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 Neurogenic Detrusor Overactivity (NDO) on Clean Intermittent Catheterization (CIC)
Phase: PHASE3
Conditions: Neurogenic Detrusor Overactivity
Sponsor: Astellas Pharma Europe B.V.

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 Neurogenic Detrusor Overactivity (NDO) on Clean 
Intermittent Catheterization (CIC)
Open-label Phase 3 Study with Mirabegron in Children From 3 to 
Less Than 18 Years of Age with Neurogenic Detrusor 
Overactivity (Crocodile Study)
ISN/Protocol 178-CL-206A
ClinicalTrials.gov Identifier: NCT02751931
Date of Protocol v2: 02 Nov 2016
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden, the Netherlands

Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
- CONFIDENTIAL -
02 Nov 2016
Astellas
Page 1 of 151
Version 2.0 Incorporating Substantial Amendment 1
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 Neurogenic Detrusor 
Overactivity (NDO) on Clean Intermittent Catheterization (CIC)
Open-label Phase 3 Study with Mirabegron in Children from 3 to Less 
Than 18 Years of Age with Neurogenic Detrusor Overactivity (Crocodile 
Study)
ISN/Protocol 178-CL-206A
Version 2.0
Incorporating Substantial Amendment 1 [See Attachment 1]
02 November 2016
EudraCT 2015-002876-25
Sponsor:
Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden, the Netherlands
Protocol History: 
Version 1.0 [09 Dec 2015]
Investigator:  Investigator information is on file at Astellas
--------------------------------------------------------------------------------------------------------------------------------------
This confidential document is the property of the Sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.

Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
- CONFIDENTIAL -
02 Nov 2016
Astellas
Page 2 of 151
Version 2.0 Incorporating Substantial Amendment 1
Table of Contents
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································15
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································25
1
INTRODUCTION·················································································28
1.1
Background ····················································································28
1.2
Nonclinical and Clinical Data ·······························································29
1.2.1
Nonclinical Data·········································································29
1.2.2
Clinical Data ·············································································31
1.3
Summary of Key Safety Information for Study Drugs ···································34
1.4
Risk-Benefit Assessment·····································································34
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································37
2.1
Study Objectives ··············································································37
2.1.1
Primary Objectives: ·····································································37
2.1.2
Secondary Objectives: ··································································37
2.2
Study Design and Dose Rationale···························································37
2.2.1
Study Design·············································································37
2.2.1.1
Pretreatment Period································································37
2.2.1.2
Efficacy Treatment Period························································38
2.2.1.3
Long-term Safety Period··························································39
2.2.2
Dose Rationale···········································································39
2.3
Endpoints·······················································································40
2.3.1
Primary Efficacy Endpoint·····························································40
2.3.2
Secondary Efficacy Endpoints·························································40
2.3.2.1
Urodynamic Measures ····························································40
2.3.2.2
Bladder Volume and Leakage Measures········································40
2.3.2.3
Patient- or Clinician-reported Questionnaire Endpoints ······················41
2.3.3
Safety Endpoints·········································································41
2.3.4
Pharmacokinetics········································································41
2.3.5
Exploratory Endpoints··································································42
2.3.5.1
Exploratory Efficacy Endpoints··················································42

Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
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Version 2.0 Incorporating Substantial Amendment 1
2.3.5.2
Exploratory Safety Endpoints····················································42
3
STUDY POPULATION··········································································42
3.1
Selection of Study Population ·······························································42
3.2
Inclusion Criteria··············································································42
3.3
Exclusion Criteria·············································································44
4
TREATMENTS····················································································45
4.1
Identification of Investigational Products ··················································45
4.1.1
Test Drug·················································································45
4.1.2
Comparative Drug(s)····································································46
4.2
Packaging and Labeling······································································46
4.3
Study Drug Handling ·········································································46
4.4
Blinding ························································································47
4.5
Assignment and Allocation ··································································47
4.5.1
Subject Numbering······································································47
4.5.2
Subject Replacement····································································47
5
TREATMENTS AND EVALUATION························································47
5.1
Dosing and Administration of Study Drug·················································47
5.1.1
Dose/Dose Regimen and Administration Period ····································47
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································48
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ··················································································49
5.1.4
Treatment Compliance··································································49
5.1.5
Restrictions for Foods and Drinks During the Study································49
5.2
Demographics and Baseline Characteristics ···············································49
5.2.1
Demographics············································································49
5.2.2
Medical History··········································································49
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············50
5.3
Efficacy and Pharmacokinetics Assessment ···············································50
5.3.1
Urodynamic Assessments ······························································50
5.3.2
Bladder Diary ············································································51
5.3.3
Questionnaires ···········································································52
5.3.4
Pharmacokinetics········································································53
5.4
Safety Assessments ···········································································54

Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
- CONFIDENTIAL -
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Version 2.0 Incorporating Substantial Amendment 1
5.4.1
Vital Signs················································································54
5.4.1.1
Clinic Measurement of Vital Signs··············································54
5.4.1.2
Self-measurement of Vital Signs ················································54
5.4.2
Adverse Events ··········································································55
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································55
5.4.3
Laboratory Assessments································································55
5.4.4
Physical Examination···································································56
5.4.5
Electrocardiograms······································································56
5.4.6
Self-measurement of Intravesical Pressure···········································57
5.4.7
Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound·····58
5.5
Adverse Events and Other Safety Aspects ·················································59
5.5.1
Definition of Adverse Events ··························································59
5.5.2
Definition of Serious Adverse Events ················································59
5.5.3
Criteria for Causal Relationship to the Study Drug ·································60
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························61
5.5.5
Reporting of Serious Adverse Events·················································61
5.5.6
Follow-up of Adverse Events··························································62
5.5.7
Monitoring of Common Serious Adverse Events ···································62
5.5.8
Procedure in Case of Pregnancy·······················································62
5.5.9
Emergency Procedures and Management of Overdose ·····························63
5.5.10
Supply of New Information Affecting the Conduct of the Study··················63
5.6
Test Drug Concentration ·····································································63
5.7
Other Measurements, Assessments or Methods ···········································63
5.8
Total Amount of Blood·······································································64
6
DISCONTINUATION············································································64
6.1
Discontinuation of Individual Subject(s)···················································64
6.2
Discontinuation of the Site···································································65
6.3
Discontinuation of the Study ································································65
7
STATISTICAL METHODOLOGY ···························································65
7.1
Sample Size····················································································65
7.2
Analysis Set····················································································66
7.2.1
Full Analysis Set ········································································66
7.2.2
Per Protocol Set··········································································66
7.2.3
Safety Analysis Set······································································67

Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
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02 Nov 2016
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Page 5 of 151
Version 2.0 Incorporating Substantial Amendment 1
7.2.4
Pharmacokinetics Analysis Set ························································67
7.3
Demographics and Other Baseline Characteristics········································67
7.4
Analysis of Efficacy ··········································································67
7.4.1
Analyses of Primary Endpoint·························································67
7.4.1.1
Primary Analysis···································································67
7.4.1.2
Secondary Analyses ·······························································68
7.4.1.3
Subgroup and Sensitivity Analyses of Primary Endpoint·····················68
7.4.2
Analysis of Secondary Endpoints ·····················································68
7.4.3
Analysis of Exploratory Endpoints····················································69
7.5
Analysis of Safety·············································································69
7.5.1
Vital Signs················································································69
7.5.2
Adverse Events ··········································································69
7.5.3
Laboratory Assessments································································69
7.5.4
Physical Examination···································································70
7.5.5
Electrocardiograms······································································70
7.5.6
Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound·····70
7.5.7
Analysis of Exploratory Endpoints····················································70
7.6
Analysis of Pharmacokinetics ·······························································70
7.6.1
Estimation of Pharmacokinetic Parameters ··········································71
7.7
Protocol Deviations and Other Analyses···················································71
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················71
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········71
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················72
8.1
Procedure for Clinical Study Quality Control ·············································72
8.1.1
Data Collection ··········································································72
8.1.1.1
Electronic Patient Reported Outcomes··········································72
8.1.2
Specification of Source Documents···················································73
8.1.3
Clinical Study Monitoring······························································74
8.1.4
Direct Access to Source Data/Documents············································74
8.1.5
Data Management ·······································································74
8.1.6
Protocol Deviations ·····································································74
8.1.7
End of Trial in All Participating Countries···········································75
8.2
Ethics and Protection of Subject Confidentiality··········································75
8.2.1
Independent Ethics Committee/Competent Authorities ····························75

Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
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8.2.2
Ethical Conduct of the Study···························································76
8.2.3
Informed Consent of Subjects ·························································76
8.2.3.1
Subject Information and Consent················································76
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information·····························77
8.2.4
Subject Confidentiality ·································································78
8.3
Administrative Matters ·······································································78
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····78
8.3.2
Documents and Records Related to the Clinical Study·····························78
8.3.3
Protocol Amendment and/or Revision················································79
8.3.4
Insurance of Subjects and Others······················································79
8.3.5
Signatory Investigator for Clinical Study Report····································79
9
QUALITY ASSURANCE········································································80
10
STUDY ORGANIZATION······································································80
10.1
Independent Data-Monitoring Committee | Data and Safety Monitoring Board | 
Monitoring Committee | Other Evaluation Committee(s)································80
10.2
Other Study Organization ····································································80
11
REFERENCES ····················································································81
12
APPENDICES ·····················································································83
12.1
List of Excluded Concomitant Medications ···············································83
12.2
Liver Safety Monitoring and Assessment··················································84
12.3
Laboratory Assessments······································································87
12.4
Pediatric Incontinence Questionnaire·······················································88
12.5
Patient Global Impression of Severity Scale···············································89
12.6
Acceptability Questionnaire for Tablets····················································90
12.7
Acceptability Questionnaire for Oral Suspension·········································91
12.8
Clinical Global Impression of Change Scale ··············································93
12.9
Centiles of heart rate for normal children from birth to 18 years of age [Fleming 
et al, 2011] ·····················································································94
12.10
CDC Data Table of Stature-for-age Chart for Males ·····································95
12.11
CDC Data Table of Stature-for-age Chart for Females································· 102
12.12
Blood Pressure Levels for Boys by Age and Height Percentile [NIH 2005]········· 109
12.13
Blood Pressure Levels for Girls by Age and Height Percentile [NIH 2005]········· 111

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13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 1 ······························· 113
14
SPONSOR’S SIGNATURES·································································· 151
List of Tables
Table 1
Schedule of Assessments·····································································26
Table 2
Overview of Current Supporting Mirabegron Studies in the Pediatric Clinical 
Development Program for NDO and OAB ················································31
Table 3
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) ····························································33
Table 4
Weight-based Doses for Tablets or Suspension ···········································48
Table 5
Total Amount of Blood Volume per Subject During the Study Period·················64

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I.
SIGNATURES
1.  SPONSOR’S SIGNATURE
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 14, Sponsor’s Signatures; e-Signatures (when applicable) are located at the 
end of this document.

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2.  INVESTIGATOR’S SIGNATURE
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 Neurogenic Detrusor Overactivity (NDO) on Clean 
Intermittent Catheterization (CIC)
ISN/Protocol 178-CL-206A
Version 2.0 Incorporating Substantial Amendment 1
02 November 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor.  I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein.  I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations.  I will also ensure that sub-investigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents.
Principal Investigator:
Signature:
<Insert name and qualifications of the investigator>
Printed Name:
Date (DD Mmm YYYY)
Address:

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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviation
Description 
APEB
Astellas Pharma Europe B.V.
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase 
AUC24
Area under the plasma concentration-time curve from time zero to 24 h
CIC
clean intermittent catheterization
CGI-C
Clinician Global Impression of Change
CL/F
apparent total clearance of the drug from plasma after oral administration
Cmax
maximum (peak) plasma drug concentration
CRO
contract research organization
CSR
clinical study report
Ctrough
trough plasma concentration (measured concentration at the end of a dosing 
interval at steady state)
CYP
cytochrome P450
DSD
detrusor sphincter dyssynergia
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
eGFR
estimated glomerular filtration rate
EOS
end of study
EOT
end of treatment
FAS
full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH 
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMPD
Investigational Medicinal Product Dossier
INR
international normalized ratio
ISN
international study number
IUD
intrauterine device
IUS
intrauterine system
LA-CRF
liver abnormality case report form
LC-MS/MS
liquid chromatography-mass spectrometry and tandem mass spectrometry
LOCF
last observation carried forward
LFT
liver function test
LQTS
long QT syndrome
MCC
maximum cystometric capacity
NDO
neurogenic detrusor overactivity
OAB
overactive bladder
PED
pediatric equivalent dose

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Abbreviation
Description 
PGI-S
Patient Global Impression of Severity Scale
P-gp
P-glycoprotein
PIN-Q
Pediatric Incontinence Questionnaire
PKAS
pharmacokinetics analysis set
PND
postnatal day
popPK
population pharmacokinetics
PPS
per protocol set
QTcB
QT interval corrected by Bazett’s formula
QTcF
QT interval corrected by Fridericia's formula
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SBPM
self blood pressure measurement
SMIP
self-measurement of intravesical pressure
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
TBL
total bilirubin
TLF
tables, listings and figures
tmax
time to reach maximum (peak) plasma concentration following drug 
administration
ULN
upper limit of normal
UTI
urinary tract infection
Vz/F
apparent volume of distribution after nonintravenous administration

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Definition of Key Study 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.  
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 completion
Status of subject who completed the last protocol-defined assessment.
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.

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Terms
Definition of terms
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 drug.

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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
02 November 2016, Version 2.0
Sponsor:  
Astellas Pharma Europe BV (APEB)
Protocol Number:  
178-CL-206A
Name of Study Drug:
Mirabegron
Phase of Development:  
Phase 3
Title of Study:  
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 Neurogenic Detrusor Overactivity 
(NDO) on Clean Intermittent Catheterization (CIC)
Planned Study Period: 
From 2Q2016 to 3Q2019.
Study Objectives:
Primary objective:
To evaluate the efficacy of mirabegron after multiple-dose administration in the pediatric 
population.  
Secondary objectives:
To evaluate the safety and tolerability of mirabegron after multiple-dose administration in the 
pediatric population.
To evaluate the pharmacokinetics of mirabegron after multiple-dose administration in the pediatric 
population.
Planned Total Number of Study Centers and Location(s):  
Approximately 50 enrolling study centers in Europe, Latin America, Africa, Middle East and
Asia-Pacific.
Study Population:  
Male and female pediatric child and adolescent subjects aged 3 to less than 18 years of age with 
neurogenic detrusor overactivity (NDO) on clean intermittent catheterization (CIC).
Number of Subjects to be Enrolled/Randomized:  
At least 44 evaluable subjects (estimate 63 enrolled), with at least 10 subjects from each age group 
(children aged 3 to less than 12 years of age; adolescents aged 12 to less than 18 years of age) are 
planned.  A subject is considered being evaluable if the subject has a valid (as by the central 
reviewer’s assessment) nonmissing maximum cystometric capacity (MCC) measurement at baseline 
and at a postbaseline visit.
Study Design Overview:  
This is a phase 3, open-label, baseline-controlled, multicenter study. The study will consist of 
3 periods:
Pretreatment period: for a maximum of 28 days before baseline, including screening, washout 
(if applicable) and baseline 
Efficacy treatment period: beginning the day after baseline and continuing to visit 8/week 24
Long-term safety period: beginning after visit 8/week 24 and continuing to visit 10/week 52 (end 
of study [EOS]), or to the end of treatment (EOT) 

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Pretreatment Period
After informed consent and visit 1/screening, subjects are grouped according to their current NDO 
therapy and/or other medication: 
Group A:  Subjects who are currently not receiving any prohibited medication including any oral 
drug treatment to manage their NDO, or when botulinum toxin is no longer considered 
effective
Group B:   Subjects who currently are receiving oral drug treatment to manage their NDO or 
receive any other prohibited medication.
After the screening visit a 2-day weekend e-diary has to be completed by the subjects to get 
acquainted with the electronic diary (e-diary) and the home assessments:
Group A: Following successful completion of the first 2-day weekend e-diary, confirmed at visit 2, 
the subjects will start to complete the 7-day baseline e-diary followed by visit 3/baseline.
Group B: Following successful completion of the first 2-day weekend e-diary, confirmed at visit 2, 
the subjects will start their 2-week washout period.  In the second week of their washout 
period, they will complete the 7-day baseline e-diary followed by visit 3/baseline.  
If a subject is suffering from a symptomatic urinary tract infection (UTI) at visit 1/screening or is 
diagnosed with one between visit 1/screening and visit 3/baseline, the UTI should be treated 
successfully (clinical recovery) prior to baseline. If a symptomatic UTI is present at baseline, all 
baseline assessments should be postponed for a maximum of 7 days until the UTI is successfully 
treated (clinical recovery). 
The 7-day baseline e-diary does not have to be repeated if at least the 2-day weekend e-diary and 
1 day of the weekday e-diary were completed while the subject did not suffer from a symptomatic 
UTI.  
Subjects will enter the efficacy treatment period if they meet the eligibility criteria and satisfactorily 
complete the pretreatment period (ability to complete bladder diary, catheterized volumes and 
questionnaires).  
In case the subject or the subject’s parent(s)/caregiver(s) are not able or willing to perform the SMIP, 
the measuring device is not available at the site, or there is a technical problem, the SMIP may be 
omitted.
Efficacy Treatment Period
Daily study drug administration will begin the day after the baseline visit.  The initial dose of 
mirabegron will be based on the subject's weight, and is predicted to achieve plasma concentrations 
equivalent to the steady state exposures expected with 25 mg mirabegron administered once daily in 
adults (pediatric equivalent dose [PED25]).
At visit 4/week 2, visit 5/week 4 or visit 6/week 8, subjects must be up-titrated to the pediatric 
equivalent dose of 50 mg in adults (PED50) based on the given dose titration criteria.  
At visit 8/week 24, the primary efficacy endpoint will be assessed, which is the change from baseline 
in MCC.
If a subject is suffering from a symptomatic UTI in the week prior to any (un)scheduled urodynamic 
investigation (e.g., visit 5/week 4, visit 8/week 24), the UTI should be treated successfully first (until 
clinical recovery). To allow for treatment of the UTI, these visits may be postponed with an additional 
maximum of 7 days on top of the already existing visit window. 
The 7-day e-diary does not have to be repeated if at least the 2-day weekend e-diary and 1 day of the 
weekday e-diary were completed while the subject did not suffer from a symptomatic UTI.  
If a subject suffers from a symptomatic UTI in the week prior to any other study visit, these visits do 
not need to be postponed and the 7-day e-diary does not have to be repeated.

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Long-term Safety Period
For long-term safety evaluation, following visit 8/week 24, subjects will stay on their individual dose 
level until visit 10/week 52 (EOS or EOT).
Dose Titration 
The aim is to obtain a safe low-pressure bladder, to inhibit overactive detrusor contractions and to 
reach continence. 
Dose up-titration to PED50 must be performed at visit 4/week 2, visit 5/week 4 or visit 6/week 8, 
unless: 
1.
The investigator considers the subject to be effectively treated with PED25, based on 
urodynamics and the e-diary;
2.
There are safety or tolerability issues with PED25.
Dose down-titration to PED25 can be performed at any time if there is a safety issue.
If an insufficient control of the NDO is observed at the highest tolerated mirabegron dose due to 
insufficient effect (based on, for example, ultrasound showing upper tract dilation; the appearance of 
a high grade reflux; high intravesical pressures; high detrusor pressures or high amplitude overactive 
contractions), the investigator should reconsider the subject’s further participation in the study and 
consider an alternative treatment.
Inclusion/Exclusion Criteria:  
Inclusion:  
Subject is eligible for the study if all of the following apply:
1.
Independent Ethics Committee (IEC)/Institutional Review Board (IRB)-approved written 
Informed Consent and privacy language as per national regulations must be obtained from the 
subject and/or from the subject’s parent(s) or legal guardian(s) prior to any study-related 
procedures (including discontinuation of prohibited medication, if applicable); assent by the 
subject is given as required by local law.  
2.
Subject is male or female from 3 to less than 18 years of age.
3.
Subject has a body weight of ≥ 11 kg.
4.
Subject suffers from NDO confirmed by urodynamic investigation at baseline. The diagnosis of 
NDO must be confirmed by the presence of at least 1 involuntary detrusor contraction > 15 cm 
H2O from baseline detrusor pressure, and/or a decrease in compliance leading to an increase in 
baseline detrusor pressure of > 20 cm H2O.
5.
Subject has been using CIC for at least 4 weeks prior to visit 1/screening.  
6.
Subject has a current indication for drug therapy to manage NDO.  
7.
Subject is able to take the study drugs in accordance with the protocol.
8.
Female subject must either:
Be of nonchildbearing potential:
o
Clearly premenarchal or in the judgment of the investigator is premenarchal,
o
Documented surgically sterile,
Or, if of childbearing potential:
o
Agree not to try to become pregnant during the study and for 28 days after the final study 
drug administration, 
o
And have a negative pregnancy test at visit 1/screening and at visit 3/baseline,
o
And, if sexually active must agree to use a highly effective method of birth control, which 
includes established use of oral, injected or implanted hormonal methods of 
contraception, OR placement of an intrauterine device (IUD) or intrauterine 
system (IUS). Birth control must be practiced from visit 1/screening and continuing 
throughout the study period, and for 28 days after the final study drug administration.

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9.
Male subject and their female spouse/partner who are of childbearing potential must be using a 
highly effective method of birth control, which includes established use of oral, injected or 
implanted hormonal methods of contraception, placement of an IUD or IUS.  Birth control must 
be practiced from visit 1/screening and continuing throughout the study period, and for 
28 days after the final study drug administration.
10. Female subject must not be breastfeeding from visit 1/screening until 28 days after last study drug 
administration.
11. Subject and subject’s parent(s)/legal guardian(s) agree that the subject will not participate in 
another interventional study while participating in the study.
12. 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.  
Waivers to the inclusion criteria will NOT be allowed.
Exclusion:  
Subject will be excluded from participation if any of the following apply:
1.
Subject has a known genitourinary condition (other than NDO) that may cause overactive 
contractions or incontinence (e.g., bladder extrophy, urinary tract obstruction, urethral 
diverticulum or fistula) or kidney/bladder stones or another persistent local pathology that may 
cause urinary symptoms.
2.
Subject has one of following gastrointestinal problems: partial or complete obstruction, decreased 
motility such as paralytic ileus, subject at risk of gastric retention.
3.
Subject has a urinary indwelling catheter within 4 weeks prior to visit 1/screening
4.
Subject has a surgically treated underactive urethral sphincter
5.
Subject has vesico-ureteral reflux grade 3 to 5.
6.
Subject has undergone bladder augmentation surgery.
7.
Subject receives electrostimulation therapy, if started within 30 days before visit 1/screening or is 
expected to start during the study period.  Subjects who are on an established regimen may remain 
on this for the duration of the study.
8.
Subject suffers from a symptomatic urinary tract infection (UTI) at baseline (symptomatic is 
defined as pain, fever, hematuria, new onset foul-smelling urine). If present at visit 1/screening or 
diagnosed between visit 1/screening and visit 3/baseline, the UTI should be treated successfully 
(clinical recovery) prior to baseline. If a symptomatic UTI is present at baseline, all baseline 
assessments should be postponed for a maximum of 7 days until the UTI is successfully treated 
(clinical recovery).  
9.
Subject has a (mean) resting pulse rate > 99th percentile [Fleming et al, 2011]. 
10. Subject has an established hypertension and a systolic or diastolic blood pressure greater than the 
99th percentile of the normal range determined by sex, age and height, plus 5 mmHg 
[NIH 2005].
11. Subject has a risk of QT prolongation (e.g., hypokalemia, long QT syndrome [LQTS]; or family 
history of LQTS, exercise-induced syncope).  
12. Subject has severe renal impairment (estimated glomerular filtration rate [eGFR] according to 
Larsson equation < 30 mL/min).
13. Subject’s aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is greater than or 
equal to 2 times the upper limit of normal (ULN) or total bilirubin greater than or equal to 1.5 
times the ULN according to age and sex.

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14. Subject has a history or presence of any malignancy prior to visit 1/screening.
15. Subject has known or suspected hypersensitivity to mirabegron, any of the excipients used in the 
current formulations or previous severe hypersensitivity to any drug.
16. Subject has participated in another clinical trial (and/or has taken an investigational drug) within 
30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is longer) prior to 
visit 1/screening.
17. Subject uses any of the following prohibited medications (after start of washout): 
Any medication, other than the study drug, used for the management of NDO;
Any drugs that are sensitive cytochrome (CYP) 2D6 substrates with a narrow therapeutic 
index or sensitive P-glycoprotein (P-gp) substrates
Any strong cytochrome P450 (CYP) 3A4 inhibitors if the subject has a mild to moderate renal 
impairment (eGFR 30 – 89 mL/min).
18. Subject has been administered intravesical botulinum toxin; except if given > 4 months prior to 
visit 1/screening and the subject experiences symptoms comparable to those existing prior to the 
botulinum toxin injections.
19. Subject has any other condition, which in the opinion of the Investigator, precludes the subject’s 
participation in the study.
20. Subject’s parent/legal guardian is an employee of the Astellas Group, the Contract Research 
Organization (CRO) involved, or the investigator site executing the study.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Products:
Mirabegron prolonged-release tablets, strengths 25 mg and 50 mg
Mirabegron oral suspension, strength 8 mg/mL
Doses:  
Selection of the formulation:
Subjects with a body weight < 35 kg: mirabegron oral suspension. 
Subjects with a body weight ≥35 kg: mirabegron tablets.
Selection of the dose:
Doses are calculated weight-based. The bodyweight at visit 3/baseline determines the weight range 
for the starting dose (PED25) and the up-titration dose (PED50) to be used in the table below:
Weight-based Doses for Tablets or Suspension
Weight Range 
Suspension Volume †
Tablet Dose 
PED25
11 - < 22 kg
3 mL
-
22 - < 35 kg
4 mL
-
≥ 35 kg
6 mL
25 mg
PED50
11 - < 22 kg
6 mL
-
22 - < 35 kg
8 mL
-
≥ 35 kg
11 mL
50 mg
PED25: Pediatric equivalent dose 25 mg; PED50: Pediatric equivalent dose 50 mg 
† Suspension strength: 8 mg/mL

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Further dosing information:
For subjects with a body weight ≥ 35 kg who do not want to or are unable to take tablets, the oral 
suspension can be supplied.
At visit 8/week 24 subjects on mirabegron oral suspension may switch to tablets if the body weight 
turns to be ≥ 35 kg.
Subjects receiving mirabegron tablets can switch to mirabegron oral suspension (and vice versa) 
for acceptability reasons after Sponsor’s prior approval and on a case-by-case basis.
Mode of Administration:
Study drug will be taken orally, once a day in the morning around the same time of day and around
time of food intake (i.e., within 1 hour before or after breakfast). 
Mirabegron tablets will be taken with a sip of water (tablet should be taken as a whole and should not 
be chewed, divided or crushed).
Mirabegron oral suspension will be administered via an oral syringe with a sip of water afterwards.
On visit days where a pharmacokinetic sample is planned in the clinic, completion of breakfast and 
study drug dosing should occur in the clinic.
Comparative Drug(s):
Not applicable
Dose(s):
Not applicable
Mode of Administration:
Not applicable
Concomitant Medication Restrictions or Requirements:   
During the study, starting from visit 2 until visit 10/week 52 (EOT/EOS), subjects are not allowed to 
use treatment with any of the following prohibited medications:
Any medication, other than the study drug, used for the management of NDO.
Any drugs that are sensitive CYP2D6 substrates with a narrow therapeutic index or sensitive P-gp 
substrates
Any strong CYP 3A4 inhibitors if the subject has a mild to moderate renal impairment (eGFR 30 –
89 mL/min).
Duration of Treatment:  
Once a day for 52 weeks
Formal Stopping Rules:
Criteria for treatment discontinuation for individual subjects:
If, within 7 days of the first dose of mirabegron:
o The centrally read urodynamic trace reveals no evidence of NDO
o The centrally read electrocardiogram (ECG) has an average QT interval corrected by Bazett’s 
formula (QTcB)  greater than 450 ms, based on the QTcB mean from the visit 1/screening and 
visit 3/baseline ECG triplicates
If signs or symptoms of hypersensitivity to mirabegron are observed (e.g., anaphylactic reaction, 
erytheme multiforme or exfoliative dermatitis).
Discontinuation of treatment should be considered if:
o ALT or AST > 8 × ULN
o ALT or AST > 5 × ULN for more than 2 weeks 
o ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated)

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o ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
o In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests is 
not possible, the drug should be discontinued.
Endpoints for Evaluation:  
Primary: 
Efficacy
Change from baseline in MCC after 24 weeks of treatment (based on filling urodynamics)
Secondary:
Efficacy
Based on filling urodynamics:
Change from baseline at visit 5/week 4 and visit 8/week 24 in:

MCC (only visit 5/week 4)

Bladder compliance (∆V/∆P) 

Number of overactive detrusor contractions (> 15 cm H20) until end of filling 

Detrusor pressure at end of filling

Filling volume until first overactive detrusor contraction (> 15 cm H20)
Based on e-diary:
Change from baseline at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 
24, visit 9/week 36 and visit 10/week 52 (EOT/EOS) in:

Average catheterized volume per catheterization

Maximum catheterized volume

Maximum catheterized daytime volume 

Average morning catheterized volume (based on first catheterization after subject woke up)

Mean number of leakage episodes per day (day and night time)

Number of dry (leakage-free) days/7 days (day and night time)
Based on questionnaires:

Change from baseline at visit 8/week 24 and visit 10/week 52 (EOT/EOS) in Pediatric 
Incontinence Questionnaire (PIN-Q) 

Change from baseline at visit 8/week 24 and visit 10/week 52 (EOT/EOS) in Patient Global 
Impression of Severity Scale (PGI-S) 

Acceptability questionnaire at visit 5/week 4, visit 8/week 24 and visit 10/week 52 (EOT/EOS)

Clinician Global Impression of Change (CGI-C) at visit 8/week 24 and visit 10/week 52 
(EOT/EOS) 
Safety

Incidence and severity of treatment-emergent adverse events (TEAEs)

Change from baseline in vital signs (clinic measurements): systolic blood pressure, diastolic 
blood pressure, pulse rate and temperature at visit 5/week 4, visit 7/week 12, visit 8/week 24 and 
visit 10/week 52 (EOT/EOS)

Change from baseline in vital signs (self blood pressure measurement [SBPM]): systolic 
blood pressure, diastolic blood pressure, pulse rate at visit 4/week 2, visit 5/week 4, visit 6/week 
8, visit 7/week 12, visit 8/week 24, visit 9/week 36 and visit 10/week 52 (EOT/EOS) and on 2 
consecutive days at around 1 and 2 weeks after start of dosing with PED25 (day 1) and after 
up-titration to PED50 (visit 4/week 2, visit 5/week 4 or visit 6/week 8), if not already covered by 
the scheduled visit 4/week 2 and/or visit 5/week 4 SBPM.

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
Change from baseline in hematology and biochemistry tests at visit 7/week 12 and visit 10/week 
52 (EOT/EOS) and urinalysis tests at visit 5/week 4, visit 7/week 12, visit 8/week 24 and visit 
10/week 52 (EOT/EOS)

Change from baseline in ECG parameters at visit 5/week 4, visit 7/week 12, visit 8/week 24  and 
visit 10/week 52 (EOT/EOS)

Change from baseline to visit 10/week 52 (EOT/EOS) in upper urinary tract ultrasound 
assessment

Change from baseline in eGFR at visit 7/week 12 and visit 10/week 52 (EOT/EOS)
Pharmacokinetics of mirabegron 

Cmax, tmax, AUC24, Ctrough, CL/F and Vz/F.  

Additional pharmacokinetic parameters may be calculated based on the model used.  
Exploratory: 
Efficacy:
Based on filling urodynamics:
Change from baseline at visit 5/week 4 and visit 8/week 24 in:

Filling volume at 20 cm, 30 cm and at 40 cm H2O detrusor pressure, given that the pressures are 
reached during the examination.
Based on e-diary:
Change from baseline at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 
24, visit 9/week 36 and visit 10/week 52 (EOT/EOS) in:

Mean grade of leakage 

Total catheterized volume per day

Change from baseline in SMIP-derived bladder compliance

Number of CICs/day

Responder in respect to leakage (complete, partial, no response)
Safety:
Intravesical pressure (SMIP):

Change from baseline at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 
8/week 24, visit 9/week 36 and visit 10/week 52 (EOT/EOS).
Body weight and height:

Change from baseline at visit 8/week 24 and visit 10/week 52 (EOT/EOS).
Assessments:
Urodynamic Assessments:
Subjects will undergo urodynamic assessment at baseline, visit 5/week 4 and visit 8/week 24.  
Additional urodynamic assessments can be performed at visit 10/week 52 (EOT/EOS), or at any other 
time point when deemed necessary by the investigator. 
Patient-reported Outcome Data: 
The following information will be collected and entered by the subject or the subject’s 
parent(s)/caregiver(s) at home in the e-diary during the week preceding the visits as indicated in the 
Schedule of Assessments.
Bladder diary:
o
Each day for 7 days: time of CICs
o
Each day for 7 days: presence of leakage between CICs

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o
Each day for 7 days: sleep time and wake-up time
o
On the 2 weekend days: catheterized volume 
o
On the 2 weekend days: SMIP (if applicable)
o
On the 2 weekend days: grade and number of leakages between CICs
o
On the 2 weekend days (visit 3/baseline and visit 8/week 24): weight of diaper/pad
SBPM (blood pressure and pulse rate): 
o
On the 2 weekend days: triplicate measurements in the morning and evening
o
On 2 consecutive 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.
Questionnaires: on 1 weekend day at selected visits
o
PIN-Q
o
PGI-S
o
Acceptability
Confirmation of study drug intake: daily
The Investigator must guide the subject and subject’s parent(s)/caregiver(s) to ensure that on the 
evening before and during the two weekend days of collection of catheterized volume and SMIP (if 
applicable), the subject’s fluid intake should be regulated to an appropriate level taking 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.
At the screening visit, detailed on-site training of the e-diary and the assessments and a booklet with 
operating instructions in local language will be provided to the subject and the subject’s 
parent(s)/caregiver(s). 
Pharmacokinetics:
When the subject reached steady state of her/his optimal dose, a total of 4 pharmacokinetic samples 
will be collected divided over 2 sampling days: 
Sampling day 1: 1 sample prior to dosing (i.e., trough sample).
Sampling day 2: 1 trough and 2 postdose samples between 2h and 5h postdose, with at least 1 hour 
in between the samples.  
On visit days where a pharmacokinetic sample is planned in the clinic, completion of breakfast and 
study drug dosing should occur in the clinic. Dosing must occur within 1 hour after completion of 
breakfast. Dosing time on the sampling day and dosing time of the previous day will be collected.  In 
addition to the dosing time, the time of completion of breakfast, and type of breakfast will be 
collected in the eCRF on the sampling day with postdose sampling.
Safety:
During the study collection of adverse events (AEs), vital signs, body temperature, laboratory tests, 
ECG parameters, renal function, and height and weight will take place.
Statistical Methods:
Sample size justification: 
In order to allow the detection of a statistically significant change from baseline in MCC in the 
overall NDO with CIC study population with 90% power, 44 evaluable subjects for the assessment of 
the endpoint need to be enrolled, i.e., subjects with a valid (as by the central reviewer’s assessment)
nonmissing MCC measurement at baseline and at a postbaseline visit. The power calculation is based 
upon a paired t-test with a 2-sided significance level of 0.05, an expected change from baseline of at 
least 52 mL and a SD of not larger than 103 mL. Assuming 30% of enrolled subjects will not be 
evaluable, a total of approximately 63 subjects may need to be enrolled.  
Four analysis populations will be defined: the safety analysis set (SAF), full analysis set (FAS), per 
protocol set (PPS), and pharmacokinetics analysis set (PKAS) for pharmacokinetic population 
analysis.

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Efficacy:  
The primary analysis will be a paired t-test for the change from baseline to visit 8/week 24 for 
subjects included in the FAS to test the hypothesis that the change from baseline in MCC is not equal 
to zero with a 2-sided alpha level of 0.05. A 95% CI will be calculated for mean change from baseline 
and it will be assessed whether the estimated lower bound of the interval is greater than zero.
Additionally 95% CIs per age group will be presented.
Continuous secondary efficacy variables will be analyzed in the same way as the primary efficacy 
variable. Discrete secondary efficacy variables will be analyzed descriptively.
Pharmacokinetics:  
Pharmacokinetic parameters will be summarized for the PKAS using descriptive statistics.
Pharmacodynamics:  
Not applicable.
Safety:  
Safety endpoints will be summarized for the SAF using descriptive statistics. Safety parameters such 
as vital signs, height and weight will also be summarized with respect to age- and sex-specific 
percentiles.  
Other Analyses:  
Descriptive statistics will be used to explore whether there is an association between certain subject
characteristics (such as medical history) and the final titrated mirabegron doses. Collected data on 
study drug compliance rates and maintenance of treatment will be analyzed using descriptive statistics
Interim analyses: 
Not applicable.

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†
For the visits where a TC is indicated there is no need for the subject to visit the clinic, provided that the e-diary data is reviewed by the investigator prior to the TC and discussed and confirmed with 
the subject or the subject’s parent(s)/caregiver(s) during the TC.
‡
Subjects who withdraw early from the study after having received study drug should complete the EOS visit. If the final dose is reached before the last possibility for up-titration at 8 weeks, the fixed-
dose treatment period will be extended to keep the entire treatment period 364 days as a minimum. The maximum is 378 days in order to allow for visit windows.
§
Triplicate vital signs with an interval of approximately 2 minutes 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. Clinic measurements will be used to assess eligibility. Single measurements for body temperature must be performed with an 
ear thermometer.  
¶
Triplicate 12-lead ECG with an interval of about 30 seconds to 5 minutes in the supine position (when possible, but always in the same position).  Subject should have been calm and without distress 
for at least 5 minutes.  
††
Additional hematology/biochemistry taken at baseline only if an AE related to hematology/biochemistry parameters occurred between visit 1/screening and visit 3/baseline. The first group of subjects 
(minimum of 5, maximum of 10) who reach study visit 5/week 4 will have an additional blood draw for a DSMB-mandated interim safety check at this visit. For sampling, preferably the left arm 
should be used. Blood sampling should occur after vital signs and ECG measurements.
‡‡
Pregnancy test in female subjects of childbearing potential in serum (if blood is drawn) or urine (at other visits).
§§
If the subject reached steady state of her/his optimal dose, a total of 4 pharmacokinetic samples will be collected, divided over 2 sampling days.  Sampling day 1: 1 trough sample; Sampling day 2: 1 
trough and 2 postdose samples between 2 h and 5 h postdose, with at least 1 hour in between the samples. These 2 sampling days do not have to be in a specific order and can be selected from the 
given options. To allow for an early assessment of the dose-response relationship by the DSMB, it is preferred the pharmacokinetic sampling takes place as early in the study as possible. Dosing on a 
sampling day with postdose samples must occur within 1 hour after completion of breakfast [Section 5.3.4 . On days where a pharmacokinetic visit is planned in the clinic, breakfast and dosing 
should occur in the clinic. Blood sampling should occur after vital signs and ECG measurements.
¶¶
Additional urodynamic assessments may be performed if deemed necessary by the investigator.
†††
Daily study drug administration will begin on Day 1 (the day after visit 3/baseline). Due to shelf-life limitations, an additional dispensing visit is foreseen at visit 9/week 36 for subjects receiving 
mirabegron oral suspension. This dispensing visit does not need to be accompanied by the subject.
‡‡‡ After a successful screening visit, all subjects start with the completion of a 2-day weekend e-diary visit to get acquainted with the e-diary and the assessments. Completion of this diary should start in 
the weekend prior to visit 2. Completion of subsequent bladder diaries should start approximately 
7 days prior to the indicated visit (or TC). If successful completion of the 2-day weekend e-diary is confirmed at visit 2, subjects from group A start with collection of the 7-day baseline e-diary, 
followed by the baseline visit. Subjects in group B start with a 14-day washout. In the second week of the washout period, collection of their 7-day baseline e-diary starts, followed by the baseline 
visit.  
§§§ Triplicate SBPM will be performed in the morning and evening during the 2-day weekend e-diary collection period and on 2 consecutive 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. Measurements to be taken with an interval of approximately 2 minutes in the sitting position (when possible, 
otherwise supine, but always in the same position). Preferably the right arm should be used. Morning measurements should be taken after waking-up, before breakfast and before study drug intake, 
evening measurements prior to bedtime. Subject should have been calm and without distress for at least 5 minutes.

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1
INTRODUCTION
1.1
Background
Protocol 178-CL-206A is part of the Sponsor’s clinical program to develop mirabegron for 
neurogenic detrusor overactivity (NDO) and overactive bladder (OAB) in pediatric patients. 
In the EU the development of mirabegron for the indication of NDO is outlined in the 
pediatric investigation plan (PIP) for mirabegron and approved by the Pediatric Committee 
(PDCO).  
In the US, the protocol 178-CL-206 is planned to fulfill the Pediatric Research Equity Act 
(PREA) requirement commitment and the Proposed Pediatric Study Request (PPSR). 
Protocol 178-CL-206A will start in the regions as mentioned in the synopsis. Protocol 178-
CL-206 will start later in the US after review and approval of further mirabegron data by the 
FDA. Protocol 178-CL-206A and 178-CL-206 will be kept identical and subject data from 
both protocols will be pooled and analyzed as outlined in the statistical section of the 
protocol [see Section 7].
The population for this pediatric clinical efficacy study with mirabegron is children and 
adolescents with NDO who require clean intermittent catheterization (CIC).  NDO is defined 
by the International Children’s Continence Society as detrusor overactivity when there is a 
relevant neurologic condition. “Detrusor overactivity is the occurrence of involuntary 
detrusor contractions during filling cystometry.  They may be spontaneous or provoked and 
produce a waveform of variable duration and amplitude. Contractions may be phasic or 
terminal.  Symptoms of urgency and/or urgency incontinence may or may not occur” 
[Austin et al, 2014].
NDO can develop as a result of a lesion at any level in the nervous system, including the 
cerebral cortex, spinal cord, or peripheral nervous system. In 85% of the children with NDO, 
the condition is caused by myelomeningocoele (spina bifida) [Bauer et al, 2012]. In a subset 
of NDO patients (typically patients who suffer from detrusor sphincter dyssynergia [DSD] or 
have a surgically repaired underactive sphincter), treatment requires constant and fastidious 
bladder management from shortly after birth, including performance of CIC [Bauer et al, 
2012].  Performance of CIC ensures that bladder volumes are regularly reduced to zero, 
thereby decreasing end-filling bladder pressure.
In the population of NDO patients requiring CIC, the medical need for treatment is the 
highest, due to the underlying pathophysiology of the urinary tract. In these patients, the 
overactive detrusor contracts against a closed or partially closed sphincter instead of a 
relaxed sphincter, due to DSD and/or sphincter surgery. The consequence is that these 
children cannot void normally, but instead leak when the pressure in the bladder exceeds the 
sphincter pressure (incontinence). This is independent of age and bladder training.  
If left untreated, NDO leads to deterioration of urinary tract function at early age. Kidney 
function deteriorates from hydronephrosis due to backpressure caused by high (end-filling) 
bladder pressure. Further renal damage can occur from ascending urinary tract infections 

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(UTIs) resulting from vesico-urethral reflux. Fibrosis of the bladder wall, induced by strong 
and uninhibited overactive contractions and frequent UTIs, contributes to the development of 
a noncompliant bladder (loss of expansile capability; high pressures at low volumes). In a 
noncompliant bladder, the critical level of detrusor pressure is reached at lower filling 
volumes, further predisposing the patient to kidney damage.
Current drug therapy consists of oral antimuscarinics or botulinum toxin injected into the 
bladder wall. The drug therapy decreases end-filling pressure, overactive contractions and 
increases bladder capacity and as such protects against kidney damage and deterioration of 
bladder wall. Although to date, the vast majority (approximately 90%) of patients can be 
treated successfully with the gold standard treatment of oxybutynin (oral or intravesical) and 
CIC [Verpoorten et al, 2008], development of alternative therapy is desirable because of 
insufficient efficacy and/or the side effects of antimuscarinics; dry mouth, constipation, 
blurred vision, headache, tiredness (somnolence), impaired school performance, facial 
flushing, gastrointestinal discomfort, and dry itchy skin [Rawashdeh et al, 2012] and the 
invasive administration of botulinum toxin, which is bothersome for the patient.
Mirabegron, a beta-3 adrenergic receptor agonist, represents a new class of drugs for 
treatment of OAB. The use of mirabegron as an alternative therapy to control detrusor 
overactivity in patients with NDO has not yet been established, although some reports of a 
positive effect of mirabegron on urodynamic parameters in patients with NDO have been 
published [Wöllner et al, 2015; Wada et al, 2015; Skobejko 2014].  
1.2
Nonclinical and Clinical Data
Detailed information on studies conducted with mirabegron can be found in the most recent 
pediatric mirabegron Investigator’s Brochure (IB). Nonclinical and clinical data are also 
summarized in the package insert for mirabegron (current locally-available product 
information for mirabegron).
Summaries of findings from nonclinical and clinical studies with mirabegron which have 
relevance for the current study are presented below.
1.2.1
Nonclinical Data
The primary pharmacology studies showed that mirabegron induced bladder relaxation 
during the filling phase and inhibited the frequency of nonvoiding activity. Other 
pharmacological effects, such as the glucogenolytic effects of mirabegron in rodents, did not 
translate to any effect in adult humans.
The safety pharmacology and toxicological studies showed that the safety profile of 
mirabegron, when administered to achieve exposures similar to those seen at the maximum 
recommended human dose, compares favorably with the currently approved antimuscarinic 
drug therapies indicated for the treatment of OAB.
The 39 toxicology studies that have been conducted with mirabegron in adult mice, rats, 
rabbits, dogs and cynomolgus monkeys support the safety of mirabegron for the treatment of 
OAB in adults and adolescents.  The ages of the rats and monkeys that were used in the 

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nonclinical repeated-dose toxicity studies were 8 weeks and 3 to 4 years old, respectively, 
which corresponds to a human age of 12 to 13 years. In support of clinical trials in children 
from 6 months of age and older, 2 repeated-dose toxicity studies were conducted in 10-day-
old juvenile rats (postnatal day 10 [PND10]): a 14-day oral dose range-finding study (Study 
178-TX-054) and a 13-week oral repeated dose toxicity study with a 4-week recovery period 
(Study 178-TX-055).
Modest elevation of alanine aminotransferase (ALT) was observed in monkeys, but the 
changes observed were below the level of toxicological significance, and there were no 
changes in liver histopathology. There were no significant changes in liver enzymes or liver 
histopathology in dogs. In the toxicology studies in juvenile rats, increased activities in 
aspartate aminotransferase (AST) and ALT were noted in male rats at doses of 30 mg/kg 
(22-fold higher than the maximum recommended human dose). Modest (less than 2-fold) 
increases in plasma alkaline phosphatase (ALP) were observed at high doses (72-fold higher 
than the maximum recommended human dose), together with reversible changes in 
hepatocytes. Single and repeated dose toxicology studies in dogs, monkeys and rats 
demonstrated cardiovascular changes at high doses (please refer to the mirabegron IB).  
In rodents, beta 3-agonists have an anti-obesity effect due to an increase in metabolic rate due 
to the activation of thermogenesis in brown adipocytes and to lipolysis in white adipocytes 
[Lafontan & Berlan, 1993]. In adult and juvenile rats treated with > 10 mg/kg mirabegron,
decreased lipid droplets were observed in the brown adipose tissues and white adipose tissues.
In addition, behavioral effects like decreased activity, which could be related to an increased 
body temperature, were also observed in juvenile rats in males and females in the 10 and 30 
mg/kg groups. However, no comparable effect in primates was seen. In clinical studies with 
mirabegron in adults no effects on weight or body temperature have been observed. In healthy 
subjects, neither single nor repeat dose administration affected mean blood glucose, C-peptide, 
triglyceride, insulin levels or oral temperature compared with placebo, suggesting that 
mirabegron does not affect lipid or glucose metabolism in healthy subjects. In subjects with 
type 2 diabetes mellitus, mirabegron induced no substantial changes from baseline in body 
weight or oral temperature. However, since brown adipose tissue is more prevalent in children 
than in adults, it could be that brown adipose tissue has a greater physiological role in children 
than in adults. Therefore, it cannot be excluded that administration of mirabegron has an effect 
on body weight and/or body temperature in young children.
In the toxicology studies, increased activities in aspartate aminotransferase (AST) and ALT
were noted in male rats at doses of 30 mg/kg (22-fold higher than the maximum recommended 
human dose). Modest (less than 2-fold) increases in plasma alkaline phosphatase (ALP) were 
observed at high doses (72-fold higher than the maximum recommended human dose), together 
with reversible changes in hepatocytes.  
Mirabegron was not found to be genotoxic, carcinogenic, or teratogenic in the battery of 
in vitro and in vivo studies.  The in vitro oxidative metabolism of mirabegron in human liver 
microsomes is primarily mediated by cytochrome P450 (CYP) 3A4, but a possible role for 

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CYP2D6 could not be excluded. In vitro CYP inhibition studies suggest that mirabegron is a 
moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A4.
Exposure levels in juvenile (PND10) rats were 5-fold to 10-fold increased compared to adult 
rats (PND100). The exposure levels of mirabegron in young (PND21) and adolescent (PND45) 
rats were 2-fold to 5-fold lower than the exposures observed in the adult rats (PND100). The 
increased exposure levels of mirabegron on PND10 and decreased exposure levels on PND21 
and PND45 are in line with the knowledge on the ontogeny of drug metabolizing (phase I and 
phase II) enzymes and (efflux) transporters in rats [de Zwart et al, 2008; Saghir et al, 2012]. 
This could translate into differences in exposures between adults/adolescents and pediatric 
subjects, in which the phase I (until 2 years of age) and/or phase II (until 11 years of age) 
enzymes are still maturing.
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 2].
Table 2
Overview of Current Supporting Mirabegron Studies in the Pediatric 
Clinical Development Program for NDO and OAB
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 neurogenic detrusor overactivity 
(NDO) or overactive bladder (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 neurogenic detrusor overactivity 
(NDO) or overactive bladder (OAB).
Ongoing
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
Ongoing
The results of studies 178-CL-201 and 178-CL-202 are reported in the most recent version of 
the pediatric IB.  The data from these studies were used to support the use of tablets in 
pediatric subjects with a body weight of ≥ 35 kg in this study.

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For those pediatric subjects that cannot be dosed with tablets because their body weight is 
35 kg or less or because they cannot swallow tablets, an oral suspension with a strength of 
2 mg/mL was developed.  The relative bioavailability was assessed in healthy subjects 
(178-CL-201) to be 53.44% lower compared to tablets. The results of this study and study 
178-CL-202 was used to support the use of the 2 mg/mL in study 178-CL-203.
That study is a single dose phase 1 study with mirabegron oral suspension in pediatric subjects 
from 3 to less than 12 years of age with NDO and in pediatric subjects from 5 to less than 
12 years of age with OAB.  This study is currently ongoing with 6 of 9 planned subjects having 
completed the study.  Single doses of mirabegron are administered that are predicted to result 
in an exposure comparable to that in adults when dosed with 50 mg mirabegron tablets once 
daily at steady-state (188 ng∙h/mL).  Subjects received mirabegron oral suspension within 
1 hour after a light breakfast. Doses were compensated for the lower bioavailability of 
suspension versus tablets (see above). This study is ongoing but the preliminary results are 
provided below.
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, three period cross over design 
in healthy subjects. Subjects received the following three treatments in random order: 1) 
11mL 8 mg/mL oral suspension of mirabegron under fasted conditions, 2) 11mL 8 mg/mL 
oral suspension of mirabegron under fed conditions and 3) 44 mL 2 mg/mL oral suspension 
of mirabegron under fasted conditions.  This study is ongoing, but a summary of the 
preliminary results is provided below.
Exposure:
The single doses of the 2 mg/mL oral suspension for Study 178-CL-203 were predicted using 
a population pharmacokinetic (popPK) model developed on pharmacokinetic data obtained in 
Study 178-CL-201, with food, dose, and formulation effects on the bioavailability, and was 
validated on data from Study 178-CL-202.  The observed exposures were in line with the 
target exposure of 188 ng∙h/mL; the median AUC24 was 207 ng∙h/mL (n=6, mean (SD): 
226.4 (152.3), range: 39.7-467).   These preliminary results suggest that the use of the popPK 
model is appropriate for dose selection.  The model predictions of the PED50 doses at a 
strength of 2 mg/mL would require large volumes of oral suspension every day (up to 44 mL).  
Therefore, to reduce the volume, a higher strength oral suspension was developed.  
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.  
The results of study 178-CL-208 show that the bioavailability of both strengths is comparable
[Table 3].

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Table 3
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)
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
(n•.h/mL)
234
232
100.9
(90.6, 112.4)
Cmax
(ng/mL)
12.1
11.3
106.7
(84.2, 135.2)
CI: confidence interval; LS: least squares.
The analysis was performed on log-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. 
The information obtained in studies 178-CL-203 and 178-CL-208 was taken into account 
when predicting the doses for this study as outlined in Section 2.2.2 of this protocol.
The doses described in Section 2.2.2 suggest tablets for pediatric subjects with a body weight 
of ≥35 kg, and the 8 mg/mL oral suspension for children with a body weight between 11 and 
35 kg, or for those subjects with a body weight ≥ 35 kg who do not want to or are unable to 
take tablets.
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 6 subjects who completed the study (3 with NDO and 3 with OAB) 1 treatment 
emergent adverse event (TEAE) was reported: pyrexia on day 1 in a 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 QTcF values > 450 ms and no QTc prolongation > 30 ms versus 
baseline was observed (mean of triplicates).
Increases in vital signs have been observed but these were not considered clinically 
significant per investigator’s assessment.  
A 24-hour Holter recording was recorded in all subjects on a reference day and on the dosing 
day.  The main objective of the Holter 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 has been observed. This was not considered as 

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clinically relevant taken into account the multiple blood draws, the low number of subjects 
and the absence of a placebo 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. 20 AEs were 
considered not related; 2 were considered possibly related (dizziness, mild and orthostatic 
dizziness mild).
1.3
Summary of Key Safety Information for Study Drugs
Mirabegron has not been approved or marketed for use in pediatric subjects.
For further information reference is made to the most recent version of the pediatric IB for 
mirabegron, and current locally-available product information for mirabegron.
Mirabegron has been approved in more than 65 countries worldwide. In adults, the safety of 
mirabegron treatment has been well characterized in 5863 subjects (95% with overactive 
bladder) 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, UTI, fetal disorders after exposure during pregnancy and events 
induced by concomitant treatment with 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.  
1.4
Risk-Benefit Assessment
Mirabegron tablets have a favorable risk-benefit profile in adults in the indication OAB.  
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.
Successful management of NDO prevents the occurrence of progressive kidney impairment 
and decrease in bladder compliance in subjects with NDO. As such, the benefit of successful 
treatment in this subject population is large, and is expected to be larger than in subjects 
suffering from OAB, provided that mirabegron is effective and has an acceptable safety 
profile in this population.
The use of mirabegron as an alternative therapy to control detrusor contraction in subjects 
with NDO has not yet been established. However some reports have been published showing 
a positive effect of mirabegron on urodynamic parameters in patients with NDO [Wöllner et 

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al, 2015; Wada et al, 2015; Skobejko 2014]. Beneficial effects are also expected on gaining 
continence.
The major risk in this study is periods of uncontrolled high end-filling detrusor pressure.  
This risk is monitored on a regular basis and can be mitigated by the investigator as follows:
●
A washout period is necessary to achieve an adequate baseline. The washout period has 
been restricted to 2 weeks in order to prevent renal damage and minimize the burden for 
the subject. At baseline a urodynamic investigation is planned, allowing the investigator 
to judge the risk to the subject in case mirabegron would not be efficacious. At this stage 
the risk can be mitigated by increasing the CIC frequency.  
●
The initial dose of mirabegron will be based on the subject's weight, and predicted to 
achieve plasma concentrations equivalent to the steady state exposures expected with 
25 mg mirabegron administered once daily in adults (pediatric equivalent dose [PED] 25).  
This low dose is chosen considering possible beta-adrenergic side effects of mirabegron.
●
After 2 weeks on PED25 all subjects will be up-titrated to PED50 unless there is a safety 
issue with mirabegron or the investigator considers that with the low mirabegron dose full 
efficacy has been reached. By striving to get an efficacious dose of mirabegron early after 
start of dosing, the risk for bladder and kidney damage is mitigated.
●
At 4 weeks of therapy, a second urodynamic investigation allows the investigator to judge 
and mitigate the risk by increasing the dose in subjects without prior dose increase or, in 
subjects on the maximum dose, by increasing the CIC frequency or by withdrawal of the 
subject.  
●
Additional urodynamic assessments may be performed at any time in the study if deemed 
necessary by the investigator.
Concerning drug safety, important identified or potential risks in adults and their monitoring 
in this study are listed below:
●
Increased heart rate and tachycardia is monitored in this study by at-home measurement 
of vital signs and measurement of vital signs at the study visits at the center;
●
Hypersensitivity reactions (immediate or nonimmediate and cutaneous or noncutaneous) 
are monitored in this study by AE monitoring;
●
Increased blood pressure is monitored in this study by at-home measurement of vital 
signs and measurement of vital signs at the study visits at the center;
●
Urinary retention does not apply in children on CIC;
●
Potential QT prolongation is monitored by ECG at each visit at the center;
●
Potential urinary tract infection is monitored by urine analysis at each visit in the center;
●
Potential fetal disorders after exposure during pregnancy is mitigated by the inclusion 
criteria;
●
Potential events by concomitant treatment with CYP2D6 substrates with narrow 
therapeutic index is mitigated by excluding these medications;
●
Although not observed in adults, the potential activation of thermogenesis will be 
monitored by temperature measurement. Weight loss due to activation of thermogenesis 
in brown fat will be monitored by regular weight measurements.

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Regarding the formulations to be administered: 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 of the United Nations (FAO) and the 
World Health Organization (WHO) (JECFA) [FAO 2015].
The protocol is designed to minimize the burden to the subject by restricting the number of 
urodynamic investigations, the number of blood draws (safety and pharmacokinetic 
sampling) and the number of study visits to a minimum.  
The use of popPK for the analysis of the pharmacokinetic profile of mirabegron allows 
reducing the number of blood draws for pharmacokinetic analysis to 4. Butterfly needles can 
be used and are allowed to stay in place to reduce the number of punctures.  
The blood draws for safety assessment have been reduced by omitting a baseline safety blood 
draw in subjects where the hematology and biochemistry results obtained at the screening 
visit did not show significant abnormalities and no AEs occurred after the screening visit that 
could influence the hematology/biochemistry results.
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. The investigator should not include any subject for whom it is 
expected that their condition will not allow protocol compliance.  
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.  
Data and Safety Monitoring Board (DSMB) assessment including review of safety and 
efficacy (no, or insufficient efficacy is a safety risk) is planned after the first 5 subjects have 
reached visit 5/week 4 allowing a risk /benefit assessment early after start of the study. In
case the DSMB cannot reach a verdict based on the safety samples of these 5 subjects, this 
group will be increased with 5 more subjects, to obtain a maximum of 10 visit 5/week 4 
safety samples for early DSMB assessment. In the DSMB charter detailed information can be 
found.  In view of the above considerations, the risk-benefit ratio for this study is considered 
to be acceptable for the subjects that will participate in this study.

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2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objectives:
●
To evaluate the efficacy of mirabegron after multiple-dose administration in the pediatric 
population.  
2.1.2
Secondary Objectives:
●
To evaluate the safety and tolerability of mirabegron after multiple-dose administration in 
the pediatric population.
●
To evaluate the pharmacokinetics of mirabegron after multiple-dose administration in the 
pediatric population.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a phase 3, open-label, baseline-controlled, multicenter study in male and female 
children and adolescents aged 3 to less than 18 years of age with NDO on CIC. 
Approximately 50 enrolling study centers in Europe, Latin America, Africa, Middle East and
Asia-Pacific are planned.  
At least 44 evaluable subjects (estimate of 63 enrolled), with at least 10 subjects from each 
age group (children aged 3 to less than 12 years of age; adolescents aged 12 to less than 
18 years of age) are planned. A subject is considered being evaluable if the subject has a 
valid (as by the central reviewer’s assessment) nonmissing maximum cystometric capacity 
(MCC) measurement at baseline and at a postbaseline visit. An enrolled subject withdrawing 
or discontinuing before dosing will be replaced. A subject discontinuing treatment after 
dosing can be replaced at the discretion of the Sponsor. The study is conducted under the 
aegis of a DSMB.  
The study will consist of 3 periods:
●
Pretreatment period: for a maximum of 28 days before baseline, including screening, 
washout (if applicable) and baseline 
●
Efficacy treatment period: beginning the day after baseline and continuing to 
visit 8/week 24
●
Long-term safety period: beginning after visit 8/week 24 and continuing to visit 10/week 
52 (end of study [EOS]), or to the end of treatment (EOT).  
2.2.1.1 Pretreatment Period
After informed consent and visit 1/screening, subjects are grouped according to their current 
NDO therapy and/or other medication: 
●
Group A: Subjects who are currently not receiving any prohibited medication including 
any oral drug treatment to manage their NDO, or when botulinum toxin is no 
longer considered effective.

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●
Group B: Subjects who currently are receiving oral drug treatment to manage their NDO
or receive any other prohibited medication.
After the screening visit, a 2-day weekend e-diary has to be completed by the subjects to get 
acquainted with the e-diary and the home assessments:
●
Group A: Following successful completion of the first 2-day weekend e-diary, confirmed 
at visit 2, the subjects will start to complete the 7-day baseline e-diary followed 
by the baseline visit (visit 3).  
●
Group B: Following successful completion of the first 2-day weekend e-diary, confirmed 
at visit 2, the subjects will start their 2-week washout period. In the second 
week of their washout period, they will complete the 7-day baseline e-diary 
followed by the baseline visit (visit 3).  
If a subject is suffering from a symptomatic UTI at visit 1/screening or is diagnosed with one 
between visit 1/screening and visit 3/baseline, the UTI should be treated successfully (clinical 
recovery) prior to baseline. If a symptomatic UTI is present at or just before visit 3/baseline, 
all baseline assessments should be postponed with a maximum of 7 days until the UTI is 
successfully treated (clinical recovery). The 7-day baseline e-diary does not have to be 
repeated if at least the 2-day weekend e-diary and 1 day of the weekday e-diary were 
completed while the subject did not suffer from a symptomatic UTI.
Subjects will enter the efficacy treatment period if they meet the eligibility criteria and 
satisfactorily complete the pretreatment period (ability to complete bladder diary, 
catheterized volumes and questionnaires).
In case the subject or the subject’s parent(s)/caregiver(s) are not able or willing to perform 
the SMIP, the measuring device is not available at the site, or there is a technical problem, 
the SMIP may be omitted.
2.2.1.2 Efficacy Treatment Period
Study drug administration will begin on the day after the baseline visit (i.e., on day 1). The 
initial dose of mirabegron is predicted to achieve plasma concentrations equivalent to the 
steady state exposures expected with 25 mg mirabegron administered once daily in adults 
(PED25).
At visit 4/week 2, visit 5/week 4 or visit 6/week 8, subjects must be up-titrated to the 
pediatric equivalent dose of 50 mg in adults (PED50), based on the given dose titration 
criteria [see Section 5.1.2].  
At visit 8/week 24, the primary efficacy endpoint will assessed, which is the change from 
baseline in MCC.
If a subject is suffering from a symptomatic UTI in the week prior to any (un)scheduled 
urodynamic investigation (e.g., visit 5/week 4, visit 8/week 24), the UTI should be treated 
successfully first (clinical recovery). To allow for treatment of the UTI, these visits may be 
postponed with an additional maximum of 7 days on top of the already existing visit window.  

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The 7-day e-diary does not have to be repeated if at least the 2-day weekend e-diary and 
1 day of the weekday e-diary were completed while the subject did not suffer from a 
symptomatic UTI.  
If a subject suffers from a symptomatic UTI in the week prior to any other study visit, these 
visits do not need to be postponed and the 7-day e-diary does not have to be repeated.
2.2.1.3 Long-term Safety Period
For long-term safety evaluation, following visit 8/week 24, subjects will stay on their 
individual dose level until visit 10/week 52 (EOT/EOS).
2.2.2
Dose Rationale
The target exposures of 69 and 188 ng·h/mL for pediatric equivalent dose 25 mg (PED25) 
and pediatric equivalent dose 50 mg (PED50) were derived from the adult phase 3 program 
and are the mean steady state AUCtau values following 25 and 50 mg prolonged-release 
tablets once daily in adults.
A population pharmacokinetic model was used to predict the PED for subjects in the 
178-CL-206A study. In brief, this popPK 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; IND 58135), 
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 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. 
Subjects with a body weight < 35 kg cannot be dosed with the 25 and 50 mg tablets because 
that would result in higher than 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.  

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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 NHANES 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.  
Suspension dosing for body weights ≥35 kg was also determined for cases in which a 
pediatric subject in that weight category does not want or would be unable to swallow a 
tablet.  The simulation resulted in the 3 body weight categories that can be found in the 
dosing schedule (see [Section 5.1.1]).
2.3
Endpoints 
2.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint will be the change from baseline in MCC after 24 weeks of 
treatment (based on filling urodynamics).
2.3.2
Secondary Efficacy Endpoints 
2.3.2.1 Urodynamic Measures
Secondary efficacy endpoints will include the change from baseline in the following 
urodynamic measures: 
●
MCC at visit 5/week 4
●
Bladder compliance (∆V/∆P) at visit 5/week 4 and visit 8/week 24
●
Number of overactive detrusor contractions (> 15 cm H20) until end of filling at 
visit 5/week 4 and visit 8/week 24
●
Detrusor pressure at end of filling at visit 5/week 4 and visit 8/week 24
●
Filling volume until first overactive detrusor contraction (> 15 cm H20) at visit 5/week 4 
and visit 8/week 24
2.3.2.2 Bladder Volume and Leakage Measures
The following endpoints will be obtained from the e-diary and be analyzed as the change 
from baseline at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, 
visit 8/week 24, visit 9/week 36 and visit 10/week 52 (EOT/EOS).
●
Average catheterized volume per catheterization
●
Maximum catheterized volume
●
Maximum catheterized daytime volume
●
Average morning catheterized volume (based on first catheterization after subject woke
up)
●
Mean number of leakage episodes per day (day and night time)
●
Number of dry (leakage-free) days/7 days (day and night time)
For this study the first morning catheterization after waking up is regarded as part of the 
‘night’, whilst the last evening catheterization before sleep time is part of the ‘day’.

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The collected urine volume will be weighed by the subject or subject’s parent(s)/caregiver(s) 
and the results will be entered in the e-diary. The conversion factor used for 
weight-to-volume is 1g = 1mL.
2.3.2.3 Patient- or Clinician-reported Questionnaire Endpoints
The following endpoints will be obtained from patient- or clinician-reported questionnaires.
●
Change from baseline at visit 8/week 24 and visit 10/week 52 (EOT/EOS) in PIN-Q 
●
Change from baseline at visit 8/week 24 and visit 10/week 52 (EOT/EOS) in PGI-S 
●
Clinician Global Impression of Change (CGI-C) at visit 8/week 24 and visit 10/week 52 
(EOT/EOS) 
●
Acceptability at visit 5/week 4, visit 8/week 24 and visit 10/week 52 (EOT/EOS)
2.3.3
Safety Endpoints
The following safety endpoints will be assessed:
●
Incidence and severity of TEAEs
●
Change from baseline in vital signs (clinic measurements): systolic blood pressure, 
diastolic blood pressure, pulse rate and temperature at visit 5/week 4, visit 7/week 12, 
visit 8/week 24 and visit 10/week 52 (EOT/EOS)
●
Change from baseline in vital signs (self blood pressure measurement [SBPM]): systolic 
blood pressure, diastolic blood pressure, pulse rate at visit 4/week 2, visit 5/week 4, visit 
6/week 8, visit 7/week 12, visit 8/week 24, visit 9/week 36 and visit 10/week 52 
(EOT/EOS) and on 2 consecutive days at around 1 and 2 weeks after start of dosing with PED25 
(day 1) and after up-titration to PED50 (visit 4/week 2, visit 5/week 4 or visit 6/week 8), if not 
already covered by the scheduled visit 4/week 2 and/or visit 5/week 4 SBPM.
●
Change from baseline in hematology and biochemistry tests at visit 7/week 12 and visit 
10/week 52 (EOT/EOS) and urinalysis tests at visit 5/week 4, visit 7/week 12, visit 
8/week 24 and visit 10/week 52 (EOT/EOS)
●
Change from baseline in ECG parameters at visit 5/week 4, visit 7/week 12, 
visit 8/week 24 and visit 10/week 52 (EOT/EOS)
●
Change from baseline to visit 10/week 52 (EOT/EOS) in upper urinary tract ultrasound 
assessment
●
Change from baseline in eGFR at visit 7/week 12 and visit 10/week 52 (EOT/EOS)
2.3.4
Pharmacokinetics
The following pharmacokinetic parameters will be determined for each individual:
●
Cmax, tmax, AUC24, Ctrough, CL/F and Vz/F 
Additional pharmacokinetic parameters may be calculated based on the model used.

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2.3.5
Exploratory Endpoints
2.3.5.1 Exploratory Efficacy Endpoints
The following efficacy endpoints will be examined:
●
Change from baseline at visit 5/week 4 and visit 8/week 24 in filling volume at 20 cm,
30 cm and at 40 cm H2O detrusor pressure, given that those pressures are reached during 
the examination
●
Change from baseline at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, 
visit 8/week 24, visit 9/week 36 and visit 10/ week 52 (EOT/EOS), as determined from 
the e-diary entries in:
o
Mean grade of leakage 
o
Total catheterized volume per day
o
Change from baseline in SMIP-derived bladder compliance 
o
Number of CICs/day
o
Responder in respect to leakage (complete, partial, no response)
2.3.5.2 Exploratory Safety Endpoints
●
Change from baseline in intravesical pressure (SMIP) at visit 4/week 2, visit 5/week 4, 
visit 6/week 8, visit 7/week 12, visit 8/week 24, visit 9/week 36 and visit 10/ week 52 
(EOT/EOS)
●
Change from baseline in body height and weight at visit 8/week 24 and visit 10/week 52 
(EOT/EOS)
3
STUDY POPULATION
3.1
Selection of Study Population 
The study population will be male and female child and adolescent subjects aged 3 to less 
than 18 years of age with NDO on CIC. The age of the subjects at the date of signing the 
informed consent or assent form at visit 1/screening will determine the age of the subject for 
inclusion into the study.
Re-screening is not allowed.
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1. Independent Ethics Committee (IEC)/Institutional Review Board (IRB)-approved written 
Informed Consent and privacy language as per national regulations must be obtained 
from the subject and/or from the subject’s parent(s) or legal guardian(s) prior to any 
study-related procedures (including discontinuation of prohibited medication, if 
applicable); assent by the subject is given as required by local law.  
2. Subject is male or female from 3 to less than 18 years of age.
3. Subject has a body weight of ≥ 11 kg.

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4. Subject suffers from NDO confirmed by urodynamic investigation at baseline. The 
diagnosis of NDO must be confirmed by the presence of at least 1 involuntary detrusor 
contraction > 15 cm H2O from baseline detrusor pressure, and/or a decrease in 
compliance leading to an increase in baseline detrusor pressure of > 20 cm H2O.
5. Subject has been using CIC for at least 4 weeks prior to visit 1/screening.  
6. Subject has a current indication for drug therapy to manage NDO.  
7. Subject is able to take the study drug in accordance with the protocol.
8. Female subject must either:
●
Be of nonchildbearing potential:
o
Clearly premenarchal or in the judgment of the investigator is premenarchal,
o
Documented surgically sterile,
●
Or, if of childbearing potential:
o
Agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration, 
o
And have a negative pregnancy test at visit 1/screening and at baseline,
o
And, if sexually active must agree to use a highly effective method of birth 
control, which includes established use of oral, injected or implanted hormonal 
methods of contraception, OR placement of an intrauterine device (IUD) or 
intrauterine system (IUS).  Birth control must be practiced from visit 1/screening
and continuing throughout the study period, and for 28 days after the final study 
drug administration.
9. Male subject and their female spouse/partner who are of childbearing potential must be 
using a highly effective method of birth control, which includes established use of oral, 
injected or implanted hormonal methods of contraception, placement of an IUD or IUS.  
Birth control must be practiced from visit 1/screening and continuing throughout the 
study period, and for 28 days after the final study drug administration.
10. Female subject must not be breastfeeding from visit 1/screening until 28 days after last 
study drug administration.
11. Subject and subject’s parent(s)/legal guardian(s) agree that the subject will not participate 
in another interventional study while participating in the study.
12. 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.  
Waivers to the inclusion criteria will NOT be allowed.

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3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1. Subject has a known genitourinary condition (other than NDO) that may cause overactive 
contractions or incontinence (e.g., bladder extrophy, urinary tract obstruction, urethral 
diverticulum or fistula) or kidney/bladder stones or another persistent local pathology that 
may cause urinary symptoms.
2. Subject has one of the following gastrointestinal problems: partial or complete 
obstruction, decreased motility such as paralytic ileus, subjects at risk of gastric retention.
3. Subject has a urinary indwelling catheter within 4 weeks prior to visit 1/screening
4. Subject has a surgically treated underactive urethral sphincter
5. Subject has vesico-ureteral reflux grade 3 to 5.
6. Subject has undergone bladder augmentation surgery.
7. Subject receives electrostimulation therapy, if started within 30 days before 
visit 1/screening or is expected to start during the study period. Subjects who are on an 
established regimen may remain on this for the duration of the study.
8. Subject suffers from a symptomatic UTI at baseline (symptomatic is defined as pain, 
fever, hematuria, new onset foul-smelling urine).  If present at visit 1/screening or 
diagnosed between visit 1/screening and visit 3/baseline, the UTI should be treated 
successfully (clinical recovery) prior to baseline. If a symptomatic UTI is present at 
baseline, all baseline assessments should be postponed for a maximum of 7 days until the 
UTI is successfully treated (clinical recovery).  
9. Subject has a (mean) resting pulse rate > 99th percentile [Fleming et al, 2011]. 
10. Subject has an established hypertension and a systolic or diastolic blood pressure greater 
than the 99th percentile of the normal range determined by sex, age and height, plus 
5 mmHg [NIH 2005].
11. Subject has a risk of QT prolongation (e.g., hypokalemia, long QT syndrome [LQTS]; or 
family history of LQTS, exercise-induced syncope).  
12. Subject has severe renal impairment (eGFR according to Larsson equation < 30 mL/min).  
13. Subject’s AST or ALT is greater than or equal to 2 times the upper limit of normal (ULN)
or total bilirubin (TBL) greater than or equal to 1.5 times the ULN according to age and 
sex.
14. Subject has a history or presence of any malignancy prior to visit 1/screening.
15. Subject has known or suspected hypersensitivity to mirabegron, any of the excipients 
used in the current formulations or previous severe hypersensitivity to any drug.

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16. Subject has participated in another clinical trial (and/or has taken an investigational drug)
within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is 
longer) prior to visit 1/screening.
17. Subject uses any of the following prohibited medications (after start of washout):
●
Any medication, other than the study drug used, for the management of NDO; 
●
Any drugs that are sensitive CYP2D6 substrates with a narrow therapeutic index or
sensitive P-glycoprotein (P-gp) substrates
●
Any strong CYP3A4 inhibitors if the subject has a mild to moderate renal 
impairment (eGFR 30 – 89 mL/min).
18. Subject has been administered intravesical botulinum toxin; except if given > 4 months 
prior to visit 1/screening and the subject experiences symptoms comparable to those 
existing prior to the botulinum toxin injections.
19. Subject has any other condition, which in the opinion of the Investigator, precludes the 
subject’s participation in the study.
20. Subject’s parent/legal guardian is an employee of the Astellas Group, the Contract 
Research Organization (CRO) involved, or the investigator site executing the study.
Waivers to the exclusion criteria will NOT be allowed.  
For exclusion criterion 9 please refer to Appendix 12.9 and for exclusion criterion 10 please 
refer to Appendix 12.10, Appendix 12.11, Appendix 12.12 and Appendix 12.13.
4
TREATMENTS
4.1
Identification of Investigational Products
4.1.1
Test Drug
Mirabegron prolonged-release (or extended-release) tablets were approved in Japan in 2011, 
and to date have been approved in more than 65 countries worldwide; trade names include 
Betanis®, Betmiga® and Myrbetriq®. 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.
For detailed information on mirabegron prolonged-release tablets and mirabegron granules 
for oral suspension, please refer to the applicable Investigational Medicinal Product Dossier 
(IMPD).
Mirabegron tablets are supplied as prolonged-release tablets containing 25 mg or 50 mg of 
active ingredient.  
For the oral suspension, mirabegron prolonged-release granules are supplied and will be
reconstituted with water to prepare an oral suspension of 8 mg/mL.  Detailed information on 
the preparation of the mirabegron oral suspension will be provided to the subject and 

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subject’s parent(s)/caregiver(s) in local language.  Due to shelf-life limitations, an additional
dispensing visit is foreseen at visit 9/week 36 for subjects receiving mirabegron oral 
suspension. This dispensing visit does not need to be accompanied by the subject.
4.1.2
Comparative Drug(s) 
Not applicable.  
4.2
Packaging and Labeling
All study drugs used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff 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 Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable local 
laws/regulations.
Each study drug 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 study 
drugs according to Directive 2003/94/EC annex 13.
4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator/or designee and
●
That such deliveries are recorded,
●
That study drug is handled and stored according to labeled storage conditions,
●
That study drug is with appropriate expiry/retest and is only dispensed to study subjects
in accordance with the protocol, and
●
That any unused study drug is returned to the Sponsor.
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/ or designee. Study drug accountability throughout the study must be 
documented and reconciled. The following guidelines are therefore pertinent:
●
The investigator agrees not to supply study drugs to any persons except the subject or 
subject’s parent(s)/caregiver(s) of the eligible subjects in this study in accordance with 
the protocol.
●
The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these test drugs.
●
A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.

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●
At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
drug accountability record. It must be possible to reconcile delivery records with those of 
used and/or returned study drugs. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.
●
The site must return study drug to the Sponsor or designee at the end of the study or 
upon expiration. If due to institutional policy or local law, used drug cannot be returned 
to the Sponsor or designee the drug may be destroyed according to local law.
4.4
Blinding
This section is not applicable as this is an open-label study.  
4.5
Assignment and Allocation
All subjects will receive active mirabegron treatment (open-label).  
Subject number assignment will be coordinated centrally by using an interactive response 
system.
4.5.1
Subject Numbering
Subjects will be assigned a subject number at study entry. The full subject number will 
consist of 10 digits; 5 for the site number (provided by the Sponsor) and 5 for the consecutive 
subject number. 
4.5.2
Subject Replacement
An enrolled subject who withdraws or discontinues before dosing will be considered a 
screening failure and will be replaced. If a subject discontinues treatment after dosing, this 
subject will be replaced at the discretion of the Sponsor.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug 
5.1.1
Dose/Dose Regimen and Administration Period
The initial dose will be PED25 [Section 2.2.2]. The dose must be up-titrated to PED50 
according to the titration criteria. Study drug will be taken orally, once a day in the morning
around the same time of day and around time of food intake (i.e., within 1 hour before or 
after breakfast). 
On visit days where a pharmacokinetic sample is planned in the clinic, completion of 
breakfast and study drug dosing should occur in the clinic and dosing will be done under 
supervision of the investigator.  
Mirabegron tablets will be taken with a sip of water. The tablet should be taken as a whole 
and should not be chewed, divided or crushed.  

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Mirabegron prolonged-release granules will be reconstituted with water to prepare a 
mirabegron oral suspension of 8 mg/mL.  Administration will be via an oral syringe with a 
sip of water afterwards.  Detailed information on the preparation of the suspension will be 
provided to the subject and subject’s parent(s)/caregiver(s) in local language.  For subjects 
receiving mirabegron oral suspension, an additional (optional) dispensing visit is scheduled 
at visit 9/week 36.
Selection of the formulation:
Subjects with a body weight < 35 kg: mirabegron oral suspension. 
Subjects with a body weight ≥ 35 kg: mirabegron tablets. 
Selection of the dose: 
Doses are calculated weight-based. The bodyweight at visit 3/baseline determines the weight 
range for the starting dose (PED25) and the up-titration dose (PED50) to be used [Table 4]. 
Table 4
Weight-based Doses for Tablets or Suspension
Weight Range 
Suspension Volume †
Tablet Dose
PED25
11 - < 22 kg
3 mL
-
22 - < 35 kg
4 mL
-
≥ 35 kg
6 mL
25 mg
PED50
11 - < 22 kg
6 mL
-
22 - < 35 kg
8 mL
-
≥ 35 kg
11 mL
50 mg
PED25: Pediatric equivalent dose 25 mg; PED50: Pediatric equivalent dose 50 mg 
† Suspension strength: 8 mg/mL
Further dosing information:
●
For subjects with a body weight ≥ 35 kg who do not want to or are unable to take tablets, 
the oral suspension can be supplied.
●
At visit 8/week 24 subjects on mirabegron oral suspension may switch to tablets if the 
body weight turns to be ≥ 35 kg.
●
Subjects receiving mirabegron tablets can switch to mirabegron oral suspension (and 
vice versa) for acceptability reasons after Sponsor’s prior approval and on a case-by-case 
basis. 
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
The aim is to obtain a safe low pressure bladder, to inhibit overactive detrusor contractions 
and to reach continence. Subject discontinuation rules apply (see [Section 6.1]).
Dose up-titration to PED50 must be performed at visit 4/week 2, visit 5/week 4 or 
visit 6/week 8, unless: 
1. The investigator considers the subject to be effectively treated with PED25, based on 
urodynamics and the e-diary;
2. There are safety or tolerability issues with PED25.

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Dose down-titration to PED25 can be performed at any time if there is a safety issue.
If an insufficient control of the NDO is observed at the highest tolerated mirabegron dose due 
to insufficient effect (based on, for example, ultrasound showing upper tract dilation; the 
appearance of a high grade reflux; high intravesical pressures; high detrusor pressures or high 
amplitude overactive contractions), the investigator should reconsider the subject’s further 
participation in the study and consider an alternative treatment.
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy)
Please refer to [Appendix 12.1] for drug classes or specific medications that are prohibited 
during participation in the study.  
5.1.4
Treatment Compliance
The investigator or designee should instruct the subject and/or subject’s 
parent(s)/caregiver(s) to meet 100% compliance with study drug intake throughout the entire 
study period. If compliance is around 80% or 120%, the investigator or designee is to counsel 
the subject and/or subject’s parent(s)/caregiver(s) and ensure steps are taken to improve 
compliance.
Compliance of the study drug taken outside the clinic will be monitored at each subsequent 
visit at the clinic by the accounting of used and unused study drugs returned by the subject.  
Subjects and their parent(s)/caregiver(s) will be clearly instructed to return all study drugs to 
the clinic at each clinic visit. This includes empty study drug containers.  
5.1.5
Restrictions for Foods and Drinks During the Study
Restrictions for foods and drinks are not applicable. On visit days where a pharmacokinetic 
sample is planned in the clinic, completion of breakfast and study drug dosing should occur 
in the clinic.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographics and baseline characteristics will be collected at visit 1/screening.
Demographics will include date of birth (or year depending on the country), age, sex and
race/ethnicity.  
Measurements for height and weight will be taken at visit 1/screening, visit 3/baseline, visit 
8/week 24 and at visit 10/week 52 (EOT/EOS).
5.2.2
Medical History
A complete medical history including a detailed NDO history will be collected at 
visit 1/screening. All relevant past and present conditions, as well as prior surgical procedures 
will be recorded for the main body systems.

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5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
A detailed NDO history for each subject will be collected at visit 1/screening. This history
includes the date of start of symptoms, underlying condition, comorbidities associated with 
NDO and treatment history for NDO.  
5.3
Efficacy and Pharmacokinetics Assessment
5.3.1
Urodynamic Assessments
Urodynamic assessments will be performed at visit 3/baseline, and at visit 5/week 4, 
visit 8/week 24.  
Additional urodynamic assessments can be performed at e.g. visit 10/week 52 (EOT/EOS), or 
at any other time point when deemed necessary by the investigator.  
Computerized urodynamic equipment should be used to allow central analysis. A manual 
with detailed SOPs will be provided to the investigators to ensure standardization of the 
procedure. On-site assessment and evaluation of the urodynamic assessments are to be 
conducted by a medically qualified & trained person.
Every effort should be taken to ensure that the rectum is free of stool. The evening before the 
urodynamic investigation, bowel preparation should be performed with the existing bowel 
regimen or when a subject is not an a bowel management program a suppository or enema 
should be applied to cleanse the rectum and increase accuracy of rectal pressure recordings 
[Bauer et al, 2015]. If digital evacuation of stool is required for the subject, this should be 
performed prior to the procedure.
The subject is placed in a stable position. The position should be the same for all procedures 
throughout the study. The bladder is then filled with room-warm saline via a pump with a 
filling rate of 10% of the mean of the catheterized volumes collected in the bladder diary 
prior to baseline. All urodynamic investigations in each subject should be done at the same 
filling rate for all visits. If the filling rate was accidentally too high or too low at the baseline 
visit, that same filling rate should be used throughout the study for this individual subject.  
Minor deviations in the filling rate (no more than 1 or 2 mL/min) caused by inaccuracy of the 
pump are accepted.
The following parameters will be determined:
●
MCC at end of filling
●
Bladder compliance
●
Filling volume until first detrusor contraction (> 15 cm H2O)
●
Filling volume at 20 cm, 30 cm and 40 cm H2O detrusor pressure (if reached)
●
Number of overactive detrusor contractions (> 15 cm H2O) until end of filling
●
Detrusor pressure at end of filling

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Filling will be stopped (end of filling) when:
●
Major leakage occurs (the rate of leakage exceeds the rate of infusion)
●
135% of maximum catheterized volume has been reached
●
The subject experiences pain or discomfort at filling which does not resolve after 
temporary stop of filling
●
The detrusor pressure exceeds 100 cm H20 or is considered dangerously high by the 
investigator or urodynamicist (for instance a prolonged passive detrusor pressure 
> 40 cm H2O).
The results of the urodynamic assessments, including the position of the subject during the 
assessments will be entered in the eCRF.
5.3.2
Bladder 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 visit 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 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.
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 this is not the case, the investigator should counsel/re-train the subject or the subject’s 
parent(s)/caregiver(s) prior to the start of the 7-day baseline e-diary. In case the subject 
and/or the subject’s parent(s)/caregiver(s) are still not able to complete the 7-day baseline e-
diary satisfactorily, the subject should be excluded from further participation in the study.
If successful completion of the 2-day weekend e-diary is confirmed at visit 2:
●
Subjects from group A start with collection of the 7-day baseline e-diary, followed by 
visit 3/baseline.  
●
Subjects in group B start with a 14-day washout. In the second week of the washout 
period collection of their 7-day baseline e-diary starts, followed by visit 3/baseline.  
Subsequent bladder diaries will be completed by the subject or the subject’s 
parent(s)/caregiver(s) in the week prior to visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 
7/week 12, visit 8/week 24, visit 9/week 36 and visit 10/week 52 (EOT/EOS). Completion of 
7-day bladder diaries should start approximately 7 days prior to the indicated visit (or telephone 
contact).  
The following information will be collected in the bladder diary.
Daily during the 7-day period:
●
Time of CICs
●
Presence of leakage between CICs
●
Sleep time and wake-up time

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On 2 consecutive weekend days within the 7-day period: 
●
Catheterized volume 
●
Grade of leakage between CICs
●
Weight of diaper/pad (visit 3/baseline and visit 8/week 24)
●
SMIP [Section 5.4.6]
The Investigator must guide the subject and subject’s parent(s)/caregiver(s) to ensure that on 
the evening before and during the two weekend days of collection of catheterized volume and 
SMIP, the subject’s fluid intake should be regulated to an appropriate level taking 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.  Detailed on-site training of the 
bladder diary and a booklet with operating instructions in local language will be provided to 
the subject and subject’s parent(s)/caregiver(s).
To ensure consistency in collection of the data and subject’s routine, assessments must be 
performed over the weekend and by the same person. As an exception, it is possible to 
perform the weekend assessments on 2 other days in the collection week (e.g., during a 
holiday period) if the subject can maintain his/her standard weekend routine for 
catheterizations and fluid intake.
Results will be directly entered by the subject or subject’s parent(s)/caregiver(s) in the
e-diary [Section 8.1.1].  
5.3.3
Questionnaires
Questionnaires will be completed as described below.
The following questionnaires will be used:
●
The PIN-Q [Appendix 12.4] will be completed on one weekend day preceding visit 
3/baseline, visit 8/week 24 and visit 10/week 52 (EOT/EOS).
●
The PGI-S [Appendix 12.5] will be completed on one weekend day preceding visit 
3/baseline, visit 8/week 24 and visit 10/week 52 (EOT/EOS).
●
The Acceptability Questionnaire [Appendix 12.6] will be completed on one weekend day 
preceding at visit 5/week 4, visit 8/week 24 and visit 10/week 52 (EOT/EOS).  For each 
formulation a separate questionnaire is available [Appendix 12.6 and Appendix 12.7].
●
The CGI-C [Appendix 12.8] will be completed at visit 8/week 24 and at visit 10/week 52 
(EOT/EOS).
The PIN-Q was chosen as the most appropriate cross-cultural pediatric quality of life 
measurement tool in this population. A Likert scale adopted for 20 measures is used [Bower 
et al, 2006].  
Questionnaires to be completed by the subject or the subject’s parent(s)/caregiver(s)
(i.e., PIN-Q, PGI-S and the Acceptability Questionnaire) will be available 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) [Section 8.1.1].  

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The CGI-C will completed by the investigator and the results will be entered in the eCRF.  
Clinically relevant adverse changes will be recorded as an AE [Section 5.5.1].
5.3.4
Pharmacokinetics
Samples of venous blood for pharmacokinetic assessments will be taken when the subject has 
reached steady state at the optimal dose (considered to be reached after 10 days of daily 
dosing). A total of 4 pharmacokinetic samples will be collected, divided over 2 sampling 
days.  These 2 days can be selected from any of the options given in the schedule of 
assessments (i.e., on visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 24,
visit 9/week 36, or visit 10/week 52) and do not have to be in a specific (consecutive) order: 
●
Sampling day 1: 1 trough sample (i.e., predose sample).
●
Sampling day 2: 1 trough and 2 postdose samples taken between 2h and 5h postdose, 
with at least 1 hour in between the samples.
To allow for an early assessment of the dose-response relationship by the DSMB, it is 
preferred the pharmacokinetic sampling takes place as early in the study as possible.
On visit days where a pharmacokinetic sample is planned in the clinic, completion of 
breakfast and study drug dosing should occur in the clinic. Dosing on a sampling day with 
postdose samples must occur within 1 hour after completion of breakfast.
In case there is a dose change within 10 days prior to a planned pharmacokinetic sampling 
visit, the subject is not considered to be at steady state, and samples should be postponed to 
another visit as per the schedule of assessments.
Trough samples must be taken within 1 hour prior to dosing. Dosing time on the sampling 
day and dosing time of the previous day will be collected in the eCRF/e-diary respectively.  
Postdose samples must be taken between 2h and 5h postdose, with at least 1 hour in between 
the samples. In addition to the dosing time, the time of completion of breakfast, and type of 
breakfast will be collected in the eCRF on this sampling day.
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.
Operational aspects of sample collection, storage and shipment of frozen samples are
described in the protocol [Section 5.6] and in the laboratory manual.  

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5.4
Safety Assessments
5.4.1
Vital Signs
5.4.1.1 Clinic Measurement of Vital Signs
Triplicate blood pressure and pulse measurements and single body temperature measurements 
(ear thermometer) will be performed at visit 1/screening, visit 3/baseline, and on visit 5/week
4, visit 7/week 12, visit 8/week 24 and visit 10/week 52 (EOT/EOS). Clinic measurements of 
vital signs at visit 1/screening and visit 3/baseline will be used to assess eligibility.
The preferred method of measurement is via the auscultatory technique. If this method is not 
available at the site, measurements will be per standard clinic practices.  The method for 
measuring vital signs should be consistent for all visits.  For each subject the correct size of the 
blood pressure cuff must be determined and used when assessing blood pressures. Blood 
pressure and pulse will be measured with approximately 2-minute intervals, after the subject
has been calm and without distress for at least 5 minutes.  
The subject should be seated with the back supported, feet on the floor and right arm supported, 
legs uncrossed and the cubital fossa at heart level. If sitting is not possible, supine is allowed, but 
measurements should always be taken in the same position. The subject should not move and 
should remain silent during the reading, as moving and talking can affect the reading. 
The right arm is preferred in repeated measures of blood pressure for consistency and 
comparison to standard tables. The same arm should be used throughout the study whenever
possible. Vital sign measurements should be performed prior to blood sampling.
The method of body temperature measurement is via an ear thermometer and should be 
consistent for all visits.  
Clinically relevant adverse changes in vital signs will be recorded as an AE [Section 5.5.1].
5.4.1.2 Self-measurement of Vital Signs
Triplicate SBPM (blood pressure and pulse rate) will be performed on the 2 weekend days 
prior to each visit.  Additional SBPM is done on 2 consecutive days at around 1 and 2 weeks after 
start of dosing with PED25 (day 1) and after up-titration to PED50 (visit 4/week 2, visit 5/week 4 or 
visit 6/week 8), if not already covered by the scheduled visit 4/week 2 and/or visit 5/week 4 SBPM.
Following successful completion [see Section 5.3.2] of the first 2-day weekend e-diary, 
confirmed at visit 2, subsequent measurements will be performed in the weekend preceding 
visit 3/baseline, visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 
24, visit 9/week 36 and visit 10/week 52 (EOT/EOS).
Devices for measuring blood pressure and pulse rate 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)/caregiver(s).

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For each subject the correct cuff size will be determined by the investigator by measuring the 
circumference of the subject’s upper arm in order to give the subject the device with the best 
cuff type.  Ideally, the bladder length of the cuff should be 80% to 100% of the arm’s 
circumference and the width of the bladder approximately 40% (the bladder is the inflatable 
part of the cuff).  The cuff should be put on according to the instructions given by investigator. 
Morning measurements should be taken after waking up, before breakfast and before study 
drug intake, evening measurements should be taken prior to bedtime. If deemed necessary by 
the Investigator, subjects may be asked to perform additional measurements. 
Self-measurements should, where possible, be performed in the same position as the clinic 
measurements for vital signs.
Results will be directly entered by the subject or subject’s parent(s)/caregiver(s) in the 
e-diary [Section 8.1.1].
5.4.2
Adverse Events
AEs will be collected from visit 1/screening until visit 10/week 52 (EOT/EOS).  See 
[Section 5.5] for information regarding AE collection and data handling. 
5.4.2.1 Adverse Events of Possible Hepatic Origin 
See [Appendix 12.2] for detailed information on monitoring and assessment of suspected 
liver abnormalities, if an AE for a subject enrolled in a study and receiving study drug is due 
to circulating liver enzymes (AST, ALT, ALP) or bilirubin, or if the AE is suspected to be 
due to hepatic dysfunction.  
Subjects with AEs of hepatic origin accompanied by liver function test (LFT) abnormalities 
should be carefully monitored.  
5.4.3
Laboratory Assessments
Hematology and biochemistry assessments will be taken at visit 1/screening, visit 7/week 12 
and visit 10/week 52 (EOT/EOS). In the event that an AE related to hematology/biochemistry 
parameters is found at visit 1/screening, an additional hematology/biochemistry assessment is 
to be taken at visit 3/baseline.
Urinalysis is to be assessed at visit 1/screening, at visit 3/baseline, and at visit 5/week 4, 
visit 7/week 12, visit 8/week 24 and visit 10/week 52 (EOT/EOS).  
To allow for an early DSMB safety assessment, the first 5-10 subjects who reach study visit 
5/week 4 will have an additional blood draw at this visit [see Section 1.4].  
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.

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All safety laboratory assessments will be performed at a central laboratory, except for urine 
pregnancy testing, which is done locally. Pregnancy test in female subjects of childbearing 
potential will be performed in serum (if blood is drawn for hematology/biochemistry) or 
urine (at the other visits).
Specimen collection and shipping procedures will be described in a laboratory manual. All 
laboratory results, including ULNs used in exclusion and discontinuation criteria, will be 
compared to age-appropriate norms. The investigator may decide to repeat the safety 
laboratory assessments, should the results be important for safety reasons and considered 
clinically relevant. Repeating safety laboratory assessments for re-screening is not allowed.
The clinical significance of out-of-range laboratory findings is to be determined and 
documented by the investigator/sub-investigator who is a qualified physician. Clinically
significant adverse changes will be recorded as an AE [Section 5.5.1].  
The laboratory parameters that will be assessed during the conduct of the study are listed in 
[Appendix 12.3].
5.4.4
Physical Examination
Physical examinations will be performed at visit 1/screening and at visit 10/week 52 
(EOT/EOS).
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
[Section 5.5.1].
5.4.5
Electrocardiograms
Triplicate 12-lead ECG will be performed at visit 1/screening, visit 3/baseline, visit 5/week 4, 
visit 7/week 12, visit 8/week 24 and at visit 10/week 52 (EOT/EOS).
ECGs will be taken in the supine position (when possible, but always in the same position), 
after the subject has been lying quietly for at least 5 minutes. ECG machines will be 
provided to the site by a central laboratory to allow for central reading (ECG recordings will 
be performed according to ICH guidelines E14 [CPMP/ICH/2711/99] to make them readable 
and interpretable for potential later assessment by an independent cardiologist).  
ECGs will be recorded with an interval of about 30 seconds to 5 minutes between each ECG.  
Recordings will be made at a speed of 25 mm/s and all leads have to include at least 
4 complexes. This is according to the standard settings on the machines. The ECGs should 
be transmitted from the machine to the central laboratory (following the steps indicated in the 
user manual). In addition, 2 prints of the original ECG traces should be made on normal, 
nonheat sensitive paper. These should be clearly marked with the subject identification 
number (in such a way that they are anonymized), include date and time, and should be kept 
with the source documents.  

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The ECG machine will produce automatically calculated interval duration measurements for 
intervals of QT, QTcB, QTcF, etc., and an evaluation on the printed ECG.  For a final safety 
assessment the manually read analysis reports of the central ECG readings (from 
cardiologists) will be made available to the investigators within 72 hours. The final ECG 
reports sent by the central laboratory must be reviewed by the investigator since there might 
be relevant differences from the initial analysis produced by the ECG machines.  
For analysis the mean values of the triplicate readings will be used (not the highest or lowest 
value). In case of incomplete triplicates, mean values of the available ECG readings will be 
taken.
Please refer to [Section 6.1] for discontinuation criteria based on centrally read results from 
the QTcB mean from the visit 1 and visit 3 ECG triplicates (at least 2 ECGs of each triplicate 
reading must be available).  
The ECG report itself will not be captured on the electronic case report from (eCRF), but will 
be captured in the central ECG laboratory database.  Only the visit, ECG date and time, 
overall ECG interpretation and relevant comments will be captured in the eCRF.  If specific 
concerns regarding the cardiac safety of a subject exist, a dual approach is recommended: 
●
On-site evaluation of the ECGs are to be conducted by a medically qualified person.
●
In addition, the central ECG laboratory can be contacted (24 hours a day) to provide the 
final centrally read ECG analysis results within a shorter timeframe than the usual 
72 hours (for contact details see the ECG Study Manual provided by the central ECG 
laboratory).  
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. Clinically significant abnormalities should be reported as an AE [Section 5.5.1].  
Detailed instructions and procedures for ECG recordings will be described in a separate 
manual.
5.4.6
Self-measurement of Intravesical Pressure
SMIP will be performed as part of the bladder diary [Section 5.3.2]. In case the measuring 
device is not available/approved for use at the site, the subject or parent(s)/caregiver(s) are 
not able or willing to perform the SMIP, or there is a technical problem, the SMIP may be 
omitted.
Following successful completion of the first 2-day weekend e-diary, confirmed at visit 2, 
subsequent measurements will be performed in the weekend preceding visit 3/baseline, visit 
4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 24, visit 9/week 36 and 
visit 10/week 52 (EOT/EOS).
SMIP is a method to measure the intravesical pressure at home. The pressure in the bladder
can be measured by the subject or subject’s parent(s)/caregiver(s) at the moment the subject
catheterizes him/herself in the course of using CIC as a therapeutic intervention.  
Measurements will be performed on a full and emptied bladder.

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The aim of this method is to verify that the intravesical pressure is in a safe range and 
particularly if the pressure at the time of CIC (the end-filling pressure), where intravesical 
pressure can be expected to be at its greatest, is at an acceptable level.  
To start measurements, the SMIP device is connected to a CIC catheter with a 3-way stopcock 
via an air tube.  By switching the handle on the stopcock, a closed circuit can be established 
between the SMIP device and the CIC catheter.  The urine from the subject exerts pressure to 
the trapped air in the closed circuit and this pressure is transferred to a sensor in the SMIP 
device. The signal from the sensor is interpreted by a microprocessor which then displays the 
pressure numerically in centimeters H2O. The zero is set to atmospheric pressure.
Once a stable read-out has been obtained, the handle on the stopcock can be switched again 
and the urine can now flow out of the catheter attached to the other outlet of the 3-way 
stopcock.
After the bladder has been emptied, the intravesical pressure is measured a second time by 
switching the handle of the stopcock again, establishing a closed circuit between the SMIP 
catheter and the SMIP device.
Devices (Peritron+, 
 for measuring intravesical 
pressure will be provided to subjects along with required auxiliaries such as special catheters
and connectors (Air Trap Tubing, 
  Detailed 
on-site training of the SMIP and a booklet with operating instructions in local language will 
be provided to the subject and the subject’s parent(s)/caregiver(s).
Results will be entered by the subject or subject’s parent(s)/caregiver(s) in the e-diary 
[Section 8.1.1].
5.4.7
Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound
Renal function will be assessed via monitoring plasma creatinine and cystatin C levels at 
visit 1/screening, visit 7/week 12 and visit 10/week 52 (EOT/EOS). 
The presence or absence of structural abnormalities of the urinary tract, upper tract dilation, 
vesicoureteral reflux, or obstruction at the ureterovesical or ureteropelvic junction will be 
assessed with an ultrasound of the upper urinary tract at visit 3/baseline, and at 
visit 10/week 52 (EOT/EOS).
For the first group of subjects (minimum of 5, maximum of 10) who reach study 
visit 5/week 4, the renal function will also be determined at visit 5/week 4 to allow for the 
early DSMB safety assessment.
Clinically significant abnormalities should be reported as an AE [Section 5.5.1].  

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5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to a serious adverse event (SAE).  In these 
cases, it is the investigator’s responsibility to ensure these AEs or other reporting requirements 
are followed and the information is appropriately recorded in the eCRF accordingly.  
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets 1 of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study drug intake
●
The abnormality or investigational value is clinically significant in the opinion of the
investigator.
5.5.2
Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes:
●
Results in death
●
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
●
Other medically important events
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above.  These events, including those that may result in disability/incapacity, should also 

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usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.  
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)
●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject exposure to 
the Sponsor medicinal product, e.g., name confusion)
All of the events of interest noted above should be recorded on the eCRF.  Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ and the SAE worksheet.  
The Sponsor has a list of events that they classify as “always serious” events.  If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
5.5.3
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out".
Causal relationship 
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal  relationship to drug administration which makes a causal 
relationship improbable, and/or in  which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or  other drugs or chemicals, and 
which follows a clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge).

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5.5.4
Criteria for Defining the Severity of an Adverse Event
The investigator will use the following definitions to rate the severity of each AE
●
Mild: 
No disruption of normal daily activities
●
Moderate:
Affects normal daily activities
●
Severe: 
Inability to perform daily activities
5.5.5
Reporting of Serious Adverse Events
In the case of an SAE, the investigator must contact the CRO by telephone or fax/e-mail
immediately (within 1 working day of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to CRO by fax/e-mail immediately (within 
1 working day of awareness). If the faxing/e-mailing of an SAE Worksheet is not possible or 
is not possible within 1 working day, the local drug safety contact should be informed by 
phone. Within 1 working day during weekdays or within 60 hours during weekends, 
whatever is shorter, after receipt of the information, the CRO will forward the SAE details to 
the Sponsor.
SAEs must be reported up to 28 days after the EOS visit or up to 28 days after early 
discontinuation of dosing.
For contact details, see [Section II] Contact Details of Key Sponsor's Personnel.  Please 
fax/email to:
Safety & Pharmacovigilance
Please use the country specific toll-free fax number provided on the SAE Fax cover sheet.
In case of fax failure, email: 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (Section II).  
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should be recorded on the medical records and on the eCRF.
The following minimum information is required:
●
International Study Number (ISN) 
●
Subject number, sex and age
●
The date of report
●
A description of the SAE (event, seriousness of the event) and
●
Causal relationship to the study drug
Where required by local requirements, the Sponsor or Sponsor's designee will submit 
expedited safety reports (e.g., IND Safety Reports) to the regulatory agencies (e.g., FDA) as 
necessary, and will inform the investigators of such regulatory reports.  Investigators must 

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submit safety reports as required by their IEC/IRB within timelines set by regional 
regulations (i.e., EU, (e)CTD, FDA). Documentation of the submission to and receipt by the 
IEC/IRB of expedited safety reports should be retained by the site.
The delegated CRO will notify all investigators responsible for ongoing clinical studies with 
the study drug of all SAEs which require submission per local requirements.
The investigators should provide written documentation of IEC/IRB notification for each 
report to the Sponsor, where required by local requirements.
You may contact the Sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare, or rights of the subject.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized.  
If during AE follow-up, the AE progresses to an SAE, or if a subject experiences a new SAE, 
the investigator must immediately report the information to the Sponsor.  
Please refer to [Appendix 12.2] for detailed instructions on Drug Induced Liver Injury.
5.5.7
Monitoring of Common Serious Adverse Events
Common serious adverse events are SAEs commonly anticipated to occur in the study 
population independent of drug exposure. For this protocol, there is no list of common 
serious adverse events that the Sponsor considers to be associated with the disease state being 
studied for which a single occurrence will be excluded from safety reporting. 
5.5.8
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 28 days from the discontinuation of dosing, the investigator should report 
the information to the CRO as if it is an SAE.  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.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs.  
Additional information regarding the outcome of a pregnancy (which is categorized as an 
SAE) is mentioned below.
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion

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●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth
●
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
5.5.9
Emergency Procedures and Management of Overdose
In the event of suspected mirabegron overdose, the subject should receive supportive care 
and monitoring.  Heart rate, blood pressure and ECG monitoring are recommended.  The 
Medical Monitor/Expert should be contacted as applicable.
5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IEC/IRB of such information when 
needed.  
5.6
Test Drug Concentration
Samples will be collected as per local standards, however a topical anesthetic cream or 
plaster must be offered at the point of venipuncture to minimize distress of the subject.
Venous blood (2 mL) for bioanalysis of mirabegron will be collected in properly labeled 
tubes containing sodium-heparin as anticoagulant and sodium fluoride as stabilizer.  
Blood samples will be kept on melting-ice until ready for centrifugation, which must be done 
within 30 minutes after collection. Blood samples will be centrifuged at 1500 g for 
10 minutes at ambient temperature in order to obtain plasma. Plasma will be harvested and 
transferred into a properly labeled polypropylene tube and stored at -20°C or below 
(preferably at -70°C) within 30 minutes after centrifugation.  
Plasma samples will be sent to the central laboratory, packed with sufficient dry ice, to keep 
the samples frozen during shipment. Bioanalysis of mirabegron in plasma will be done at a 
designated CRO using a validated liquid chromatography-tandem mass spectrometry method.
5.7
Other Measurements, Assessments or Methods
If deemed relevant, the remaining plasma may be used for retrospective mirabegron 
metabolite profiling, identification and/or quantification studies. Analysis of these 
metabolites will be done at Astellas or at a designated CRO using LC-MS/MS or other 
appropriate analytical techniques. The results from these tests will be described in (a) 
separate report(s) and will not be incorporated in the integrated clinical study report.

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5.8
Total Amount of Blood
The total amount of blood that is to be taken as foreseen over the entire study period is 
approximately 25 to 30 mL per subject [Table 5]:
Table 5
Total Amount of Blood Volume per Subject During the Study Period
Amount for pharmacokinetic sampling
(2.0 mL/sample x 4 samples)
8 mL
Amount for safety hematology & biochemistry †
(5.5 mL/sample x 3‡ samples)
16.5 mL
Total §
24.5 mL
† 
If applicable, pregnancy test will be done from the same sample; no additional blood is required.
‡ 
The first group of subjects (minimum of 5, maximum of 10) who reach study visit 5/week 4 will have an 
additional blood draw of about 5 mL at study visit 5/week 4 for DSMB safety monitoring.  The total 
amount of blood drawn from these subjects will thus be approximately 30.0 mL
§ 
Volume does not take any unscheduled visits or re-tests into account (e.g., follow-up of AEs)
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who received study drugs and for whom study treatment is 
permanently discontinued prematurely 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 terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant.  
Discontinuation criteria from treatment for individual subjects:
●
If, within 7 days of the first dose of mirabegron:
o
The centrally read urodynamic trace reveals no evidence of NDO
o
The centrally read ECG has an average QTcB interval greater than 450 ms, based on 
the QTcB mean from the visit 1 and visit 3 ECG triplicates
●
If signs or symptoms of hypersensitivity to mirabegron are observed (e.g., anaphylactic 
reaction, erytheme multiforme or exfoliative dermatitis).
●
Discontinuation of treatment should be considered if:
o
ALT or AST > 8 × ULN
o
ALT or AST > 5 × ULN for more than 2 weeks 
o
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated)

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o
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%).
o
In addition, if close monitoring for a subject with moderate or severe hepatic 
laboratory tests is not possible, the drug should be discontinued.
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of Astellas. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures (TLFs) to be produced. The SAP will be 
finalized before the database soft lock at the latest. Any changes from the analyses planned 
in SAP will be justified in the clinical study report (CSR).
Prior to database lock, a final meeting will be held to allow a review of the clinical trial data 
and (TLFs) 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 lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
The primary endpoint will be the change from baseline in MCC after 24 weeks of mirabegron 
treatment. There are data from previous studies that indicate the effect size that can be 
expected as a result of the treatment with mirabegron. Franco et al. (2005) analyzed 2 age 
groups (1 to 5 years, and 6 to 15 years) and reported mean (SD) MCC changes from baseline 
of 71.5 (88) mL and 75.4 (102.7) mL respectively after 24 weeks treatment with oxybutynin.  
Goessl et al. (2000) reported an increase of 52.8 mL after 3 months treatment with 
tolterodine. Cartwright et al. (2009) reported an increase of 98 mL after 14 weeks treatment 
with oxybutynin and a corresponding SD of 87 mL.

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A study with 44 evaluable subjects who have valid (as by the central reviewer’s assessment) 
nonmissing MCC measurements at visit 8/week 24 and at baseline would have a 90 percent 
power to detect a statistical significant change from baseline, if the real change from baseline 
in the subject population is at least 52 mL and the real SD for change from baseline is 
≤ 103 mL. The power calculation was done assuming a paired t-test with 2-sided significance 
level of 0.05.  
Assuming 30% of enrolled subjects will discontinue or will not be evaluable for the primary 
endpoint, a total of approximately 63 subjects may need to be enrolled so that 44 subjects are 
evaluable in total.
These sample size considerations should allow sufficient precision for the assessment of the 
primary objective in this nonrandomized pediatric trial.
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 hard-lock.
7.2
Analysis Set
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 hard-lock.  
7.2.1
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who: 
●
Took at least 1 dose of study drug, and 
●
Had a valid (as by the central reviewer’s assessment) nonmissing MCC measurement at 
baseline and at a postbaseline visit for the primary efficacy endpoint.
The FAS will be used for primary analyses of efficacy data, for sensitivity and subgroup 
analyses [Section 7.4.1.3] and for summaries of some demographic and baseline 
characteristics.
7.2.2
Per Protocol Set
The per protocol set (PPS) will include all subjects of the FAS who fulfill the protocol in 
terms of their eligibility, interventions and outcome assessments, and for whom valid MCC 
measurements at visit 3/baseline and at visit 8/week 24 are reported.
A list of the protocol deviations that may result in a subject in the FAS being excluded from 
the PPS will be provided in the SAP.  The final selection of subjects for the PPS will be 
confirmed in the Analysis Set Classification Meeting based upon a review of all the pertinent 
data.
The PPS will be used for secondary analyses of efficacy data.  Also, selected demographic 
and baseline characteristics may also be summarized for the PPS.

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7.2.3
Safety Analysis Set
The safety analysis set (SAF) will consist of all subjects who took at least 1 dose of study 
drug.
The SAF will be used for all summaries of demographic and baseline characteristics and all 
safety and tolerability related variables.
7.2.4
Pharmacokinetics Analysis Set
The pharmacokinetics analysis set (PKAS) consists of the subset of subjects of the SAF for 
whom plasma concentration data are available to facilitate derivation of at least 1 
pharmacokinetic parameter and for whom the time of last dose prior to sampling is known.
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.
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 pharmacokineticist. These data points will be reported in the CSR.  
7.3
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by using descriptive 
statistics. Summaries of demographic data will be provided for each analysis set within and 
across age groups.  
7.4
Analysis of Efficacy 
Efficacy analysis will be conducted on the FAS. The 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.
7.4.1
Analyses of Primary Endpoint 
7.4.1.1 Primary Analysis
Baseline for efficacy variables is the last assessment made prior to the first intake of study 
drug at visit 3 (day -1).
The primary efficacy variable is change from baseline in MCC after 24 weeks of treatment 
(based on filling urodynamics). The primary analysis will be a paired t-test for the change 
from baseline to week 24 to test the hypothesis that the change from baseline in MCC is not 
equal to zero with a 2-sided alpha level of 0.05.  A 95% CI will be calculated for mean 
change from baseline. It will be assessed whether the estimated lower bound of the 95% CI 
excludes 0 mL. No adjustment for multiplicity will be made.
Missing MCC observations at visit 8/week 24 will be imputed using the last observation 
carried forward method (LOCF).  The data will be summarized with descriptive statistics as a 
continuous variable (n, mean, SD, SEM, 95% CI, min, median, max).

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7.4.1.2 Secondary Analyses
A repeat of the primary analysis will be performed on the FAS without imputing missing data 
as well as based on the PPS.  
A repeated measures analysis of covariance (ANCOVA) will be performed considering the 
change from baseline (without LOCF) and baseline MCC. This analysis will serve as a 
sensitivity analysis to the LOCF methods used in the primary model to assess robustness of 
those findings.  For this analysis, data will be windowed according to predefined study visit 
windows.
Details of these analyses, including study visit windows, will be provided in the SAP.
7.4.1.3 Subgroup and Sensitivity Analyses of Primary Endpoint
For the primary efficacy endpoint, MCC, 95% CI will be calculated for mean change from 
baseline per age group, per formulation, and per dosing regimen (with and without LOCF).
Dosing regimen here refers to whether the subjects had been up-titrated to PED50 at least 
once or maintained at PED25 for safety reasons at least until visit 8/week 24.
A subgroup analysis of the primary efficacy endpoint by whether NDO medication treatment 
was received at screening/prior to start of washout for both groups of subjects will be 
performed if there are sufficient subject numbers (with and without LOCF) on the FAS.
A subgroup analysis of the primary efficacy endpoint of subjects with insufficient efficacy 
under antimuscarinics specifically intended for NDO treatment (i.e. stopping the medication 
for lack of efficacy prior to start of treatment) will be performed if there are sufficient subject 
numbers (with and without LOCF) on the FAS.  
The following sensitivity analyses of the primary efficacy endpoint will be performed if there 
are sufficient subject numbers (without LOCF only) on the FAS:
●
Excluding those subjects who had a positive urine culture at visit 3/baseline and/or 
visit 8/week 24.
●
For any of the subgroups specified, at least 10 subjects by stratum are required.
7.4.2
Analysis of Secondary Endpoints 
Each of the secondary efficacy endpoints will be summarized and, if applicable, plotted by 
visit.
The change from baseline for secondary endpoint based on urodynamic assessments, the 
subject’s e-diary (including bladder diary) and questionnaires will be summarized and 
analyzed using similar primary statistical methods as for the primary endpoint, where 
appropriate.
CGI-C and acceptability results will be tabulated per time point of assessment.
These analyses of secondary endpoints will be produced for subjects in the FAS.  Details of 
these analyses and of any further analyses will be defined in the SAP.

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7.4.3
Analysis of Exploratory Endpoints 
Each of the exploratory efficacy endpoints will be summarized and analyzed in the same way 
as the secondary efficacy endpoints [Section 7.4.2].
Details of these analyses and of any further analyses will be defined in the SAP.
7.5
Analysis of Safety
The baseline for safety variables is the last assessment made prior to first intake of study drug
(visit 3/day -1).  
For safety variables relating to the ECG intervals, baseline values are taken from the mean of 
the visit 1 and visit 3 mean values.
All safety data will be summarized descriptively based on the SAF.  The continuous safety 
data will be summarized using the following descriptive statistics: n, mean, SD, min, median, 
max, at each time point and for change from baseline.  Categorical data will be summarized 
by absolute and relative frequencies. All safety data from subjects in the SAF will be listed.  
Safety parameters such as vital signs and weight will also be summarized with respect to 
height- and sex-specific percentiles.  Height will also be summarized with respect to age- and 
sex-specific percentiles.
Subgroup presentations regarding age (children and adolescents), formulation (tablets and 
suspension) and dosing regimen (PED25 and PED 50) will be tabulated for the following 
parameters: AEs, vital signs and ECGs.  For any of the subgroups specified, at least 
10 subjects by stratum are required.
7.5.1
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time.  For clinic 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.  
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].
7.5.2
Adverse Events
AEs will be coded using MedDRA.  The number and percentage of AEs, SAEs, AEs leading 
to discontinuation, and AEs related to study drug will be summarized by system organ class
and preferred term.  The number and percentage of AEs by severity will also be summarized.  
7.5.3
Laboratory Assessments
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline time point.  Shifts relative to normal ranges from baseline to 
each time point during treatment period in lab tests will also be tabulated.  

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7.5.4
Physical Examination
Abnormal findings/conditions identified during the physical examinations will be summarized 
and listed as part of the medical history for the screening visit, or as AEs at later visits.
7.5.5
Electrocardiograms
12-lead ECG parameters (QT, QT interval corrected by Fridericia's formula [QTcF], HR, PR, 
QRS and RR) and their changes from baseline will be summarized with descriptive statistics 
by visit. The following thresholds will be used to characterize an individual subject’s QTcF
data: QTcF interval > 440 ms for children, and QTcF interval > 450 ms and >500 ms for 
male adolescents and >480 ms and >500 ms for female adolescents.  These categories are 
cumulative in that subjects satisfying criterion for a more extreme category will also be 
counted in each applicable less extreme category. A summary of normal, abnormal not 
clinical significant and abnormal clinical significant findings will be provided.
In addition for QTcF, the impact of concomitant medications potentially prolonging QTc will 
be evaluated. 
To perform this analysis, all QTcF post-baseline values will be presented (regardless of time 
point). If anomalies occur, an additional presentation will be provided using only QTcF 
values not under the influence of respective concomitant medications. 
Details on how these will be derived, will be described in the SAP.
7.5.6
Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound
For eGFR and upper urinary tract ultrasound, descriptive statistics will be used to summarize 
results and change from baseline by time point.  The eGFR results will be summarized based 
upon the Larsson, the modified Schwartz 2009 (for children < 12 years old) and the 
Cockcroft-Gault equation (for adolescents).
7.5.7
Analysis of Exploratory Endpoints 
Each of the exploratory safety endpoints will be summarized and analyzed in the same way 
as the safety endpoints [Sections 7.5.1 to 7.5.6]. For SMIP descriptive statistics will be used 
to summarize results and change from baseline by time point.  
All analyses of exploratory safety endpoints will be produced for subjects in the SAF.
Details of these analyses and of any further analyses will be defined in the SAP.
7.6
Analysis of Pharmacokinetics
Descriptive statistics (N, mean, SD, minimum, median, maximum, coefficient of variation 
and geometric mean) will be provided for plasma concentration data. Further details will be 
specified in the SAP.

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7.6.1
Estimation of Pharmacokinetic Parameters
The plasma concentrations will be analyzed with nonlinear mixed effects modeling 
(population pharmacokinetics) using NONMEM (version 7.3 or higher,
 
 USA). 
The following plasma pharmacokinetic parameters of mirabegron will be calculated for each 
subject:
●
Cmax, tmax, AUC24, Ctrough, CL/F and Vz/F.
7.7
Protocol Deviations and Other Analyses
Protocol deviations as defined in [Section 8.1.6] will be summarized for all subjects by site.  
A data listing will be provided by site and subject.
The protocol deviation criteria will be uniquely identified in the summary table and listing.  
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. 
Descriptive statistics will be used to explore whether there is an association between certain 
subject characteristics (such as medical history) and the final titrated mirabegron doses.  
Collected data on study drug compliance rates and maintenance of treatment will be analyzed 
using descriptive statistics.
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data (with exception of visit 8/week 24, 
LOCF analysis for MCC) will be performed. Values lower than the limit of quantification for 
laboratory parameters will be set to 0 for the calculation of descriptive statistics.
See the SAP for details of the definitions for windows to be used for analyses by visit.

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8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
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 site 
designee should record data (including laboratory values, if applicable) in the eCRF within
5 working days after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents.  
These documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests (except for the locally performed pregnancy tests) are performed at a central 
laboratory and results are visible for the site shortly after analysis has been completed.  
Laboratory data will be transferred electronically to the Sponsor or designee at predefined 
intervals during the study.  The laboratory will provide the Sponsor or designee with a 
complete and clean copy of the data.  
ECG analysis and interpretation are performed at a central ECG reading vendor and results 
are visible for the site shortly after analysis has been completed.  Central ECG read data will 
be transferred electronically to the Sponsor or designee at predefined intervals during the 
study.  The central ECG vendor will provide the Sponsor or designee with a complete and 
clean copy of the data.
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF and listed.
8.1.1.1 Electronic Patient Reported Outcomes
Subject bladder diaries, questionnaires and other data completed by the subject or the 
subject’s parent(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 correct completion before each planned visit of the subject (on site or phone visit) and 
discuss the results or retrain the subject and/or subject’s parent(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 [Section 5.5.1].
The bladder 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.

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For this study the following information will be collected and entered by the subject or 
subject’s parent(s)/caregiver(s) in the e-diary (see [Sections 5.3.2, 5.3.3, and 5.4.1.2] for 
detailed information per visit):
●
Bladder diary:
o
Each day for 7 days: time of CICs
o
Each day for 7 days: presence of leakage between CICs
o
Each day for 7 days: sleep time and wake-up time
o
On the 2 weekend days: catheterized volume
o
On the 2 weekend days: SMIP (if applicable)
o
On the 2 weekend days: grade and number of leakages between CICs
o
On the 2 weekend days (selected visits): weight of diaper/pad
●
SBPM (blood pressure and pulse rate): 
o
On the 2 weekend days: triplicate measurements in the morning and evening
o
On 2 consecutive 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.
●
Questionnaires: on 1 weekend day at selected visits
o
PIN-Q
o
PGI-S
o
Acceptability
●
Confirmation of study drug intake: daily
The Investigator must guide the subject and subject’s parent(s)/caregiver(s) to ensure that on 
the evening before and during the two weekend days of collection of catheterized volume and 
SMIP (if applicable), the subject’s fluid intake should be regulated to an appropriate level 
taking 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.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected.  Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject. 
The following information should be included in the source medical records (not exhaustive):
●
Demographic data (e.g., date of birth/age, sex, race/ethnicity, height and body weight)
●
Subject number 
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated informed consent forms (ICFs)
●
Visit dates
●
Dispensing and return of study drug details
●
Medical history and physical examination details
●
Key efficacy and safety data (as specified in the protocol)

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●
AEs and concomitant medication 
●
Results of relevant examinations (e.g., ECG printouts, physical examination)
●
Laboratory printouts
●
Reason for premature discontinuation (if applicable)
8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IEC/IRB and relevant regulatory authorities.  
In these instances, they must provide all study-related records, such as source documents 
[Section 8.1.2] when they are requested by the Sponsor monitors and auditors, the IEC/IRB, 
or regulatory authorities. The confidentiality of the subjects’ identities shall be well 
protected consistent with local and national regulations when the source documents are 
subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Global Data Science Department of the 
Sponsor in accordance with the SOPs for data management. All study-specific processes and 
definitions will be documented by Data Management. eCRF completion will be described in 
the eCRF instructions. Coding of medical terms and medications will be performed using 
MedDRA and the World Health Organization Drug Dictionary respectively.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited.

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For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 
●
Entered into the study even though they did not satisfy entry criteria†
●
Developed withdrawal criteria during the study and not withdrawn
●
Received wrong treatment or incorrect dose
●
Received excluded concomitant treatment 
†
Subjects who are discontinued within the first 7 days of dosing, after the centrally read urodynamic trace
or the ECG results from visit 3/baseline show the subject is no longer fulfilling the eligibility criteria, will 
not result in a protocol deviation.
When a 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 the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and/or 
efficacy of the subject to determine subject continuation in the study.  
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately. 
The investigator will also assure that deviations meeting IEC/IRB and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IEC/IRB and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File. 
NOTE:  Other deviations outside of the categories defined above will be reported to the 
IEC/IRB as required in accordance with local requirements, as applicable.  
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the last subject’s last visit.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Independent Ethics Committee/Competent Authorities 
GCP requires that the clinical protocol, any protocol amendments, the IB, the informed 
consent/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 IEC/IRB.  The IEC/IRB will review the ethical, scientific and medical appropriateness of 
the study before it is conducted. IEC/IRB approval of the protocol, informed consent/assent
and subject information and/or advertising, as relevant, will be obtained prior to the 
authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH-GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required. During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 

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Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB
of any changes that affect the conduct of the study and/or increase the risk to subjects.  
Written documentation of the submission to the IEC/IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year.  The 
investigator shall make an accurate and adequate final report to the IEC/IRB within 1 year 
after last subject out or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
For this pediatric study in subjects aged 3 to less than 18 years, in addition to information 
sheets and consent/assent forms for subjects (according to applicable local regulations), 
parent/legal guardian information sheets and consent forms will also be prepared.  
Prior to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject, the subject’s 
parent(s) or legal guardian(s), the person who administered the informed consent/assent, and 
any other signatories according to local requirements.  
The following general rules apply but these may vary by local regulations for pediatric 
studies:
●
The investigator/sub-investigator is responsible for explaining the nature and purpose of 
the study as well as other study-related matters to subjects and their parents or legal 
guardians, using the written information, and for obtaining the child’s assent and the 
parent(s)’/guardian(s)’ full understanding and written consent 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 trial at any time, this will have to be considered by 
the investigator, even if consent 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 
parent(s)/legal guardian(s) should sign and date the written information, or write down 
his/her name, and date the form.  

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●
Informed consent/assent must be obtained prior to any study-related procedures 
(including discontinuation of prohibited medication, if applicable).  Consent should be 
obtained from the subject and his/her parent(s)/legal guardian(s), before start of pre-
investigational period. Assent and consent 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): 
o
No subject may be subjected to undue influence, such as compulsory enrollment into 
a study.  
o
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/sub-investigator, 
collaborators, or the Sponsor from liability for negligence.  
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.  
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
●
The investigator or his/her representative will immediately inform the subject or 
subject’s parent(s)/guardian(s) orally whenever new information becomes available that 
may be relevant to the subject’s consent or may influence the subject’s willingness to 
continue to participate in the study (e.g., report of serious drug adverse drug reaction). 
The communication must be documented in the subject’s medical records and must 
document whether the subject is willing to remain in the study or not.  
●
The investigator must update their ICF and submit it for approval to the IEC/IRB.  The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study.  The investigator 
or his/her designee must reconsent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the informed consent 
form. A copy of the signed ICF will be given to the subject and the original will be 
placed in the subject’s medical record. An entry must be made in the subject’s records 
documenting the re-consent process. 

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8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being. 
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IEC/IRB and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information.  
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
Sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study.  The investigator may use this information for the purpose of the study only. It 
is understood by the investigator that the Sponsor will use the information obtained during 
the clinical study in connection with the development of the drug and therefore may disclose 
it as required to other clinical investigators or to regulatory agencies. In order to allow for the 
use of the information derived from this clinical study, the investigator understands that 
he/she has an obligation to provide the Sponsor with all data obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, CRFs, and Investigator's File) and relevant correspondence. These documents are to be 
kept on file for the appropriate term determined by local regulation (for US sites, 2 years 
after approval of the NDA or discontinuation of the IND).  The Sponsor will notify the 
site/investigator if the MAA is approved or if the IND/IMPD 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.

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Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes.  All data will be entered on the eCRFs supplied 
for each subject.
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.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or nonsubstantial amendments.  
Depending on the nature of the amendment, either IEC/IRB, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the Sponsor, the investigator, the regulatory authority, and the IEC/IRB (if applicable).  
Amendments to this protocol must be signed by the Sponsor and the investigator. Written 
verification of IEC/IRB approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IEC/IRB approval, but will be 
submitted to the IEC/IRB for their information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IEC/IRB approval must 
be forwarded to the Sponsor. An approved copy of the new ICF must also be forwarded to 
the Sponsor.
8.3.4
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.  
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which 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 
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.

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9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee | Data and Safety 
Monitoring Board | Monitoring Committee | Other Evaluation 
Committee(s)
A DSMB will be installed to act in an advisory capacity to the Sponsor to monitor participant 
safety and data quality.  
Subject safety 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.
10.2
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. 
Bauer SB,  Austin PF, Rawashdeh YF,  de Jong TP, Franco I, Siggard C, et al. International 
Children’s Continence Society’s recommendations for initial diagnostic evaluation and follow-
up in congenital neuropathic bladder and bowel dysfunction in children. Neurourol Urodyn 
2012;31:610-14.
Bauer SB, Nijman RJ, Drzewiecki BA, Sillen U, Hoebeke P. International Children's Continence 
Society standardization report on urodynamic studies of the lower urinary tract in children. 
Neurourol Urodyn. 2015 May 21. doi:10.1002/nau.22783.
Bower WF, Sit FK, Bluyssen N, Wong EM, Yeung CK. PinQ: a valid, reliable and reproducible 
quality-of-life measure in children with bladder dysfunction. J Pediatr Urol. 2006;2:185-9. 
Cartwright PC, Coplen DE, Kogan BA, Volinn W, Finan E, Hoel G. Efficacy and safety of 
transdermal and oral oxybutynin in children with neurogenic detrusor overactivity. J Urol. 
2009;182:1548–54.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. (1976); 
16(1):31–41. doi:10.1159/000180580. PMID 1244564.
de Zwart L, Scholten M, Monbaliu JG, Annaert PP, Van Houdt JM, Van den Wyngaert I, et al. The 
ontogeny of drug metabolizing enzymes and transporters in the rat. Reprod Toxicol. 
2008;26:220-30.
Food and Agriculture Organization of the United Nations; Food Safety and Quality: Online Edition: 
‘Combined compendium of food additive specifications’; 2015. Available from: 
http://www.fao.org/food/food-safety-quality/scientific-advice/jecfa-additivies/en/
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.
Franco I, Horowitz M, Grady R, Adams RC, de Jong TP, Lindert K, et al. Efficacy and safety of 
oxybutynin in children with detrusor hyperreflexia secondary to neurogenic bladder 
dysfunction. J. Urol. 2005;173:221-5.
Goessl C, Sauter T, Michael T, Bergé B, Staehler M, Miller K. Efficacy and tolerability of tolterodine 
in children with detrusor hyperreflexia. Urology. 2000;55:414-8.
Lafontan M, Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell 
function. J Lipid Res. 1993;34:1057-91.
Larsson A, Malm J, Grubb A, Hansson LO. Calculation of glomerular filtration rate expressed in 
mL/min from plasma cystatin C values in mg/L. Scand J Clin Lab Invest 2004;64:25-30.
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(10):926-932. doi:10.1001/jamapediatrics.2013.465.

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Rawashdeh YF, Austin P, Siggaard C, Bauer SB, Franco I, de Jong TP, et al. International Children’s 
Continence Society’s Recommendations for Therapeutic Intervention in Congenital 
Neuropathic Bladder and Bowel Dysfunction in Children. Neurourol Urodyn 2012;31:615-20.
Saghir SA, Khan SA, McCoy AT. Ontogeny of mammalian metabolizing enzymes in humans and 
animals used in toxicological studies. Crit Rev Toxicol 2012;42:323-57.
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. 
Skobejko L. Mirabegron in management of neurogenic patients with resistance to anticholinergic 
medicaments. Paper presented at ICS2014 - 44th Annual Meeting of the International 
Continence Society (ICS), October 20-24, 2014, Rio de Janeiro, Brazil.
Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15:241-3.
The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and 
adolescents. 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
Verpoorten C, Buyse GM. The neurogenic bladder: medical treatment. Pediatr Nephrol. 2008 
May;23(5):717-25. Epub 2007 Dec 19.
Wada N, Okazaki S, Kobayashi S, Hashizume K, Kita M, Matsumoto S, et al. Efficacy of 
combination therapy with mirabegron for anticholinergic-resistant neurogenic bladder: 
videourodynamic evaluation. Hinyokika Kiyo. 2015 Jan;61(1):7-11.
Wöllner J, Pannek J. Initial experience with the treatment of neurogenic detrusor overactivity with a 
new β-3 agonist (mirabegron) in patients with spinal cord injury. Spinal Cord. 2015 Oct 27. 
doi: 10.1038/sc.2015.195. [Epub ahead of print].

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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases to > 3 × ULN, or bilirubin > 2 × ULN, should undergo detailed 
testing for liver enzymes (including at least ALT, AST, ALP) and TBL. Testing should be 
repeated within 48-72 hours of notification of the test results. For studies for which a central 
laboratory is used, alerts will be generated by the central lab regarding moderate and severe 
liver abnormality to inform the investigator, study monitor and study team.  Subjects or 
his/her parent(s)/caregiver(s) 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:
ALT or AST
Total Bilirubin
Moderate
> 3× ULN 
or
> 2× ULN
Severe*
> 3× ULN
and
> 2× ULN
In addition, the subject should be considered to have severe hepatic abnormalities 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 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%).  
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests.  The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) that has been developed globally and can be activated for any 
study or an appropriate document.  Subjects with confirmed abnormal liver function testing 
should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less frequently if abnormalities stabilize or the study drug has been discontinued and the 
subject is asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as an SAE.  

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The Sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new onset-diseases should be recorded as ‘adverse events’ on the AE page of the 
eCRF.  Illnesses and conditions such as hypotensive events, and decompensated cardiac 
disease that may lead to secondary liver abnormalities should be noted.  Nonalcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic, and/or diabetic subjects and may be 
associated with fluctuating aminotransferase 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, including dose, should be entered on the concomitant 
medication page of the eCRF. Information on alcohol, other substance use, and diet 
should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history,  other testing may be appropriate including: 
o
acute viral hepatitis (A,B, C, D, E or other infectious agents) 
o
ultrasound or other imaging to assess biliary tract disease
o
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study. The investigator may determine that it is not in the subject’s best 
interest to continue study enrollment. Discontinuation of treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks 
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, the drug should be discontinued.
*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality 
(or transplant). The 2 “requirements” for Hy’s Law are: 

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1) Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase 
in transaminase elevations higher 3 times the upper limit of normal (“2 x ULN elevations are 
too common in treated and untreated subjects to be discriminating”); 
2) Cases of increased bilirubin (at least 2 x ULN) with concurrent transaminase elevations at 
least 3x ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
alkaline phosphatase) or Gilbert’s syndrome [Temple 2006].
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009. 

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12.4
Pediatric Incontinence Questionnaire
1. I get shy because of my bladder problem
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
2. People in my family treat me in a different way because of my bladder problem
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
3. I am worried that people might think my clothes smell of wee
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
4. I think that my bladder problem won’t get better
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
5. Mum and Dad worry about me because of my bladder problem 
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
6. I would feel better about myself if I didn’t have a bladder problem
    □  No   □  Maybe    □  Probably   □  Yes      □  Definitely
7. My bladder problem makes me feel nervous 
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
8. Mum or Dad sometimes seem a bit cranky because of my bladder problem
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
9. My bladder problem stops me going on sleepovers or holidays
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
10. My bladder problem makes me feel bad about myself
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
11. I wake up during my sleep because of my bladder problem
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
12. I miss out on doing things because of my bladder problem
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
13. I feel unhappy because of my bladder problem
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
14. My bladder problem makes me feel sad
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
15. I think about my bladder problem when choosing which sport to play
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
16. I have to go to the toilet when I’m watching a movie
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
17. If my bladder problem was fixed I would invite more friends to my house
    □  No   □  Maybe    □  Probably   □  Yes    □  Definitely
18. I choose hobbies that won’t be spoiled by stopping to go to the toilet
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
19. My bladder problem makes me feel different to other people
    □  No   □  Hardly ever   □  Sometimes   □  Often     □  All the time
20. I miss out on being with friends because of my bladder problem
    □  No   □  Hardly ever   □ Sometimes    □  Often     □  All the time
PINQ (UK-English) Astellas Pharma Europe Ltd   FINAL  V1 Oxford, Version 30NOV2011

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12.9
Centiles of heart rate for normal children from birth to 18 years of 
age [Fleming et al, 2011]

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12.10 CDC Data Table of Stature-for-age Chart for Males

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12.11 CDC Data Table of Stature-for-age Chart for Females

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12.12 Blood Pressure Levels for Boys by Age and Height Percentile 
[NIH 2005]

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12.13 Blood Pressure Levels for Girls by Age and Height Percentile 
[NIH 2005]

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13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
Substantial Changes
1.
Add Mirabegron Oral Suspension as a Formulation of the Study Drug
DESCRIPTION OF CHANGE:
Mirabegron oral suspension (8 mg/mL) is added to the protocol as a second study drug 
formulation.
RATIONALE:
As part of the pediatric mirabegron development program, a suspension formulation of the 
study drug has been developed. This is to ensure availability of an appropriate formulation 
for smaller children or children who have difficulties with swallowing tablets. This 
formulation is now available to be included into the study.
2.
Update of Inclusion Criterion 3
DESCRIPTION OF CHANGE:
The lower weight range for inclusion of subjects in the study is updated to ≥ 11 kg.
RATIONALE:
Due to the addition of mirabegron oral suspension to the protocol, subjects below 35 kg can 
now be included. Based on the dose prediction performed, the minimum body weight for 
inclusion of subjects in the study is updated to 11 kg. 
3.
Update of the Age Range for the Study Population
DESCRIPTION OF CHANGE:
The age range for the study population to enter the study is updated to male and female 
children from 3 to less than 18 years of age.
RATIONALE:
This study is targeted to fulfill both the EMA and FDA requirements related to the conduct 
of pediatric trials. A "Written Request" received from the FDA includes a stipulation to 
decrease the lower limit of the age range from 5 to 3 years of age.  Therefore, in order to 
ensure that the current study meets the needs of both the FDA and the EMA, the age range is 
adjusted. 
Lowering the age range from 5 to 3 years is possible because dose predictions in this study 
cover doses from a body weight of 11 kg onwards. The cut-off of 11 kg body weight is 
considered appropriate for the age range of 3 to less than 18 years old.

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4.
Add Extra Self Blood Pressure Measurements
DESCRIPTION OF CHANGE:
Extra Self Blood Pressure Measurements (SBPM) are included at week 1 and 2 after the start 
of dosing and after a dose escalation. 
RATIONALE:
The EMA and FDA requested additional blood pressure measurements to be performed. This 
change implements additional SBPM done around 1 and 2 weeks after start of mirabegron 
(PED25) treatment and after up-titration from PED25 to PED50 (if not already covered by 
the scheduled SBPM). Triplicate home measurements will be taken in the morning and in the 
evening.
Non-Substantial Changes
1.
Remove IND Number on Cover Page
The IND number on the cover page of the protocol is removed.
RATIONALE:
The study is not conducted under IND. The IND reference number was cited on the cover 
page of the protocol in error.
2.
Update Available Clinical Data
DESCRIPTION OF CHANGE:
Preliminary data of ongoing studies 178-CL-203 and 178-CL-208 are included in the 
protocol. Data from completed study 178-CL-202 are moved to the Investigator’s Brochure.
RATIONALE:
After the finalization of the protocol new data from mirabegron studies within the pediatric 
program has become available. This preliminary data has now been included in the 
introduction of the protocol to support dosing in children/adolescents with a body weight 
< 35 kg. Since the protocol was finalized, the final clinical study report for Study 
178-CL-202 has become available and so this information has been removed from the 
protocol and has been incorporated in the Investigator’s Brochure.
3.
Update Mirabegron Approval Information
DESCRIPTION OF CHANGE:
The number of countries that Mirabegron has been approved in is updated.
RATIONALE:

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The pediatric Investigator’s Brochure has been updated and this change makes the two 
documents consistent.
4.
Remove SMIP Measurement as a Dose Titration Criteria
DESCRIPTION OF CHANGE:
The Self Measurement of Intravesical Pressure (SMIP) is removed from the dose titration 
criteria.
RATIONALE:
The SMIP was intended to be included as a safety parameter to assess the intravesical 
pressure in an at-home situation. In the FDA Advice Letter the Sponsor was asked to exclude 
the results of SMIP as a basis for dose titration in this study.   
5.
Correct Exploratory Efficacy Endpoints
DESCRIPTION OF CHANGE:
For the e-Diary, the maximum confirmed daytime dry period is removed as an exploratory 
endpoint and for the endpoints on total catheterized volume an explanation is included on 
how catheterizations are assigned to a certain period of the day.
RATIONALE:
The maximum confirmed daytime dry period and the maximum confirmed dry daytime 
period/7 days were included to take into account the intervals between the catheterizations.  
It was deleted to reduce the number of exploratory parameters. 
To ensure a correct assignment of the catheterization times to daytime and/or night-time, a 
clarification is included to explain that the first morning catheterization after waking up is 
regarded as part of the ‘night’, whilst the last evening catheterization before sleep time is part 
of the ‘day’.
6.
Include Missing Variable for Bladder Diary
DESCRIPTION OF CHANGE:
The number of leakages between CICs is included in the sections on collected Patient 
Reported Outcome data in the protocol.
RATIONALE:
The number of leakages between CICs is used in the calculation of secondary and 
exploratory endpoints. The collection of this variable is included in the eDiary and its’
submitted documentation, but was not correctly specified as a collected variable in the 
protocol.

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7.
Include Preferred Method for Clinic Vital Signs Measurements
DESCRIPTION OF CHANGE:
Auscultation is included in the protocol as the preferred method for measuring vital signs in 
the clinic.
RATIONALE:
The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in 
Children and Adolescents, which is used as the basis for the blood pressure percentiles used 
in this study states that “The BP tables are bases on auscultatory measurements, therefore 
the preferred measurement is auscultation” †. 
This method has been included in the protocol as the preferred method for measuring vital 
signs.
† The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in 
Children and Adolescents. 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
8.
Add Conversion Factor for Urine Weight-to-Volume
DESCRIPTION OF CHANGE:
A gram-to-milliliter conversion factor is included in the protocol to calculate urine volume 
based on the subject’s reported urine weight in the eDiary.
RATIONALE:
The protocol did not include the conversion factor to calculate the urine volume based on the 
urine weight that is reported by the subject in the eDiary. 
9.
Add eGFR Parameters 
DESCRIPTION OF CHANGE:
Two additional eGFR parameters are included for reporting in the Clinical Study Report. For 
subjects from 3 to 12 years of age, the modified Schwartz formula (2009) is added and for 
subjects from 12 to 18 years of age, the Cockcroft-Gault equation.
RATIONALE:
The calculation of eGFR according to both the modified Schwartz formula and the 
Cockcroft-Gault Equation will be summarized in line with a request form the FDA. No 
additional assessment or increase in collected blood volume is required. Both parameters will 
be derived based on already collected biochemistry results.

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10. Amend Text for Start of Adverse Event Collection
DESCRIPTION OF CHANGE:
The text on the start of adverse event collection is updated to avoid any misunderstanding.
RATIONALE:
The current text in the protocol was ambiguous, possibly leading to confusion on when the 
collection of AEs start. The sentence has been re-worded to provide clarity.
11. Correct Text for Safety Reporting
DESCRIPTION OF CHANGE:
The text related to the safety reporting timeline between the CRO and the Sponsor is updated 
from 24 hours, to 1 working day.
RATIONALE:
In line with ICH-GCP E6, chapter 5.2, Astellas has outsourced the safety reporting process 
for sites to the CRO 
). The ultimate responsibility for safety reporting will 
remain with the Sponsor, as will be the responsibility for adhering to the reporting timelines 
according to section 5.1.5 of the EU guideline “Detailed guidance on the collection, 
verification and presentation of adverse event/reaction reports arising from clinical trials on 
medicinal products for human use” (CT3). Instead of a reporting timeline of 1 working day 
between receipt of the SAE worksheet at the CRO and forwarding of this worksheet to the 
Sponsor, the protocol listed a 24 hour reporting timeline. This has been corrected.
For the Sponsor’s reporting obligations, the clock starts at the time the CRO has first 
knowledge of the minimum criteria for expedited reporting. This correction will not affect 
the regulatory reporting timelines.
12. Add SAE Reporting Procedure after End of Treatment
DESCRIPTION OF CHANGE:
Timelines for SAE reporting after End of Study are included in the protocol.
RATIONALE:
The protocol did not mention the cut-off timelines for reporting of new SAEs occurring after 
the End of Study visit. This timeline is 28 days and the information has now been included 
into the protocol.
13. Amend Text for Pharmacokinetic Sampling Times
DESCRIPTION OF CHANGE:
The preferred timing of pharmacokinetic sampling is added to the protocol.
RATIONALE:
To allow for an early assessment of the dose-response relationship by the Data Safety 

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Monitoring Board (DSMB), it is preferred the pharmacokinetic sampling takes place as early 
in the study as possible.
14. Addition of Subgroup Analyses
DESCRIPTION OF CHANGE:
Subgroup analyses for selected safety parameters are added to the statistical section of the 
protocol.
RATIONALE:
Subgroup analyses related to formulation (tablet or suspension) and dosing regimen (PED25 
or PED50) for selected safety parameters have been added to further characterize the safety 
profile.
15. Administrative-type Changes
DESCRIPTION OF CHANGE:
Various edits related to consistency, formatting and numbering are made throughout the 
protocol.
RATIONALE:
To provide clarification to the protocol and to ensure complete understanding of the study 
procedures. 
II. Amendment Summary of Changes: Substantial
Cover Page, 2 Investigator’s Signature and IV Synopsis, Title of Study and Study 
Population
WAS:
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 5 to Less Than 18 Years of Age With 
Neurogenic Detrusor Overactivity (NDO) on Clean Intermittent Catheterization (CIC)
IS AMENDED TO:
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 5 3 to Less Than 18 Years of Age Wwith 
Neurogenic Detrusor Overactivity (NDO) on Clean Intermittent Catheterization (CIC)
IV Synopsis, Number of Subjects to be Enrolled/Randomized and 2 Study Objectives(s), Design, 
and Endpoints
2.2.1 Study Design

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WAS:
At least 44 evaluable subjects (estimate 63 enrolled), with at least 10 subjects from each age 
group (children aged 5 to less than 12 years of age; adolescents aged 12 to less than 18 years 
of age) are planned.  A subject is considered being evaluable if the subject has a nonmissing 
maximum cystometric capacity (MCC) measurement at baseline and at a postbaseline visit.
IS AMENDED TO:
At least 44 evaluable subjects (estimate 63 enrolled), with at least 10 subjects from each age 
group (children aged 5 3 to less than 12 years of age; adolescents aged 12 to less than 18 
years of age) are planned.  A subject is considered being evaluable if the subject has a valid 
(as by the central reviewer’s assessment) nonmissing maximum cystometric capacity 
(MCC) measurement at baseline and at a postbaseline visit.
IV Synopsis, Inclusion/Exclusion Criteria, 2 Study Objectives(s), Design, and 
Endpoints, 3 Study Population and 8 Operational and Administrative Considerations
2.2.1 Study Design, 3.1 Selection of Study Population, 3.2 Inclusion Criteria and 
8.2.3.1 Subject Information and Consent
WAS:
2. Subject is male or female from 5 to less than 18 years of age.
IS AMENDED TO:
2.
Subject is male or female from 5 3 to less than 18 years of age.
IV Synopsis, Inclusion/Exclusion Criteria and 3 Inclusion/Exclusion Criteria
3.2 Inclusion Criteria
WAS:
3. Subject has a body weight of ≥ 35 kg.
IS AMENDED TO:
3. Subject has a body weight of ≥ 3511 kg.
IV Synopsis, Investigational Product(s)
WAS:
Investigational Product(s):
Mirabegron tablets, strengths 25 mg and 50 mg
Dose(s):  
The initial dose will be PED25.  The dose may be up-titrated to PED50 according to the 
dose-titration criteria.  
Mode of Administration:
Study drug will be taken orally, once a day in the morning around the same time of day and 
around time of food intake (i.e., within 1 hour before or after breakfast). Tablet to be taken 
with a sip of water (tablet should be taken as a whole and should not be chewed, divided or 

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crushed).
On visit days where a pharmacokinetic sample is planned in the clinic, completion of 
breakfast and study drug dosing should occur in the clinic.
IS AMENDED TO:
Investigational Product(s):
Mirabegron prolonged-release tablets, strengths 25 mg and 50 mg
Mirabegron oral suspension, strength 8 mg/mL
Dose(s):  
The initial dose will be PED25.  The dose may be up titrated to PED50 according to the 
dose titration criteria.  
Selection of the formulation:
Subjects with a body weight < 35 kg: mirabegron oral suspension. 
Subjects with a body weight ≥35 kg: mirabegron tablets.
Selection of the dose:
Doses are calculated weight-based. The bodyweight at visit 3/baseline determines the 
weight range for the starting dose (PED25) and the up-titration dose (PED50) to be 
used in the table below:
Weight-based Doses for Tablets or Suspension
PED
Weight Range 
Suspension Volume †
Tablet Dose
PED25
11 - < 22 kg
3 mL
-
22 - < 35 kg
4 mL
-
≥ 35 kg
6 mL
25 mg
50
11 - < 22 kg
6 mL
-
22 - < 35 kg
8 mL
-
≥ 35 kg
11 mL
50 mg
PED25: Pediatric equivalent dose 25 mg; PED50: Pediatric equivalent dose 50 mg 
† Suspension strength: 8 mg/mL
Further dosing information:
For subjects with a body weight ≥ 35 kg who do not want to or are unable to take 
tablets, the oral suspension can be supplied.
At visit 8/week 24 subjects on mirabegron oral suspension may switch to tablets if 
the body weight turns to be ≥ 35 kg.
Subjects receiving mirabegron tablets can switch to mirabegron oral suspension 
(and vice versa) for acceptability reasons after Sponsor’s prior approval and on a 
case-by-case basis.
Mode of Administration:
Study drug will be taken orally, once a day in the morning around the same time of day and 
around time of food intake (i.e., within 1 hour before or after breakfast). 
Mirabegron Ttablets to will be taken with a sip of water (tablet should be taken as a whole 
and should not be chewed, divided or crushed).
Mirabegron oral suspension will be administered via an oral syringe with a sip of water 
afterwards. 

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On visit days where a pharmacokinetic sample is planned in the clinic, completion of 
breakfast and study drug dosing should occur in the clinic.
IV Synopsis, Endpoints for Evaluation and 2 Study Objectives(s), Design, and 
Endpoints
2.3.2.3 Patient- or Clinician-reported Questionnaire Endpoints
WAS:
Based on questionnaires:

Acceptability questionnaire at visit 8/week 24 and visit 10/week 52 (EOT/EOS)
IS AMENDED TO:
Based on questionnaires:

Acceptability questionnaire at visit 5/week 4, visit 8/week 24 and visit 10/week 52 
(EOT/EOS)
IV Synopsis, Endpoints for Evaluation, safety, Assessments, 2 Study Objective(s), 
Design, and Endpoints and 5 Treatments and Evaluation 
2.3.3 Safety Endpoints and 5.4.1.2 Self-measurement of Vital Signs
WAS:

Change from baseline in vital signs (SBPM): systolic blood pressure, diastolic blood 
pressure, pulse rate at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 
8/week 24, visit 9/week 36 and visit 10/week 52 (EOT/EOS)
IS AMENDED TO:

Change from baseline in vital signs (self blood pressure measurement [SBPM]): 
systolic blood pressure, diastolic blood pressure, pulse rate at visit 4/week 2, visit 
5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 24, visit 9/week 36 and visit 
10/week 52 (EOT/EOS) and on 2 consecutive days at around 1 and 2 weeks after 
start of dosing with PED25 (day 1) and after up-titration to PED50 (visit 4/week 2, 
visit 5/week 4 or visit 6/week 8), if not already covered by the scheduled visit 4/week
2 and/or visit 5/week 4 SBPM.
1 Introduction
1.4 Risk-Benefit Assessment
WAS:
Mirabegron has a favorable risk-benefit profile in adults in the indication OAB. In the 
pediatric phase 1 study executed thus far, mirabegron has an acceptable safety profile and 
was well tolerated.
IS AMENDED TO:
Mirabegron tablets has have a favorable risk-benefit profile in adults in the indication OAB. 
Mirabegron oral suspension has been shown to be safe and well tolerated in 2 phase 1 

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studies in healthy adult subjects (Studies 178-CL-201 and 178-CL-208).  In the pediatric 
phase 1 studyies executed thus far, mirabegron tablets and mirabegron oral suspension
hasd an acceptable safety profile and wasere well tolerated.
1 Introduction
1.4 Risk-Benefit Assessment
WAS:
Regarding the formulation to be administered: the tablets are the same as used in adults. All 
excipients are pharmaceutical materials and are considered safe for the intended pediatric 
population.
IS AMENDED TO:
Regarding the formulations to be administered: the tablets are the same as used in adults. for 
both the tablet and the suspension formulation, Aall excipients are pharmaceutical grade
materials and are considered safe for the intended pediatric population.
2 Study Design and Dose Rationale
2.2.2 Dose Rationale
WAS:
The approved posology in adults for the treatment of OAB is either once daily 25 or 50 mg 
prolonged-release tablets. In children, the dosing strategy is based on extrapolation of 
efficacious doses in adults. Based on data obtained from adult and pediatric subjects 
following tablet and oral suspension dosing, a popPK model of steady state exposures will 
be used to predict the pediatric doses equivalent to 25 and 50 mg mirabegron administered 
once daily in adults. The target exposures for these pediatric equivalent doses (PED25 and 
PED50) are 69 ng∙h/mL and 188 ng∙h/mL, respectively. The popPK model indicates that 
pediatric subjects with a body weight of 35 kg or above can safely be dosed with the 
available tablets.  
For pediatric subjects with a weight too low for dosing with tablets, or who cannot swallow 
the tablets, an oral suspension is under development. All subjects will start with the PED25 
dose.  Based on the criteria as described in [Section 5.1.2], the dose will be up-titrated to 
PED50 or will remain at PED25.  
IS AMENDED TO:
The approved posology in adults for the treatment of OAB is either once daily 25 or 50 mg 
prolonged release tablets. In children, the dosing strategy is based on extrapolation of 
efficacious doses in adults. Based on data obtained from adult and pediatric subjects 
following tablet and oral suspension dosing, a popPK model of steady state exposures will 
be used to predict the pediatric doses equivalent to 25 and 50 mg mirabegron administered 
once daily in adults. The target exposures for these pediatric equivalent doses (PED25 and 
PED50) are 69 ng h/mL and 188 ng h/mL, respectively. The popPK model indicates that 
pediatric subjects with a body weight of 35 kg or above can safely be dosed with the 
available tablets.  

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For pediatric subjects with a weight too low for dosing with tablets, or who cannot swallow 
the tablets, an oral suspension is under development. All subjects will start with the PED25 
dose.  Based on the criteria as described in [Section 5.1.2], the dose will be up titrated to 
PED50 or will remain at PED25.  
The target exposures of 69 and 188 ng·h/mL for pediatric equivalent dose 
25 mg (PED25) and pediatric equivalent dose 50 mg (PED50) were derived from the 
adult phase 3 program and are the mean steady state AUCtau values following 25 and 
50 mg prolonged-release tablets once daily in adults.
A population pharmacokinetic model was used to predict the PED for subjects in the 
178-CL-206A study. In brief, this popPK 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; IND 58135), 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 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. Subjects with a body weight < 35 kg cannot be dosed with the 25 and 50 mg 
tablets because that would result in higher than 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 11 kg (the 
approximate body weight of a 3-year-old child, according to the NHANES 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.  Suspension dosing for body weights ≥35 kg was also determined for cases in 
which a pediatric subject in that weight category does not want or would be unable to 
swallow a tablet.  The simulation resulted in the 3 body weight categories that can be 
found in the dosing schedule (see [Section 5.1.1]). 

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4 Treatment(s)
4.1.1 Test Drug
WAS:
For detailed information on mirabegron tablets, please refer to the Investigational Medicinal 
Product Dossier (IMPD) or IND.
Mirabegron is supplied as tablets containing 25 mg or 50 mg of active ingredient.  
IS AMENDED TO:
Mirabegron oral suspension has been developed as an appropriate formulation for 
weight based dosing in smaller children.
For detailed information on mirabegron prolonged-release tablets and mirabegron 
granules for oral suspension, please refer to the applicable Investigational Medicinal 
Product Dossier (IMPD) or IND.
Mirabegron tablets are is supplied as prolonged-release tablets containing 25 mg or 50 mg 
of active ingredient.  
For the oral suspension, mirabegron prolonged-release granules are supplied and will 
be reconstituted with water to prepare an oral suspension of 8 mg/mL.  Detailed 
information on the preparation of the mirabegron oral suspension will be provided to 
the subject and subject’s parent(s)/caregiver(s) in local language.  Due to shelf-life 
limitations, an additional dispensing visit is foreseen at visit 9/week 36 for subjects 
receiving mirabegron oral suspension. This dispensing visit does not need to be 
accompanied by the subject.
5 Treatments and Evaluation
5.1.1 Dose/Dose Regimen and Administration Period
WAS:
Each tablet is to be taken with a sip of water. The tablet should be taken as a whole and
should not be chewed, divided or crushed.  
IS AMENDED TO:
Each Mirabegron tablets is to will be taken with a sip of water. The tablet should be taken 
as a whole and should not be chewed, divided or crushed.  
Mirabegron prolonged-release granules will be reconstituted with water to prepare a 
mirabegron oral suspension of 8 mg/mL.  Administration will be via an oral syringe 
with a sip of water afterwards.  Detailed information on the preparation of the 
suspension will be provided to the subject and subject’s parent(s)/caregiver(s) in local 
language. For subjects receiving mirabegron oral suspension, an additional (optional) 
dispensing visit is scheduled at visit 9/week 36.
Selection of the formulation:
Subjects with a body weight < 35 kg: mirabegron oral suspension. 
Subjects with a body weight ≥ 35 kg: mirabegron tablets. 
Selection of the dose: 
Doses are calculated weight-based. The bodyweight at visit 3/baseline determines the 

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weight range for the starting dose (PED25) and the up-titration dose (PED50) to be 
used [Table 4].  
Table 4
Weight-based doses for tablets or suspension
Weight Range
Suspension Volume †
Tablet Dose
PED25
11 - < 22 kg
3 mL
-
22 - < 35 kg
4 mL
-
≥ 35 kg
6 mL
25 mg
PED50
11 - < 22 kg
6 mL
-
22 - < 35 kg
8 mL
-
≥ 35 kg
11 mL
50 mg
PED25: Pediatric equivalent dose 25 mg; PED50: Pediatric equivalent dose 50 mg 
† Suspension strength: 8 mg/mL
Further dosing information:

For subjects with a body weight ≥ 35 kg who do not want to or are unable to take 
tablets, the oral suspension can be supplied.

At visit 8/week 24 subjects on mirabegron oral suspension may switch to tablets if 
the body weight turns to be ≥ 35 kg.

Subjects receiving mirabegron tablets can switch to mirabegron oral suspension 
(and vice versa) for acceptability reasons after Sponsor’s prior approval and on a 
case-by-case basis.
5 Treatments and Evaluation
5.3.3 Questionnaires
WAS:

The PIN-Q [Appendix 12.4] will be administered on one weekend day preceding visit 
3/baseline, visit 8/week 24 and visit 10/week 52 (EOT/EOS).

The PGI-S [Appendix 12.5] will be administered on one weekend day preceding visit 
3/baseline, visit 8/week 24 and visit 10/week 52 (EOT/EOS).

The Acceptability Questionnaire [Appendix 12.6] will be administered on one weekend 
day preceding visit 8/week 24 and at visit 10/week 52 (EOT/EOS).

The CGI-C [Appendix 12.7] will be administered at visit 8/week 24 and at visit 
10/week 52 (EOT/EOS).
IS AMENDED TO:

The PIN-Q [Appendix 12.4] will be administered completed on one weekend day 
preceding visit 3/baseline, visit 8/week 24 and visit 10/week 52 (EOT/EOS).

The PGI-S [Appendix 12.5] will be administered completed on one weekend day 
preceding visit 3/baseline, visit 8/week 24 and visit 10/week 52 (EOT/EOS).

The Acceptability Questionnaire [Appendix 12.6] will be administered completed on 
one weekend day preceding visit 5/week 4, visit 8/week 24 and at visit 10/week 52 
(EOT/EOS). For each formulation a separate questionnaire is available [Appendix 
12.6 and Appendix 12.7].

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weekend e-diary and 1 day of the weekday e-diary were completed while the subject did 
not suffer from a symptomatic UTI.
IV. Synopsis
Study Design Overview
ADDED:
The 7-day e-diary does not have to be repeated if at least the 2-day weekend e-diary and 
1 day of the weekday e-diary were completed while the subject did not suffer from a 
symptomatic UTI.  
If a subject suffers from a symptomatic UTI in the week prior to any other study visit, 
these visits do not need to be postponed and the 7-day e-diary does not have to be 
repeated.
IV Synopsis, Study Design Overview and 2 Study Objective(s), Design, and Endpoints
2.2.1.1 Pretreatment Period
WAS:
Subjects will enter the efficacy treatment period if they meet the eligibility criteria and 
satisfactorily complete the pretreatment period (ability to complete bladder diary, 
catheterized volumes, self-measurement of intravesical pressures [SMIP], questionnaires and 
self blood pressure measurement [SBPM]).
IS AMENDED TO:
Subjects will enter the efficacy treatment period if they meet the eligibility criteria and 
satisfactorily complete the pretreatment period (ability to complete bladder diary, 
catheterized volumes, self measurement of intravesical pressures [SMIP], and
questionnaires).
IV Synopsis, Dose Titration and 5 Treatments and Evaluation
5.1.2 Increase or Reduction in Dose of the Study Drug(s)
WAS:
1. The investigator considers the subject to be effectively treated with PED25, based on
urodynamics, e-diary and SMIP (if available);
IS AMENDED TO:
1. The investigator considers the subject to be effectively treated with PED25, based on
urodynamics, and the e-diary and SMIP (if available);
IV. Synopsis, Exploratory Efficacy and 2 Study Objective(s), Design, and Endpoints
2.3.5.1 Exploratory Efficacy Endpoints
WAS:

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Based on e-diary:
Change from baseline at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 
24, visit 9/week 36 and visit 10/week 52 (EOT/EOS) in:

Mean grade of leakage 

Total catheterized volume per 24 h

Maximum confirmed daytime dry period/24 h 

Maximum confirmed daytime dry period/7 days 

Change from baseline in SMIP-derived bladder compliance

Number of CICs/day

Responder in respect to leakage (complete, partial, no response)
IS AMENDED TO:
Based on e-diary:
Change from baseline at visit 4/week 2, visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 
24, visit 9/week 36 and visit 10/week 52 (EOT/EOS) in:

Mean grade of leakage 

Total catheterized volume per 24 hday

Maximum confirmed daytime dry period/24 h 

Maximum confirmed daytime dry period/7 days 

Change from baseline in SMIP-derived bladder compliance

Number of CICs/day

Responder in respect to leakage (complete, partial, no response)
IV Synopsis, Assessments and 5 Treatments and Evaluation
5.3.1 Urodynamic Assessments
WAS:
Additional urodynamic assessments can be performed at visit 10/week 52 (EOT/EOS), or at 
any other time point when deemed necessary by the investigator (e.g., confirmatory 
urodynamic assessments at visit 7/week 12 if up-titration or down-titration was done at visit 
6/week 8, or when the SMIP was not performed). 
IS AMENDED TO:
Additional urodynamic assessments can be performed at visit 10/week 52 (EOT/EOS), or at 
any other time point when deemed necessary by the investigator (e.g., confirmatory 
urodynamic assessments at visit 7/week 12 if up titration or down titration was done at visit 
6/week 8, or when the SMIP was not performed).
IV. Synopsis, Patient Reported Outcome Data and 8 Operational and Administrative 
Considerations
8.1.1.1 Electronic Patient Reported Outcomes
WAS:
Bladder diary:
o
Each day for 7 days: time of CICs
o
Each day for 7 days: presence of leakage between CICs
o
Each day for 7 days: sleep time and wake-up time

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o
On the 2 weekend days: catheterized volume 
o
On the 2 weekend days: SMIP (if applicable)
o
On the 2 weekend days: grade of leakage between CICs
o
On the 2 weekend days (visit 3/baseline and visit 8/week 24): weight of diaper/pad
SBPM (blood pressure and pulse rate): 
o
On the 2 weekend days: triplicate measurements in the morning and evening
Questionnaires: on 1 weekend day at selected visits
o
PIN-Q
o
PGI-S
o
Acceptability
Confirmation of study drug intake: daily
IS AMENDED TO:
Bladder diary:
o
Each day for 7 days: time of CICs
o
Each day for 7 days: presence of leakage between CICs
o
Each day for 7 days: sleep time and wake-up time
o
On the 2 weekend days: catheterized volume 
o
On the 2 weekend days: SMIP (if applicable)
o
On the 2 weekend days: grade and number of leakages between CICs
o
On the 2 weekend days (visit 3/baseline and visit 8/week 24): weight of diaper/pad
SBPM (blood pressure and pulse rate): 
o
On the 2 weekend days: triplicate measurements in the morning and evening
o
On 2 consecutive 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.
Questionnaires: on 1 weekend day at selected visits
o
PIN-Q
o
PGI-S
o
Acceptability
Confirmation of study drug intake: daily
The Investigator must guide the subject and subject’s parent(s)/caregiver(s) to ensure 
that on the evening before and during the two weekend days of collection of 
catheterized volume and SMIP (if applicable), the subject’s fluid intake should be 
regulated to an appropriate level taking 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.
IV. Synopsis, Statistical Methods
WAS:
Sample size justification: 
In order to allow the detection of a statistically significant change from baseline in MCC in 
the overall NDO with CIC study population with 90% power, 44 evaluable subjects for the 
assessment of the endpoint need to be enrolled, i.e., subjects with a nonmissing MCC 
measurement at baseline and at a postbaseline visit. The power calculation is based upon a 
paired t-test with a 2-sided significance level of 0.05, a real change from baseline of at least 
52 mL and a SD of not larger than 103 mL. Assuming 30% of enrolled subjects will not be 

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evaluable, a total of approximately 63 subjects may need to be enrolled.  
Four analysis populations will be defined: the safety analysis set (SAF), full analysis set 
(FAS), per protocol set (PPS), and pharmacokinetic analysis set (PKAS) for pharmacokinetic 
population analysis.
IS AMENDED TO:
Sample size justification: 
In order to allow the detection of a statistically significant change from baseline in MCC in 
the overall NDO with CIC study population with 90% power, 44 evaluable subjects for the 
assessment of the endpoint need to be enrolled, i.e., subjects with a valid (as by the central 
reviewer’s assessment) nonmissing MCC measurement at baseline and at a postbaseline 
visit. The power calculation is based upon a paired t-test with a 2-sided significance level of 
0.05, an real expected change from baseline of at least 52 mL and a SD of not larger than 
103 mL. Assuming 30% of enrolled subjects will not be evaluable, a total of approximately 
63 subjects may need to be enrolled.  
Four analysis populations will be defined: the safety analysis set (SAF), full analysis set 
(FAS), per protocol set (PPS), and pharmacokinetics analysis set (PKAS) for 
pharmacokinetic population analysis.
V Flowchart and Schedule of Assessments
Table 1: Schedule of Assessments
See next page.

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†
For the visits where a TC is indicated there is no need for the subject to visit the clinic, provided that the e-diary data is reviewed by the investigator prior to the TC and 
discussed and confirmed with the subject or parent(s)/caregiver(s) during the TC.
‡ 
Subjects who withdraw early from the study after having received study drug should complete the EOS visit. If the final dose is reached before the last possibility for up-
titration at 8 weeks, the fixed-dose treatment period will be extended to keep the entire treatment period 364 days as a minimum. The maximum is 378 days in order to 
allow for visit windows.
§
Triplicate vital signs with an interval of approximately 2 minutes 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. Clinic measurements will be used to assess eligibility. Single 
measurements for body temperature must be performed with an ear thermometer.  
¶
Triplicate 12-lead ECG with an interval of about 30 seconds to 5 minutes in the supine position (when possible, but always in the same position).  Subject should have 
been calm and without distress for at least 5 minutes.  
†† Additional hematology/biochemistry taken at baseline only if an AE related to hematology/biochemistry parameters occurred between visit 1/screening and visit 
3/baseline. The first group of subjects (minimum of 5, maximum of 10) who reach study visit 5/week 4 will have an additional blood draw for a DSMB-mandated interim 
safety check at this visit.  For sampling, preferably the left arm should be used. Blood sampling should occur after vital signs and ECG measurements.
‡‡ Pregnancy test in female subjects of childbearing potential in serum (if blood is drawn) or urine (at other visits).
§§ If the subject reached steady state of her/his optimal dose, a total of 4 pharmacokinetic samples will be collected, divided over 2 sampling days.  Sampling day 1: 1 trough 
sample; Sampling day 2: 1 trough and 2 postdose samples between 2 h and 5 h postdose, with at least 1 hour in between the samples. These 2 sampling days do not have 
to be in a specific order and can be selected from the given options. Dosing on a sampling day with postdose samples must occur within 1 hour after completion of 
breakfast [Section 5.3.4]. On days where a pharmacokinetic visit is planned in the clinic, breakfast and dosing should occur in the clinic. Blood sampling should occur 
after vital signs and ECG measurements.
¶¶ Additional urodynamic assessments may be performed if deemed necessary by the investigator (e.g., if SMIP is not performed at visit 4/week 2, confirmatory urodynamic 
assessments at visit 7/week 12 if up-titration or down-titration was done at visit 6/week 8, or an additional urodynamic assessment at visit 10/week 52 [EOT/EOS]).
††† Daily study drug administration will begin on Day 1 (the day after visit 3/baseline).
‡‡‡ After a successful screening visit, all subjects start with the completion of a 2-day weekend e-diary visit to get acquainted with the e-diary and the assessments. 
Completion of this diary should start in the weekend prior to visit 2. Completion of subsequent bladder diaries should start approximately 7 days prior to the indicated visit 
(or TC). If successful completion of the 2-day weekend e-diary is confirmed at visit 2, subjects from group A start with collection of the 7-day baseline e-diary, followed 
by the baseline visit. Subjects in group B start with a 14-day washout. In the second week of the washout period, collection of their 7-day baseline e-diary starts, followed 
by the baseline visit.  
§§§ Triplicate SBPM will be performed in the morning and evening during the 2-day weekend e-diary collection period. Measurements to be taken with an interval of 
approximately 2 minutes in the sitting position (when possible, otherwise supine, but always in the same position). Preferably the right arm should be used. Morning 
measurements should be taken after waking-up, before breakfast and before study drug intake, evening measurements prior to bedtime. Subject should have been calm and 
without distress for at least 5 minutes.

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†
For the visits where a TC is indicated there is no need for the subject to visit the clinic, provided that the e-diary data is reviewed by the investigator prior to the TC and 
discussed and confirmed with the subject or the subject’s parent(s)/caregiver(s) during the TC. 
‡ 
Subjects who withdraw early from the study after having received study drug should complete the EOS visit. If the final dose is reached before the last possibility for up-
titration at 8 weeks, the fixed-dose treatment period will be extended to keep the entire treatment period 364 days as a minimum. The maximum is 378 days in order to 
allow for visit windows.
§
Triplicate vital signs with an interval of approximately 2 minutes 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. Clinic measurements will be used to assess eligibility. Single 
measurements for body temperature must be performed with an ear thermometer.  
¶
Triplicate 12-lead ECG with an interval of about 30 seconds to 5 minutes in the supine position (when possible, but always in the same position).  Subject should have 
been calm and without distress for at least 5 minutes.  
†† Additional hematology/biochemistry taken at baseline only if an AE related to hematology/biochemistry parameters occurred between visit 1/screening and visit 
3/baseline. The first group of subjects (minimum of 5, maximum of 10) who reach study visit 5/week 4 will have an additional blood draw for a DSMB-mandated interim 
safety check at this visit.  For sampling, preferably the left arm should be used. Blood sampling should occur after vital signs and ECG measurements.
‡‡ Pregnancy test in female subjects of childbearing potential in serum (if blood is drawn) or urine (at other visits).
§§
If the subject reached steady state of her/his optimal dose, a total of 4 pharmacokinetic samples will be collected, divided over 2 sampling days.  Sampling day 1: 1 trough 
sample; Sampling day 2: 1 trough and 2 postdose samples between 2 h and 5 h postdose, with at least 1 hour in between the samples. These 2 sampling days do not have 
to be in a specific order and can be selected from the given options. To allow for an early assessment of the dose-response relationship by the DSMB, it is preferred 
the pharmacokinetic sampling takes place as early in the study as possible. Dosing on a sampling day with postdose samples must occur within 1 hour after 
completion of breakfast [Section 5.3.4]. On days where a pharmacokinetic visit is planned in the clinic, breakfast and dosing should occur in the clinic. Blood sampling 
should occur after vital signs and ECG measurements.
¶¶ Additional urodynamic assessments may be performed if deemed necessary by the investigator (e.g., if SMIP is not performed at visit 4/week 2, confirmatory urodynamic 
assessments at visit 7/week 12 if up titration or down titration was done at visit 6/week 8, or an additional urodynamic assessment at visit 10/week 52 [EOT/EOS]).
††† Daily study drug administration will begin on Day 1 (the day after visit 3/baseline). Due to shelf-life limitations, an additional dispensing visit is foreseen at visit 9/week 36 for 
subjects receiving mirabegron oral suspension. This dispensing visit does not need to be accompanied by the subject.
‡‡‡ After a successful screening visit, all subjects start with the completion of a 2-day weekend e-diary visit to get acquainted with the e-diary and the assessments. 
Completion of this diary should start in the weekend prior to visit 2. Completion of subsequent bladder diaries should start approximately 7 days prior to the indicated visit 
(or TC). If successful completion of the 2-day weekend e-diary is confirmed at visit 2, subjects from group A start with collection of the 7-day baseline e-diary, followed 
by the baseline visit. Subjects in group B start with a 14-day washout. In the second week of the washout period, collection of their 7-day baseline e-diary starts, followed 
by the baseline visit.  
§§§ Triplicate SBPM will be performed in the morning and evening during the 2-day weekend e-diary collection period and on 2 consecutive 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. Measurements to be taken 
with an interval of approximately 2 minutes in the sitting position (when possible, otherwise supine, but always in the same position). Preferably the right arm should be 
used. Morning measurements should be taken after waking-up, before breakfast and before study drug intake, evening measurements prior to bedtime. Subject should 
have been calm and without distress for at least 5 minutes.

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1 Introduction
1.2.2 Clinical Data
WAS:
The global pediatric development program for mirabegron in NDO and OAB currently 
consists of 8 studies in various stages of completion. 
The first available clinical data of  mirabegron in children comes from study 178-CL-202: a 
single ascending dose phase 1 study with mirabegron tablets in pediatric subjects diagnosed 
with OAB or NDO. 
Cohort 1: male and female adolescents (12 to less than 18 years); low dose and fed 
Cohort 2: male and female children (5 to less than 12 years); low dose and fed 
Cohort 3: male and female adolescents (12 to less than 18 years); high dose and fed 
Cohort 4: male and female children (5 to less than 12 years); high dose and fed 
Cohort 5: male and female children (5 to less than 12 years); high dose and fasted 
Fed: within one hour after a light breakfast
Low dose:  single oral doses that are predicted to result in an exposure comparable to that in 
adults when dosed with 25 mg mirabegron tablets once daily at steady-state (69 ng.h/mL).
High dose: single oral doses that are predicted to result in an exposure comparable to that in 
adults when dosed with 50 mg mirabegron tablets once daily at steady-state (188 ng.h/mL). 
The doses in Study 178-CL-202 were predicted applying an allometric scaling approach of 
the data obtained in adults under non standardized food conditions.
A dose escalation committee including a pediatric nephrologist and pediatric cardiologist has 
reviewed the data obtained in these cohorts and concluded that mirabegron exposure was 
within the predicted target ranges for all cohorts and that mirabegron showed an acceptable 
safety profile at the doses tested. 
5 TEAEs were reported: ‘vomiting’(2x), ‘fever’, ‘mean QT interval corrected by Bazett’s 
formula (QTcB) of 452 ms’ and  ‘QTcB prolongation’. The intensity for all TEAEs was  
mild and only one (QTcB prolongation versus baseline) was judged by the investigator to be 
possibly related to study drug. No QTc prolongation > 60 ms versus baseline was observed 
(mean of triplicates).
No clinically significant increases in vital signs have been observed. Increases in pulse rate 
were observed across all cohorts but these were not considered clinically significant/relevant 
per investigator’s assessment.  
The centrally read Holter observations in cohort 4 and 5 showed a trend towards 2 episodes of 
a mean and median increase in mean hourly heart rate; the first one starting 4 to 6 hours 
postdose and reaching the highest values at 6 to 8 hours after dosing and the second one 
starting 10-12h after dosing and continuing until the end of the recording, without a change in 
circadian rhythm. This was not considered as clinically relevant by the dose escalation 
committee.
For pediatric subjects an oral suspension is under development.  
IS AMENDED TO:
The global pediatric development program for mirabegron in NDO and OAB currently 
consists of 8 studies in various stages of completion. 
The first available clinical data of  mirabegron in children comes from study 178 CL 202: a 
single ascending dose phase 1 study with mirabegron tablets in pediatric subjects diagnosed 
with OAB or NDO. 

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●
Cohort 1: male and female adolescents (12 to less than 18 years); low dose and fed 
●
Cohort 2: male and female children (5 to less than 12 years); low dose and fed 
●
Cohort 3: male and female adolescents (12 to less than 18 years); high dose and fed 
●
Cohort 4: male and female children (5 to less than 12 years); high dose and fed 
●
Cohort 5: male and female children (5 to less than 12 years); high dose and fasted 
Fed: within one hour after a light breakfast
Low dose:  single oral doses that are predicted to result in an exposure comparable to that i
adults when dosed with 25 mg mirabegron tablets once daily at steady state (69 ng.h/mL).
High dose: single oral doses that are predicted to result in an exposure comparable to that in
adults when dosed with 50 mg mirabegron tablets once daily at steady state (188 ng.h/mL)
The doses in Study 178 CL 202 were predicted applying an allometric scaling approach of 
the data obtained in adults under non standardized food conditions.
A dose escalation committee including a pediatric nephrologist and pediatric cardiologist has 
reviewed the data obtained in these cohorts and concluded that mirabegron exposure was 
within the predicted target ranges for all cohorts and that mirabegron showed an acceptable 
safety profile at the doses tested. 
5 TEAEs were reported: ‘vomiting’(2x), ‘fever’, ‘mean QT interval corrected by Bazett’s 
formula (QTcB) of 452 ms’ and  ‘QTcB prolongation’. The intensity for all TEAEs was  
mild and only one (QTcB prolongation versus baseline) was judged by the investigator to be 
possibly related to study drug. No QTc prolongation > 60 ms versus baseline was observed 
(mean of triplicates).
No clinically significant increases in vital signs have been observed. Increases in pulse rate 
were observed across all cohorts but these were not considered clinically significant/ relevant 
per investigator’s assessment.  
The centrally read Holter observations in cohort 4 and 5 showed a trend towards 2 episodes of 
a mean and median increase in mean hourly heart rate; the first one starting 4 to 6 hours 
postdose and reaching the highest values at 6 to 8 hours after dosing and the second one 
starting 10 12h after dosing and continuing until the end of the recording, without a change in 
circadian rhythm. This was not considered as clinically relevant by the dose escalation 
committee.
For pediatric subjects an oral suspension is under development.  
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 2].
Table 2
Overview of Current Supporting Mirabegron Studies in the Pediatric 
Clinical Development Program for NDO and OAB
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 
Completed

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female subjects.
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 neurogenic detrusor overactivity 
(NDO) or overactive bladder (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 neurogenic 
detrusor overactivity (NDO) or overactive 
bladder (OAB).
Ongoing
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
Ongoing
The results of studies 178-CL-201 and 178-CL-202 are reported in the most recent 
version of the pediatric IB.  The data from these studies 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 less or because they cannot swallow tablets, an oral suspension with a 
strength of 2 mg/mL was developed.  The relative bioavailability was assessed in 
healthy subjects (178-CL-201) to be 53.44% lower compared to tablets. The results of 
this study and study 178-CL-202 were used to support the use of the 2 mg/mL in study 
178-CL-203.
That study is a single dose phase 1 study with mirabegron oral suspension in pediatric 
subjects from 3 to less than 12 years of age with NDO and in pediatric subjects from 5 
to less than 12 years of age with OAB.  This study is currently ongoing with 6 of 9 
planned subjects having completed the study.  Single doses of mirabegron are 
administered that are predicted to result in an exposure comparable to that in adults 
when dosed with 50 mg mirabegron tablets once daily at steady-state (188 ng∙h/mL).  
Subjects received mirabegron oral suspension within 1 hour after a light breakfast. 
Doses were compensated for the lower bioavailability of suspension versus tablets (see 
above). This study is ongoing but the preliminary results are provided below.
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, three period cross 
over design in healthy subjects. Subjects received the following three treatments in 

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random order: 1) 11mL 8 mg/mL oral suspension of mirabegron under fasted 
conditions, 2) 11mL 8 mg/mL oral suspension of mirabegron under fed conditions and 
3) 44 mL 2 mg/mL oral suspension of mirabegron under fasted conditions.  This study 
is ongoing, but a summary of the preliminary results is provided below.
Exposure:
The single doses of the 2 mg/mL oral suspension for Study 178-CL-203 were predicted 
using a population pharmacokinetic (popPK) model developed on pharmacokinetic 
data obtained in Study 178-CL-201, with food, dose, and formulation effects on the 
bioavailability, and was validated on data from Study 178-CL-202.  The observed 
exposures were in line with the target exposure of 188 ng∙h/mL; the median AUC24 was 
207 ng∙h/mL (n=6, mean (SD): 226.4 (152.3), range: 39.7-467).   These preliminary 
results suggest that the use of the popPK model is appropriate for dose selection.  The 
model predictions of the PED50 doses at a strength of 2 mg/mL would require large 
volumes of oral suspension every day (up to 44 mL).  Therefore, to reduce the volume, a 
higher strength oral suspension was developed.  
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.  The results of study 178-CL-208 show that the bioavailability of both 
strengths is comparable [Table 3].
Table 3
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)
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)
CI: confidence interval; LS: least squares.
The analysis was performed on log-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. 
The information obtained in studies 178-CL-203 and 178-CL-208 was taken into account 
when predicting the doses for this study as outlined in Section 2.2.2 of this protocol.
The doses described in Section 2.2.2 suggest tablets for pediatric subjects with a body 
weight of ≥ 35 kg, and the 8 mg/mL oral suspension for children with a body weight 
between 11 and 35 kg, or for those subjects with a body weight ≥ 35 kg who do not want 
to or are unable to take tablets.
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 6 subjects who completed the study (3 with NDO and 3 with OAB) 1 

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treatment emergent adverse event (TEAE) was reported: pyrexia on day 1 in a 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 QTcF values > 450 ms and no QTc 
prolongation > 30 ms versus baseline was observed (mean of triplicates).
Increases in vital signs have been observed but these were not considered clinically 
significant per investigator’s assessment.  
A 24-hour Holter recording was recorded in all subjects on a reference day and on the 
dosing day.  The main objective of the Holter 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 has been observed. This 
was not considered as clinically relevant taken into account the multiple blood draws, 
the low number of subjects and the absence of a placebo 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. 20 
AEs were considered not related; 2 were considered possibly related (dizziness, mild 
and orthostatic dizziness mild).    
1 Introduction and 4 Treatment(s)
1.3 Summary of Key Safety Information for Study Drugs and 4.1.1 Test Drug
WAS:
Mirabegron has been approved in more than 50 countries including the US, Japan and the 
EU. 
IS AMENDED TO:
Mirabegron has been approved in more than 50 65 countries including the US, Japan and the 
EU worldwide. 
1 Introduction
1.4 Risk-Benefit Assessment
WAS:
●
Beyond 4 weeks of therapy, repeated home measurements of the intravesical pressure and 
at least 1 urodynamic investigation allow the investigator to adapt the CIC-regimen or to 
withdraw the subject if considered necessary. If SMIP evaluations are not done, the 
investigator can perform additional urodynamic assessments if deemed necessary.
IS AMENDED TO:

Beyond 4 weeks of therapy, repeated home measurements of the intravesical pressure 
and at least 1 urodynamic investigation allow the investigator to adapt the CIC regimen 
or to withdraw the subject if considered necessary. If SMIP evaluations are not done, the 
investigator can perform additional urodynamic assessments if deemed necessary.

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
Additional urodynamic assessments may be performed at any time in the study 
study if deemed necessary by the investigator.
2 Study Objective(s), Design, and Endpoints
2.3.2.2 Bladder Volume and Leakage Measures
ADDED:
For this study the first morning catheterization after waking up is regarded as part of 
the ‘night’, whilst the last evening catheterization before sleep time is part of the ‘day’.
The collected urine volume will be weighed by the subject or subject’s 
parent(s)/caregiver(s) and the results will be entered in the e-diary. The conversion 
factor used for weight-to-volume is 1g = 1mL.
2 Study Objective(s), Design, and Endpoints
2.3.3 Safety Endpoints
WAS:
●
Change from baseline in ECG parameters at visit 5/week 4 and visit 10/week 52 
(EOT/EOS)
IS AMENDED TO:

Change from baseline in ECG parameters at visit 5/week 4, visit 7/week 12, visit 
8/week 24, and visit 10/week 52 (EOT/EOS)
2 Study Objective(s), Design and, Endpoints
2.3.4 Pharmacokinetics
WAS:
The following pharmacokinetic parameters will be determined at visit 5/week 4, visit 6/week 
8, visit 7/week 12, visit 8/week 24 and/or visit 9/week 36:
●
Cmax, tmax, AUC24, Ctrough, CL/F and Vz/F 
Additional pharmacokinetic parameters as may be calculated based on the model used.
IS AMENDED TO:
The following pharmacokinetic parameters will be determined for each individual at visit 
5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 24 and/or visit 9/week 36:
●
Cmax, tmax, AUC24, Ctrough, CL/F and Vz/F 
Additional pharmacokinetic parameters as may be calculated based on the model used.
3 Study Population
3.3 Exclusion Criteria

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WAS:
1.
Subject has a known genitourinary condition (other than NDO) that may cause 
overactive contractions or incontinence (e.g., bladder extrophy, urinary tract obstruction, 
urethral diverticulum or fistula) or kidney/bladder stones or another persistent urinary 
tract pathology that may cause symptoms.
IS AMENDED TO:
1.
Subject has a known genitourinary condition (other than NDO) that may cause 
overactive contractions or incontinence (e.g., bladder extrophy, urinary tract obstruction, 
urethral diverticulum or fistula) or kidney/bladder stones or another persistent local
urinary tract pathology that may cause urinary symptoms.
3 Study Population
3.3 Exclusion Criteria
ADDED:
For exclusion criterion 9 please refer to Appendix 12.9 and for exclusion criterion 10 
please refer to Appendix 12.10, Appendix 12.11, Appendix 12.12 and Appendix 12.13.
5 Treatments and Evaluation
5.3.4 Pharmacokinetics
WAS:
These 2 days can be selected from the options given in the schedule of assessments (i.e., on 
visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 24 or visit 9/week 36) and do not 
have to be in a specific (consecutive) order:
IS AMENDED TO:
These 2 days can be selected from any of the options given in the schedule of assessments 
(i.e., on visit 5/week 4, visit 6/week 8, visit 7/week 12, visit 8/week 24, or visit 9/week 36, or 
visit 10/week 52) and do not have to be in a specific (consecutive) order:
5 Treatments and Evaluation
5.3.4 Pharmacokinetics
ADDED:
To allow for an early assessment of the dose-response relationship by the DSMB, it is 
preferred the pharmacokinetic sampling takes place as early in the study as possible.
5 Treatments and Evaluations
5.4.1.1 Clinic Measurement of Vital Signs
WAS:
The measurements will be per standard clinic practices and should be consistent for all visits.  

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IS AMENDED TO:
The preferred method of measurement is via the auscultatory technique. If this method 
is not available at the site, measurements will be per standard clinic practices. The method 
for measuring vital signs and should be consistent for all visits.  
5 Treatments and Evaluation
5.4.2 Adverse Events
WAS:
AEs will be collected from visit 1/screening until visit 10/week 52 (EOT/EOS).  See 
[Section 5.5] for information regarding AE collection and data handling. Collection of AEs 
will start once the ICF is signed.
IS AMENDED TO:
AEs will be collected from visit 1/screening until visit 10/week 52 (EOT/EOS).  See 
[Section 5.5] for information regarding AE collection and data handling. Collection of AEs 
will start once the ICF is signed.
5 Treatments and Evaluation
5.4.6 Self-measurement of Intravesical Pressure
WAS:
SMIP will be performed as part of the bladder diary [Section 5.3.2].  
IS AMENDED TO:
SMIP will be performed as part of the bladder diary [Section 5.3.2]. In case the measuring 
device is not available/approved for use at the site, the subject or parent(s)/caregiver(s) are not 
able or willing to perform the SMIP, or there is a technical problem, the SMIP may be omitted.
5 Treatments and Evaluation
5.5.5 Reporting of Serious Adverse Events
WAS:
In the case of an SAE, the investigator must contact the CRO by telephone or fax/e-mail 
immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to CRO by fax/e-mail immediately (within 
24 hours of awareness). If the faxing/e-mailing of an SAE Worksheet is not possible or is not 
possible within 24 hours, the local drug safety contact should be informed by phone. Within 
24 hours after receipt of the information, the CRO will forward the SAE details to the 
Sponsor.
IS AMENDED TO:
In the case of an SAE, the investigator must contact the CRO by telephone or fax/e-mail 
immediately (within 24 hours 1 working day of awareness).

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The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to CRO by fax/e-mail immediately (within 24 
hours 1 working day of awareness). If the faxing/e-mailing of an SAE Worksheet is not 
possible or is not possible within 24 hours 1 working day, the local drug safety contact 
should be informed by phone. Within 24 hours 1 working day during weekdays or within 
60 hours during weekends, whatever is shorter, after receipt of the information, the CRO 
will forward the SAE details to the Sponsor.
SAEs must be reported up to 28 days after the End of Study visit or up to 28 days after 
early discontinuation of dosing.
7 Statistical Methodology
7.1 Sample Size
WAS:
A study with 44 evaluable subjects who have MCC measurements at treatment week 24 and 
at baseline would have a 90 percent power to detect a statistical significant change from 
baseline, if the real change from baseline in the subject population is at least 52 mL and the 
real SD for change from baseline is ≤ 103 mL.
IS AMENDED TO:
A study with 44 evaluable subjects who have valid (as by the central reviewer’s 
assessment) nonmissing MCC measurements at treatment visit 8/week 24 and at baseline 
would have a 90 percent power to detect a statistical significant change from baseline, if the 
real change from baseline in the subject population is at least 52 mL and the real SD for 
change from baseline is ≤ 103 mL.
7 Statistical Methodology
7.2.1 Full Analysis Set
WAS:
The full analysis set (FAS) will consist of all subjects who: 

Took at least 1 dose of study drug, and 

Provided both valid baseline and at least 1 postbaseline value for the primary efficacy 
endpoint (MCC).
IS AMENDED TO:
The full analysis set (FAS) will consist of all subjects who: 

Took at least 1 dose of study drug, and

Provided both Had a valid (as by the central reviewer’s assessment) nonmissing 
MCC measurement at baseline and at least 1 a post baseline value visit for the primary 
efficacy endpoint (MCC).
7 Statistical Methodology
7.2.4 Pharmacokinetics Analysis Set

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WAS:
Since the actual bioanalytical results from the last treatment group 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 pharmacokineticist. 
IS AMENDED TO:
Since the actual bioanalytical results from the last treatment group 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 pharmacokineticist. 
7 Statistical Methodology
7.4.1.3 Subgroup and Sensitivity Analyses of Primary Endpoint
WAS:
For the primary efficacy endpoint, MCC, 95% CI will be calculated for mean change from 
baseline per age group.
A subgroup analysis of the primary efficacy endpoint by whether NDO medication treatment 
was received at screening/prior to start of washout for both groups of subjects will be 
performed if there are sufficient subject numbers (with and without LOCF) on the FAS.
A subgroup analysis of the primary efficacy endpoint of patients with insufficient efficacy 
under antimuscarinics specifically intended for NDO treatment (i.e. stopping the medication 
for lack of efficacy prior to start of treatment) will be performed if there are sufficient subject 
numbers (with and without LOCF) on the FAS.  
The following sensitivity analyses of the primary efficacy endpoint will be performed if there 
are sufficient subject numbers (without LOCF only) on the FAS:
●
Excluding those subjects who had a positive urine culture at visit 3/baseline and/or 
visit 8/week 24.
IS AMENDED TO:
For the primary efficacy endpoint, MCC, 95% CI will be calculated for mean change from 
baseline per age group, per formulation, and per dosing regimen (with and without 
LOCF).
Dosing regimen here refers to whether the subjects had been up-titrated to PED50 at 
least once or maintained at PED25 for safety reasons at least until visit 8/week 24.
A subgroup analysis of the primary efficacy endpoint by whether NDO medication treatment 
was received at screening/prior to start of washout for both groups of subjects will be 
performed if there are sufficient subject numbers (with and without LOCF) on the FAS.
A subgroup analysis of the primary efficacy endpoint of patients subjects with insufficient 
efficacy under antimuscarinics specifically intended for NDO treatment (i.e. stopping the 
medication for lack of efficacy prior to start of treatment) will be performed if there are 
sufficient subject numbers (with and without LOCF) on the FAS.  
The following sensitivity analyses of the primary efficacy endpoint will be performed if there 
are sufficient subject numbers (without LOCF only) on the FAS:

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●
Excluding those subjects who had a positive urine culture at visit 3/baseline and/or 
visit 8/week 24.
●
For any of the subgroups specified, at least 10 subjects by stratum are required.
7 Statistical Methodology
7.4.2 Analysis of Secondary Endpoints
WAS:
The change from baseline for secondary endpoint based on urodynamic assessments, the 
subject’s e-diary (including bladder diary) and questionnaires will be summarized and 
analyzed using similar statistical methods as for the primary endpoint, where appropriate.
IS AMENDED TO:
The change from baseline for secondary endpoint based on urodynamic assessments, the 
subject’s e-diary (including bladder diary) and questionnaires will be summarized and 
analyzed using similar primary statistical methods as for the primary endpoint, where
appropriate.
CGI-C and acceptability results will be tabulated per time point of assessment.
7 Statistical Methodology
7.5 Analysis of Safety
WAS:
Safety parameters such as vital signs, height and weight will also be summarized with respect 
to age- and sex-specific percentiles.
IS AMENDED TO:
Safety parameters such as vital signs, height and weight will also be summarized with respect 
to ageheight- and sex-specific percentiles. Height will also be summarized with respect to 
age- and sex-specific percentiles.
Subgroup presentations regarding age (children and adolescents), formulation (tablets 
and suspension) and dosing regimen (PED25 and PED50) will be tabulated for the 
following parameters: AEs, vital signs and ECGs. For any of the subgroups specified, at 
least 10 subjects by stratum are required.
7 Statistical Methodology
7.5.1 Vital Signs
WAS:
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time.  Z-scores and percentiles for SBP and DBP will be calculated 
and summarized based on a comparison with age and sex norms supplied by the Center for 
Disease Control and Prevention.  

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IS AMENDED TO:
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time.  For clinic measurements Z-scores and percentiles for SBP 
and DBP will be calculated and summarized based on a comparison with age and sexheight
norms supplied by the Center for Disease Control and Prevention.  
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].
7 Statistical Methodology
7.5.2 Adverse Events
WAS:
AEs will be coded using MedDRA.  The number and percentage of AEs, SAEs, AEs leading 
to discontinuation, and AEs related to study drug will be summarized by system organ class, 
preferred term and treatment group.  The number and percentage of AEs by severity will also 
be summarized.  
IS AMENDED TO:
AEs will be coded using MedDRA.  The number and percentage of AEs, SAEs, AEs leading 
to discontinuation, and AEs related to study drug will be summarized by system organ class,
and preferred term and treatment group.  The number and percentage of AEs by severity will 
also be summarized.  
7 Statistical Methodology
7.5.3 Laboratory Assessments
WAS:
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment group and time point.  Shifts relative to normal 
ranges from baseline to each time point during treatment period in lab tests will also be 
tabulated.
IS AMENDED TO:
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment group and time point.  Shifts relative to normal 
ranges from baseline to each time point during treatment period in lab tests will also be 
tabulated.
7 Statistical Methodology
7.5.5 Electrocardiograms
WAS:
12-lead ECG parameters (QT, QTc, QT interval corrected by Fridericia's formula [QTcF], 
QTcB, HR, PR, QRS and RR) and their changes from baseline will be summarized with 
descriptive statistics by visit. The following thresholds will be used to characterize an 

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individual subject’s QTc data: QTc interval > 450 ms for children, and QTc interval 
> 450 ms and >500 ms for male adolescents and >480 ms and >500 ms for female 
adolescents.  These categories are cumulative in that subjects satisfying criterion for a more 
extreme category will also be counted in each applicable less extreme category. Similar 
tables will be provided for QTcF and QTcB as well. A summary of normal, abnormal not 
clinical significant and abnormal clinical significant findings will be provided.
IS AMENDED TO:
12-lead ECG parameters (QT, QTc, QT interval corrected by Fridericia's formula [QTcF], 
QTcB, HR, PR, QRS and RR) and their changes from baseline will be summarized with 
descriptive statistics by visit. The following thresholds will be used to characterize an 
individual subject’s QTcF data (QTcB and QTcF): QTcF interval > 4540 ms for children, 
and QTcF interval > 450 ms and >500 ms for male adolescents and >480 ms and >500 ms 
for female adolescents.  These categories are cumulative in that subjects satisfying criterion 
for a more extreme category will also be counted in each applicable less extreme category. 
Similar tables will be provided for QTcF and QTcB as well. A summary of normal, abnormal 
not clinical significant and abnormal clinical significant findings will be provided.
In addition for QTcF, the impact of concomitant medications potentially prolonging 
QTc will be evaluated. 
To perform this analysis, all QTcF post-baseline values will be presented (regardless of 
time point). If anomalies occur, an additional presentation will be provided using only 
QTcF values not under the influence of respective concomitant medications. 
Details on how these will be derived, will be described in the SAP.
7 Statistical Analyses
7.5.6 Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound
WAS:
For eGFR and upper urinary tract ultrasound, descriptive statistics will be used to summarize 
results and change from baseline by time point.  
IS AMENDED TO:
For eGFR and upper urinary tract ultrasound, descriptive statistics will be used to summarize
results and change from baseline by time point.  The eGFR results will be summarized 
based upon the Larsson, the modified Schwartz 2009 (for children < 12 years old) and 
the Cockcroft-Gault equation (for adolescents).
7 Statistical Methodology 
7.6 Analysis of Pharmacokinetics
WAS:
Descriptive statistics (N, mean, SD, minimum, median, maximum, coefficient of variation 
and geometric mean) will be provided for plasma concentration data and derived 
pharmacokinetic parameters.  Further details will be specified in the SAP.

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IS AMENDED TO:
Descriptive statistics (N, mean, SD, minimum, median, maximum, coefficient of variation 
and geometric mean) will be provided for plasma concentration data and derived 
pharmacokinetic parameters.  Further details will be specified in the SAP.
7 Statistical Methodology 
7.6.1 Analysis of Pharmacokinetics
WAS:
Noncompartmental methods will be used to derive the PK parameters using WinNonlin 
software (
 USA).
The following plasma PK parameters of mirabegron will be calculated for each individual:
Cmax, tmax, AUC24, Ctrough, CL/F and Vz/F.
IS AMENDED TO:
Noncompartmental methods will be used to derive the PK parameters using WinNonlin 
software (
 USA). 
The plasma concentrations will be analyzed with nonlinear mixed effects modeling 
(population pharmacokinetics) using NONMEM (version 7.3 or higher, 
 
 USA). 
The following plasma PK pharmacokinetic parameters of mirabegron will be calculated for 
each individual subject:
Cmax, tmax, AUC24, Ctrough, CL/F and Vz/F.
8 Operational and Administrative Considerations
8.1.1 Data Collection
WAS:
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.
IS AMENDED TO:
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF and listed.
11 References
WAS:
U.S. Department of Health and Human Services, National Institutes of Health. The fourth 
report on the diagnosis, evaluation, and treatment of high blood pressure in children 
and adolescents. Available from: 
https://www.nhlbi.nih.gov/files/docs/resources/heart/hbp_ped.pdf [Accessed 25 
November 2015]

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IS AMENDED TO:
U.S. Department of Health and Human Services, National Institutes of Health. The fourth 
report on the diagnosis, evaluation, and treatment of high blood pressure in children 
and adolescents. 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 [Accessed 25 
November 2015]
11 References
ADDED:
Cockcroft DW, Gault MH (1976). Prediction of creatinine clearance from serum 
creatinine. Nephron. 16 (1): 31–41. doi:10.1159/000180580. PMID 1244564.
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.
12.3 Laboratory Assessments
Biochemistry
WAS:
Estimated glomerular filtration rate (Larsson)
IS AMENDED TO:
Estimated glomerular filtration rate (Larsson, modified Schwartz and Cockcroft-Gault)

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SPONSOR’S SIGNATURES