age group and overall, by 
treatment group and visit using mean, standard deviation, median, minimum, and maximum 
at each visit, including changes from baseline.  Summary of body weight, height and BMI 
will be presented for visits 1, 3 and 7, and for EoT values. 
Body weight, height and BMI data will be provided in listing format by country, site and 
subject for the SAF. 
6.5.6.3 Acceptability and Palatability Questionnaires 
Results from the acceptability and palatability questionnaire for tablets (see protocol 
Section 12.8) and for oral suspension (see protocol Section 12.9) will be summarized at 
week 12/EoT, for each age group and overall, by treatment group. 
Data obtained from the questionnaires will be provided in listing format by country, site and 
subject for the SAF. 
6.5.7 
Subgroups of Interest for Safety 
In addition to the analyses described above, selected safety variables (TEAEs, drug-related 
TEAEs and Vital Signs) will be summarized for each age group and overall by treatment 
group for several subgroups.  
For TEAEs and drug-related TEAEs the subgroups are: sex, race, ethnicity, geographical 
region, formulation (tablets vs. oral suspension), prior OAB treatment and symptomatic UTI, 
and for vital signs: sex, race, ethnicity, and formulation (tablets vs. oral suspension).   
For any of the subgroups specified for vital signs, at least 10 subjects by stratum are required. 
6.6 
Analysis of Pharmacokinetics 
Plasma concentrations for mirabegron will be sampled at visit 5/week 4 and visit 7/week 12 
(EoT) (Table 9). One predose sample will be collected on both pharmacokinetic sampling 
days. 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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Table 9 
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 
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.  Plasma concentration values below 
the lower limit of quantification (LLOQ, 0.0500 ng/mL) will be set equal to 0 in the 
calculation of summary statistics.  
The following plot will be produced: Box plots of plasma concentration-time profiles (normal 
scale and semi-log scale). 
Further details will be described in the TLF specifications. 
Pharmacokinetic analysis will be conducted on the PKAS and parameters will be summarized 
for children, adolescents, and overall in the modeling report. Results of the pharmacokinetic 
analysis will be provided in a separate PK modeling report. 
6.6.1 
Statistical Analysis 
Plasma concentration data from this study will be pooled with other pediatric PK data and 
will be analyzed using a population modeling approach. Details of the pharmacokinetic 
analysis will be presented in a separate population PK modeling analysis plan.  
6.7 
Analysis of Pharmacodynamics  
Not applicable. 
6.8 
Other Analyses  
Not applicable. 
6.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
One comparative interim analysis will be performed after 50% of children planned to be 
randomized have had their week 12/EoT assessment.  Only data from those children with 
week 12/EoT assessment will be used in the interim analyses.  The interim analysis will 
determine if the chance of a positive study with respect to the primary endpoint at the final 
analysis is high enough to justify continuation of the study; otherwise, the study will be 
stopped for futility. 
Given the data at the interim analysis, a predictive probability of a positive study will be 
calculated.  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]).  


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If the predictive probability is ≤ 5% at this interim evaluation, the study will be 
recommended to stop for futility.  Otherwise, the study will continue. 
No efficacy analyses will be performed except for determination of futility.  
At the interim analysis, the following predictive probability will be calculated: 
  Predictive Probability of ({final one-sided p-value of mirabegron vs. placebo ≤ 0.05} |Data). 
Since we use non-informative prior distribution of difference in mean change from Baseline 
to week 12/EoT in mean number of micturitions per 24 hours between the mirabegron group 
and the placebo group and assume the mean change from Baseline to week 12/EoT in mean 
number of micturitions per 24 hours follows a Gaussian distribution, the Bayesian predictive 
probability for the event of a final one-sided p-value of mirabegron vs. placebo ≤ 0.05 
(denoted by PP) can be obtained using a closed form based on the methods described in 
Geisser and Johnson (1994), Spiegelhalter etc. (2004), Dmitrienko and Wang (2006).  
Appendix 9.5 contains a detailed derivation.  
𝑃𝑃=  Φ
{  
  
√
2
𝑀𝑃
𝑁𝑃+ 𝑀𝐴
𝑁𝐴
[√82
𝑦̅𝑁𝑃−𝑥̅𝑁𝐴
√2𝜎̂
−𝑧0.95]
}  
  
                                                       (1) 
where 
● 
Φ stands for the cumulative distribution function for the standard Gaussian 
distribution. Φ(Z0.95) = 0.95. 
● 
𝑁𝑃 and 𝑁𝐴 denote the number of subjects observed at the interim analysis for 
placebo group and mirabegron group, respectively.  
● 
𝑀𝑃 and 𝑀𝐴 denote the number of subjects as yet unobserved at the interim 
analysis for placebo group and mirabegron, respectively. 𝑀𝑃= 82 −𝑁𝑃, 𝑀𝐴=
82 −𝑁𝐴. 
● 
𝑦̅𝑁𝑃and 𝑥̅𝑁𝐴 are the LS means for placebo group and mirabegron group, 
respectively, and will be obtained from the ANCOVA model described in 
Section 6.4.1.1.  
● 
𝜎̂ is the estimated pooled standard deviation and will be obtained from the same 
ANCOVA model as described in Section 6.4.1.1.   
Detailed information on the decision rule for futility and simulations illustrating the 
operational characteristics of such futility criteria can be found in Appendix 9.4.  
The interim analysis will be conducted by an Independent Data Analysis Center (IDAC).  An 
independent statistician at this IDAC will be unblinded to conduct the interim analysis. 
Documentation of the interim analysis will be kept at the IDAC until after end of study 
treatment unblinding, and will then be transferred to the Study TMF. 
The recommendation from the IDAC (to stop the study for futility or continue as planned) 
will be forwarded to the Therapeutic Area Head Medical Specialties, to act upon this 


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recommendation (see Appendix 9.6:  Interim Analysis Report Template).  His decision to 
stop or continue the study will be communicated to the study manager. 
6.9.1 
Data Sources 
There are 2 databases: the IRT database provided by Cenduit and the clinical database.  The 
IRT database will include all randomization and study drug supply data collected through 
IRT.  The clinical database for the study is based on electronic data capture (EDC) 
technology.  All clinical data should be captured electronically in the clinical database after 
the corresponding visits. 
The unblinded randomization data and study drug supply data will only be located in the IRT 
database prior to the final database lock.  The unblinded randomization data and study drug 
supply data will be transferred to the IDAC directly from the IRT database or IRT vendor for 
generating the Report.  This process will maintain the confidentiality of the treatment codes 
by having only the IDAC statistician access the IRT independently of any Astellas personnel 
(e.g., clinical supply).  This process will be documented by IRT vendor SOPs. 
6.9.2 
Data Cut-off and Data Extraction 
The data cut-off date will be the target date for priority data cleaning.  Data collected prior to 
data cut-off date will undergo standard data review and cleaning procedures by Signant 
Health and APGD Data Management. When priority data cleaning is deemed sufficient, the 
database will be extracted in SAS data format.  All relevant (efficacy, disposition, study 
medication and demographic) data collected in the clinical database prior to the data 
extraction date will be included in the report. 
6.9.3 
Report Generation 
The IDAC will develop analysis programs based on surrogate treatment codes prior to the 
cut-off date.  The unblinded IDAC statistician that is not affiliated with APGD will receive 
the unblinded randomization data from the IRT.  The IDAC statistician will replace surrogate 
treatment codes with actual treatment codes and generate outputs using the programs 
developed by the IDAC. 
The IDAC statistician will prepare a statistical report, being the Interim Analysis Report 
(Appendix 9.6) and the TFL (Table, figure and listing) outputs, see below, for the 
Therapeutical Area Head Medical Specialties.  
For the interim report the following tables will be presented: 
Table Number 
Table Title 
1.1 
Disposition Prior to Randomization, All Subjects With Informed Consent 
1.2 
Subject Classification, All Randomized Subjects 
1.3 
Subject Enrollment, Overall and by Country/Site, All Randomized Subjects 
2 
Demographics, Full Analysis Set 
3 
Results of ANCOVA of Change from Baseline in Mean Number of 
Micturitions per 24 hours at Week 12/EoT,  Full Analysis Set 
Note: no safety data will be presented 


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6.10 
Additional Conventions  
6.10.1 Analysis Windows 
The study protocol gives the overall study schedule and the permissible intervals for these 
visits expressed as the number of days relative to visit 3/baseline. The total time each subject 
will be in the study will not exceed 18 weeks with a maximum of a screening period of 
4 weeks and a maximum of 14 weeks for the investigational period. 
Analyses will not exclude subject data due to the subject’s failure to comply with the visit 
schedule.  
All the assessments will be allocated to CRF visit based on Table 10. 
Table 10 
Visit Windows for Efficacy and Safety Parameters  
CRF visit 
Target day relative to 
Baseline (Visit 3, Day -1) 
Analysis Window 
Analysis visit 
Bladder e-diary 
Visit 3 
Last value prior to first dose 
Day -7 to Day 1 (prior to first 
dose) 
Baseline 
Visit 4 
Day 14 
Day 7 to Day 21 
Week 2 
Visit 5 
Day 28 
Day 22 to Day 42 
Week 4 
Visit 6 
Day 56 
Day 43 to Day 70 
Week 8 
Visit 7 
Day 84 
Day 71 to Day 91 
Week 12 
EoT 
Day 84 
Day 1 to ≤ Last dose of double-
blind study drug 
EoT 
Acceptability questionnaires 
Visit 7 
Day 84 
Day 71 to Day 91  
Week 12 
EoT 
Day 84 
Day 1 to ≤ Last dose of double-
blind study drug 
EoT 
SBPM 
Visit 3 
Last value prior to first dose 
Day -7 to Day 1 (prior to first 
dose) 
Baseline 
Visit 4 
Day 14 
Day 7 to Day 21 
Week 2 
Visit 5 
Day 28 
Day 22 to Day 42 
Week 4 
Visit 6 
Day 56 
Day 43 to Day 70 
Week 8 
Visit 7 
Day 84 
Day 71 to Day 91 
Week 12 
EoT 
Day 84 
Day 1 to ≤ Last dose of double-
blind study drug 
EoT 
Table continued on next page 


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CRF visit 
Target day relative to 
Baseline (Visit 3, Day -1) 
Analysis Window 
Analysis visit 
Vital signs 
Visit 1 
 
 
Screening 
Visit 3 
Last value prior to first dose 
Day -7 to Day 1 (prior to first 
dose) 
Baseline 
Visit 5 
Day 28 
Day 22 to Day 56 
Week 4 
Visit 7  
Day 84 
Day 57 to Day 91 
Week 12 
EoT 
Day 84 
Day 1 to ≤ Last dose of double-
blind study drug 
EoT 
Visit 8# 
Day 98 
Day 92 or EoT + 1 to no more 
than 17 days after EoT 
Week 14 (EoS) 
ECG 
Visit 1 
 
 
Screening 
Visit 3 
Last value prior to first dose 
Day -7 to Day 1 (prior to first 
dose) 
Baseline 
Visit 5 
Day 28 
Day 22 to Day 56 
Week 4 
Visit 7  
Day 84 
Day 57 to Day 91 
Week 12 
EoT 
Day 84 
Day 1 to ≤ Last dose of double-
blind study drug 
EoT 
Clinical Laboratory Tests (Hematology, Biochemistry and Urinalysis) 
Visit 1 
 
 
Screening 
Visit 3 
Last value prior to first dose 
Day -7 to Day 1 (prior to first 
dose) 
Baseline 
Visit 5 
Day 28 
Day 22 to Day 56 
Week 4 
Visit 7  
Day 84 
Day 57 to Day 91 
Week 12 
EoT 
Day 84 
Day 1 to ≤ Last dose of double-
blind study drug 
EoT 
Visit 8#  
Day 98 
Day 92 or EoT to no more than 17 
days after EoT  
Week 14 (EoS) 
Post Void Residual (PVR) Volume 
Visit 3 
Last value prior to first dose 
Day -7 to Day 1 (prior to first 
dose) 
Baseline 
Visit 5 
Day 28 
Day 22 to Day 56 
Week 4 
Visit 7  
Day 84 
Day 57 to Day 91 
Week 12 
EoT 
Day 84 
Day 1 to ≤ Last dose of double-
blind study drug 
EoT 
Visit 8#  
Day 98 
Day 92 or EoT to no more than 17 
days after EoT  
Week 14 (EoS) 
#Visit 8 may occur earlier due to early discontinuation as it is the last scheduled study visit. 


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For non-diary data, if a subject has more than one non-missing value within a visit window, 
the non-missing assessment which is closest to the target day within a window will be used.  
If two or more values are equally close and on different days, the latest non-missing value 
will be used.  If two or more values are equally close and on the same day, the mean will be 
used for continuous variables or the worst observed case for categorical variables. 
For diary data, the assessment date for the whole diary will be considered to be the date of 
the last valid day of the diary.  If more than one diary has an assessment date within the same 
window, and if this results in more than one non-missing value of a diary variable, the non-
missing value with the diary assessment day that is closest to the target day will be used. In 
case of ties on different days, the later non-missing value will be used. In case of ties located 
on the same side of the target day (i.e., more than one value for the same day), the mean of 
the values will be used for continuous variables and the worst value for categorical variables. 
For analyzing diary data the labels of the study visits will not be used, they will be assigned 
based on the dates of assessment. 
A two-day window around the visit date will be applied for the assignment of study period 
for exposure data. 
6.10.2 Imputation Rules for Incomplete Dates  
Missing primary and secondary efficacy endpoints will be handled by Last Observation 
Carried Forward (LOCF) for continuous variables.  More details are provided in the relevant 
sections for those endpoints (Sections 6.4.1 and 6.4.2).  
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start dates of AEs and start and stop dates of concomitant medication.  
The imputed dates will be used to allocate the concomitant medication and AEs to a 
treatment group, in addition to determining whether an AE is/is not treatment emergent.  
Listings of the AEs and concomitant medications will present the actual partial dates; 
imputed dates will not be shown. 
Values (visit 7/week 12) for certain safety variables (lab values, vital signs values and ECG) 
and the go-to-bed time for Sunday (eDiary) will be imputed, see below. 
For calculation of percentiles the not collected day of birthday, in the eCRF, will be imputed. 
6.10.2.1 Imputation Rules for Diary Dates  
The go-to-bed time for Sunday is not captured in the diary.  This time will be imputed as 
occurring a short time after the second (evening) SBPM was performed: time of second 
SBPM plus 1 hour.  If there is no time entered in the diary for the evening SBPM, then the 
go-to-sleep time will be imputed as 23:59 (on Sunday), see Section 5. 
6.10.2.2 Imputation Rules for Adverse Events  
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 
If an onset date is missing or only the year is known, the imputed onset date will be the date 
of first dose of study drug. 


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If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates: 
● 
Date of first dose of study drug 
● 
January 1 of the year of AE onset date  
If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
● 
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date. 
● 
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates: 
○ Date of first dose of study drug 
○ Surrogate onset date 
If the imputed onset date is after the adverse event end date, the imputed onset date will be 
the same as the adverse event end date. 
6.10.2.3 Imputation Rules for Concomitant Medications 
In case of missing partial start and stop dates for concomitant medications, the following 
rules will be used: 
If the start date is missing or partial: 
● if the month is missing, use January 
● if the day is missing, use the first day of the month under consideration 
● if the year is missing, use year of the informed consent date 
● if the entire date is missing, use informed consent date 
If the stop date is missing or partial: 
● if the month is missing, use December 
● if the day is missing, use the last day of the month under consideration 
● if the year or the entire date is missing, set the stop date to December 31st, 2099 
If the imputed start date is after the stop date, then the imputed start date will be 1 day prior 
to the stop date. 
6.10.2.4 Imputation Rules for Missing Safety Variables (Lab values, Vital Signs, ECGs 
or PVR) 
In case subject safety data of lab values, vital signs, PVR or ECGs at EoT (visit 7/week 12) is 
missing, the LOCF method will be used for the summaries or shifts from baseline to EoT 
only.  No values at baseline and no data from more than 5 days after the last dose of study 
medication will be carried forward to post-baseline visits.  


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6.10.2.5 Imputation of Age in Months 
For the calculation of percentiles of height and weight the age in months is required. Since 
we capture in the eCRF for birthday only the month and year and not the day, the 15th of the 
month will be imputed for day. 
6.10.3 Outliers 
All values will be included in the planned analyses.  A sensitivity analysis excluding outliers 
may be performed as an additional secondary analysis, if considered appropriate by the study 
statistician or the medical expert.   


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7 
REVISION AND RATIONALE 
7.1 
List of Changes in SAP Version 2.0 from Version 1.0 
The changes from the approved SAP Version 1.0 (Dated 07-Aug-2020) to Version 2.0 that 
impact analyses are listed with the rationale in the table below. 
SAP 
Section 
Description 
Rationale 
2.1 
Secondary Objective regarding PK 
analysis updated 
To be consistent with protocol 
 
Exploratory Objective: age group is 
added and endpoint “mean number of 
micturitions per 24 hours” is added to list 
of endpoints. 
To be consistent with protocol 
2.3 
Text added at the end of the paragraph 
Text added for clarification 
3 
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. 
This update is made for clarification of 
assumptions. 
5.4.1 
Text regarding TEAEs updated to reflect 
text in protocol. 
Text differed from the text in protocol. 
 
“In any of the treatment groups” is added 
to “Common TEAEs are defined as 
preferred terms (PTs) that have been 
reported by at least 5% of the subjects” 
To be in agreement with other studies 
5.5.2 
Weight categories in the 2 tables are 
updated 
To be consistent with protocol. The 
minimum weight of subjects is changed 
from 11 kg to 13 kg 
6.4.1.4 
Added section on scoring by caregiver 
and subject 
To perform a descriptive analysis to 
investigate the effect of scores by caregiver 
and subject differ. 
6.4.1.5 
Added “Symptomatic UTI” as subgroup 
To be consistent with protocol. This was 
added in version 2 of the protocol 
6.4.3 
Added Mean Number of Micturitions per 
24 hours as exploratory endpoint 
To be consistent with protocol. This 
endpoint was added in version 2 of the 
protocol 
6.5.2.1 
Added section on Central and Local 
Laboratories 
Lab data can also come from local 
laboratories, version 2 of protocol.  
6.5.7 
Subgroup analyses also done for vital 
signs. 
Vital signs was missing 
 
Added Symptomatic UTI as subgroup 
To be consistent between efficacy and 
safety analyses 
6.10.1 
Table 10: Day 2 → Day 1 
Subject may stop treatment on the day of 
the first administration of study drug 
6.10.2 
The time to-go-to sleep on Sunday is not 
captured on the eDiary 
To describe here that this missing time will 
be imputed.  Imputation also described in 
Section 5 of SAP 
 
 


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7.2 
List of Changes in SAP Version 3.0 from Version 2.0 
The changes from the approved SAP Version 2.0 (dated 24-Sep-2021) to Version 3.0 that 
impact analyses are listed with the rationale in the table below. 
SAP 
Section 
Description 
Rationale 
2.1 
Secondary efficacy variable “Mean 
number of nighttime incontinence 
episodes per 24 hours” was deleted  
Endpoint will no longer be analyzed due to 
changes in inclusion and exclusion criteria 
 
Exploratory Endpoints. 
The following exploratory endpoints are 
added: 
● 
Mean number of micturitions per 
24 hours, adjusted for fluid intake: 
o 
Number of micturitions per 24 
hours that would be required 
at week 12/EoT to void the 
same total volume as voided at 
baseline 
o 
Difference in mean number of 
micturitions per 24 hours 
adjusted for fluid intake 
compared to the expected 
mean number 
● 
Mean volume voided per 
micturition as a percentage of 
expected bladder capacity 
● Categorized mean volume voided 
per micturition as a percentage of 
expected bladder capacity (results 
and changes from baseline).  
To be in line with previous studies 
 
 
Added exploratory endpoint: “Change 
from baseline at the end of the 12-week 
treatment period (adolescents only) in 
Maximum Volume Voided” 
To correct an omission. In previous version 
this end-point was only mentioned for 
children. 
4.5.1 
Eligibility Deviations:  
Inclusion criterion 16 has been removed  
Not part of ICCS criteria; unduly restrictive 
for enrollment 
 
Exclusion criterion 1 has been removed 
Not part of ICCS criteria; unduly restrictive 
for enrollment 
 
Exclusion criteria 3 and 27 have been 
removed 
No reason to exclude these subjects as 
monosymptomatic enuresis is known to  
co-occur with OAB 
5.4.2.3  
For calculations reference is made to 
Center for Disease Control and 
Prevention website  
Using validated SAS® code 
5.2.1 
Derivation of mean volume voided was 
corrected. 
Derivation was not correct 
Table continued next page 


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SAP 
Section 
Description 
Rationale 
5.2.5 
Text in paragraph was updated 
For clarification 
5.4.1 
An AE designated as serious by either 
the investigator or determined by 
Important Medical Event process will 
be summarized as an SAE.  
This paragraph was added with 
“However, if the event is on IME list 
but medical monitor agrees with 
investigator that event is not SAE, then 
event can be downgraded.” 
Sentence was added for further clarification 
regarding the process. 
5.4.5 and 
9.5 
Deletion of text with respect to External 
ECG data and Abnormal ECGs 
No external ECG data will be collected 
6.2.3 
Summaries for percentiles of height and 
weight, with respect to age and sex, will 
be provided using SAS code and dataset 
from Center for Disease Control and 
Prevention website 
Using validated SAS® code. 
6.4.1.3.4 
Description for a (nonparametric) 
estimate for the difference between 
placebo and mirabegron, with 
associated (asymptotic) 90% CI was 
added 
To present a nonparametric estimate of the 
treatment difference 
6.4.1.4 
Definition of valid diary for caregiver 
and for subject was added 
For clarification and was missing in 
previous version 
6.4.3 
Text on mean number of micturitions 
per 24h adjusted for fluid intake was 
updated 
For clarification 
6.5.1 
Text regarding “Sponsor’s list of 
Always Serious terms” was updated by 
adding “or upgraded according to the 
Important Medical Event process”. 
New process: IME 
6.5.3 
Blood pressure will also be presented by 
age groups 5 - <8 and 8 - <12 years of 
age 
As suggested by FDA 
6.5.3.2 
Calculation of SBPM values added 
For clarification 
6.5.6.2 
Section of Body Weight and Height was 
added 
Missing in previous version 
6.10.1 
Analysis window for PVR volume 
added in Table 10 
Missing in previous version 
Table 10: for SBPM the row with EoS 
was removed and row (visit 8) was 
added for vital signs  
No SBPM assessment planned for End of 
Study, but one for vital signs  
6.10.2.4 
Imputation of missing PVR Volume 
was updated 
To be in line with other variables 
Table continued next page 


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SAP 
Section 
Description 
Rationale 
6.10.2.5 
For birthday, only the month and year 
are captured, and not the day. If day is 
needed for calculations the 15th of the 
month will be imputed for day 
Added because for some calculations the 
day of birthday is needed  
8 
List of references was updated 
Two new references added and one 
removed. 
9.1 
Table which presents not allowed 
medication is deleted. Reference is 
made to Table 12.6 in protocol. 
New table is presented in protocol 
9.3 
Appendix 9.3 Calculation of Z-score for 
height by age and sex has been removed 
For calculation of Z-score the SAS code 
and dataset stored on website from Center 
for Disease Control and Prevention will be 
used 
9.8 and 
9.9 
Names and titles updated 
New titles and contributors/approvers 
 
 
 
 


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8 
REFERENCES 
2017 American Academy of Pediatric Clinical Practice Guidelines, Flynn JT, Kaelber DC, Baker-
Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood 
Pressure in Children and Adolescents. Pediatrics.2017;140(3):e20171904) 
Dmitrienko A. and Wang M.D.  Bayesian predictive approach to interim monitoring in clinical trials. 
Statistical in Medicine, 2006;25:2178-2195.  
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, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and 
Management of High Blood Pressure in Children and Adolescents. Pediatrics. 
2017;140(3):e20171904) 
Geisser S. and Johnson W. Interim analysis for normally distributed observables. Multivariate 
Analysis and Its Applications, IMS Lecture Notes – Monograph Series, 1994;Volume 24, 263-
279.  
Hollander M, Wolfe DA. Nonparametric Statistical Methods. 2nd ed. John Wiley, 75-81. 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 
Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information Journal. Vol 
37, 101-107, 2003. 
Kliegman RM, Stanton BMD, St. Geme J, Schor NF, Behrman RE. Nelson Textbook of Pediatrics, 
19th edition. Elsevier Science Health 2007 
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. 
Sender Herschorn, Christopher R. Chapple, Robert Snijder, Emad Siddiqui, Linda Cardozo. Could 
Reduced Fluid Intake Cause the Placebo Effect Seen in Overactive Bladder Clinical Trials? 
Analysis of a Large Solifenacin Integrated Database. Urology, April 2017:106 
Spiegelhalter D.J., Abrams K.R., and Myles, J.P.. Bayesian Approaches to Clinical Trials and Health-
care Evaluation. 2004, Chichester, England: John Wiley & Sons. 
The Fourth Report on the diagnosis, evaluation, and treatment of high blood pressure in children and 
adolescents. 2005. U.S. Department of Health and Human Services, National Institutes of 
Health National Heart, Lung, and Blood Institute. NIH Publication No. 05-5267. Originally 
printed September 1996 (96-3790) Revised May 2005. 
Available from: https://www.nhlbi.nih.gov/files/docs/resources/heart/hbp_ped.pdf 


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9 
APPENDICES 
9.1 
Example of SAS Code for Nonparametric ANCOVA 
As sensitivity analysis for the primary efficacy endpoint a nonparametric ANCOVA on rank-
transformed data (changes from baseline) will be performed (stratified rank ANCOVA).  The 
p-value of the treatment difference will be assessed using a rank ANCOVA stratified by 
region, see Section on Sensitivity Analysis for Primary Efficacy Endpoint. 
The SAS code used to implement this test will be similar to that shown below: 
** Ranks within each region will be derived across the two treatment groups for the baseline 
value (base) and the change from baseline value (chg) stored in the SAS dataset called ranks; 
PROC RANK   NPLUS1   TIES=MEAN   OUT=ranks   DATA=dataset; 
BY          Region; 
RANKS  Base_r   Chg_r; 
VAR        Base   Chg; 
RUN; 
 
** Linear regression models will be applied to these ranks by region; 
PROC REG   DATA=ranks   NOPRINT; 
BY  Region; 
MODEL   Chg_r = Base_r   Sex ; 
OUTPUT  OUT = residual   R = Resid; 
RUN; 
 
** The p-value will be assessed using the stratified mean score test: 
PROC FREQ    DATA=residual ; 
TABLES   Region*Sex*Trt*Resid /  CMH2   noprint; 
ODS   OUTPUT   CHM = outp; 
RUN; 
 
 
 




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9.3 
2017 American Academy of Pediatric Clinical Practice Guidelines 
From 2017 (American Academy of Pediatric) Clinical Practice Guidelines, Table 4, Males, see Reference Flynn, et al, 2017 
Age 
(years) 
BP 
Percentile 
Systolic Blood Pressure (mmHg) 
Diastolic Blood Pressure (mmHg) 
Percentiles 
Percentiles 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5 
Height (cm) 
104.4 
106.2 
109.1 
112.4 
115.7 
118.6 
120.3 
104.4 
106.2 
109.1 
112.4 
115.7 
118.6 
120.3 
 
90th 
103 
104 
105 
106 
107 
108 
108 
63 
64 
65 
65 
66 
67 
67 
 
95th 
107 
108 
109 
109 
110 
111 
112 
66 
67 
68 
69 
70 
70 
71 
 
95th+12mmHg 
119 
120 
121 
121 
122 
123 
124 
78 
79 
80 
81 
82 
82 
83 
6 
Height (cm) 
110.3 
112.2 
115.3 
118.9 
122.4 
125.6 
127.5 
110.3 
112.2 
115.3 
118.9 
122.4 
125.6 
127.5 
 
90th 
105 
105 
106 
107 
109 
110 
110 
66 
66 
67 
68 
68 
69 
69 
 
95th 
108 
109 
110 
111 
112 
113 
114 
69 
70 
70 
71 
72 
72 
73 
 
95th+12mmHg 
120 
121 
122 
123 
124 
125 
126 
81 
82 
82 
83 
84 
84 
85 
7 
Height (cm) 
116.1 
118 
121.4 
125.1 
128.9 
132.4 
134.5 
116.1 
118 
121.4 
125.1 
128.9 
132.4 
134.5 
 
90th 
106 
107 
108 
109 
110 
111 
111 
68 
68 
69 
70 
70 
71 
71 
 
95th 
110 
110 
111 
112 
114 
115 
116 
71 
71 
72 
73 
73 
74 
74 
 
95th+12mmHg 
122 
122 
123 
124 
126 
127 
128 
83 
83 
84 
85 
85 
86 
86 
8 
Height (cm) 
121.4 
123.5 
127 
131 
135.1 
138.8 
141 
121.4 
123.5 
127 
131 
135.1 
138.8 
141 
 
90th 
107 
108 
109 
110 
111 
112 
112 
69 
70 
70 
71 
72 
72 
73 
 
95th 
111 
112 
112 
114 
115 
116 
117 
72 
73 
73 
74 
75 
75 
75 
 
95th+12mmHg 
123 
124 
124 
126 
127 
128 
129 
84 
85 
85 
86 
87 
87 
87 
9 
Height (cm) 
126 
128.3 
132.1 
136.3 
140.7 
144.7 
147.1 
126 
128.3 
132.1 
136.3 
140.7 
144.7 
147.1 
 
90th 
107 
108 
109 
110 
112 
113 
114 
70 
71 
72 
73 
74 
74 
74 
 
95th 
112 
112 
113 
115 
116 
118 
119 
74 
74 
75 
76 
76 
77 
77 
 
95th+12mmHg 
124 
124 
125 
127 
128 
130 
131 
86 
86 
87 
88 
88 
89 
89 
10 
Height (cm) 
130.2 
132.7 
136.7 
141.3 
146.9 
150.1 
152.7 
130.2 
132.7 
136.7 
141.3 
146.9 
150.1 
152.7 
 
90th 
108 
109 
111 
112 
113 
115 
116 
72 
73 
74 
74 
75 
75 
76 
 
95th 
112 
113 
114 
116 
118 
120 
121 
76 
76 
77 
77 
78 
78 
78 
 
95th+12mmHg 
124 
125 
126 
128 
130 
132 
133 
88 
88 
89 
89 
90 
90 
90 
11 
Height (cm) 
134.7 
137.3 
141.5 
145.4 
151.3 
155.8 
158.5 
134.7 
137.3 
141.5 
145.4 
151.3 
155.8 
158.5 
 
90th 
110 
111 
112 
114 
116 
117 
118 
74 
74 
75 
75 
75 
76 
76 
 
95th 
114 
114 
116 
118 
120 
123 
124 
77 
78 
78 
78 
78 
78 
78 
 
95th+12mmHg 
126 
126 
128 
130 
132 
135 
136 
89 
90 
90 
90 
90 
90 
90 
12 
Height (cm) 
140.3 
143 
147.5 
152.7 
157.9 
162.6 
165.5 
140.3 
143 
147.5 
152.7 
157.9 
152.6 
165.5 
 
90th 
113 
114 
115 
117 
119 
121 
122 
75 
75 
75 
75 
75 
76 
76 
 
95th 
116 
117 
118 
121 
124 
126 
128 
78 
78 
78 
78 
78 
79 
79 
 
95th+12mmHg 
128 
129 
130 
133 
136 
138 
140 
90 
90 
90 
90 
90 
91 
91 
 


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From 2017 (American Academy of Pediatric) Clinical Practice Guidelines, Table 5, Females, see References 
Age 
(years) 
BP 
Percentile 
Systolic Blood Pressure (mmHg) 
Diastolic Blood Pressure (mmHg) 
Percentiles 
Percentiles 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5 
Height (cm) 
103.6 
105.3 
108.2 
111.5 
114.9 
118.1 
120 
103.6 
105.3 
108.2 
111.5 
114.9 
118.1 
120 
 
90th 
104 
105 
106 
107 
108 
109 
110 
64 
65 
66 
67 
68 
69 
70 
 
95th 
108 
109 
109 
110 
111 
112 
113 
68 
69 
70 
71 
72 
73 
73 
 
95th+12mmHg 
120 
121 
121 
122 
123 
124 
125 
80 
81 
82 
83 
84 
85 
85 
6 
Height (cm) 
110 
111.8 
114.9 
118.4 
122.1 
125.6 
127.7 
110 
111.8 
114.9 
118.4 
122.1 
125.6 
127.7 
 
90th 
105 
106 
107 
108 
109 
110 
111 
67 
67 
68 
69 
70 
71 
71 
 
95th 
109 
109 
110 
111 
112 
113 
114 
70 
71 
72 
72 
73 
74 
74 
 
95th+12mmHg 
121 
121 
122 
123 
124 
125 
126 
82 
83 
84 
84 
85 
86 
86 
7 
Height (cm) 
115.9 
117.8 
121.1 
124.9 
128.8 
132.5 
134.7 
115.9 
117.8 
121.1 
124.9 
128.8 
132.5 
134.7 
 
90th 
106 
106 
107 
109 
110 
111 
112 
68 
68 
69 
70 
71 
72 
72 
 
95th 
109 
110 
111 
112 
113 
114 
115 
72 
72 
73 
73 
74 
74 
75 
 
95th+12mmHg 
121 
122 
123 
124 
125 
126 
127 
84 
84 
85 
85 
86 
86 
87 
8 
Height (cm) 
121 
123 
126.5 
130.6 
134.7 
138.5 
140.9 
121 
123 
126.5 
130.6 
134.7 
138.5 
140.9 
 
90th 
107 
107 
108 
110 
111 
112 
113 
69 
70 
71 
72 
72 
73 
73 
 
95th 
110 
111 
112 
113 
115 
116 
117 
72 
73 
74 
74 
75 
75 
75 
 
95th+12mmHg 
122 
123 
124 
125 
127 
128 
129 
84 
85 
86 
86 
87 
87 
87 
9 
Height (cm) 
125.3 
127.6 
131.3 
135.6 
140.1 
144.1 
146.6 
125.3 
127.6 
131.3 
135.6 
140.1 
144.1 
146.6 
 
90th 
108 
108 
109 
111 
112 
113 
114 
71 
71 
72 
73 
73 
73 
73 
 
95th 
112 
112 
113 
114 
116 
117 
118 
74 
74 
75 
75 
75 
75 
75 
 
95th+12mmHg 
124 
124 
125 
126 
128 
129 
130 
86 
86 
87 
87 
87 
87 
87 
10 
Height (cm) 
129.7 
132.2 
136.3 
141 
145.8 
150.2 
152.8 
129.7 
132.2 
136.3 
141 
145.8 
150.2 
152.8 
 
90th 
109 
110 
111 
112 
113 
115 
116 
72 
73 
73 
73 
73 
73 
73 
 
95th 
113 
114 
114 
116 
117 
119 
120 
75 
75 
76 
76 
76 
76 
76 
 
95th+12mmHg 
125 
126 
126 
128 
129 
131 
132 
87 
87 
88 
88 
88 
88 
88 
11 
Height (cm) 
135.6 
138.3 
142.8 
147.8 
152.8 
157.3 
160 
135.6 
138.3 
142.8 
147.8 
152.8 
157.3 
160 
 
90th 
111 
112 
113 
114 
116 
118 
120 
74 
74 
74 
74 
74 
75 
75 
 
95th 
115 
116 
117 
118 
120 
123 
124 
76 
77 
77 
77 
77 
77 
77 
 
95th+12mmHg 
127 
128 
129 
130 
132 
135 
136 
88 
89 
89 
89 
89 
89 
89 
12 
Height (cm) 
142.8 
145.5 
149.9 
154.8 
159.6 
163.8 
166.4 
142.8 
145.5 
149.9 
154.8 
159.6 
163.8 
166.4 
 
90th 
114 
115 
116 
118 
120 
122 
122 
75 
75 
75 
75 
76 
76 
76 
 
95th 
118 
119 
120 
122 
124 
125 
126 
78 
78 
78 
78 
79 
79 
79 
 
95th+12mmHg 
130 
131 
132 
134 
136 
137 
138 
90 
90 
90 
90 
91 
91 
91 
 


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9.4 
Futility Analysis Simulation Report 
1.0 
Background 
This is a Phase 3 study of mirabegron in subjects with an Overactive Bladder (OAB).  The 
study includes mirabegron and placebo.  The primary efficacy endpoint is the change from 
baseline in mean number of micturitions per 24 hours at the end of the 12-week treatment 
period for children (week 12/EoT).   A negative change from baseline is considered a 
beneficial effect.  A total sample size of 184 evaluable subjects will be randomized in a 1:1 
ratio to the two treatment groups.  It is expected that 164 subjects will be evaluable for the 
primary analysis.  For the calculations it is assumed that 82 subjects per arm are evaluable. 
2.0 
Interim Evaluation 
One comparative interim evaluation is planned to take place when 50%, i.e., 41 per treatment 
arm, of planned subjects to be randomized have had their week 12/EoT assessment.  The 
intent of planning and conducting an interim efficacy analysis is to evaluate whether the 
mirabegron group meets futility criteria. 
At the interim evaluation, a Bayesian predictive probability for the event of a final 1-sided 
p-value ≤ 0.05 will be calculated, comparing the mirabegron group with placebo.  If the 
predictive probability for the interim evaluation is ≤ 0.05 (i.e., there is a ≤5% chance of 
obtaining a statistically significant result for the primary efficacy analysis for mirabegron 
group at the final analysis), the mirabegron will be considered to have met futility criteria. 
2.1 
Decision Rule for Futility 
At the interim evaluation, the following predictive probability will be calculated: 
Predictive Probability of ({final 1-sided p-value of mirabegron vs. placebo ≤ 0.05} | Data). 
Given the data at the interim analysis, a predictive probability of a positive study will be 
calculated.  A positive study is defined as the final 1-sided p-value ≤ 0.05 when comparing 
mirabegron vs. placebo in the primary efficacy analysis.  If the predictive probability is no 
more than 0.05 at this interim evaluation, the study will be recommended to stop for futility.  
Otherwise, the study will continue. 
2.2 
Calculation of Predictive Probability 
At the interim evaluation, the predictive probability is expressed as an integration of the 
probability of {final one-sided p-value of mirabegron vs. placebo ≤ 0.05} over the posterior 
distribution of the treatment difference given the observed data: 
∫Pr({Final one-sided p - value ≤ 0.05}|θ) × Pr(θ|data)dθ,  
where θ stands for the difference in mean change from baseline to week 12/EoT in mean 
number of micturitions per 24 hours between mirabegron group and placebo group.  Such 
predictive probability can be computed through simulation. 
Since we use non-informative prior distribution of difference in mean change from baseline 
to week 12/EoT in mean number of micturitions per 24 hours between mirabegron group and 


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placebo group, it is assumed that the mean number of micturitions per 24 hours follows a 
Normal distribution and equal sample size per arm at the interim evaluation, the Bayesian 
predictive probability for the event of a final 1-sided p-value of mirabegron vs. placebo 
≤ 0.05 (denoted by PP) can be calculated using a closed form based on the methods described 
in Geisser and Johnson (1994), Dmitrienko and Wang (2006). 
𝑃𝑃= Φ [ 1
√𝑀
(√𝑁+ 𝑀 𝑍𝑁−√𝑁 𝑍0.95)]                               (1) 
where 
Φ stands for the cumulative distribution function for the standard normal distribution; 
N = number of subjects per arm observed at the interim evaluation, here N=41; 
M = number of subjects per arm as yet unobserved at the interim evaluation, here M = 82 – N 
ZN = test statistic, where the numerator (difference in mean change between mirabegron and 
placebo) will be obtained from the sample means of the mirabegron group and placebo 
group, 
𝑍𝑁 = Difference in LS mean change (mirabegron −placebo)
𝜎 2
𝑁
       (2) 
The least squares (LS) means for placebo group and mirabegron group will be obtained from 
the ANCOVA with treatment (mirabegron and placebo), visit, geographical region, sex, and 
treatment by visit interaction as fixed effects and baseline value (mean number of 
micturitions per 24 hours at baseline) as covariate.  The estimated pooled standard deviation 
(σ) will also be obtained from the same ANCOVA model. 
3.0 
Simulation Algorithm 
Simulations were conducted to evaluate the operating characteristics of this design, including 
the probability of meeting the futility criteria at the interim evaluation, and the probability of 
continuing to the end and having final 1-sided p-value ≤ 0.05.  
Change from baseline to week 12 in mean number of micturitions per 24 hours for each 
subject is generated from a Normal distribution.  The common standard deviation for 
mirabegron group and placebo group is fixed at 2.3 (see Section 3, Sample Size).  The 
planned sample size is 82 subjects per arm.  The scheduled interim evaluation is the moment 
when 82 subjects (i.e., 41 subjects per arm) have their week 12/EoT mean number of 
micturitions per 24 hours.  The outcome of the simulation is based on 50,000 runs (i.e., 
repeated trials). 
Six (6) scenarios were evaluated.  Each scenario specifies a mean change from baseline to 
week 12 in mean number of micturitions per 24 hours in the mirabegron group, while it keeps 
the mean change from baseline to week 12 in mean number of micturitions per 24 hours for 
placebo group fixed as –0.9.  


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See Table 7.1-1 for the six scenarios, where δ denotes the treatment difference between 
mirabegron group and placebo group in mean change from baseline to week 12 mean number 
of micturitions per 24 hours and a negative value of δ indicates a favorable treatment effect, 
and μA denotes the corresponding mean change from baseline to week 12 in mean number of 
micturitions per 24 hours for mirabegron group. 
Table 7.1-1: Simulation Scenarios 
Scenario # 
1 
2 
3 
4 
5 
6 
CfB for mirabegron 
-0.9 
-1.1 
-1.3 
-1.5 
-1.7 
-1.8 
 * 
0.0 
-0.2 
-0.4 
-0.6 
-0.8 
-0.9 
CfB: Change from Baseline 
*: Treatment difference () = mirabegron – placebo.  Negative value of  indicates favorable 
treatment effect. σ = 2.3 for both treatment groups. 
The simulation steps are as follows: 
1. Generate 41 observations  from a Normal distribution with mean = 0.0 and standard 
deviation = 2.3 for placebo group and 41 observations from a Normal distribution with 
mean  (any scenario in Table 7.1-1) and standard deviation = 2.3 for mirabegron group. 
2. Obtain the treatment difference between mirabegron group and placebo group using mean 
difference (mirabegron minus placebo) as fixed effect described in formula (2) based on 
the generated data. 
3. Apply formula (1) using σ = 2.3 to calculate the predictive probability of {final one-sided 
p-value of mirabegron vs. placebo ≤ 0.05}, where for the interim evaluation N = 41, and 
M = 41. 
4. If the futility criteria are not met, then generate for each treatment group data for 41 
subjects to complete the trial. 
5. Repeat Step 1-4 50,000 times (i.e., 50,000 simulated trials) for each scenario.  Count the 
number of simulated trials which meet the futility criterion.  In simulation, as long as 
mirabegron group meets the futility criterion, the simulated trial will be stopped.  The 
probability of meeting the futility criterion for a given scenario is the percentage of the 
trials meeting the futility criterion out of the 50,000 simulated trials.  Likewise, the 
probability of success is the percentage of the trials continuing to the end and having final 
1-sided p-value of mirabegron vs. placebo ≤ 0.05. 
The above simulation procedure was performed for a number of treatment difference 
scenarios.  The simulations were conducted using the software package SAS®. 
3.1 
Operating Characteristics 
Table 7.1-2 presents the probabilities of futility at the interim evaluation, as well as the 
probability of success (defined as continuing to the end and having final 1-sided p-value of 
mirabegron vs. placebo ≤ 0.05), for each treatment difference scenario.  In each treatment 


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difference scenario, we assume the common standard deviation of mean change from 
baseline to week 12/EoT in mean number micturitions per 24 hours is 2.3. 
Table 7.1-2: Probability of Futility and Success, σ = 2.3  
Treatment difference mirabegron vs. placebo (δ)* 
Pr (Futility)  
Pr (Success) 
0.0 
0.501 
0.050 
-0.2 
0.345 
0.134 
-0.4 
0.217 
0.289 
-0.6 
0.118 
0.503 
-0.8 
0.057 
0.713 
-0.9 
0.038 
0.797 
* Negative value of 𝛿 indicates favorable treatment effect. 
When there is no treatment difference between the mirabegron and placebo group (δ = 0), 
study success would be a false positive one.  Table 7.1-2 shows that in 50.1% of the 
simulations the trial would stop for futility.  Furthermore, 5.0% of the simulated trials 
continued to the end and had a 1-sided p-value ≤ 0.05 for the test to compare the mean 
changes between the mirabegron and placebo group.  Therefore, the false positive rate for 
this scenario is 5.0%.  
When the treatment difference is -0.9 mean number of micturitions per 24 hours, favoring 
mirabegron over placebo, the study would only be stopped for futility with a probability of 
3.8%, whereas 79.7% of the simulated trials continued to the end and had a 1-sided p-value 
≤ 0.05.  
In addition, a sensitivity analysis for the assumption regarding the common standard 
deviation of mean change from baseline to week 12 in mean number of micturitions per 
24 hours was performed on the same six treatment difference scenarios as described in  
Table 7.1-1 to assess the robustness of the design.  The probabilities of futility and success 
assuming σ = 2.5 for each of the treatment difference scenarios are presented in Table 7.1-3. 
For the efficacious scenarios where mirabegron shows favorable treatment effect over 
placebo (δ < 0), the probabilities of futility are relatively higher and the probabilities of 
success are relatively lower compared to the results assuming σ = 2.3.  For example, when 
the treatment difference is -0.6 points favoring mirabegron over placebo, the probability of 
futility in this scenario is 14.3% as compared to 11.8% assuming σ = 2.3, and the probability 
of success is 44.6%, as compared to 50.3% assuming σ = 2.3. 
Table 7.1-3: Probability of Futility and Success, σ = 2.5  
Treatment difference mirabegron vs. placebo (δ)* 
Pr (Futility)  
Pr (Success) 
0.0 
0.501 
0.052 
-0.2 
0.357 
0.127 
-0.4 
0.234 
0.260 
-0.6 
0.143 
0.446 
-0.8 
0.073 
0.646 
-0.9 
0.051 
0.739 
* Negative value of 𝛿 indicates favorable treatment effect.  
 


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9.5 
Derivation of Formula to Calculate Bayesian Predictive Probability  
Derivation of Formula (1) as presented in Section 6.9 is described below. 
Suppose two arms, placebo group and mirabegron group. The following notations are used:  
• 𝜇𝑃 and 𝜇𝐴 denote the mean change from Baseline to Week 12/EoT in mean number of 
micturitions per 24 hours for the placebo and mirabegron group, respectively.  
• 𝜎 denotes the common standard deviation.  
• In total 164 subjects will be randomized to each of the two arms and will be in the FAS.  
Let 𝑁𝑁 denotes the total sample size per arm planned for the study to have a baseline and 
a Week 12/EoT value for the mean number of micturitions per 24 hours, 𝑁𝑁= 82. 
• 𝑁𝑃 and 𝑁𝐴 denote the number of subjects observed, with data, at the interim analysis for 
the placebo and mirabegron group, respectively.  
• 𝑀𝑃 and 𝑀𝐴 denote the number of subjects as yet unobserved at the interim analysis for 
the placebo and mirabegron group, respectively. 𝑀𝑃= 𝑁𝑁−𝑁𝑃= 82 −𝑁𝑃, 𝑀𝐴=
𝑁𝑁−𝑁𝐴= 82 −𝑁𝐴. 
Suppose that:  
• For placebo group: 𝑌1, 𝑌2, ⋯, 𝑌𝑁𝑃, 𝑌𝑁𝑃+1, ⋯, 𝑌𝑁𝑁 ~𝑖. 𝑖. 𝑑. 𝑁(𝜇𝑃, 𝜎2). 
• For mirabegron group: 𝑋1, 𝑋2, ⋯, 𝑋𝑁𝐴, 𝑋𝑁𝐴+1, ⋯, 𝑋𝑁𝑁~ 𝑖. 𝑖. 𝑑. 𝑁(𝜇𝐴, 𝜎2).  
At the interim analysis when 𝑁𝑃 and 𝑁𝐴 subjects have their Week 12/EoT data for placebo 
group (i.e., 𝑦1, 𝑦2, ⋯, 𝑦𝑁𝑃 have been observed) and mirabegron group (i.e., 𝑥1, 𝑥2, ⋯, 𝑥𝑁𝐴 
have been observed), respectively, the posterior distribution of 𝜇𝑃 and 𝜇𝐴 assuming non-
informative priors are: 
𝜇𝑃|𝑦1, 𝑦2, ⋯, 𝑦𝑁𝑃~𝑁(𝑦̅𝑁𝑃, 𝜎2
𝑁𝑃
) , where 𝑦̅𝑁𝑃= 1
𝑁𝑃
∑𝑦𝑖
𝑁𝑃
𝑖=1
. 
𝜇𝐴|𝑥1, 𝑥2, ⋯, 𝑥𝑁𝐴~𝑁(𝑥̅𝑁𝐴, 𝜎2
𝑁𝐴
) , where 𝑥̅𝑁𝐴= 1
𝑁𝐴
∑𝑥𝑖
𝑁𝐴
𝑖=1
.  
For placebo group, the mean of as yet unobserved future data 𝑌𝑁𝑃+1, 𝑌𝑁𝑃+2 ⋯, 𝑌𝑁𝑁  is 
denoted as 𝑌̅𝑀𝑃, 𝑌̅𝑀𝑃=
1
𝑀𝑃∑
𝑌𝑖
𝑁𝑁
𝑖=𝑁𝑃+1
. The expectation and variance of 𝑌̅𝑀𝑃 given observed 
data 𝑦1, 𝑦2, ⋯, 𝑦𝑁𝑃 can be expressed as follows 
𝐸(𝑌̅𝑀𝑃|𝑑𝑎𝑡𝑎) = 𝐸(𝐸(𝑌̅𝑀𝑃|𝜇𝑃)|𝑑𝑎𝑡𝑎) = 𝐸(𝜇𝑃|𝑑𝑎𝑡𝑎) = 𝑦̅𝑁𝑃 
𝑉𝑎𝑟(𝑌̅𝑀𝑃|𝑑𝑎𝑡𝑎) = 𝑉𝑎𝑟(𝐸(𝑌̅𝑀𝑃|𝜇𝑃)|𝑑𝑎𝑡𝑎) + 𝐸(𝑉𝑎𝑟(𝑌̅𝑀𝑃|𝜇𝑃)|𝑑𝑎𝑡𝑎) 
= 𝑉𝑎𝑟(𝜇𝑃|𝑑𝑎𝑡𝑎) + 𝐸(𝜎2
𝑀𝑃
) = 𝜎2
𝑁𝑃
+ 𝜎2
𝑀𝑃
= 𝜎2 ( 1
𝑁𝑃
+ 1
𝑀𝑃
) 


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Similarly for mirabegron group, the mean of as yet unobserved future data 
𝑋𝑁𝐴+1, 𝑋𝑁𝐴+2, ⋯, 𝑋𝑁𝑁  is denoted as 𝑋̅𝑀𝐴, 𝑋̅𝑀𝐴=
1
𝑀𝐴∑
𝑋𝑖
𝑁𝑁
𝑖=𝑁𝐴+1
. The expectation and 
variance of 𝑋̅𝑀𝐴 given observed data 𝑥1, 𝑥2, ⋯, 𝑥𝑁𝐴 can be expressed as follows 
𝐸(𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎) = 𝐸(𝐸(𝑋̅𝑀𝐴|𝜇𝐴)|𝑑𝑎𝑡𝑎) = 𝐸(𝜇𝐴|𝑑𝑎𝑡𝑎) = 𝑥̅𝑁𝐴 
𝑉𝑎𝑟(𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎) = 𝑉𝑎𝑟(𝐸(𝑋̅𝑀𝐴|𝜇𝐴)|𝑑𝑎𝑡𝑎) + 𝐸(𝑉𝑎𝑟(𝑋̅𝑀𝐴|𝜇𝐴)|𝑑𝑎𝑡𝑎) 
= 𝑉𝑎𝑟(𝜇𝐴|𝑑𝑎𝑡𝑎) + 𝐸(𝜎2
𝑀𝐴
) = 𝜎2
𝑁𝐴
+ 𝜎2
𝑀𝐴
= 𝜎2 ( 1
𝑁𝐴
+ 1
𝑀𝐴
) 
Hence the predictive distribution of 𝑌̅𝑀𝑃and 𝑋̅𝑀𝐴given observed data are as follows 
𝑌̅𝑀𝑃|𝑑𝑎𝑡𝑎 ~𝑁(𝑦̅𝑁𝑃, 𝜎2 ( 1
𝑁𝑃
+ 1
𝑀𝑃
))                                                                  (1) 
𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎 ~𝑁(𝑥̅𝑁𝐴, 𝜎2 ( 1
𝑁𝐴
+ 1
𝑀𝐴
))                                                                  (2) 
Using (1) and (2), we have 
𝐸(𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎) = 𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴 
𝑉𝑎𝑟(𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎 ) = 𝑀𝑃
2𝑉𝑎𝑟(𝑌̅𝑀𝑃|𝑑𝑎𝑡𝑎) + 𝑀𝐴
2𝑉𝑎𝑟(𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎) 
= 𝜎2𝑀𝑃
2 ( 1
𝑁𝑃
+ 1
𝑀𝑃
) + 𝜎2𝑀𝐴
2 ( 1
𝑁𝐴
+ 1
𝑀𝐴
) 
= 𝜎2 [𝑀𝑃
2 (𝑁𝑃+ 𝑀𝑃
𝑁𝑃𝑀𝑃
) + 𝑀𝐴
2 (𝑁𝐴+ 𝑀𝐴
𝑁𝐴𝑀𝐴
)] 
= 𝜎2 (𝑀𝑃
2 𝑁𝑁
𝑁𝑃𝑀𝑃
+ 𝑀𝐴
2 𝑁𝑁
𝑁𝐴𝑀𝐴
) 
= 𝜎2𝑁𝑁(𝑀𝑃
𝑁𝑃
+ 𝑀𝐴
𝑁𝐴
) 
Hence, the predictive distribution of (𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴) given observed data is 
𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎 ~𝑁(𝑀𝑃𝑦𝑁𝑃−𝑀𝐴𝑥𝑁𝐴, 𝜎2𝑁𝑁(𝑀𝐴
𝑁𝐴
+ 𝑀𝑃
𝑁𝑃
))          (3) 
We are interested in predicting whether the as yet unobserved future data together with the 
observed data will result in a one-sided p-value for the null hypothesis(𝐻0): 𝜇𝐴−𝜇𝑃≥0, 
and the alternative hypothesis (𝐻1): 𝜇𝐴−𝜇𝑃< 0. The standard test for testing 𝐻0 versus 𝐻1 
at significance level 𝛼= 0.05 is to reject 𝐻0 if  
𝑌̅𝑁𝑁−𝑋̅𝑁𝑁
𝜎 2
𝑁𝑁
> 𝑧0.95                                                                                       (4) 


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Now we compute the predictive probability of the rejection set in (4), which is denoted as 
PP. 
𝑃𝑃= Pr
{
 
 𝑌̅𝑁𝑁−𝑋̅𝑁𝑁
𝜎 2
𝑁𝑁
> 𝑧0.95
}
 
 
                                                            
= Pr {𝑌̅𝑁𝑁−𝑋̅𝑁𝑁> 𝑧0.95𝜎√2
𝑁𝑁} 
= Pr {𝑁𝑃𝑦̅𝑁𝑃+ 𝑀𝑃𝑌̅𝑀𝑃
𝑁𝑁
−𝑁𝐴𝑥̅𝑁𝐴+ 𝑀𝐴𝑋̅𝑀𝐴
𝑁𝑁
> 𝑧0.95𝜎√2
𝑁𝑁} 
Note that the observed 𝑦̅𝑁𝑃and 𝑥̅𝑁𝐴are fixed, but the as yet unobserved (𝑌̅𝑀𝑃−𝑋̅𝑀𝐴) are 
random following the predictive distribution specified in (3). Therefore,  
𝑃𝑃= Pr {(𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴) + (𝑁𝑃𝑦̅𝑁𝑃−𝑁𝐴𝑥̅𝑁𝐴) > 𝑧0.95𝜎𝑁𝑁√2
𝑁𝑁} 
= Pr{𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴> 𝑧0.95𝜎√2𝑁𝑁−(𝑁𝑃𝑦̅𝑁𝑃−𝑁𝐴𝑥̅𝑁𝐴)} 
= Pr
{
 
 (𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴) −(𝑀𝑃𝑦𝑁𝑃−𝑀𝐴𝑥𝑁𝐴)
𝜎 𝑁𝑁(𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃)
>
𝑧0.95𝜎√2𝑁𝑁−(𝑁𝑃𝑦̅𝑁𝑃−𝑁𝐴𝑥̅𝑁𝐴) −(𝑀𝑃𝑦𝑁𝑃−𝑀𝐴𝑥𝑁𝐴)
𝜎 𝑁𝑁(𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃)
}
 
 
 
= Pr
{
 
 (𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴) −(𝑀𝑃𝑦𝑁𝑃−𝑀𝐴𝑥𝑁𝐴)
𝜎 𝑁𝑁(𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃)
>
𝑧0.95𝜎√2𝑁𝑁−𝑁𝑁(𝑦̅𝑁𝑃−𝑥̅𝑁𝐴)
𝜎 𝑁𝑁(𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃)
}
 
 
 


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= Pr
{
 
 (𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴) −(𝑀𝑃𝑦𝑁𝑃−𝑀𝐴𝑥𝑁𝐴)
𝜎 𝑁𝑁(𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃)
>
𝑧0.95𝜎√2 −√𝑁𝑁(𝑦̅𝑁𝑃−𝑥̅𝑁𝐴)
𝜎 𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃
}
 
 
 
From (3) we have  
𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴|𝑑𝑎𝑡𝑎~𝑁(𝑀𝑃𝑦𝑁𝑃−𝑀𝐴𝑥𝑁𝐴, 𝜎2𝑁𝑁(𝑀𝐴
𝑁𝐴
+ 𝑀𝑃
𝑁𝑃
)) 
Let 𝑍=
(𝑀𝑃𝑌̅𝑀𝑃−𝑀𝐴𝑋̅𝑀𝐴) −(𝑀𝑃𝑦𝑁𝑃−𝑀𝐴𝑥𝑁𝐴)
𝜎 𝑁𝑁(𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃)
,     𝑍~𝑁(0,1) 
Hence, 
𝑃𝑃= Pr
{
 
 
𝑍> 𝑧0.95𝜎√2 −√𝑁𝑁(𝑦̅𝑁𝑃−𝑥̅𝑁𝐴)
𝜎 𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃
}
 
 
 
= Pr
{  
  
𝑍> √
2
𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃
[𝑧0.95 −√𝑁𝑁𝑦̅𝑁𝑃−𝑥̅𝑁𝐴
√2𝜎
]
}  
  
 
= 1 −Pr
{  
  
𝑍≤√
2
𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃
[𝑧0.95 −√𝑁𝑁𝑦̅𝑁𝑃−𝑥̅𝑁𝐴
√2𝜎
]
}  
  
 
= 1 −Φ
{  
  
√
2
𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃
[𝑧0.95 −√𝑁𝑁
𝑦̅𝑁𝑃−𝑥̅𝑁𝐴
√2𝜎
]
}  
  
 
=  Φ
{  
  
√
2
𝑀𝐴
𝑁𝐴+ 𝑀𝑃
𝑁𝑃
[√𝑁𝑁𝑦̅𝑁𝑃−𝑥̅𝑁𝐴
√2𝜎
−𝑧0.95]
}  
  
 
By substituting 𝑁𝑁 by 82, 𝑀𝐴 by 82 −𝑁𝐴,  𝑀𝑃 by 82 −𝑁𝑃, and 𝜎 by 𝜎̂, we have 


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𝑃𝑃=  Φ
{  
  
√
2
82 −𝑁𝐴
𝑁𝐴
+ 82 −𝑁𝑃
𝑁𝑃
[√82
𝑦̅𝑁𝑃−𝑥̅𝑁𝐴
√2𝜎̂
−𝑧0.95]
}  
  
 
where 
● 
Φ stands for the cumulative distribution function for the standard normal 
distribution.  
● 
𝑦̅𝑁𝑃and 𝑥̅𝑁𝐴 are the LS means for placebo group and mirabegron group, 
respectively, and will be obtained from the ANCOVA model (using LOCF), 
described in Section 6.4.1.1 of the SAP.  
● 
𝜎̂ is the estimated pooled standard deviation and will be obtained from the same 
ANCOVA model as described above.  
Note that when the numbers of subjects observed at the interim analysis for the mirabegron 
and placebo group are equal (i.e., 𝑁𝐴= 𝑁𝑃= 𝑁), let 𝑀= 𝑁𝑁−𝑁= 82 −𝑁, the formula 
can be simplified to  
𝑃𝑃=  Φ
{
 
 
√1
𝑀
[
 
 
 
√82
𝑦̅𝑁𝑃−𝑥̅𝑁𝐴
 2
𝑁𝜎̂
−√𝑁𝑧0.95
]
 
 
 
}
 
 
, 
which is the same as the one used in the Appendix 9.4.  
 
 
 


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9.6 
Interim Analysis Report Template  
 
 
Study 178-CL-204 Interim Analysis 
Futility Analysis Results 
Generated by [IDAC Statistician’s Full Name] on ddMMMyyyy 
 
The performed Interim Analysis should determine if the chance of a positive study with 
respect to the primary endpoint at the final analysis is high enough to justify continuation of 
the study (Predictive Probability is ≥ 0.05); otherwise, the study should be stopped for 
futility. 
Based on the following statistics calculated using the data by the cut-off date ddMMMyyyy: 
• The number of subjects observed at the interim analysis for placebo and mirabegron 
group are XX and XX, respectively.  
• The least squares means for placebo group and mirabegron group are XX.X and XX.X, 
respectively, for the mean change from baseline in mean number of micturitions per 
24 hours at week12/EoT.  The results are obtained from an ANCOVA model with 
treatment group, sex and geographical region as fixed effects and the mean number of 
micturitions per 24 hours at baseline as covariate.  This analysis was performed with 
imputation of missing visit 7/week 12 data using the last observation carried forward 
(LOCF) method.  
• The estimated pooled standard deviation is XX.X, obtained from the same ANCOVA 
model as described above.  
Predictive Probability of ({final one-sided p-value of mirabegron vs. placebo ≤ 0.05}|Data) = 
0.XXX 
Hence, the study [did or did not] meet the futility criteria “Predictive Probability is ≥ 0.05”.  
The IDAC recommends the study to [continue or stop].  
 
 
 


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9.7 
Key Contributors 
 
Name, Degree, Title And Function 
Department 
 
 
Labcorp 
 
 
 
 
Data Science 
 
 
 
 
Clinical Operations 
 
 
 
Therapeutical Area 
Medical Specialties 
 
 
 
 
Therapeutical Area 
Medical Specialties 
 
 
 
PAREXEL  
 
 
 
Medical Specialties TA, 
Pharmacovigilance 
 
 
 
Data Science 
 
 
 
Labcorp 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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9.8 
Author and Approver Signatures  
Signatures 
 
 
 
 
Prepared by: 
 
Date: 
 
 
 
 
 
 
Date (DD MMM YYYY) 
 
 
 
 
 
 
 
 
Approved by: 
E-signatures are attached at end of document 
Date: 
 
 
 
 
 
 
Date (DD MMM YYYY) 
 
 
 
 
 
 
 
 
Approved by: 
E-signatures are attached at end of document 
Date: 
 
 
 
  
 
Date (DD MMM YYYY) 
   
PPD
PPD
PPD