Conditions: Neurogenic Detrusor Overactivity
Keywords: Pediatrics Urodynamics Mirabegron Phase 3 Neurogenic Detrusor Overactivity
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 91
Healthy volunteers: no

Brief summary:
The objective of the study was to evaluate the efficacy, safety, tolerability and pharmacokinetics of mirabegron after multiple-dose administration in the pediatric population.

Detailed description:
This was a phase 3, open-label, baseline-controlled, multicenter study. The study consisted 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 week 24. Long-term safety period: beginning after week 24 and continuing to week 52 (end of study \[EOS\]), or to the end of treatment (EOT).

Arms:
arm 1: Participants aged 3 to \< 12 years received initial dose of 25 milligram (mg) of mirabegron orally once daily based on weight (pediatric equivalent dose of 25 mg (milligram) \[PED25\]) on day 1. At weeks 2, 4 or 8, participant's were up-titrated to the pediatric equivalent dose of 50 mg in adults \[PED50\], orally once daily based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT). arm 2: Participants aged 12 to \< 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight \[PED25\] on day 1. At weeks 2, 4 or 8, participant's were up-titrated to the pediatric equivalent dose of 50 mg in adults \[PED50\] orally once daily based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT.

Interventions: intervention 1: Mirabegron
Intervention descriptions: intervention 1: Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were up-titrated to PED50 based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT. Participants with a body weight \>=35 kg received mirabegron tablets or body weight \<35 kg received mirabegron oral suspension. At week 24, participants on mirabegron oral suspension could switch to tablets if the body weight became \>=35 kg or participants on mirabegron tablets could switch to oral suspension if the body weight became \<35 Kg or participants could switch to either of the dosage form for acceptability reasons after sponsor's prior approval and on a case-by-case basis. Mirabegron extended-release granules were reconstituted with water to prepare a mirabegron oral suspension of 8 mg/mL. Administration was via an oral syringe with a sip of water afterwards.

Protocol document:
Prot_000.pdf: 
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
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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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02 Nov 2016
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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 -
02 Nov 2016
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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
- CONFIDENTIAL -
02 Nov 2016
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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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02 Nov 2016
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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


Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
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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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ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
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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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ISN/Protocol 178-CL-206A
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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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ISN/Protocol 178-CL-206A
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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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ISN/Protocol 178-CL-206A
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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.


Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
- CONFIDENTIAL -
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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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Version 2.0 Incorporating Substantial Amendment 1
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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Version 2.0 Incorporating Substantial Amendment 1
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


Sponsor: APEB
ISN/Protocol 178-CL-206A
EudraCT number 2015-002876-25
- CONFIDENTIAL -
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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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14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
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 SAP v3: 21 May 2019
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden, the Netherlands


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
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STATISTICAL ANALYSIS PLAN
Final Version 3.0, dated 21-May-2019
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: 178-CL-206A
EudraCT number: 2015-002876-25 
IND number: IND 69,416
Astellas Pharma Europe B.V. (APEB)/
Sylviusweg 62
2333 BE Leiden, the Netherlands
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Global Development, Inc.
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21-May-2019
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Table of Contents
TABLE OF CONTENTS ··················································································· 2
LIST OF TABLES··························································································· 6
LIST OF ABBREVIATIONS AND KEY TERMS ···················································· 7
1
INTRODUCTION·················································································11
2
FLOW CHART AND VISIT SCHEDULE···················································12
3
STUDY OBJECTIVE(S) AND DESIGN······················································15
3.1
Study Objective(s) ············································································15
3.1.1
Primary Objectives······································································15
3.1.2
Secondary Objectives ···································································15
3.2
Study Design···················································································15
3.3
Assignment and Allocation ··································································17
4
SAMPLE SIZE·····················································································18
5
ANALYSIS SETS ·················································································19
5.1
All Screened Set···············································································19
5.2
All Allocated Set ··············································································19
5.3
Full Analysis Set (FAS) ······································································19
5.4
Per Protocol Set (PPS)········································································19
5.4.1
Reasons for Exclusion From PPS ·····················································20
5.5
Safety Analysis Set (SAF) ···································································21
5.6
Pharmacokinetics Analysis Set (PKAS)····················································21
5.7
Pharmacodynamic Analysis Set (PDAS)···················································22
6
ANALYSIS VARIABLES ·······································································23
6.1
Efficacy Endpoints············································································23
6.1.1
Primary Efficacy Endpoint ·····························································30
6.1.2
Primary Estimand ·······································································30
6.1.3
Secondary Efficacy Endpoints·························································31
6.1.4
Exploratory Efficacy Endpoints ·······················································36
6.2
Safety Endpoints ··············································································37
6.2.1
Vital signs ················································································40
6.2.2
Adverse Events ··········································································43
6.2.3
Clinical Laboratory Variables··························································45


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6.2.4
Physical Examinations··································································47
6.2.5
12-lead Electrocardiogram (ECG)·····················································48
6.2.6
Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound·····48
6.2.7
Height, Weight and BMI ·······························································49
6.3
Pharmacokinetic Variables···································································49
6.4
Pharmacodynamic Variables·································································50
6.5
Other Variables················································································50
6.5.1
Baseline Characteristics ································································50
6.5.2
Previous and Concomitant Medications and Therapies·····························50
6.5.3
Exposure to Study Drug ································································51
6.5.4
Compliance to Study Drug ·····························································52
7
STATISTICAL METHODOLOGY ···························································56
7.1
General Considerations·······································································56
7.2
Study Population ··············································································56
7.2.1
Disposition of Subjects ·································································56
7.2.2
Protocol Deviations ·····································································57
7.2.3
Demographic and Other Baseline Characteristics ···································57
7.2.4
Previous and Concomitant Medications ··············································58
7.3
Study Drugs····················································································59
7.3.1
Dosing ····················································································59
7.3.2
Exposure··················································································60
7.3.3
Treatment Compliance··································································60
7.4
Analysis of Efficacy ··········································································61
7.4.1
Analysis of Primary Endpoint ·························································61
7.4.2
Analysis of Secondary Endpoints ·····················································64
7.4.3
Analysis of Exploratory Endpoints····················································65
7.4.4
Analysis of Other Variables····························································65
7.4.5
Sensitivity Analysis ·····································································65
7.5
Analysis of Safety·············································································66
7.5.1
Adverse Events ··········································································66
7.5.2
Clinical Laboratory Evaluation ························································68
7.5.3
Vital Signs················································································70
7.5.4
Height and Weight ······································································73
7.5.5
Electrocardiograms (ECGs)····························································74


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7.5.6
Pregnancies···············································································75
7.5.7
Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound·····75
7.6
Analysis of PK·················································································75
7.6.1
Estimation of Pharmacokinetic Parameters ··········································75
7.6.2
Statistical Analysis ······································································75
7.7
Analysis of PD·················································································76
7.8
Subgroups of Interest ·········································································76
7.9
Other Analyses ················································································77
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················77
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········77
7.11.1
Missing Data ·············································································77
7.11.2
Outliers ···················································································80
7.11.3
Visit Windows ···········································································80
8
DOCUMENT REVISION HISTORY ·························································82
9
REFERENCES ····················································································88
10
APPENDICES ·····················································································90
10.1
Appendix 1: Inclusion and Exclusion Criteria·············································90
10.2
Appendix 2: List of Excluded Concomitant Medications ································93
10.3
Appendix 3: AEs of Interest not covered by Standard MedDRA SMQs V16.0·······94
10.4
Appendix 4:  Questionnaires·································································95
Appendix 4.1 Pediatric Incontinence Questionnaire ············································95
Appendix 4.2 Patient Global Impression of Severity Scale ····································96
Appendix 4.3 Acceptability Questionnaire for Tablets ·········································97
Appendix 4.4 Acceptability Questionnaire for Oral Suspension ······························98
Appendix 4.5 Clinical Global Impression of Change Scale·································· 100
10.5
Appendix 5 Centiles of heart rate for normal children from birth to 18 years of 
age [Fleming et al, 2011]··································································· 101
10.6
Appendix 6  CDC Data Table of Stature-for-age Chart for Males ···················· 102
10.7
Appendix 7  CDC Data Table of Stature-for-age Chart for Females ················· 109
10.8
Appendix 8  CDC Data Table of Weight-for-age Chart for Males ···················· 116
10.9
Appendix 9  CDC Data Table of Weight-for-age Chart for Females·················· 122
10.10
Blood Pressure Levels for Males by Age and Height Percentile ······················ 128
Appendix 10.1
Fourth (4th) Report ·························································· 128


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Appendix 10.2
2017 Clinical Practice Guidelines·········································· 129
10.11
Blood Pressure Levels for Females by Age and Height Percentile···················· 130
Appendix 11.1
Fourth (4th) Report ·························································· 130
Appendix 11.2
2017 Clinical Practice Guidelines·········································· 131
10.12
Appendix 12:  Calculation of Z-Scores for Height, Weight and BMI for Age and 
Sex Norms ··················································································· 132
10.13
Appendix 13:  ECG Abnormality Codes ················································· 154
10.14
Appendix 14:  Key Contributors and Approvers ········································ 159


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List of Tables
Table 1
Schedule of Assessments·····································································13
Table 2
Efficacy Endpoints············································································26
Table 3
Summary of Efficacy Endpoints ····························································28
Table 4
Safety Endpoints ··············································································38
Table 5
Summary of Safety Endpoints·······························································39
Table 6
Coefficients for Conversion of Blood Pressure to Percentiles···························42
Table 7
Percentiles for Resting Pulse Rate in Relation to Age and Gender ·····················43
Table 8
Standardized MedDRA Queries, Version 16.0 ············································45
Table 9
Laboratory Assessments······································································46
Table 10
Number of Kits to be Dispensed at each Visit·············································54
Table 11
Weight based Doses for Suspension ························································54
Table 12
Definitions of Blood Pressure Categories and Stages·····································70
Table 13
Percentiles for Pulse Rate in Relation to Age··············································71
Table 14
Systolic and Diastolic Home Blood Pressure Values ·····································72
Table 15
Time Windows for Summary of Plasma Concentration Data····························76
Table 16
Visit Windows for Efficacy and Safety Parameters·······································80


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LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviation
Description 
APEB
Astellas Pharma Europe B.V.
APGD
Astellas Pharma Global Development
ASCM
Analysis Set Classification Meeting
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
DRM
Data Review Meeting
DSMB
Data and Safety Monitoring Board
EBC
Expected Bladder Capacity
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
FSI
First Subject In
HLT
High Level Term
IB
Investigator’s Brochure
ICF
informed consent form
ICH 
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISN
international study number
IUD
intrauterine device
IUS
intrauterine system
LOCF
last observation carried forward
LQTS
long QT syndrome
MCC
maximum cystometric capacity
M&S
Modeling & Simulation
NDO
neurogenic detrusor overactivity
OAB
overactive bladder
PCR
Potentially Clinically Relevant
PED
pediatric equivalent dose


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


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Terms
Definition of terms
Trough sample
Pharmacokinetic sample taken just prior to the next dose of study medication.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol 178-CL-206A (version 2.0, dated 
02 November 2016), the current EU PIP (EMEA-000597-PIP-03-M03, EMA Decision 17 
March 2017, ref. P/0056/2017) and US Written Request (NDA 202611, dated 18 March 
2016), and includes detailed procedures for executing the statistical analysis of the primary 
and secondary endpoints and safety data. 
The SAP will be finalized and signed prior to First Subject In (FSI). If needed, revisions to 
the approved SAP may be made prior to the database hard lock. Revisions will be version 
controlled.
This statistical analysis is coordinated by the responsible biostatistician of Astellas Pharma 
Global Development, Inc. (APGD).  Any changes from the analyses planned in the SAP will 
be justified in the Clinical Study Report (CSR).
Prior to database hard lock, a final review of data and Tables Listings and Figures (TLFs)
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented. A meeting to determine analysis set classifications may 
also be held prior to database hard lock.
Pharmacokinetic (PK) analyses will be described in a separate data analysis plan (PKDAP) 
which will be finalized prior to the analysis commencement and will be reported separately.
A SAP for the Data and Safety Monitoring Board (DSMB) will also be provided separately 
and finalized prior to FSI. If needed, revisions to the approved DSMB SAP may be made 
prior to the database hard lock. Revisions will be version controlled.






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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).
§§
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 post-dose samples 
between 2 h and 5 h post-dose, 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 post-dose samples must occur within 1 hour after completion of breakfast [Protocol 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.
¶¶
Mandatory at visit 3/baseline, visit 5/week 4 and visit 8/week 24. When the urodynamic trace is believed not to be in accordance with the subject’s clinical condition, it is 
allowed to repeat the urodynamic assessment once. Additional urodynamic assessments at other visits 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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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objectives
●
To evaluate the efficacy of mirabegron after multiple-dose administration in the pediatric 
population. 
3.1.2
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.
3.2
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.
The study consists of 3 periods:
●
Pretreatment period: for a maximum of 28 days before baseline, including screening
(visit 1), washout (if applicable) (visit 2) and baseline (visit 3)
●
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).  
Pretreatment Period: From screening (visit 1) to baseline (visit 3)
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 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.


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●
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 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 e-diary, 
catheterized volumes, questionnaires and self blood pressure measurement [SBPM]).
Efficacy Treatment Period: From the first dose the day after baseline measurements 
visit 3/baseline to visit 8/week 24
Study drug administration will begin the day after the baseline visit (i.e., on day 1).  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 (PED25).
At visit 4/week 2, visit 5/week 4 and visit 6/week 8, subjects are expected to be up-titrated to 
the pediatric equivalent dose of 50 mg in adults (PED50), unless:
1.
The investigator considers the subject to be effectively treated with PED25, based on 
urodynamics and 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 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.  
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.
Long-term Safety Period: From visit 8/week 24 to visit 10/week 52 (EOT or EOT)
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).


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3.3
Assignment and Allocation
No randomization is performed for the study and all subjects will receive active mirabegron
treatment (open-label).
Subject number assignment will be coordinated centrally by using an interactive response 
system.  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.
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.


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4
SAMPLE SIZE
The primary endpoint will be the change from baseline in maximum cystometric capacity
(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.
A study with 44 evaluable subjects who have valid (as by the central reviewer’s assessment) 
nonmissing 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. 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.


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5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. 
5.1
All Screened Set
The All Screened Set will consist of all subjects for whom a valid informed consent/assent is 
available, as per applicable local law.
Three signatures might be available from the informed consent/assent.  For calculations using 
the date of informed consent/assent the last available date will be used.
The All Screened Set will be used to summarize disposition of subjects who were screened.
5.2
All Allocated Set
The All Allocated Set will consist of all allocated subjects, i.e. all those subjects with a non-
missing registration date at visit 3 (baseline).
This set will be used to summarize disposition of subjects who were allocated to mirabegron 
treatment.
5.3
Full Analysis Set (FAS)
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 post-baseline visit for the primary efficacy endpoint.
The final selection of subjects for the FAS will be confirmed in the Analysis Set 
Classification Meeting (ASCM) based upon a review of all the pertinent data.
The FAS will be used for primary analyses of efficacy data, for sensitivity and subgroup 
analyses [Sections 7.4.1.2.5 and 7.8] and for summaries of some demographic and baseline
characteristics.
5.4
Per Protocol Set (PPS)
The per protocol set (PPS) includes 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.
The list of the protocol deviations that may result in a subject in the FAS being excluded 
from the PPS is provided below (Section 5.4.1).  The final selection of subjects for the PPS 
will be confirmed in the ASCM 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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5.4.1
Reasons for Exclusion From PPS
A subject may be excluded from the PPS if there has been a deviation from the protocol 
sufficient to affect the assessment of the efficacy of the study drug. Such deviations may 
include (but are not limited to) reasons why a subject was ineligible to have been included in 
the study, whether there were interventions that were prohibited by the protocol, or whether 
the subject did not adhere adequately to the study treatment or outcome assessments.
There will be no partial exclusion (e.g. of particular timepoints only) of a subject from the 
PPS; all of a subject’s data will be excluded.
Some reasons for exclusion of a subject from the PPS are given below; however the final 
decision on whether or not a particular protocol deviation (see Section 7.2.2) requires the 
exclusion of a subject will be confirmed at the ASCM with all reasons for the decision 
documented in the meeting minutes.
Eligibility Deviations
The inclusion and exclusion criteria for the study are detailed in Appendix 1: Inclusion and 
Exclusion Criteria  These are all assessed at Visit 1/screening and Visit 3/baseline.
A subject will be excluded from the PPS if:
●
Any of inclusion criteria 4 or 5 are not met.
●
Any of exclusion criteria 1, 3, 4, 5, 6, 7, 8, 17, or 18 are met.
Violations of other inclusion and exclusion criteria may also result in exclusion of the PPS if 
it is considered that there is a risk that the violation affects the assessment of the efficacy of 
the study drug.  All such violations will be considered on an individual basis at the ASCM.
NDO not confirmed
A subject will be excluded from the PPS if NDO cannot be confirmed by the expert review of 
the urodynamic traces recorded at visit 3/baseline, whether or not it is recorded that inclusion 
criterion 4 has been met.  However, the decision for inclusion/exclusion of the subject from 
the PPS will be part of the Central Review Committee Data.
Prohibited medications 
A subject will be excluded from the PPS if he/she received prohibited medications from start 
of wash-out period (visit 2) to baseline and from visit 7 to visit 8.  Except for Botox which is 
not allowed if taken from <4 months before screening and/or during the whole study period.
These include, but are not limited to, the following (see Appendix 2 for a more complete list):
Prohibited medications:
●
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).


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Compliance to study medication
A subject will be excluded from the PPS for either of the reasons below based on compliance 
to the study medication (see Section 6.5.4 for details on the calculation of the compliance rate 
between study visits):
●
Treatment stopped before the primary endpoint has been reached (MCC at 
visit 8/week 24);
●
Treatment compliance of less than 80% between visit 7/week 12 and visit 8/week 24.
All evidence and reasons for determining a violation based on compliance to the study 
medication will be documented in the minutes of the ASCM.
Missing primary efficacy endpoint
A subject will be excluded from the PPS if he/she does not have a valid baseline (visit 3) 
value and a valid visit 8 value (based on the week 24 efficacy visit windows [Day 99 to 
Day 237]– see Section 7.11.3; and not imputed from earlier weeks) of the primary efficacy 
variable (MCC).
Development of discontinuation criteria
A subject may be excluded from PPS if they developed discontinuation criteria prior to visit 
8/week 24 but were not withdrawn from the study. The decision for inclusion/exclusion of 
the subject from the PPS will be determined at the ASCM and documented in the minutes of 
this meeting.
5.5
Safety Analysis Set (SAF)
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 summaries of demographic and baseline characteristics and all 
safety and tolerability related variables.
5.6
Pharmacokinetics Analysis Set (PKAS)
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 one PK 
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 Global Clinical 
Modeling & Simulation Lead (GCMSL).  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 GCMSL. These data points will be reported in the modeling report.
The PKAS is used for all tables and graphical summaries of the PK data.


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5.7
Pharmacodynamic Analysis Set (PDAS)
The PDAS is not defined for this study.


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6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
Urodynamic assessments:
Urodynamic assessments will be performed at visit 3/baseline, visit 5/week 4, and 
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. 
The following parameters will be determined:
●
MCC at end of filling (mL)
●
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
●
MCC expressed as percentage of Expected Bladder Capacity (EBC)
Except for Bladder compliance and MCC expressed as % of EBC, the results of the 
urodynamic assessments will be entered in the eCRF.  Bladder compliance will be calculated 
by external experts and will be obtained from an external database.  MCC expressed as % of 
EBC will be calculated using EBC = 24.5 x age(years) + 62 (Palmer et al, 1997).
Bladder diary:
The bladder diary is part of the subject’s e-diary. After a successful visit 1/screening, all 
subjects should 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 3 and discussed and 
confirmed with the subject or parent(s)/caregiver(s) during the (telephone) visit. If the 
investigator is under the impression that the subject and/or 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 completion is not considered successful, the investigator should counsel/re-train the subject 
or parent(s)/ caregiver(s) prior to the start of the 7-day baseline e-diary. In case the subject 
and/or 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.  


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Subsequent bladder diaries will be completed by the subject or the subject’s parent/caregiver  
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
On 2 consecutive weekend days within the 7-day period (weekend e-diary):
●
Catheterized volume 
●
Grade of leakage between CICs
●
Weight of diaper/pad (visit 3/baseline and visit 8/week 24)
●
Number of Leakages between CICs
●
Position of measure
●
Urine weight
Results will be directly entered by the subject or subject’s parent(s)/caregiver(s) in the e-
diary.
Questionnaires:
The following questionnaires will be used:
●
The PIN-Q [Appendix 4.1] 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 4.2] will be completed on one weekend day preceding visit 
3/baseline, visit 8/week 24 and visit 10/week 52 (EOT/EOS).
●
The Acceptability Questionnaires [Appendix 4.3 and Appendix 4.4] will be completed
on one weekend day preceding visit 5/week 4, visit 8/week 24 and visit 10/week 52 
(EOT/EOS).
●
The CGI-C [Appendix 4.5] will be completed at visit 8/week 24 and at visit 10/week 52
(EOT/EOS).
The PIN-Q with a Likert scale adopted for 20 measures is used. Questionnaires (i.e., PIN-Q, 
PGI-S and the Acceptability Questionnaires) will be provided via the e-diary. Results will be 
directly entered in the e-diary by the subject or subject’s parent/caregiver. The CGI-C will be 
completed by the investigator and the results will be entered in the eCRF.


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The primary and secondary variables will be calculated based on the following:
●
Valid urodynamic assessments made at visit 3/baseline, visit 5/week 4 and visit 
8/week 24,
●
Diary data collected at each visit from Visit 3 to Visit 10/EOS. Only valid diary days
from week end diary and/or week day diary as appropriate will be used.
●
Quality of Life data (valid PIN-Q and PGI-S questionnaires) collected at Visits 3, 8 
and 10/EOS (baseline, week 24, and week 52 respectively),
●
Clinician reported Questionnaire (valid CGI-C) collected at Visit 8/Week 24 and 
Visit 10/Week 52).
A valid urodynamic assessment is an urodynamic assessment confirmed to be valid by 
central reviewers.
A valid bladder diary day in the weekday diary is any e-diary day for which at least 1
catheterization with complete date and time is recorded.
A valid bladder diary day in the weekend diary is any e-diary day for which at least one 
catheterized volume greater than 0 mL and complete date and time is recorded. See 
section 6.1.3.2 for calculating catheterized volume.
A valid PIN-Q questionnaire is a questionnaire with answers to at least 18 of the 20 
individual items used to create the total score. A PGI-S questionnaire is considered valid 
when subject answer to the question “How did you feel about your bladder condition during 
the past 3 days?”
A CGI-C is considered valid when the physician rates the change in the subject’s overall 
bladder symptoms.
Analysis windows will be used, as described in section 7.11.3
The efficacy endpoints are described in Table 2
A summary of the efficacy endpoints is presented in Table 3


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Table 2
Efficacy Endpoints 
Endpoint 
Number
Endpoint Description
Primary Efficacy Endpoint based on Urodynamic Measures
1
Change from baseline in MCC at visit 8/week 24
Secondary Efficacy Endpoints based on Urodynamic Measures 
2
Change from baseline in MCC at visit 5/week 4 
3,4
Change from baseline in Bladder compliance (∆V/∆P) at visit 5/week 4 
and visit 8/week 24
5,6
Change from baseline in number of overactive detrusor contractions 
(> 15 cm H2O) until end of filling at visit5/week 4 and visit 8/week 24
7,8
Change from baseline in detrusor pressure at end of filling at visit 5/week 
4 and visit 8/week 24
9,10
Change from baseline in filling volume until first overactive detrusor 
contraction (> 15 cm H2O) at visit 5/week 4 and visit 8/week 24
Secondary Efficacy Endpoints: Bladder Volume and Leakage Measures based on 7-day diary
11
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
12
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 maximum catheterized volume
13
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 maximum catheterized daytime volume
14
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 morning catheterized volume (based on first 
catheterization after subject woke up)
15
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 number of leakage episodes per day (day and night 
time)
16
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 number of dry (leakage-free) days/7 days (day and night 
time)
Table continued on next page


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Endpoint 
Number
Endpoint Description
Secondary Efficacy Endpoints: Subject- or Clinician reported Questionnaire Endpoints
17, 18
Change from baseline at visit 8/week 24 and visit 10/week 52 
(EOT/EOS) in PIN-Q
19, 20
Change from baseline at visit 8/week 24 and visit 10/week 52 
(EOT/EOS) in PGI-S
21, 22
Clinician Global Impression of Change (CGI-C) at visit 8/week 24 and 
visit 10/week 52 (EOT/EOS)
23, 24, 25
Acceptability at visit 5/week 4, visit 8/week 24 and visit 10/week 52 
(EOT/EOS)
Exploratory Efficacy Endpoints based on Urodynamic Measures
26, 27
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
28, 29
Change from baseline at visit 5/week 4 and visit 8/week 24 in MCC 
expressed as percentage of EBC
Exploratory Efficacy Endpoints based on 7-day diary
30
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
31
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 total catheterized volume per day
32
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 number of CICs/day
33
Shift 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 Responder with respect to leakage (complete responder, 
partial responder, non-responder)
34
For subjects with no leakage during the sleeping time: 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 morning catheterized volume (based on first catheterization after 
subject woke up)
35
For subjects with leakage during the sleeping time: 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 
morning catheterized volume (based on first catheterization after subject 
woke up)
36
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 percentage of catheterizations without intermittent leakage 
accident


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Table 3
Summary of Efficacy Endpoints 
Variable
Outcome
Endpoints
Visit 4/
week 2
Visit 5/
week 4
Visit 6/
week 8
Visit 7/
week 12
Visit 8/ 
week 24
Visit 9/
week 36
Visit 10/
week 52 (EOT/EOS)
Primary and secondary urodynamic
endpoints :
MCC
Bladder compliance
NODC*
Detrusor pressure
Filling volume
Change from baseline
Change from baseline
Change from baseline
Change from baseline
Change from baseline
2
3
5
7
9
1
4
6
8
10
Secondary bladder volume and leakage 
measures endpoints (7-day diary)
Average CV£
Maximum CV£ per day
Maximum CV£ (daytime)
Average CV£ (morning)
Mean NLE& per day (day and night time)
Number of dry$ days/7 days (day and night 
time)
Change from baseline
Change from baseline
Change from baseline
Change from baseline
Change from baseline
Change from baseline
11
12
13
14
15
16
Secondary questionnaire endpoints
PIN-Q
PGI-S
CGI-C
Acceptability (tablets and oral suspension) 
Change from baseline
Change from baseline
N (%)
N (%)
23
17
19
21
24
18
20
22
25
Exploratory urodynamic and 7-day diary 
endpoints
Filling volume (20, 30 and 40 cm H2O)
Change from baseline
26
27
Table continued on next page


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Variable
Outcome
Endpoints
Visit 4/
week 2
Visit 5/
week 4
Visit 6/
week 8
Visit 7/
week 12
Visit 8/ 
week 24
Visit 9/
week 36
Visit 10/
week 52 (EOT/EOS)
MCC expressed as % of EBC
Change from baseline
28
29
Mean Grade of leakage
Total CV£ per 24 h
No of CICs/day
Responder with respect to leakage
Subjects with no leakage during the sleeping 
time: Average CV£ (morning)
Subjects with leakage during the sleeping time: 
Average CV£ (morning)
Reduction in percentage of Catheterizations 
without intermittent leakage accident
N(%)
Change from baseline
Change from baseline
Shift from baseline
By Visit
By Visit
Shift from Baseline
30
31
32
33
34
35
36
* Number of Overactive Detrusor Contractions (NODC); £ Catheterized Volume (CV); & Number of Leakage Episodes (NLE), $ Leakage free


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6.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint will be the change from baseline in MCC at visit 8/week 24 
(based on filling urodynamics).
6.1.1.1 Maximum Cystometric Capacity (MCC)
MCC (mL) is recorded in the “VOLUME” section of the “Urodynamic Testing” pages of the 
eCRF under “Volume at the end of filling”. 
Baseline MCC is the MCC recorded at the baseline visit.  The change from baseline at visit 
8/week 24 in MCC is the MCC at the week 24 visit minus the baseline MCC.
For the primary analysis no imputation of missing data will be performed, ie, only non-
missing (week 24) data will be used for analysis. 
In addition, MCC will be calculated using the last observation carried forward (LOCF) 
method (see section 7.11.1): ie, the latest available post-baseline value from before week 24
will be carried forward and used for analysis. To calculate the change from baseline, the 
baseline MCC must be available and at least the visit 5/week 4 MCC, any unscheduled visit 
MCC before week 24, or the visit 8/week 24 MCC, else the primary efficacy variable is 
missing.  Missing values at visit 8/week 24 will be imputed from previous post-baseline 
values using the last observation carried forward (LOCF) method (see section 7.11.1).
In addition, the MCC will also be calculated without using the LOCF technique, ie., only 
non-missing data will be used for analysis.
6.1.2
Primary Estimand
The estimand of most clinical importance, following a hypothetical strategy, for this study is 
defined by the following 4 attributes:
●
Target population: all subjects who took at least 1 dose of the study drug, and in whom a 
valid non-missing MCC measurement at baseline and after administration of the study 
drug is available;
●
Outcome measurement: MCC at visit 8/week 24;
●
Intercurrent event: had the subject not discontinued the study drug for any reason;
●
Population-based summary: difference of MCC at visit 8/week 24 (or prior, due to study 
drug discontinuation) compared to baseline.
For a single arm baseline controlled study, this “de jure” estimand is considered the 
appropriate choice.  As some effect is expected early in the study and with continued 
treatment could be expected to be maintained, it’s considered appropriate to impute for 
subjects with missing values at visit 8/week 24 by their visit 5/week 4 value (if available).
A “de facto” estimand (treatment policy) was not chosen for this study. As this is a single 
arm treatment, a treatment policy estimand (which typically compares two randomized arms 
regardless of treatment changes) was not considered suitable for this type of study. A further 
reason against the use of the treatment policy estimand is the fact that subjects need to
immediately start a different treatment after study drug discontinuation, which may differ 


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across different investigators, and is likely different from the treatment they took before 
entering this study. The impact of such a treatment mix on the effect of mirabegron would be 
difficult to interpret.
Difference of MCC at visit 8/week 24 (or prior, due to study drug discontinuation) compared 
to baseline is the primary estimator.
As a sensitivity analysis, Mixed-Effect Model Repeated Measure (MMRM) will be used to 
handle any missing endpoint at visit 8/week 24.
6.1.3
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are described in Table 2 and Table 3 above.
6.1.3.1 Urodynamic Measures
For each of these endpoints, the change from baseline at the post-baseline value is the value 
at the post-baseline visit minus the value at the baseline visit. If either the baseline value or 
the post-baseline visit value is missing, the change from baseline will be missing. No 
imputation will be done.
6.1.3.1.1
Overactive Detrusor Contractions (>15 cmH2O)
The volume (mL) of fluid instilled until the first detrusor contraction (>15 cm H2O) is
recorded in the “VOLUME” section of the “Urodynamic Testing” pages of the eCRF. If no 
contraction occurred, the bladder volume will be missing in the eCRF and the MCC at that 
visit will be used.
6.1.3.1.2
Number of Overactive Detrusor Contractions and Detrusor Pressure at end 
of filling
The number of overactive detrusor contractions (>15 cm H2O) until end of filling is recorded 
in the same section as the Overactive Detrusor Contractions of the “Urodynamic Testing” 
pages of the eCRF. Detrusor pressure at end of filling (cm H2O) is recorded in the same 
section of the eCRF.
6.1.3.1.3
Bladder Compliance
Bladder compliance (V/Pdet) will be assessed by the independent central reviewers and 
reported as annotations on the urodynamic trace and in an external database, not in the eCRF. 
The calculation of the bladder compliance will be performed by the central reviewers. To 
standardize this calculation, the most linear part of the volume/pressure relationship will be 
isolated and used for calculating compliance. The values for V and P at the beginning and the 
end of this portion of the tracing are then used to calculate ΔV/ΔPdet [Bauer, 2015].
6.1.3.2 Bladder Volume and Leakage Measures
For each of these endpoints (see Table 2 and Table 3), the change from baseline to the post-
baseline value is the value at the post-baseline visit minus the value at the baseline visit.  If 
either the baseline value or the post-baseline visit value is missing, the change from baseline 
will be missing. No imputation will be done.


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The value calculated from the 7-day diary period before visit 3 will be regarded as the 
baseline value.  Each post-baseline value will be calculated using the 7-day diary period 
before the post-baseline visit.
Catheterized volume per catheterization is not directly collected in the 7-day diary, instead 
the weight of the pee per catheterization is entered.  If the subject recorded the presence of 
poo this measurement will be invalid and considered as missing for analysis purposes.
Catheterized volume per catheterization [mL] will be calculated as weight of the pee per 
catheterization [mg], using the following conversion formula: 1 g = 1 mL.
6.1.3.2.1
Average catheterized volume per catheterization (weekend diary)
For each subject, the average catheterized volume per catheterization is calculated as the sum 
of all available (non-missing) catheterized volumes recorded over both of the 2 measuring 
days in the weekend diary, whether or not these 2 days are consecutive divided by the 
number of catheterizations with non-missing volumes.
If volumes are recorded on 1 single day of the weekend diary, then the average catheterized 
volume per catheterization is calculated using all available (non-missing) catheterized 
volumes recorded on that day.
If no volumes are recorded on any day of the weekend diary, then the average catheterized 
volume per catheterization will be missing.
6.1.3.2.2
Maximum catheterized volume per day (weekend diary)
For each subject, the maximum catheterized volume per day is calculated using all available 
(non-missing) catheterized volumes recorded for the 2 measuring days in the weekend e-
diary, whether or not these 2 days are consecutive. The maximum value will be calculated 
separately for each measuring day and the mean of these two values will be used.
If volumes are recorded on 1 single day of the weekend e-diary, then the maximum 
catheterized volume per day is calculated using all available (non-zero) catheterized volumes
recorded on that day.
If no volumes are recorded on any day of the weekend e-diary, then the maximum 
catheterized volume per day will be missing.
6.1.3.2.3
Maximum catheterized daytime volume (weekend diary)
For each subject, the maximum catheterized daytime volume is calculated using all available 
(non-missing) catheterized daytime volumes for the 2 measuring days in the weekend e-diary, 
whether or not these 2 days are consecutive. The maximum value will be calculated 
separately for each measuring day and the mean of these two values will be used.
If volumes are recorded on 1 single day of the weekend e-diary, then the maximum 
catheterized daytime volume is calculated using all available (non-zero) catheterized daytime 
volumes recorded on that day.
If no volumes are recorded on any day of the weekend e-diary, then the maximum 
catheterized daytime volume will be missing.


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Daytime is defined as the time between wake-up time (minus 30 min) and time to sleep (plus 
29 minutes) recorded in the e-diary; e.g. if the wake-up time is HH:MM=08:30 and sleep 
time is HH:MM=22:00, then daytime is defined from 08.00 to 22.29. 
If wake up time and/or time sleeps is missing imputation rules will be applied as per 
section 7.11.1.2
6.1.3.2.4
Average morning catheterized volume (weekend diary)
On a volume-measuring day in the e-diary, the first morning catheterized volume is the first 
recorded non-zero volume within or after the hour of the wake-up time, e.g. if the wake-up 
time is HH:MM=08:30, then the first non-zero volume recorded during the 8-9am hour 
period or later period is used. If the wake-up time is missing on a measuring day, the first 
non-zero recorded volume after 06:00 will be used. If no non-zero volume is recorded before 
15:00 on a measuring day, the first morning catheterized volume will be missing for that e-
diary day.
The average first morning catheterized volume is calculated as the average of the available 
first morning catheterized volumes recorded for the 2 measuring days in the weekend e-diary, 
whether or not these 2 days are consecutive.
If the first morning catheterized volume is recorded on 1 single day of the weekend e-diary, 
then the average morning catheterized is the first morning catheterized on that day.
If no first morning catheterized volumes are recorded on any day of the weekend e-diary, 
then the average first morning catheterized volume will be missing.
6.1.3.2.5
Mean number of leakage episodes per day (day and night time) (weekend 
diary)
For each subject, the mean number of leakage episodes per day (during day and night time) is 
calculated using all available (non-missing) number of leakage episodes for the 2 measuring 
days in the weekend diary during day and night time.
If the number of leakage episodes is recorded on 1 single day in the 7-day diary during day 
and night time, then the mean number of leakage episodes per day during day and night time 
is equal to the total number of leakage episodes recorded on that day during day and night 
time.
If no leakage episodes are recorded on any day of the weekend diary during day and night 
time, then the mean number of leakage episodes per day will be zero. If nothing is recorded, 
e.g., not completing the diary, the result is missing.
6.1.3.2.6
Number of dry (leakage-free) days per 7 days (day and night time) (7-day 
diary)
Let Ddry be the number of valid diary days where the response to the question ‘Did you leak 
between this catheterization and the last one’ is ‘No’ each time a new catheterization is 
entered during the day and night time period.


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Let Dwet be the number of valid diary days where the response to the question ‘Did you leak 
between this catheterization and the last one’ is ‘Yes’ for at least one catheterization entered 
during the day and night time period.
If  + 
 > 3, then the number of dry days per 7 days is calculated as

 + 
 × 7
Otherwise its value is missing.
6.1.3.2.7
Number of dry (leakage -free) nights per 7 days
Let Ndry be the number of valid diary days where the response to the question ‘Did you leak 
between this catheterization and the last one’ is ‘No’ each time a new catheterization is 
entered during the night time period.
Let Nwet be the number of valid diary days where the response to the question ‘Did you leak 
between this catheterization and the last one’ is ‘Yes’ for at least one catheterization entered 
during the night time period.
If  + 
 > 3, then the number of dry nights per 7 days is calculated as

 + 
 × 7
Otherwise its value is missing.
6.1.3.2.8
Identification of leakage during sleeping time
For identification of a leakage during the sleeping time: since time for sleep and time for 
wake up are available, all leakages which occurred during this period are considered as 
‘Sleeping time Leakages’.
For identification, at a visit, of a leakage during the sleeping time all leakages which occurred 
during this period are considered as ‘Sleeping time Leakages’. If there are:
●
0 leakages, the subject is considered as “Subject with no leakage” at that visit
●
≥1 leakages, the subject is considered as “Subject with leakage” at the visit
6.1.3.3 Subject- or Clinician-reported Questionnaire
6.1.3.3.1
Pediatric Incontinence Questionnaire (PIN-Q)
The total PinQ score (Bower, 2006) is 20 multiplied by the average of the individual PinQ 
items where each of the 20 Likert scales have been converted to a score: 
●
For items 6 and 17; 0: “No” to 4: “Definitely” will be used; and 
●
For the other 18 items; 0: “No” to 4: “All the time” will be used.
It is expected that completed questionnaires will have at most a limited number of missing 
values; if the answers to more than two questions are missing, the total score will not be 
calculated and will be missing.


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Individual item scores will not be directly imputed.
The change from baseline to each post-baseline visit in the total PinQ score is the value at the 
post-baseline visit minus the value at the baseline visit. If either the baseline value or the 
post-baseline visit value is missing, the change from baseline will be missing.
If change is: 
●
Less than 0, there is an improvement between the two time-points;
●
Equal 0, there is no change between the two time-points;
●
Greater than 0, there is a worsening between the two time-points.
6.1.3.3.2
Patient Global Impression of Severity Scale (PGI-S)
The Patient Global Impression of Severity Scale (PGI-S) is an answer of the question: “How 
did you feel about your bladder condition DURING THE PAST 3 DAYS?”
Subjects will evaluate their recent condition ticking one of the following categories: “Really 
Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) and “Really Good” (4).
PGI-S will be summarized as a continuous variable.  The change from baseline to each post-
baseline visit in the PGI-S score is the value at the post-baseline visit minus the value at the 
baseline visit.  If either the baseline value or the post-baseline visit value is missing, the 
change from baseline will be missing.
A positive change indicates an improvement while a negative change indicates a worsening.
6.1.3.3.3
Clinician Global Impression of Change (CGI-C)
The Clinician Global Impression of Change (CGI-C) is a 7 point scale that requires the 
clinician to assess how much the subject’s overall bladder symptoms since the start of the 
study on day 1 has improved or worsened and rated as: very much improved (1); much 
improved (2); minimally improved (3); no change (4); minimally worse (5); much worse (6); 
or very much worse (7).
CGI-C will be summarized as a categorical variable. 
6.1.3.3.4
Acceptability (for tablets)
Subjects will evaluate the taste of the study medication ticking one of the following 
categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) and “Really 
Good” (4).
Subjects will evaluate the swallow of the study medication ticking one of the following 
categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) 
and “Really Easy” (4).
Taste and swallow acceptability will be summarized as categorical variables.


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6.1.3.3.5
Acceptability (for oral suspension)
Subjects will evaluate the taste of the study medication ticking one of the following 
categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) and “Really 
Good” (4).
Subjects will evaluate the smell of the study medication ticking one of the following 
categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) and “Really 
Good” (4).
Subjects will evaluate the consumption of the study medication ticking one of the following 
categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) 
and “Really Easy” (4).
Subjects will evaluate the preparation of the study medication ticking one of the following 
categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) 
and “Really Easy” (4).
Taste, smell, consumption and preparation acceptability will be summarized as categorical 
variables.
6.1.4
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are summarized in Table 2 and Table 3. 
No imputation will be done.
6.1.4.1 Exploratory efficacy endpoints based on urodynamic measures
6.1.4.1.1
Filling volume at 20 cm, 30 cm and at 40 cm H2O detrusor pressure
Bladder volumes at 20, 30 and 40 cm H2O detrusor pressure are recorded in the “VOLUME” 
section of the “Urodynamic Testing” pages of the eCRF. If detrusor pressure cannot be 
reached during the examination, the volume will be missing.
6.1.4.2 Exploratory efficacy endpoints based on 7-day diary
6.1.4.2.1
MCC expressed as percentage of EBC
MCC expressed as % of EBC will be as: 
100% x MCC/EBC, where EBC = 24.5 x age(years) + 62.
6.1.4.2.2
Grade of leakage (weekend diary)
Grade of worst leakage will be assessed by answering to 1 of the 2 questions as appropriate: 
“How wet was your diaper/pad?” or “How wet were your clothes?”.
Subjects will evaluate the grade of leakage by ticking one of the following categories: “Fully 
Wet” (0), “Quite Wet” (1), “Slightly Wet” (2).
If a subject experiences leakage episodes but there is no answer to the leakage question, the 
leakage grade will be missing.


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6.1.4.2.3
Total catheterized volume per day (weekend diary)
The total catheterized volume per 24h is calculated using all available (non-missing) 
catheterized volumes recorded for the 2 measuring days in the diary, whether or not these 
2 days are consecutive. The total value will be calculated separately for each measuring day 
and the mean of these two values will be used.
If no volumes are recorded on any day of the weekend diary, then the total catheterized 
volume per day will be missing.
6.1.4.2.4
Number of CICs/day (weekday diary)
The number of CICs per day will be calculated as the total number of CICs reported during 
valid diary days in the weekday diary divided by the total number of valid weekday diary 
days).
6.1.4.2.5
Responder in respect to leakage (weekend diary)
The percent change from baseline to a post-baseline visit in the number of leakage episodes 
during the weekend diary will be calculated as follows:
 = .   . ! " ! # −.   . ! % &'
.   . ! % &'
 × 100
A complete responder will be defined as a subject with a 100% improvement from baseline 
(i.e. RX= -100%). A partial responder will be defined as a subject with a percent 
improvement from baseline ≥50% and <100% (i.e. -100% < RX ≤ -50%). A non-responder 
will be defined as a subject with an improvement from baseline <50% or a worsening from 
baseline (i.e. RX > -50%).
If the number of leakage episodes at baseline is equal to zero, a constant equal to 0.5 will be 
added to the baseline number of leakages to allow denominator calculation.
If the number of leakage episodes at baseline and/or at a post-baseline visit is missing then 
the response category in respect to leakage will be missing.
6.1.4.2.6
Percentage of Catheterizations without Intermittent Leakage Accident
For each visit the percentage of catheterizations without intermittent leakage accident is: 
100% x (total number of catheterizations without intermittent leakage accident / total 
number of catheterizations).
For reporting 3 response criteria are defined:
●
No response; <50% reduction from baseline;
●
Partial response; 50-99% reduction from baseline; and
●
Complete response; 100% reduction from baseline.
6.2
Safety Endpoints
The following safety endpoints will be assessed:


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Table 4
Safety Endpoints
Endpoint Number
Endpoint Description
Safety Endpoints†
1
Incidence and severity of treatment-emergent adverse events (TEAEs)
2,3,4,5
Change from baseline in vital signs (clinic measurements): systolic blood 
pressure, at visit 5/week 4, visit 7/week 12, visit 8/week 24 and visit 10/week 
52 (EOT/EOS)
6,7,8,9
Change from baseline in vital signs (clinic measurements): diastolic blood 
pressure at visit 5/week 4, visit 7/week 12, visit 8/week 24 and visit 10/week 
52 (EOT/EOS)
10,11,12,13
Change from baseline in vital signs (clinic measurements): pulse rate at visit 
5/week 4, visit 7/week 12, visit 8/week 24 and visit 10/week 52 (EOT/EOS)
14,15,16,17
Change from baseline in vital signs (clinic measurements): temperature at visit 
5/week 4, visit 7/week 12, visit 8/week 24 and visit 10/week 52 (EOT/EOS)
18,19,20,21,22,23,2
4
Change from baseline in vital signs (self blood pressure measurement SBPM): 
systolic blood pressure 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.
25,26,27,28,29,30,3
1
Change from baseline in vital signs (SBPM): diastolic blood pressure 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.
32,33,34,35,36,37,3
8
Change from baseline in vital signs (SBPM): 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.
39,40
Change from baseline in hematology and biochemistry tests at visit 7/week 12 
and visit 10/week 52 (EOT/EOS)
41,42,43,44
Change from baseline in urinalysis tests at visit 5/week 4, visit 7/week 12, visit 
8/week 24 and visit 10/week 52 (EOT/EOS)
45,46,47,48
Change and categorized shift 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)
49
Categorized shift summary from baseline to visit 10/week 52 (EOT/EOS) in 
upper urinary tract ultrasound assessment
50,51
Change from baseline in eGFR at visit 7/week 12 and visit 10/week 52 
(EOT/EOS)
Exploratory Safety Endpoints
52,53
Change from baseline in body height and weight at visit 8/week 24 and visit 
10/week 52 (EOT/EOS)
†
Physical Examination will be analyzed as part of subject medical history or AEs depending on the time of 
the finding.


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Table 5
Summary of Safety Endpoints
Variable
Endpoints
Week 2
Week 4
Week 8
Week 12
Week 24
Week 36
Week 52
TEAE
N (%)
1
SBPCM
DBPCM
PRCM
Body TemperatureCM
Change from baseline
Change from baseline
Change from baseline
Change from baseline
2
6
10
14
3
7
11
15
4
8
12
16
5
9
13
17
SBPSM
Change from baseline
18
19
20
21
22
23
24
DBPSM
Change from baseline
25
26
27
28
29
30
31
PRSM
Change from baseline
32
33
34
35
36
37
38
Hematology and biochemistry
Change from baseline
39
40
Categorized shift from baseline
Urinalysis
Change from baseline
Categorized shift from baseline
41
42
43
44
ECG
Change from baseline
Categorized shift from baseline
45
46
47
48
Upper Urinary Tract Ultrasound
eGFR#
Categorized shift from baseline
Change from baseline
50
49
51
Height and Weight
Change from baseline
52
53
CM Clinic Measurements
SM Self Measurements
# will be calculated according to the Larson Formula (Larson et al, 2004], and the modified Schwartz 2009 (for children < 12 years old) and the Cockcroft-Gault equation (for 
adolescents) formulas


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6.2.1
Vital signs
6.2.1.1 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 measurements will be per standard clinic practices and 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.
For the purpose of the analyses of vital signs, the average per visit for vital signs measured at 
the clinic will be calculated as follows:
●
If three or more measurements are reported, the average of all values will be used.
●
If only two measurements are reported, the average of the two values will be used.
●
If only one measurement is reported, it will be displayed for the average.
●
If all measurements are missing, then the average will be missing.
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 6.2.3].
6.2.1.2 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 will be 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 of the first 2-day weekend e-diary, confirmed at visit 2, 
subsequent measurements will be performed in the weekend preceding visit 3/baseline, 


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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 
parent(s)/caregiver(s).
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/caregiver in the e-diary.
For the purpose of the analyses, the average self-measurement vital signs will be calculated 
using all values from the 2-days diary collection separately for the regular measurements and 
the extra measurements. If all measurements are missing, then the average will be missing. 
However, if the extra measurements are not performed because they are covered by the 
regular ones, the regular measurements values will be duplicated so that they are included in 
both the regular and the extra analyses.
6.2.1.3 Conversion of Blood Pressure to Percentiles
Both the systolic and diastolic blood pressure site measurements will additionally be 
converted to percentiles specific to the age (years), sex and height (cm) of the subject using 
the following steps [NIH, 2005]:
●
The height of a subject is measured at Visits 1, 3, 8, 10/EOS and, if applicable, at the 
Early Discontinuation Visit. As the children and adolescents in this study may be 
expected to increase in height during the course of the study, the height of the child at 
a study visit will be imputed by linearly interpolating between Visit 3 and a post-
baseline visit as follow:
o
Let Dvisit be the date of the study visit, H1 be the most recent height measurement 
at or prior to the study visit, D1 be the date of H1, H2 be the earliest height 
measurement at or after the study visit, and D2 be the date of H2.
o
The height at Dvisit is estimated as: 


1
2
1
2
1
1
H
H
D
D
D
D
H
H
visit
visit













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●
Let Z = the z-score (i.e. the number of standard deviations above or below the mean) 
of the height (cm) of the subject at the study visit relative to healthy subjects of the 
same age and gender using CDC growth charts [CDC, 2000]. The formula and 
example SAS code to calculate this are given in Appendix 12
●
Let BP = the blood pressure (mmHg) that is being converted (either systolic or 
diastolic) and Y=the age of the child in years.
●
Taking the coefficients from the appropriate column in Table 6 below, compute ZBP, 
the Z-score for the blood pressure:



















4
1
4
1
)
10
(
j
k
k
k
j
j
BP
Z
Y
BP
Z
●
If (.) is the area under the standard normal curve to the left of Z, calculate P, the 
gender, age and height specific percentile of the blood pressure as P=(ZBP)*100%.
●
The exact age at a visit will be calculated as:
* = 
(, −- + 1)
365.25
where Dv is the visit date and DB is the subject’s date of birth. When the exact age at a 
visit is missing and cannot be calculated because of a missing date of birth, but where the 
age entered at screening is known only to be Y years (an integer), the percentile will be 
calculated for age=Y+0.5.
Table 6
Coefficients for Conversion of Blood Pressure to Percentiles
Systolic BP
Diastolic BP
Variable
Symbol
Male
Female
Male
Female
Intercept
Α
102.19768
102.01027
61.01217
60.50510
Age
(Age-10)
β1
1.82416
1.94397
0.68314
1.01301
(Age-10)2
β2
0.12776
.00598
-0.09835
0.01157
(Age-10)3
β3
0.00249
-0.00789
0.01711
0.00424
(Age-10)4
β4
-0.00135
-0.00059
0.00045
-0.00137
Height
Z
1
2.73157
2.03526
1.46993
1.16641
Z-Score
Z2
2
-0.19618
0.02534
-0.07849
0.12795
Z3
3
-0.04659
-0.01884
-0.03144
-0.03869
Z4
4
0.00947
0.00121
0.00967
-0.00079
Standard Deviation

10.7128
10.4855
11.6032
10.9573
To illustrate, a boy born on 1st January 2001 comes for a study visit on 13th January 2013.  
His height is measured as 159 cm and his systolic blood pressure (the mean of the triplicate) 
is 120 mmHg. In Appendix 12 the z-score for the boy’s height is worked through as an 
example and Z is found to equal 1.2836. The coefficients for the conversion of the blood 
pressure are taken from the appropriate column (systolic BP, Male) of Table 6 The value of 


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ZBP is found to equal 0.97623 which equates to the 83.6th percentile of the standard normal 
curve.
6.2.1.4 Pulse Rate in Relation to Age
Resting pulse rate will be compared to age-related norms [Fleming et al., 2011] according to 
the percentiles shown in Table 7
Table 7
Percentiles for Resting Pulse Rate in Relation to Age and Gender
Percentile
Age
1st
10th
25th
50th
75th
90th
99th
3-4y
70
86
94
104
113
123
136
4-6y
65
81
89
98
108
117
131
6-8y
59
74
82
91
101
111
123
8-12y
52
67
75
84
93
103
115
12-15y
47
62
69
78
87
96
108
15-18y
43
58
65
73
83
92
104
Each value of pulse rate will be categorized as either being above the age-specific 99th
percentile or below the 1st percentile.
6.2.1.5 Body Temperature
Body Temperature will be compared to a reference range of 35.4 to 37.7 degrees [Kliegman
et al, 2007].
6.2.2
Adverse Events
Collection of details of adverse events will begin at visit 1 after the signing of informed 
consent and will continue for all subsequent study visits. Adverse events will be evaluated 
during the telephone assessments at visit 2/wash-out period, visit 4/week 2, visit 6/week 8 
and visit 9/week 36 and at each time the subject visits the clinic in person.
An AE with an onset date prior to the first dose of study drug is not considered treatment-
emergent but rather as part of the baseline signs and symptoms of the study.  These AEs will 
be listed in the AE listing.
A treatment-emergent adverse event (TEAE) is defined as an adverse event with date of onset 
occurring on or after the first dose of study medication and up to the end of study. If the 
adverse event occurs on Day 1 and the onset check box is marked “Onset after first dose of 
study drug” or the onset check box is left blank, then the adverse event will be considered 
treatment emergent. If the adverse event occurs on Day 1 and the onset check box is marked 
“Onset before first dose of study drug”, then the adverse event will not be considered 
treatment emergent. If a subject experiences an event both before and after the first dose of 
study drug, the event will be considered a TEAE only if it has worsened in severity (i.e. it is 
reported with a new start date). All adverse events collected that begin within 7 days after 
taking the last dose of study drug will also be counted as a TEAE and for Serious Adverse 
Events (SAE) the follow-up period will be until the end of the study.


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All AEs will be compared with a list of AEs that Astellas considers to be “Always Serious” 
and those AEs that are on the list will be upgraded to “Serious”.
A drug-related TEAE is defined as any TEAE with at least a possible relationship to study 
treatment as assessed by the investigator or with a missing assessment of the causal 
relationship.
Common TEAEs are defined as preferred terms (PTs) that have been reported by at least 5% 
of the subjects.
When an AE start or stop date is missing, the date will be imputed using the rules in 
Section 7.11.1.3
Adverse events of interest are:
●
CV
o Increased blood pressure
o QT prolongation
o Increased heart rate, tachycardia, atrial fibrillation, or palpitations
(Note: these 3 CV events will be analyzed combined and separately)
●
Urinary Tract Infection (UTI)
●
Hypersensitivity reactions
●
Urinary retention
●
Neoplasm
●
Seizure
●
Syncope
●
Fetal disorders after exposure during pregnancy
●
Concomitant treatment with cytochrome P450 (CYP) 2D6 substrates with narrow 
therapeutic indices or individually dose-titrated.
AEs of interest will be identified using Standardized MedDRA queries (SMQ), version 16.0, 
see Table 8, or sponsor-defined list of search terms, see Appendix 3. 


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Table 8
Standardized MedDRA Queries, Version 16.0
CV - Increased blood pressure
Hypertension SMQ – Narrow search
CV - QT prolongation 
Torsade de pointes/QT prolongation SMQ –
Broad search
CV - Increased heart rate, tachycardia, atrial 
fibrillation, and palpitations 
Arrhythmia related investigations signs and 
symptoms SMQ – Broad search,
Supraventricular tachyarrhythmias (SMQ) 
Broad search, 
Tachyarrhythmia terms nonspecific (SMQ) 
– Narrow search, 
Ventricular tachyarrhythmias (SMQ) -
narrow search plus Ventricular tachycardia
Hypersensitivity reactions 
Hypersensitivity SMQ – Narrow search
Neoplasm 
Neoplasm SMQ – Narrow search
Seizure
Lower Level Term 10039906
Syncope
Syncope SMQ – Narrow search (also 
included as part of the CV - Increased heart 
rate, tachycardia, atrial fibrillation, and 
palpitations)
PT 10042772
Fetal disorders after exposure during 
pregnancy
Congenital, familial and genetic disorders -
SMQ Narrow
Fetal disorders – SMQ Broad search
Neonatal disorders – SMQ Broad search
Concomitant treatment with cytochrome 
P450 (CYP) 2D6 substrates with narrow 
therapeutic indices or individually dose-
titrated
PT Drug interaction 
PT Potentiating drug interaction
6.2.3
Clinical Laboratory Variables
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 Table 1].  These data will 
be summarized in a table.
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 






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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.
6.2.5
12-lead Electrocardiogram (ECG)
A 12-lead ECG will be performed in triplicate one minute apart 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). The ECGs will be taken with the subject in the supine position, after the subject 
has been lying quietly for at least 5 minutes. ECG traces will be evaluated by the investigator 
who will give an overall interpretation and may leave a qualifying comment in the eCRF. 
The overall interpretation will be recorded as 
●
Normal, or
●
Abnormal - not clinically significant, or
●
Abnormal - clinically significant
All ECGs will be further evaluated by a cardiologist at the central laboratory. When the 
central laboratory cardiologist’s overall interpretation is abnormal, an applicable abnormality 
code will be assigned. ECG abnormalities are coded for the particular class of abnormality 
(rhythm, QT interval, etc.) as well as the specific abnormality within each class. Details of 
this coding are given in Appendix 13:  ECG Abnormality Codes
As well as the overall interpretation, the following ECG variables will be supplied by the 
central laboratory: PR Interval (msec), RR Interval (msec), QRS Duration (msec), QT
Interval (msec), QTcF interval (msec) and Heart rate (HR) (beats/min).  QT with Bazett 
correction range (QTcB interval<=450 ms, all ages) will be only used for the inclusion 
criteria evaluation and won’t be presented.
The mean of each triplicate of ECG measurements recorded during the study will be used for 
each ECG variable. If fewer or more than 3 results are recorded the mean of all available 
values will be used.
Let M1 and M3 equal the means of a continuous ECG variable at Visit 1 and Visit 3, 
respectively.  The baseline value of the variable, used to assess study eligibility and all 
changes from baseline during the study, will equal (M1+M3)/2.
6.2.6
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). In addition, the estimated 
glomerular filtration rate (eGFR) will be calculated by the central laboratory using the 
Larsson formula [Larsson et al, 2004]:
eGFR = 94.577 * [Cys C (mg/L)]^1.2623
In addition, BARC will calculate the eGFR using the modified Schwartz 2009 (for children 
< 12 years old) and the Cockcroft-Gault equation (for adolescents) formulas.-


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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.
6.2.7
Height, Weight and BMI
Height and weight will be recorded at visit 1/screening, visit 3/baseline, visit 8/week 24 and 
at visit 10/week 52 (EOT/EOS).
As the study subjects are children and adolescents who are still growing, assessment of any 
effect of treatment on height and weight will be based on comparison with age (at screening)
and gender norms from growth charts supplied by the Centers for Disease Control and 
Prevention. These charts enable the calculation of z-scores for height and weight based on the 
age (in months) and sex for children, adolescents and young adults up to the age of 20 years 
[Kuczmarski et al, 2002].  The formulae and example SAS code for the calculation of these 
Z-scores are given in Appendix 12
The change from baseline in the z-score for height and the z-score for weight will be 
calculated as the value at the relevant visit minus the baseline value. If either of these values 
is missing, the change from baseline will be missing.
6.3
Pharmacokinetic Variables
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 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., pre-dose sample).
●
Sampling day 2: 1 trough and 2 post-dose samples taken between 2h and 5h post-
dose, 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 on a sampling day with 
post-dose samples must occur within 1 hour after completion of breakfast.
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.
The following plasma pharmacokinetic parameters will be calculated for each subject:
●
Maximum concentration (Cmax) at steady state
●
Time to attain Cmax (tmax)


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●
Area under the plasma concentration–time curve (AUC) for a dose interval (AUC24)
●
Plasma concentration before drug administration (Ctrough) at steady state
●
Terminal elimination half-life (t1/2)
●
Apparent oral clearance (CL/F)
●
Apparent volume of distribution (Vz/F).
Additional pharmacokinetic parameters may be calculated based on the model used.
Further details of the derivation of the pharmacokinetic parameters are given in the 
pharmacokinetics data analysis plan (PKDAP).
6.4
Pharmacodynamic Variables
There are no pharmacodynamic variables in this study.
6.5
Other Variables
6.5.1
Baseline Characteristics
Baseline characteristics and other variables that will be collected or derived are:

Informed consent/assent (collected at screening);

Demographic characteristics (collected at screening);

Inclusion/Exclusion (collected at screening and baseline);

Medical history (collected at screening), including a detailed NDO history;

Current NDO medications (collected at screening and start of washout);

Antimuscarinics medication stopped for lack of efficacy prior to start of treatment
(yes/no).
If Ddiag is the date of diagnosis and DScr is the date of last informed consent given at 
Screening, the years since diagnosis of NDO at Screening is 
23456 = 78 −3456 + 1
365.25
When one of these dates is partial, the rules in Section 7.11.1.2 will be used to impute it.
If DB is the subject’s date of birth, the age at Screening is 
*78 = (78 −- + 1)
365.25
If the date of birth is not given, the age at Screening will be equal to the value recorded on 
the demographics page of the eCRF (an integer number of years) plus 0.5. e.g. if the age is 
given as 12 years in the eCRF, a value of 12.5 will be used in calculations/statistical analyses 
involving age (an exception to this rule is given for the conversion of blood pressure values 
to percentiles; see Section 6.2.1.3).
6.5.2
Previous and Concomitant Medications and Therapies
All treatments, both drug and non-drug therapies, whether prescribed, over the counter 
(OTC) or “alternative” that are used during the study will be recorded on the case report 


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form. Details include generic and/or brand names of medications, reason for use, route, dose, 
and start and end dates.  This also includes drugs used on a chronic or as-needed basis.
Previous medication is defined as medication with at least one dose taken before the date of 
the first dose of the study drug.
Concomitant medication is defined as medication with at least one dose taken between the 
date of first dose (inclusive) and the date of last dose (inclusive) of the study drug.
A list of prohibited medications is given in Appendix 2: List of Excluded Concomitant 
Medications
When the start and stop dates of a medication or therapy are partial/missing, the dates will be
imputed using the rules in Section 7.11.1.5.
6.5.3
Exposure to Study Drug
The duration of exposure to each dose of study drug (PED25 and PED50) by visit and for the 
whole period will also be calculated using the following information that is recorded in the 
eCRF:

Overall start date and stop date of the study medication.
The first dose of study drug is to be administered on Day 1, the day after the baseline 
visit (Visit 3). The initial dose will be PED25 for all subjects. The last dose of 
treatment is to be taken in the morning of Visit 10.

Start date and new dose of study drug at each titration step.
At Visits 4, 5 and 6 the dose may be up-titrated, down-titrated, or may remain the 
same.

Start date and new dose of study drug after each unscheduled dose change.

At any time during the treatment period, the subject may have an unscheduled dose 
interruption or reduction. At each unscheduled change in dose, the new dose, start 
date and reason are recorded. Dose increasing is scheduled only during time window 
between Visit 4/Week 2 and Visit 6/Week 8.
In addition, the return date of study medication is assumed to be the date of clinical visit.
In all cases where there is a dose change, either because of dose titration or an unscheduled 
dose interruption, reduction or increase, the last dose of the medication at the old level will be 
assumed to be the day before the given date of first dose at the new level. In this way, the 
subject’s dosing history can be reduced to a series of unbroken intervals within each of which, 
the dose level is constant. From these, the subject’s exposure at each dose can be calculated.
To illustrate, consider a subject with the following dose information on the eCRF:
●
The dates of the very first and very last dose of the study medication given as 
D1=1st July 2016, Dlast=24th September 2016.
●
Up-titration to PED50 at Visit 4. The first dose at the new level is given as D2=15th 
July 2016.


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●
Study drug interrupted at an unscheduled visit. The date of last dose at the PED 50 
level is given as D3=18th July 2016
●
Study drug re-started at PED25 at an unscheduled visit. The first dose at the new 
level is given as D4=22 July 2016.
●
Remains at PED25 at Visit 5 (D5=29th July 2016). Up-titration to PED50 at Visit 6. 
First dose at the new level is given as D6=29thAugust 2016.
From these dates we calculate the following:
●
The duration of exposure to the treatment can be calculated as ETOT=Dlast-D1+1-
(D4-D3-1)=83 days.
●
Between Visits 3 and 4, the subject is on PED25. The last dose at PED25 is given on 
D2-1, the day before the subject has the first dose at the new level PED50. The 
exposure at PED25 between Visits 3 and 4 is, therefore, (D2-1)-D1+1=14 days
●
Between Visits 4 and 5, the study drug is temporarily suspended and then restarted 
at a new level. The subject will be considered to be exposed to the PED50 dose from 
D2 until D3, i.e. D3-D2+1=4 days.
●
For the calculation of the exposure, suspension of the study drug is not ignored. The 
dose will be considered interrupted between D3 to D4-1, i.e. (D4-1-D3)=3 days.
●
The study drug is at PED25 from D4 to D6-1, the date of the last dose prior to Visit 
6, i.e. (D6-1)-D4+1=38 days.
●
Subject is on PED50 from D6 to Dlast, a total of Dlast-D6+1=27 days.
●
The total exposure at PED50 is EPED50=31 days, at PED25 is EPED25=52 days
●
The total exposure between Visits 3 and 4 is E1=14 days, between Visits 4 and 5 is 
E2=11 days, between Visits 5 and 6 is E3=31 days and between Visits 6 and 7 is 
E4=27 days.
6.5.4
Compliance to Study Drug
Tablet compliance
Compliance will be calculated according to the number of tablets of study medication 
dispensed, the number of kits used and the duration of exposure between the applicable visits 
and overall.
Each kit of study medication contains 35 tablets.  At each dispensing visit, subjects will 
receive an adequate number of kits of both PED25 and PED50 as follows:
●
At Visit 3, 1 kit of 25 mg and 1 kit of 50 mg will be dispensed
●
At Visit 5, 2 kits of 25 mg and 2 kits of 50 mg will be dispensed
●
At Visit 7, 3 kits of 25 mg or 3 kits of 50 mg will be dispensed
●
At Visit 8, 7 kits of 25 mg or 7 kits of 50 mg will be dispensed
The total number of tablets used between Visits i and j (i<j) is calculated as:
Nused = Total number of tablets dispensed at Visit i - Total number of tablets returned at Visit j


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When a kit is not returned it will be assumed that all the medication from this kit was not 
used.
When a kit is returned late, it will be assumed that the medication was used during the study 
period that it was dispensed for, e.g. all the medication used from a kit dispensed at Visit 3 
and returned at Visit 5 will be assumed to have been used between Visits 3 and 5.
The amount of expected study drug intake depends on the number of days of study drug 
treatment and the number of prescribed daily tablets.  Since subjects are supposed to take 
1 tablet per day, the total number of expected tablets to be used between Visits i and j is 
calculated as follows:
Nprescribed = (Number of Exposure Days between Visit_i and Visit_j) x 1 tablet,
where Number of Exposure Days is calculated as: (Return date – Dispense date ) + 1.
Between Visits i and j the compliance to study medication will be calculated as follows:
Compliance = (Nused / Nprescribed) x 100%.
To illustrate, at Visit 3 a subject was dispensed 1 kit of 25 mg and 1 kit of 50 mg.  The date 
of first dose was 1st July 2016.  When the subject returned at Visit 4 (18th July 2016), the 
25 mg kit contained 20 tablets and the 50 mg kit was full (35 tablets).
Nused = (35-20) + (35-35) = 15 tablets
Number of exposure days = (18Jul2016 – 01Jul2016) + 1day = 18 days, 
Hence, Nprescribed = 18 tablets
Compliance between Visits 3 and 4 = (15/18) x 100% = 83.3%.
For the whole study period, the total amount of study drug used (TOTNused) is equal to the 
sum of the values of Nused at each applicable visit.  Similarly, the total amount of study drug 
prescribed (TOTNprescribed) is equal to the sum of the values of Nprescribed at each 
applicable visit.  Using these total values, the subject’s compliance over the whole study 
period can be calculated as 100% x (TOTNused / TOTNprescribed).
Suspension Compliance
Compliance for suspension will be calculated according to:
●
Number of bottles dispensed at each visit (see Table 10); 
●
Weight of the bottles returned to the site; and 
●
Duration of exposure between the applicable visits and overall.


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Table 10
Number of Kits to be Dispensed at each Visit
Dose Level
Number of kits 
Weight
Visit 3 /
Baseline
Visit 5 /
Week 4
Visit 7 /
Week 12
Visit 8 /
Week 24
Visit 9 /
Week 36
PED25
<22 kg
4
6
5
6
7
22 - <35 kg
5
8
6
7
8
≥ 35 kg
6
10
8
9
11
PED50
<22 kg
NA
6
8
9
11
22 - <35 kg
NA
8
11
11
14
≥ 35 kg
NA
10
14
15
19
NA: Not Applicable
Each kit of study medication contains a bottle with mirabegron granules.  After filling the 
bottle containing the granules with 100 mL drinking water, the weight of the bottle with 
content should be 137 g. 
Doses are calculated weight-based, see Table 11 The body weight at Visit 3/baseline 
determines the weight range for the starting dose (PED25) and the up-titration dose (PED50) 
to be used.
Table 11
Weight based Doses for Suspension
Dose Level
Weight Range 
Suspension Volume † 
PED25
11 - < 22 kg
3 mL
22 - < 35 kg
4 mL
≥ 35 kg
6 mL
PED50
11 - < 22 kg
6 mL
22 - < 35 kg
8 mL
≥ 35 kg
11 mL
PED25: Pediatric equivalent dose 25 mg; PED50: Pediatric equivalent dose 50 mg
† Suspension strength: 8 mg/mL
At each dispensing visit, subjects will receive an adequate number of kits of both PED25 and 
PED50 following the same procedure as descripted above for tablets.
The total dose of suspension used between Visits i and Visit j (i<j) is calculated as:
Wused = Total weight of bottles dispensed at Visit i - Total weight of bottles returned at Visit j, 
and taking into account the suspension strength of 8 mg/mL.
where: 
●
Total weight  dispensed = Number of kits dispensed at the Visit i x 137; and 
●
Total weight returned = Sum of the unused amount of study medication in each kit 
returned at Visit j.
When a kit is not returned it will be assumed that all the medication from this kit was not 
used.
When a kit is returned late, it will be assumed that the medication was used during the study 


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period that it was dispensed for, e.g. all the medication used from a kit dispensed at Visit 3 
and returned at Visit 5 will be assumed to have been used between Visits 3 and 5.
The amount of expected study drug intake depends on the number of days of study drug 
treatment and the number of prescribed daily suspension pouches.  Since subjects are 
supposed to administer 1 dose per day, the total amount of expected suspension to be used 
between Visit i and Visit j is calculated as follows:
Wprescribed = Duration in days between Visit i and Visit j times the subject’s specific dose, 
see Table 11
The weight of the subject’s specific dose is determined by using a conversion factor of 1 mL 
corresponds to 1.0216 g.
The compliance to study medication between Visits i and j will be calculated as follows:
Compliance = (Wused / Wprescribed) x 100%.
To illustrate, a subject, who weighted 25 kg and with dose level PED25, was dispensed with 
5 kits at Visit 3.  The date of first dose was 1st July 2016.  When the subject returned at 
Visit 4 (31th July 2016), 3 kits were not used and the weight of the 2 used kits was: 32 and 
124 g.
Compliance calculation:
1.
Total amount of reconstituted study drug administered was resolved in (137-32) + (137-
124) = 118 g of suspension, which is equal to 118/1.0216 mL = 115.5 mL.
2.
Given that the solution strength is 8 mg/mL this means that in total 115.5 mL x 8 mg/mL 
= 924 mg of study drug was administered to the subject.
3.
Duration was 31 days (= 31 July – 1 July +1), hence expected amount of study drug to be 
administered is 31 x 4 mL  = 124 mL (based on the weight of the subject the suspension 
volume is 4 mL, see Table 11).  This results in 124 mL x 8 mg/mL = 992 mg of study 
drug.
4.
Compliance between Visits 3 and 4 = (924/992) x 100% = 93.15%.
For the whole study period, the total amount of study drug used (TOTWused) is equal to the 
sum of the values of Wused at each applicable visit.  Similarly, the total amount of study drug 
prescribed (TOTWprescribed) is equal to the sum of the values of Wprescribed at each 
applicable visit.  Using these total values, the subject’s compliance over the whole study 
period can be calculated as 100%*TOTWused/TOTWprescribed.


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7
STATISTICAL METHODOLOGY
7.1
General Considerations
All statistical analyses and summary information are to be generated according to this 
analysis plan. Any deviation from this plan will be documented in the final study report.
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g.10%, 25%, 75% and 90%) will be mentioned in the relevant section. 
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of subjects with no missing data, i.e. will add up to 100%. 
Subjects who were screening failures or who were treated but withdrew from the study will 
be counted only once in summary tables. Information from both screening numbers will be 
shown in the individual subject listings.
Listings will be produced separately for children and adolescents, unless specified otherwise.
All statistical comparisons will be made using 2-sided tests at the α=0.05 significance level
unless specifically stated otherwise. All summaries will be presented by age group and 
overall, unless specifically stated otherwise. All null hypotheses will be of no change from
baseline, all alternative hypotheses will be 2-sided, unless specifically stated otherwise.
Missing primary efficacy endpoint values will be analyzed using the Last Observation 
Carried Forward (LOCF) method at Week 24. More details are provided in the relevant 
sections of this SAP.
All data processing, summaries, and analyses will be performed using SAS® Version 9.3 or 
higher on Unix. Specifications for table, figure, and data listing formats can be found in the 
TLF specifications for this study.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
●
Number and percentage of subjects who 
○
were included in the All Screened Set (i.e. who gave informed consent/assent);
○
were a screening failure;
○
were eligible for study drug treatment.
●
Number and percentage of subjects in the All Allocated Set, FAS, PPS, SAF and 
PKAS;
●
Number and percentage of subjects in the All Screened Set who completed or 
discontinued pretreatment period, by the primary reason for screening status;
●
Number and percentage of subjects who completed or discontinued treatment period, 
by the primary reason for discontinuation, for All Allocated Set, SAF, FAS, PPS and 
PKAS;


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●
Number and percentage of subjects who completed or discontinued end of study 
period, by the primary reason for discontinuation, for All Allocated Set, SAF, FAS, 
PPS and PKAS;
●
Number and percentage of subjects in the FAS who were excluded from the PPS by 
reason for exclusion (defined in Section 5.4.1).
The number of subjects will be tabulated by protocol version for the All Subjects Screened.
A listing of all early withdrawals, subjects who withdraw within 7 days, will be presented 
irrespectively whether they were dosed or not.  The reason for withdrawal will be included in 
this listing. 
A listing of screen failure with the primary screen failure reason will be provided for the 
screening failure subjects. In addition, disposition will be listed for All Allocated Subjects 
with treatment and study discontinuations.
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (see Section 8.1.6 Protocol Deviations) 
will be assessed for All Allocated Set.
The number and percentage of subjects with any deviation criterion will be summarized for 
each criterion and overall, by age group as well as by study site. Subjects deviating from a 
criterion more than once will be counted once for the corresponding criterion. Any subjects 
who have more than one protocol deviation will be counted once in the overall summary. A 
data listing will be provided by site and subject for the All Allocated Set.
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
† 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.
A listing of inclusion and exclusion criteria, listing of first and last evaluations as well as a
listing of subjects who were excluded from at least 1 analysis set will be provided for the All 
Allocated Set.
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by age category and 
overall.
Demographic and other baseline characteristics data will be provided in listing format by site 
and subject for the All Screened Set.


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The number and percentage of subjects allocated to treatment in each region, country and site
will be presented for the SAF.
Regions are defined as follows:
●
Europe: Norway, Latvia, Lithuania, Denmark, Belgium, Poland, Slovakia, Romania 
and Serbia
●
Asia and Pacific (APAC): Philippines, South Korea, Australia, Taiwan and Malaysia
●
Middle East and North Africa (MENA): Turkey, Israel and Jordan
●
Latin America (LatAm): Mexico and Colombia
The final list of participating/enrolling countries might be updated after end of recruitment 
when the list becomes final.
If sites in additional countries will be opened due to changes in recruitment strategy, these 
countries will be allocated respectively and reported in the CSR.
Descriptive statistics for age, height, weight, and BMI at screening will be presented as well 
as frequency tabulations for sex, ethnicity and race. In addition, summaries for height with 
respect to age- and sex-specific percentiles (Charts from the Centers for Disease Control and 
Prevention (CDC), See 10.6 and 10.7), and weight with respect to height- and sex- specific 
percentiles (CDC, See 10.8 and 10.9) will be provided.  These summaries will be produced 
for the SAF, FAS and PPS.
Collection of date of birth depends on local regulations. Day of birth will be recorded in the 
eCRF as the first of the month when the day is not allowed to be collected. In cases where 
only year of birth is allowed to be collected, day and month will be recorded in the eCRF as 
the first of January. Age at Screening will be recalculated in SDTM and ADAM datasets.
Demographic characteristics of subjects on previous antimuscarinic treatment (oxybutynin at 
screening vs. other treatment from concomitant medications dataset) will be summarized for 
the FAS, PPS and SAF.
Medical history (NDO Medical History and Medical History Other than NDO) is coded in 
MedDRA and will be summarized by System Organ Class (SOC) and Preferred Term (PT)
using SAF.  Subjects will only be counted once per MedDRA level and the medical history 
will be sorted by descending incidence of the overall SOCs and within PTs.
The data on NDO diagnosis and history, including duration of NDO disease (at first dose of 
mirabegron), NDO medical condition(s), urethral sphincter activity, retardation, wheelchair 
bound, surgery (including for closure of spina bifida, shunt for hydrocephalus, other) and 
time since surgery (calculated in months) will be summarized with descriptive statistics and 
frequency tabulations as appropriate using SAF.
7.2.4
Previous and Concomitant Medications
Previous and concomitant medications (for NDO or other indications) will be coded with 
WHO-DD, and will be summarized by therapeutic subgroup (ATC 2nd level), chemical 


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subgroup (ATC 4th level) and preferred WHO name for the SAF. Subjects taking the same 
medication multiple times will be counted once per ATC level. A medication which can be 
classified into several chemical and/or therapeutic subgroups is presented in all chemical and 
therapeutic subgroups.  Previous and concomitant medications will be sorted by alphabetical 
order by Therapeutic Subgroup and Chemical Subgroup and Preferred WHO Name.
A summary of all previous medications and concomitant medications will be produced for 
the NDO and non-NDO medications separately using SAF. Only the last NDO medication 
before start of study medication will be used for calculations.
Previous and concomitant NDO medications, non-NDO medications and non-NDO non-
medication therapies will be listed using All Screened Subjects. 
A listing of previous and concomitant NDO medications with ATC codes by WHO preferred 
name will be provided for All Screened Subjects.
7.3
Study Drugs
All summaries of this section will be presented by age group, dose group (see below) and 
overall, unless specifically stated otherwise.
7.3.1
Dosing
As per study schedule (Table 1), all subjects will start with a PED equal to 25 mg of 
mirabegron (PED25). From visit 4/week 2 to visit 6/week 8 subjects can be:
1.
up-titrated to PED50 at least once (dose group labelled “25/50”) or,
2.
maintained at PED25 for any reasons for the whole study (dose group labelled “25only”).
These 2 dose groups are mutually exclusive and add up to the total number of subjects in the 
SAF population.
A subject who is up-titrated to PED50 can remain at that dose level, but can also experience a 
reduction, an interruption or a further increase of the dose. For these reasons, all subjects up-
titrated to PED50 will also be categorized on the basis of the duration of their exposure to 
PED50 (see Section 6.5.3 for more details).
In particular, the following 2 dose groups (within the dose group “25/50”) are of interest: 
a.
Subjects up-titrated to PED50 for at least of 4 weeks (28 days) [dose group labelled 
“50min4w”],
b. Subjects up-titrated to PED50 for at least 2 weeks (14 days) [dose group labelled 
“50min2w”].
These two groups are not mutually exclusive and do not add up to the total number of 
subjects in the “25/50” dose group.
The following information on the study drug dose titration will be presented for the SAF:
●
Number and percent of subjects in each dose group (“25/50”, “25only”, “50min4w” 
and “50min2w”) at each follow-up visit (Visits 4, 5, 6, 7, 8, 9 and 10), 


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●
Number and percent of subjects with dose increases, decreases or no changes at each 
titration step (from Visit 4 to 6),
●
Unscheduled dose changes and interruptions (will be listed only).
Details of dose calculation and drug dispensing will be listed for each subject at each visit.
7.3.2
Exposure
The following information on drug exposure will be presented for the SAF:
●
Descriptive statistics for cumulative amount of the drug subject was exposed to and 
average daily dose; and
Duration of exposure will be summarized in the following ways.
●
Descriptive statistics
●
Exposure time will be categorized according to the following categories for both the 
titration period and the fixed dose period:
○
less than 14 days
○
at least 14 days, less than 28 days 
○
at least 28 days, less than 56 days
○
at least 56 days
○
Unknown
and by the following categories for the whole treatment period:
○
less than 84 days
○
at least 84 days, less than 168 days
○
at least 168 days, less than 252 days
○
at least 252 days, less than 364 days
○
at least 364 days
○
Unknown
Counts and percentages of subjects in each of these categories will be summarized for each 
dose group and overall for the SAF.
7.3.3
Treatment Compliance
Compliance with the dosing schedule will be summarized for subjects in the SAF.
The following summaries will be produced separately for the titration period (Visit 3 to 
Visit 7)*, for the period between Visit 7 and Visit 8, and for the whole treatment period:
●
Descriptive statistics 
●
Percent compliance will be categorized according to the following categories:
○
less than 70%
○
at least 70%, less than 80%
○
at least 80%, less than 120%
                                                
* Period from Visit 3 to Visit 7 was chosen because no drug dispensing and collecting data is obtained at Visit 4 
and Visit 6.


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○
at least 120%, less than 130%
○
at least 130%
○
Unknown.
A subject will be considered compliant if the calculated compliance over the whole treatment
period is at least 70% and is additionally at least 80% between Visit 7 and Visit 8.
Treatment compliance details, including all data relevant to the calculation, will be listed by 
for each subject by study visit and overall.
7.4
Analysis of Efficacy
Efficacy data will be summarized for the FAS and the PPS for all visits.
Baseline for efficacy variables is the last assessment made prior to the first intake of study 
drug at visit 3 (day -1).
Visit windows will be applied as defined in Section 7.11
7.4.1
Analysis of Primary Endpoint
7.4.1.1 Primary Analysis of Primary Endpoint/Estimand
The primary efficacy variable is the change from baseline in MCC at visit 8/week 24.
MCC and change from baseline in MCC at visit 8/week 24 will be summarized using 
descriptive statistics for continuous variable (n, mean, SD, min, median, and max) for the 
FAS. Missing MCC observations at visit 8/week 24 will be imputed using the Last 
Observation Carried Forward (LOCF) method.
In accordance with the definition of the estimand, the change from baseline in MCC at 
visit 8/week 24 will be analyzed using a paired t-test.  The following hypotheses will be 
tested at the 2-sided significance level 0.05:
H0: Mean change from baseline in MCC at visit 8/ week 24 is equal to zero 
H1: Mean change from baseline in MCC at visit 8/ week 24 in MCC is not equal to zero
The mean change from baseline estimate in MCC at visit 8/week 24, together with two-sided 
95% CI and the t-test p-value will be provided using the UNIVARIATE procedure in SAS.
Example SAS code is as follows:
proc univariate;
class time;
var   chgebc;
run;
In addition to the test of the null hypothesis, it will be assessed whether the lower bound of 
the two-sided 95% CI excludes 0 mL.  No adjustment for multiplicity will be made.
MCC at each visit and change from baseline in MCC at visit 8/week 24 (without LOCF) will 
be also plotted and listed for SAF and PPS.


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7.4.1.2 Secondary Analyses of Primary Endpoint
The following secondary analyses of the primary endpoint will be produced. 
7.4.1.2.1
Analysis without LOCF
The same analysis described in Section 7.4.1.1 will be repeated both for FAS without 
imputing for missing data and for PPS. 
7.4.1.2.2
Analysis using Baseline Value Carried Forward 
For cases were the MCC value is non-missing at baseline but missing at visit 8/week 24, the 
same analysis as described in Section 7.4.1.1 will be performed using a Baseline Observation 
Carried Forward (BOCF) approach.  For this analysis the baseline value will be imputed for 
the missing value at Visit 8/week 24.
This analysis will be performed for the All Enrolled Subjects. 
7.4.1.2.3
Analysis using Repeated Measures ANCOVA 
A repeated measures 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 method used in the primary model to assess the robustness of the findings. Data 
obtained at baseline (visit 3), at visit 5/week 4 and at visit 8/week 24 will be used. Since 
there are only 2 post-baseline time points in a 24 week period, the model will assume an 
unstructured covariance among the within subject repeated measurements.  If there is a 
convergence problem due to the unstructured covariance matrix, the unstructured covariance 
matrix will be replaced by the compound symmetry covariance matrix. This analysis will be 
performed both for FAS and PPS.
Example SAS code is as follows:
proc mixed;
class subject agegroup visit;
model change = visit agegroup agegroup*visit MCC_baseline;
repeated visit / subject=subject type=un;
lsmeans visit agegroup*visit / diff cl alpha=0.05;
run;
In this code the LSMEANS statement will produce least squares mean (LS mean) estimates 
for both age groups combined and also within each age group using a single analysis of 
covariance (ANCOVA) model.
Model fitting will be visually assessed.  A scatter plot of residuals versus predicted values,
along with histogram and normal probability plots will be produced.
7.4.1.2.4
Effect of age and gender
The p-value of the change from baseline to week 24 (with and without LOCF) will be 
assessed using an ANCOVA model including gender, age group and a gender by age group 
interaction as fixed effects and the baseline MCC as a covariate.
LS mean estimates, together with 95% CIs, will be provided.


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Example SAS code is as follows:
proc mixed;
class agegroup gender;
model change = agegroup gender agegroup*gender 
MCC baseline;
lsmeans gender agegroup*gender / diff cl alpha=0.05;
run;
In this code the LSMEANS statement will produce LS mean estimates for both age groups 
combined and also within each age group using a single ANCOVA model.
7.4.1.2.5
Nonparametric Analysis of Primary Endpoint
A Wilcoxon signed-rank test will be used as a sensitivity analysis. This test is produced by 
the UNIVARIATE procedure in SAS and ranks the absolute values of the differences 
between the paired data and calculates a statistic on the number of negative and positive 
differences.  Analysis will be done on the FAS, with (LOCF) and without imputation. 
Example SAS code is as follows:
proc univariate;
var chg;
run;
Box-Whisker plots of the change from baseline data will be presented for getting insight into 
the distribution of the data.
7.4.1.2.6
Overall Impact on Primary Endpoint
For the MCC, the 95% CI will be calculated for mean change from baseline per age group, 
per formulation, and per dosing regimen†(with and without LOCF), using an ANCOVA 
model. 
In addition to the hypothesis testing test, it will be assessed whether the lower bound of the 
two-sided 95% CI excludes 0 mL.
In addition, the nonparametric Wilcoxon signed-rank test on change from baseline data will 
be performed.  Only statistical hypothesis testing (p-values) will be performed.
Analyses will be performed on the FAS, with (LOCF) and without imputation.
7.4.1.2.7
Sensitivity Analysis of the Primary Estimand
As a sensitivity analysis for the estimand, the change from baseline to weeks 4 and 24 in 
MCC will be analyzed using a mixed-effect model repeated measures (MMRM) with week 
as fixed effect and baseline value and week by baseline interaction as covariates.  The 
contrast between baseline and week 24 will be the primary statistical inference obtained from 
this model.
                                                
† 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.


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The MMRM analysis will present the least square (LS) mean estimate, standard error (SE), 
and 2-sided 90% CI for change from baseline to each treatment week. The differences in the 
LS mean estimates will be used to obtain 1-sided P values for MCC at week 24 versus MCC 
at baseline.
Since there are only 2 post-baseline time points in a 24 week period, the model will assume 
unstructured covariance among the within subject repeated measurements.  If this is not 
feasible, an additional covariance structure will be considered the compound symmetry 
covariance matrix.
7.4.2
Analysis of Secondary Endpoints
Each of the secondary efficacy endpoints will be summarized with descriptive statistics (n, 
mean, SD, min, median, max for continuous variables; frequency and percentage for 
categorical variables) at each visit and for change from baseline at each visit when applicable.  
Each of the secondary efficacy endpoints will be plotted by visit change from baseline will 
also be plotted at each visit, if applicable.
The change from baseline for each continuous secondary efficacy endpoint (without LOCF) 
will be summarized and analyzed using the same t-test (see section 7.4.1.1) as for the primary 
efficacy endpoint.  The mean change from baseline estimate together with 95% CI and the 
relative p-value will be provided using the UNIVARIATE procedure in SAS.
For the analysis of Bladder Volume until first detrusor contraction (>15 cm H2O mL) 
expressed as MCC, a Wilcoxon signed-rank test will be used to compare Change from 
Baseline at Week 4 and at Week 24 (without LOCF) with 0.  
The following hypotheses will be tested:
H0: Medians of bladder volumes expressed as MCC are equal at Baseline and Week 24 
(Change from Baseline=0)
H1: Medians of bladder volumes expressed as MCC differ at Baseline and Week 24 
(Change from Baseline differs from 0)
The Wilcoxon signed-rank test p-value will be provided.
Example SAS code is as follows:
proc univariate;
class time;
var   chgebc;
run;
The medians (with first and third quartiles) of the Bladder Volumes as MCC will be 
presented for Baseline and Week 24. Furthermore, Box-whisker plots will be presented.
Additionally, a graph will present the Bladder Volumes as MCC (on the horizontal axis) 
using Detrusor Contraction as event indicator variable. The percentage of subjects will be 
shown on the vertical axis. Baseline and week 24 values will be overlaid on the same graph.


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Example SAS code is as follows (where ‘Status’=0 if the value is censored, and 1 otherwise):
ods trace on/listing;
ods output ProductLimitEstimates= RisKNumbers;
proc lifetest data=km     atrisk plots=survival(cb=hw
atrisk) outsurv=s1;
time change * Status(0);
strata visit ;
run;
ods trace off;
Separate analyses will be performed including and excluding subjects who had censored 
change from baseline.
All analyses of secondary endpoints will be produced for subjects in the FAS.
CGI-C and acceptability results will be tabulated per time point of assessment.
7.4.3
Analysis of Exploratory Endpoints 
Each of the exploratory efficacy endpoints and changes from baseline will be summarized 
and plotted by visit.
The change from baseline for each continuous exploratory endpoint (without LOCF) will be 
summarized and analyzed using the same t-test (see section 7.4.1.1) as for the primary 
efficacy endpoint.
All analyses of exploratory endpoints will be produced for subjects in the FAS.
The data will be summarized with descriptive statistics according to the nature of variables
(n, mean, SD, SEM, 95% CI, min, median, max for continuous; frequency and percentage for 
categorical) at each visit and for change from baseline.
A listing will be presented for subjects with a filling volume of >40 cm H2O detrusor 
pressure at week 24. Listing will, among other, present the MCC and MCC expressed as % of 
EBC. 
7.4.4
Analysis of Other Variables 
There are no other efficacy endpoints in this study.
7.4.5
Sensitivity Analysis
Due to measurement mistakes it was found that for some assessments negative values were 
recorded in e-diary for the weight of urine.  This affected the following parameters:
●
Average catheterized volume per catheterization
●
Maximum catheterized volume
●
Maximum catheterized daytime volume
●
Average morning catheterized volume (based on first catheterization after subject woke 
up)
●
Total catheterized volume per day


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●
Average morning catheterized volume for subjects with no leakage during the sleeping 
time (based on first catheterization after subject woke up)
●
Average morning catheterized volume for subjects with leakage during the sleeping time 
(based on first catheterization after subject woke up)
As a consequence of this measurement mistake a sensitivity analysis will be performed for 
these parameters, which will exclude all subjects with at least 1 negative value.
For each visit, the change from baseline for each efficacy endpoints will be summarized and 
analyzed using the same t-test (see section 7.4.1.1) as for the primary efficacy endpoint. The 
mean change from baseline estimate together with 95% CI and the relative p-value will be
provided using the UNIVARIATE procedure in SAS.
7.5
Analysis of Safety
Unless specified otherwise, safety data will be summarized for the SAF.
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 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.
Summaries will be provided for the SAF unless otherwise specified, whereas listings will be 
provided for the All Allocated Set. Visit windows will be applied to all data except AEs, as 
defined in Section 7.11.3
Summaries and listings of SAEs and Serious TEAEs include SAEs upgraded by the sponsor 
based on review of the Sponsor’s list of Always Serious terms if any upgrade was done.
7.5.1
Adverse Events
The MedDRA coding dictionary will be used to summarize the AEs in this study by SOC, 
HLT and PT.
An overview table will include the following details:
●
Number of TEAEs and number and percentage of subjects with TEAEs
●
Number of drug-related TEAEs and number and percentage of subjects with drug-
related TEAEs
●
Number of serious TEAEs and number and percentage of subjects with serious 
TEAEs,
●
Number of serious drug-related AEs and number and percentage of subjects with 
serious drug-related AEs
●
Number of TEAEs leading to permanent discontinuation of study drug and number 
and percentage of subjects with TEAEs leading to permanent discontinuation of study 
drug, 


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●
Number of drug-related TEAEs leading to permanent discontinuation of study drug 
and number and percentage of subjects with drug-related TEAEs leading to 
permanent discontinuation of study drug,
●
Number of TEAEs leading to death and number and percentage of subjects with 
TEAEs leading to death,
●
Number of drug-related TEAEs leading the death and number and percentage of 
subjects with TEAEs leading to death
●
Number and percentage of subjects who died.
The number and percentage of AEs which started after Visit 1 and before the first dose of 
study drug will be summarized by SOC, HLT (only for the table presenting TEAEs) and PT, 
as well as by worst intensity (mild, moderate or severe) using SAF.  
All summaries will be sorted alphabetically by SOC and within SOC by descending 
frequency of PT for all subjects combined (overall), or alphabetically by SOC and within 
SOC by HLT (descending frequency) and within HLT by descending frequency of PT for all 
subjects combined (overall), the latter only for the table presenting TEAEs.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized using SAF. Summaries will be provided for:
●
TEAEs (by SOC, HLT and PT)
●
Drug-related TEAEs
●
Serious TEAEs
●
Drug-related serious TEAEs
●
TEAEs leading to permanent discontinuation of study drug
●
Drug-related TEAEs leading to permanent discontinuation of study drug 
●
TEAEs leading to death
●
Drug-related TEAEs leading to death
●
TEAEs excluding serious adverse events that equal or exceed a threshold of 5.0%, 
regardless of dose
●
TEAEs including serious adverse events that equal or exceed a threshold of 2.0%,
regardless of dose
The number of TEAEs and the number and percentage of subjects with TEAEs as classified 
by SOC and PT will also be summarized by worst severity (mild, moderate, severe), by worst 
relationship to study drug (not related, possibly related, probably related) and by time 
intervals categories. In the subject count, if a subject has multiple TEAEs with the same SOC 
or PT, but with differing severity, then the subject will be counted only once with the worst 
severity, however, if any of the severity values are missing then the subject will be counted 
only once with missing severity. Similarly, in the subject count, if a subject has multiple 
TEAEs with the same SOC or PT, but with differing relationship, then the subject will be 
counted only once with the highest degree of relationship, however, if any of the relationship 
values are missing then the subject will be counted only once with missing relationship.  If 
category for the same AE is missing, missing should be used, else use maximum relationship. 


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Time intervals are based on time from first dose of study drug and will be categorized 
according to the following categories:
●
less than 2 weeks (i.e. less than 14 days);
●
at least 2 weeks, less than 4 weeks (i.e. at least 14 days and less than 28 days);
●
at least 4 weeks, less than 8 weeks (i.e. at least 28 days and less than 56 days);
●
at least 8 weeks, less than 12 weeks (i.e. at least 56 days and less than 84 days);
●
at least 12 weeks, less than 24 weeks (i.e. at least 84 days and less than 168 days);
●
at least 24 weeks, less than 36 weeks (i.e. at least 168 days and less than 252 days);
●
at least 36 weeks, less than 52 weeks (i.e. at least 252 days and less than 364 days); 
and
●
at least 52 weeks (i.e. at least 364 days).
At risk denominators for summaries by time interval for onset and by time interval for 
prevalence will be the same across all AE categories (Overall, SOC and PT), i.e. a subject is 
at risk in all time period denominators up to EOS.
At risk denominators for summary by time intervals for first onset will depend on AE 
category and time interval according to the following algorithm:
●
For each subject, day of first AE onset is determined for each AE category (Overall, 
SOC and PT).
●
Within each AE category, a subject is at risk in all time intervals denominators up to 
the first AE onset.
If there is no first AE then the subject will be included in all time intervals up to EOS.  
Drug related TEAEs will be presented in a similar way.
AEs of interest are described in Section 6.2.2, and will be summarized for PT only (no SOC).
7.5.1.1 Adverse Events of Interest 
For each of the TEAEs of interest, the frequency of TEAEs will be summarized by PT.
7.5.2
Clinical Laboratory Evaluation
All laboratory data will be summarized using SAF. 
The baseline visit is the last measurement taken prior to initial study drug administration.  
Quantitative clinical laboratory variables, i.e. hematology, biochemistry, and urinalysis will 
be summarized separately using mean, standard deviation, minimum, maximum and median 
at each visit. Additionally, a within-subject change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized in the same way.
Values lower than the limit of quantification (LOQ) for laboratory parameters will be set to 0 
for the calculation of descriptive statistics.
Each laboratory result will be classified as low (L), normal (N), or high (H) at each visit 
according to the laboratory supplied reference ranges. The number and percentage of subjects 


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below and above reference range will be summarized at each visit according to the laboratory 
supplied reference ranges.
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented at each visit.
Hematology and biochemistry results will be collected at visit 1/screening, visit 3/baseline, 
visit 7/week 12 and visit 10/EoT visit. Shifts from Baseline to Week 12 and EoT will be 
summarized by two types of shift tables:
●
Shift tables of reference range (low, normal, high) changes from baseline to Week 
12 and EOT, and.
●
Summary shifts of reference range changes from baseline to Week 12 and EOT. 
These shifts are categorized as:
○“Shift to Low” : shift from normal or high to low
○“Shift to High”: shift from normal or low to high
○“Categorized Increase”: shift from low to normal or from normal to high
○“Categorized No Change”: value stays in the same reference range
○“Categorized Decrease”: shift from high to normal or from normal to low.
All clinical laboratory data collected during the study and variables derived from it will be 
listed using SAF.
7.5.2.1 Liver function tests
The following potentially clinically significant criteria for liver tests – defined as Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the 
investigational period will be used. 
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
ALT or AST
> 3xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN
ALT and/or AST AND Total Bilirubin *
(ALT and/or AST > 3xULN) and 
total bilirubin > 2xULN
ALT and/or AST AND Alkaline Phosphatase
ALT and/or AST > 3xULN AND Alkaline
AND Total Bilirubin *
Phosphatase < 2xULN AND Total Bilirubin 
> 2xULN
* 


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The number and percentage of subjects with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the investigational period will be presented
7.5.3
Vital Signs
7.5.3.1 Clinic Measurement
Values and changes from baseline for vital signs (SBP, DBP, pulse rate and measurement for 
temperature) and percentiles of SBP, DBP and Pulse Rate compared to age and height norms 
(see section 10.6 and 10.7 for Blood Pressures and section 10.5 for Pulse Rate) will be listed 
and summarized at each scheduled visit using mean, standard deviation, minimum, maximum 
and median. The number and percentage of subjects outside reference ranges will be shown.
For shifts from baseline to each post-baseline visit the categories used for presentation were 
obtained from the Fourth Report (NIH, 2005), considered primary presentation, and from the 
2017 (American Academy of Pediatric) Clinical Practice Guidelines, considered supportive
presentation.
Using data from Fourth Report
For each scheduled post-baseline visit, shift tables from baseline to each post-baseline visit 
will be created with respect to the changes from normal blood pressure (<90th percentile): to 
prehypertension (for children between 90th to 95th percentile, or for adolescents  if
≥120/80 mmHg, but less than the 95th percentile); to stage 1 (95th to 99th percentile + 5
mmHg); and to stage 2 (>99th percentile + 5 mmHg), using cut-points reported by the Fourth 
(4th) Report (NIH, 2005).  For the cut-off points (90th, 95th and 99th percentiles) see Appendix 
10.1 and Appendix11.1.
Using data from 2017 Clinical Practice Guidelines
For each scheduled post-baseline visit, shift tables from baseline to each post-baseline visit 
will be presented with respect to the changes from normal blood pressure to elevated blood 
pressure; stage 1 HTN, or stage 2 HTN, see Table 12  For the cut-off points (90th, and 95th
percentiles) see Appendix10.2 and Appendix 11.2. 
Table 12
Definitions of Blood Pressure Categories and Stages
Children Aged 1–<13 years
Adolescents Aged ≥13 years
Normal BP: <90th percentile 
Normal BP: <120/<80 mm Hg
Elevated BP: ≥90th percentile to <95th 
percentile or 120/80 mmHg to <95th percentile 
(whichever is lower)
Elevated BP: 120/<80 to 129/<80 mmHg
Stage 1 HTN: ≥95th percentile to <95th 
percentile + 12 mmHg, or 130/80 to 139/89 
mmHg (whichever is lower)
Stage 1 HTN: 130/80 to 139/89 mmHg
Stage 2 HTN: ≥95th percentile + 12 mmHg, or 
≥140/90 mmHg (whichever is lower)
Stage 2 HTN: ≥140/90 mmHg
Table obtained from: 2017 American Academy of Pediatric Clinical Practice Guidelines, Table 3
Note: the age classification into children and adolescents in the Clinical Practice Guidelines (2017) differs 
from the definition used in the protocol




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7.5.3.2 Self-Measurements
Similarly to the clinic vital signs measurements (section 7.5.3.1), values and changes from 
baseline for self vital signs measurements (SBP, DBP, pulse rate) and percentiles of self-
measurements SBP and DBP compared to age and gender norms will be listed and 
summarized at each visit using mean, standard deviation, minimum, maximum and median. 
The number and percentage of subjects outside reference ranges will be shown.
For shifts from baseline to each post-baseline visit the categories used for presentation were 
obtained from Stergiou [2007], considered primary presentation, and from the 2017 
(American Academy of Pediatric) Clinical Practice Guidelines, considered supportive
presentation.
Using data from Stergiou [2007]
For each scheduled post-baseline visit, shift tables from baseline to each post-baseline visit 
will be created with respect to the changes from normal blood pressure (≤95th percentile) to 
abnormal blood pressure  (>95th percentile), using cut-points reported in Table 14
Table 14
Systolic and Diastolic Home Blood Pressure Values
Height 
(cm)
Boys
Girls
n
50th a
95th a
n
50th a
95th a
120–129
23
105/64
119/76
36
101/64
119/74
130–139
51
108/64
121/77
51
103/64
120/76
140–149
39
110/65
125/77
61
105/65
122/77
150–159
41
112/65
126/78
71
108/66
123/77
160–169
45
115/65
128/78
148
110/66
124/78
170–179
91
117/66
132/78
46
112/66
125/79
180–189
57
121/67
134/79
7
114/67
128/80
a Values are systolic/diastolic blood pressure (Stergiou, 2007)
Using data from Clinical Practice Guidelines [2017]
For each scheduled post-baseline visit, shift tables from baseline to each post-baseline visit 
will be presented with respect to the changes from normal blood pressure to elevated blood 


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pressure; stage 1 HTN, or stage 2 HTN, see Table 12  For the cut-off points (90th, and 95th
percentiles) see Appendix10.2 and Appendix 11.2. 
Potentially Clinically Relevant (PCR)
 
 
 
 
 
 
 
 
 
 
 
 
7.5.4
Height and Weight
Height, weight and BMI, and in addition, z-scores and percentiles compared to age and sex 
norms, will be listed and summarized overall for the SAF for each visit using mean, SD, 95% 
CI of the mean, median, minimum, and maximum.
The change from baseline to EoT in the z-score will additionally be summarized by 
displaying the number and percentage of subjects with changes in each of the following 
categories: <-1.0, >=-1.0 to <-0.5, >=-0.5 to <=0.5, >0.5 to <=1.0, >1.0.


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The summary statistics for percentiles will be calculated by transforming the relevant z-score 
statistic to a percentile of the standard normal curve, e.g. the mean percentile will be the 
transformed mean z-score, rather than the mean of the individual percentiles. No estimate of 
SD will be calculated for the percentiles, and no summary statistics will be generated for the 
change from baseline in percentile.
7.5.5
Electrocardiograms (ECGs)
ECG variables (QT, QTcF, HR, PR, QRS and RR) will be listed and summarized using mean, 
standard deviation, minimum, maximum and median at each treatment visit, including 
changes from baseline.
For categorical ECG variables reported by the local investigator, the worst non-missing value
among the assessments will be used in the analyses. Number and percentage of subjects with 
normal, not clinically significant abnormal and clinically significant abnormal results as 
assessed by the local investigator for the 12 lead ECG will be tabulated at each visit. 
Abnormal results will be presented for a certain visit if abnormal interpretation was recorded 
for at least one of the ECGs taken during the measurements for the particular visit.
All abnormalities will be listed together with the respective abnormality code and description. 
For categorical ECG variables reported by the central laboratory, the worst non-missing 
value among the assessments will be used in the analysis. Number and percentage of subjects 
with abnormalities and number and percentage of subjects with normal and abnormal results 
as assessed by the central laboratory will be tabulated at each visit. Abnormal results will be 
presented for a certain visit if abnormal interpretation was recorded for at least one of the 
ECGs taken during the measurements for the particular visit.
Shift tables will be presented for changes from baseline at each visit including local 
interpretation categories. Shift tables will also be presented as above from baseline to worst 
post-baseline value during the treatment period. Similar shift tables will summarize Central 
Reader interpretation categories.
The corrected QT interval (i.e. QTcF) will be summarized for at each visit showing the 
number and percentage of subjects with a mean of the triplicate QTc values (ms) in each of 
the following categories: 
For the children category
●
> 440 ms
For the male adolescents category
●
> 450 ms
●
> 500 ms 
For the female adolescents category
●
> 480 ms
●
> 500 ms


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Note that these categories are cumulative in that subjects satisfying criterion for more 
extreme category will also be counted in each applicable less extreme category.
The corrected QT interval (i.e. QTcF) will also be summarized for each age group at each 
visit showing the frequencies of subjects with the following changes from baseline: <0, ≥0
and <30, ≥30 and <60, and ≥ 60 ms.
7.5.6
Pregnancies
A detailed listing of all pregnancies will be provided if any occur using All Screened Set.
7.5.7
Estimated Glomerular Filtration Rate and Upper Urinary Tract Ultrasound
Values and changes from baseline of plasma creatinine, plasma cystatin C and eGFR levels 
will be summarized together with the other Biochemistry variables (described in 
section 7.5.2). 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) using mean, standard deviation, minimum, maximum and median overall at each 
visit.
Number and percent of subjects with normal, not clinically significant abnormal and 
clinically significant abnormal ultrasound of the upper urinary tract results will be tabulated 
for overall at each visit. The results of the ultrasound of the upper urinary tract will be listed. 
Any clinically-significant abnormality should be recorded as an AE and will be included in 
the summaries of the AE tables.
7.6
Analysis of PK
7.6.1
Estimation of Pharmacokinetic Parameters
Pharmacokinetic data analysis will be performed by the GCMSL with mixed effects 
modeling using NONMEM (version 7.3 or higher, 
 
 USA). For the analysis, actual sampling times will be used.
Since the PK sampling is sparse and skewed towards the early phase of the profile with less 
information in the terminal phase, it is likely that the data from this study may be pooled with 
other pediatric pharmacokinetic data with richer sampling; this will support the model-based 
assessment of the following pharmacokinetic parameters for each subject:
●
Cmax, tmax, AUC24, Ctrough, CL/F, and Vz/F 
Additional pharmacokinetic parameters may be calculated based on the model used.  Further 
details of the derivation of the pharmacokinetic parameters are given in the PK DAP.
7.6.2
Statistical Analysis
Descriptive statistics (n, mean, SD, minimum, median, maximum, coefficient of variation 
[%CV], and geometric means) will be calculated for all plasma concentrations of mirabegron. 
Plasma concentration values below the limit of quantification (LOQ, 0.2 ng/mL) will be set 
equal to 0 in the calculation of summary statistics.


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Plasma concentration data in each time window (see Table 15) will be summarized by age 
category (children and adolescents) and the subjects’ treatment dose of mirabegron (PED25, 
PED50) within the age category.
Table 15
Time Windows for Summary of Plasma Concentration Data
Target time 
Actual Time
2 trough samples
Within 1 hour prior to dosing (on sampling day 1 and 2)
2 samples between 2 h and 5 h post-dose 
> 1 hour to 6 hours post-dose (with at least 1 hour in between the 
samples, on sampling day 2)
Note: Measurements from plasma concentrations outside the time windows will not be included in the 
summary of the plasma concentrations, but can still be considered for the derivation of pharmacokinetic 
parameters, which is based on the actual sampling time after study drug intake.
The following plots will be produced:
●
Mean (+/-SD) plasma concentration-time profiles (normal scale) 
●
Mean plasma concentration-time profiles (semi-log scale) 
●
Box plots of plasma concentration-time profiles (normal scale and semi-log scale)
●
Individual subject plasma concentration-time profiles (normal scale “spaghetti plots”) 
●
Individual subject plasma concentration-time profiles (normal scale and semi-log 
scale plots) 
The first two plots will be produced for the PK report.
Further details will be described in the TLF specifications.  
The pharmacokinetic analysis and results will be provided in a separate PK modeling report, 
which will supplement the CSR.
7.7
Analysis of PD
There are no PD data to be analyzed in this study.
7.8
Subgroups of Interest 
The primary efficacy endpoint will be summarized descriptively with and without LOCF 
(unless otherwise specified) using FAS for the following subgroups:
●
Age group (children vs. adolescents);
●
Racial subgroups;
●
Ethnicity (Hispanic or Latino / Not Hispanic or Latino)
●
Formulation (tablets vs. oral suspension);
●
Dosing regimen (“25/50” group vs. “25 only”, please refer to section 7.3.1)
●
NDO medication treatment received at screening/prior to start of washout (yes vs. 
no);
●
Stop of antimuscarinics medication specifically intended for NDO treatment (prior 
to study treatment) for lack of efficacy (yes vs. no [i.e., use of antimuscarinics 
stopped but for other reasons than for lack of efficacy]), if there are sufficient 
subject numbers;


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●
Excluding those subjects who had a positive urine culture at visit 3/baseline, 
visit 5/week 4, and/or visit 8/week 24 (without LOCF only), if there are sufficient 
subject numbers.
In addition, selected safety variables (all TEAEs and drug related TEAEs, vital signs, height 
and weight) will be summarized descriptively using SAF for the same subgroups.
Moreover, the selected safety variables, except for TEAEs, will be summarized with respect 
to age and sex-specific percentiles.
7.9
Other Analyses
There are no other analyses of data in this study.
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
No interim analysis of the data for this study is planned.
However, safety data will be reviewed by an independent Drug Safety and Monitoring Board 
(DSMB). Details are described in the DSMB charter and the corresponding DSMB analysis 
plan.
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.11.1
Missing Data
Missing primary efficacy endpoint values will be handled by using the Last Observation 
Carried Forward (LOCF) method. No values at baseline and no data from more than 5 days 
after the last dose of study medication will be carried forward to post-baseline visits for the 
analysis of the primary efficacy endpoint on the FAS.
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are EoT values for certain safety variables (lab values, vital signs, and ECGs), the 
start and stop dates of AEs and concomitant treatments, the date of diagnosis of NDO, the 
diary dates and the times of wake up and go to bed. Listings will present the actual partial 
dates/times; imputed dates/times will not be shown but derived parameters (e.g. duration of 
an AE) will be flagged.
7.11.1.1 Imputation Rules for Missing Safety Variables
In case subject safety data (lab values, vital signs, or ECGs) at EoT (visit 10/week 52) is 
missing, the LOCF method will be used for the summaries of shift from baseline to EoT only.  
No values at baseline and no data from more than 5 days after the last dose of study 
medication will be carried forward to post-baseline visits. 
7.11.1.2 Imputation Rules for Diary Dates
Each item of diary data is collected with the corresponding page number of the diary on 
which it was recorded. This page number will be used to match “day” pages of the diary with 
the corresponding “night” pages. When the date for one of the two pages is missing, it will be 
imputed with the date from the other page.


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When the dates for both pages are missing, or when the dates are present but different, the 
dates will be queried prior to database hard lock.
The time of waking up and going-to-bed may be imputed when they are missing to enable
categorization of hour periods as “day time” or “night time”.
If the hour of the wake-up time is missing, the wake-up time will be imputed as occurring a  
little time prior to the first catheterization, e.g. if the first catheterization is recorded in the 
09:00-10:00 hour-period, then the hour of the wake-up time will be imputed as being “09:00”.  
If there is no catheterization before 12:00, then the wake-up time will not be imputed.
If the hour of going-to-bed time is missing, the going-to-bed time will be imputed as 
occurring a short time after the last catheterization , e.g. if the last catheterization is recorded 
in the 20:00-21:00 hour-period, then the hour of going-to-bed will be imputed as being 
“21:00”. If there is no catheterization before 24:00, then the going-to-bed time will not be 
imputed.
If the minutes of the wake-up time or going-to-bed time are missing, they will be imputed as 
“00:30”.
7.11.1.3 Imputation Rules for Adverse Events
If there are missing or incomplete onset dates of AEs, then a worst case scenario will be used
for the classification of AEs as TEAEs and for the calculation of the longest possible duration 
of the AE that is consistent with available information. The eCRF includes a checkbox that 
asks “If the onset date is the same day as study drug start date or if a complete onset date is 
unknown, please select one (of the following)” and the 2 options are:
3.
Onset before first dose of study drug
4.
Onset after first dose of the study drug
Let these 2 answers be referred to as Onset=Pre and Onset=Post respectively and also 
consider that the question may be unanswered (i.e. Onset=Missing).
Let the date of the first dose of study medication (not imputed) be DATEPOST, and the date of 
onset of the AE be DATEAE.
On the assumption that inconsistencies in the data (e.g. Onset=Post, yet the year of onset is 
too early for this to be possible) have already been corrected, the method for imputing 
missing parts of a partial AE start date is as follows:
●
When Onset=Pre, there will be no imputation of the AE onset date and the AE is not
considered a TEAE;
●
When Onset=Post, a worst case scenario will impute DATEAE to be the earliest date 
on or after DATEPOST which is compatible with the non-missing parts of the date;
●
When Onset=Missing, a worst case scenario will impute DATEAE as though 
Onset=Post. If no such date is possible (e.g. the year of the AE or the AE stop date are 
given and either are earlier than any part of the treatment period) then the AE is not
considered a TEAE  and no further attempt will be made to impute it.


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When imputing the missing parts of a partial AE stop date, the following steps will be 
followed in order:
●
If the year is unknown, the date will not be imputed and will be assigned a missing 
value;
●
If the month is unknown, then assign December;
●
If the day is unknown, then assign the last day of the month.
Imputation of start and/stop date should not result in having start dates after stop dates.  If 
start date is completely missing, set it to stop date, and vice-versa.
If the AE is ongoing, the stop date will remain missing.
7.11.1.4 Imputation Rules for NDO Diagnosis Onset Date
The following steps will be followed when the onset date of NDO diagnosis is partially 
missing:
●
Missing year, whether day and month are present or not: No imputations will occur;
●
Missing day, but month and year are present: the day will be imputed as the 15th day 
of the month;
●
Missing day and month, but year is present: the day and month will be imputed as 
30 June of the year;
●
If any such imputed date falls after the informed consent date, then the onset date will 
be taken as equal to the earliest informed consent date.
7.11.1.5 Imputation Rules for Start and End Dates for Concomitant Medications and 
Non-Medication Therapies
Start and stop dates for all concomitant medications and non-medication therapies are 
collected on the CRF. However, in case of missing or partial information in these dates, the 
following rules will be used:
If the start date is missing or partial:
●
If the entire date is missing, use the earliest date of informed consent;
●
If the year is missing, use the year of informed consent. If this makes the imputed date 
beyond the last visit date, reduce the year by 1;
●
If the month is missing, use January;
●
If the day is missing, use the first day of the month under consideration.
If the stop date is missing or partial:
●
If year or the entire date is missing, no imputation is performed;
●
If month is missing, use December;
●
If day is missing, use the last day of the month under consideration;
Imputation of start and/stop date should not result in having start dates after stop dates. 






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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
Draft 0.1
25-MAR-2016
NA
NA
Final 1.0
21-APR-2016
Set version to Final 1.0
Finalization of document
Final 2.0
04-May-2018
Whole document 
Minor textual updates/changes and typing 
errors are not mentioned 
Whole document 
SMIP is removed from the exploratory safety 
endpoints. All text related to SMIP is removed 
from the document
List of Tables
List of Tables was added
List of abbreviations
List is updated
Section 6.1.3.1.3
The calculation of bladder compliance is 
updated according to the central reviewers’ 
algorithm. 
Sections 6.2.1.1 and 
6.2.1.2
Calculations of average vital signs are updated 
to align with the DSMB SAP.
Sections 7.5.3.1 and 
7.5.3.2
Normal blood pressure ranges are updated to 
align with DSMB SAP.
Section 1
Text is updated to include CT206.
Text on PK Analysis is updated.
Table 1
Table 1 is updated according to protocol of 
CT206.
Section 5.3
Second bullet updated: 
New text:  
Had a valid (as by the central reviewer’s 
assessment) nonmissing MCC measurement at 
baseline and at a post-baseline visit for the 
primary efficacy endpoint.
Old text: 
Provided both valid baseline and at least 1 
postbaseline value for the primary efficacy 
endpoint (MCC)
Section 5.4.1
Text on “Prohibited Medication” is updated 
with respect to Botox. 
New text (added text in italic): 
“Except for Botox which is not allowed if 
taken from <4 months before screening 
and/or during the whole study period.”
Section 5.4.1
Eligibility Deviations: the 2 bullets are
updated
Section 6.1
Urodynamic 
assessments
Parameter “MCC expressed as percentage of 
Expected Bladder Capacity (EBC)”added plus 
additional text to describe the parameter
Section 6.1  
Questionnaires
Text from sentence below is deleted: “to be 
completed by the subject or the subject’s 
parent/caregiver” 
Section 6.1  
Questionnaires
Text now reads: Questionnaires (i.e., PIN-Q, 
PGI-S and the Acceptability Questionnaires) 


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Version
Date
Changes
Comment/rationale for change
will be provided via the e-diary.
Section 6.1  
Questionnaires
Sentence “Clinically relevant adverse changes 
will be recorded as an AE.” just above “The 
primary and secondary variables will be ….”
is deleted
Section 6.1
Table 2 and Table 3 are updated with respect 
to deleted and added variables.
Section 6.1.2
Section on Estimand is added
Section 6.1.3.2.1 –
6.1.3.2.4
Text:
“…2 days are concurrent” is replaced by 
“…2 days are consecutive”
Note: in version 1.0 it was section 6.1.2.2.1 –
6.1.2.2.4
Section 6.1.3.2.2 and 
6.1.3.2.3
Text “An alternative version of this variable 
will be calculated as the maximum of all the 
daytime values recorded over the two 
measuring days.” is deleted. 
Note: In version 1.0 it was section 6.1.2.2.2 
and 6.1.2.2.3
Section 6.1.3.2.5 and 
6.1.3.2.6
Section title now reads: Mean number of 
leakage episodes per day (day and night time)
(weekend diary)
In title header “day and night time” is 
presented instead of “night time” 
Note in version 1.0 it was section 6.1.2.2.5 
and 6.1.2.2.6
Section 6.1.3.3.1
Text on items of PIN-Q is updated
Note in version 1.0 it was section 6.1.2.3.1
Section 6.1.3.3.5
Section on Acceptability (for oral suspension) 
is added
Section 6.1.4.2.1
Section is added to describe MCC expressed 
as percentage EBC
Section 6.1.4.2.3
Last sentence: “total catheterized volume” 
instead of “maximum catheterized volume”
Note in version 1.0 it was section 6.1.3.2.2
Section 6.1.4.2.6
Section is added to describe “Percentage of 
Catheterizations without Intermittent Leakage 
Accident”
Section 6.2
Table 5  footnote added 
Section 6.2.1.2
As second sentence added: “Additional SBPM 
will be 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.”
Section 6.2.1.4
Table 7 is updated, now based on Fleming et 
al. [2011], instead of on Ostchega et al. [2011]
Section 6.2.2
Timeframe for defining a TEAE is clarified.


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Version
Date
Changes
Comment/rationale for change
AEs of interest: First bullet (CV), the 
following text is added for clarification: 
“(Note: these 3 CV events will be analyzed 
combined and separately)”
Section 6.2.3
Table 9  
“Estimated glomerular filtration rate 
(Larsson)” is replaced by
“Estimated glomerular filtration rate 
(Larsson, modified Schwartz and Cockcroft-
Gault)”
Section 6.5.4
Text on “Suspension Compliance” is added
Section 7.2.1
Wash out failures summary is removed as 
washout failure is not defined in the protocol.
Follow-up summary is replaced by end of 
treatment summary.
Analysis Sets are added.
Text added with respect to a listing of all early 
withdrawals and a listing of screen failures.
Section 7.2.3
Updated countries participating in the study 
and added text below this paragraph to explain 
that countries may be added to the list
Section 7.4.1.1
The following text is added at end of section: 
“MCC at each visit and change from baseline 
in MCC at visit 8/week 24 (without LOCF) 
will be also plotted and listed for SAF and 
PPS.”
Section 7.4.3
The following text is added at end of section: 
“A listing will be presented for subjects with a 
filling volume of >40 cm H2O detrusor 
pressure at week 24. Listing will, among 
other, present the MCC and MCC expressed 
as % of EBC.”
Section 7.4.5
Section on “Sensitivity analysis” is added. 
Section was added to investigate the effect of 
the urine measurement mistakes made.
Section 7.5
SAEs upgraded by the Sponsor is added. This 
was an omission in the previous version. Text 
added with respect to summarizing safety 
parameters with respect to height- and sex-
specific percentiles. Height will be 
summarized with respect to age- and sex-
specific percentiles.
Section 7.5
Text added: “Subgroup presentations 
regarding age (children and adolescents), 
formulation (tablets and suspension) and 
dosing regimen (PED25 and PED50) will be 
tabulated for a number of safety parameters.
Added text at end of Section “For any of the 
subgroups specified, at least 10 subjects by 
stratum are required.”.


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Version
Date
Changes
Comment/rationale for change
Section 7.5.1
Number and percentage of subjects who 
died” instead of “Number of Deaths”.
Section 7.5.2.1
Text on “Liver Function Tests” is updated
Sections 7.5.3.1 and 
7.5.3.2
Text on PCR for SBP and for DBP is updated
Text on prehypertension is updated
Section 7.6.2
Table 15 is updated to reflect the sampling 
strategy
Section 9
List of References is updated.
Section 10.1
List of In- and Exclusion criteria is updated 
according to protocol of 206 study”.
Section 10.14
List of Key Contributors and Approvers is 
updated
Final 3.0
21-May-2019
Whole document
Typos were corrected
Introduction
Introduction was updated to reflect it is the 
SAP for 206A. Reference to EU PIP, EMEA 
Decision, and US Written Request was added.
Section 3.2 and 7.2.3
Deleted reference to USA
Section 6.1
Full + Empty Bladder Pressure is deleted
Section 6.1, Table 2 
and Table 3
Tables are updated to show that change from 
baseline in MCC expressed as % of EBC is 
analyzed at Week 4 and Week 24.
Section 6.1.2 
Title updated: Estimand instead of Estimator 
and 1 sentence added: “Difference of MCC at 
visit 8/week 24 (or prior, due to study drug 
discontinuation) compared to baseline is the 
primary estimator.”
Text was added why the “de facto” estimand 
was not chosen for this study.
Last sentence of his section: to impute was 
changed by “to handle” 
Section 6.1.3.2.8 (new)
Added section on identification of leakage 
during sleeping time
Section 6.1.3.2.8
New section added for clarification 
“Identification of leakage during sleeping 
time”
Section 6.2.2
AEs of Interest: 
Deleted is: Thermogenesis (brown fat).
Added are: Seizure: Syncope; Fetal disorders 
after exposure during pregnancy; and 
Concomitant treatment with cytochrome P450 
(CYP) 2D6 substrates with narrow therapeutic 
indices or individually dose-titrated.
Last sentence of Section 6.2.2: text “and AEs 
related to mirabegron” is deleted 
Section 6.5.4
Compliance text was updated
Section 7.2.1
A table was added which presented the 
number of subjects screened under  each 
protocol version
Section 7.2.2
PD4: “excluded” instead of “prohibited” 


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Version
Date
Changes
Comment/rationale for change
concomitant medication
Section 7.2.3
Added Analysis Set (SAF) for summary of 
Medical History data.
Section 7.3.3
Titration period: Visit 3 to Visit 7 instead of 
Visit 4 to Visit 6
Section 7.4.1.1
SAS procedure TTEST was replaced by 
UNIVARIATE
Section 7.4.1.2.6
Text was updated, no pooling of data from 
206 and 206A and statistical method adapted. 
Section 7.4.5
Added to Average morning catheterized 
volume: once “for subjects with no leakage 
during the sleeping time” and “for subjects 
with leakage during the sleeping time”
Section 7.5.1
AE will be summarized by SOC, HLT and PT 
instead of by SOC and PT for “All TEAEs” 
table only
Section 7.5.1.2
Second paragraph is deleted
Section 7.5.2.1
Old text replaced by standard text from SAP 
template
Section 7.5.3.1
In addition to shift tables referencing to 
“Fourth Report” also shift table will be 
presented based on a more recent reference: 
“2017 American Academy of Pediatric 
Clinical Practice Guidelines”, based on FDA 
request.
Results based on Fourth Report are considered 
primary, results based on other reference are 
considered secondary.
Additional table (Table 12) was inserted. 
Text updated for clinical measurements and 
home measurements (same lay-out for both)
Section 7.5.3.1
For presenting the number of subjects with PR 
values below or above the normal range, the 
normal range is defined.
Footnote was added to Table 12 to explain 
that the age classification into children and 
adolescents in the Clinical Practice Guidelines 
(2017) differs from the definition used in the 
protocol
Section 7.6.2
Mean plasma concentration-time profiles only 
on semi-log scale.
Added: Box plots of plasma concentration-
time profiles (normal scale and semi-log 
scale). And text that “First 2 plots will be 
produced for PK report.”
Section 7.8
Ethnicity was added as subgroup based on 
request from FDA.
Sentence “For any of these subgroups, at least 


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Version
Date
Changes
Comment/rationale for change
10 subjects by stratum are required.” was 
deleted.
Section 7.11.3
Title of table 16 was adapted and footnote was 
added to the table for clarification of visit 10.  
Two sentences were added at end of section: 
one to clarify that for the diary data the labels 
will not be used for analysis, and another one 
to explain for exposure data the assignment of 
study period 
Table 13 (new)
Table is added with data from Stergiou 2007 
reference
REFERENCES
Reference added: “2017 American Academy 
of Pediatric Clinical Practice Guidelines”
Section 10: 
Appendices 
Numbering has changed
Section 10.1
Exclusion criteria are re-numbered, starting 
now at 1. To be in line with numbering in 
Section 5.4.1
Section 10.3, 
Appendix 3.2
Section is deleted
Sections 10.10 and 
10.11
Tables with results for males and females 
from “2017 American Academy of Pediatric 
Clinical Practice Guidelines” reference are 
included
Section 10.14 
List of Key Contributors and Approvers is 
updated due to internal Astellas reorganization


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9
REFERENCES
2017 American Academy of Pediatric Clinical Practice Guidelines (Flynn JT, Kaelber DC, Baker-
Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood 
Pressure in Children and Adolescents. Pediatrics.2017;140(3):e20171904)
Bauer SB et al. 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 W.F. et al. PinQ: A valid, reliable and reproducible quality-of-life measure in children with 
bladder dysfunction, Journal of Pediatric Urology (2006) 2, 185-189
Cartwright PC, Coplen DE, Kogan BA,  et al. Efficacy and safety of transdermal and oral oxybutynin 
in children with neurogenic detrusor overactivity. J Urol 2009;82:1548-54.
Cockcroft DW, Gault MH (1976). Prediction of creatinine clearance from serum creatinine.
Nephron. 16 (1): 31–41. doi:10.1159/000180580. PMID 1244564.
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, et al. Efficacy and safety of oxybutynin in children with detrusor hyperreflexia secondary to 
neurogenic bladder dysfunction. J Urol 2005;173:221-25. 
Goessl C, Sauter T, Michael T, et al.  Efficacy and tolerability of tolterodine in children with detrusor 
hyperreflexia. Urology 2000;55:414-18.
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Kliegman RM, Stanton BMD, St. Geme J, Schor NF, Behrman RE. Nelson Textbook of Pediatrics, 
19th edition. Elsevier Science Health 2007
Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United States: Method 
and development. National Center for Health Statistics. Vital Health Stat 11(246). 2002
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
Ostchega Y, Porter KS, Hughes J, Dillon CF, Nwankwo T. Resting pulse rate reference data for 
children, adolescents and adults: United states, 1999-2008. National Health Statistics Report 
No.41 (August 2011)
Palmer LS, Richards I and Kaplan WE. Age related bladder capacity and bladder capacity growth in
children with myelomeningocele. J Urol 1997;158: 1261.r


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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.
Stergiou G, Yiannes N, Rarra V and Panagiotakos D. Home blood pressure normalcy in children and 
adolescents: the Arsakeion School study. J Hypertens 2007, 25:1375–1379
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3.
The Fourth Report on the diagnosis, evaluation, and treatment of high blood pressure in children and 
adolescents. 2005. U.S. Department of Health and Human Services, National Institutes of
Health National Heart, Lung, and Blood Institute. NIH Publication No. 05-5267. Originally
printed September 1996 (96-3790) Revised May 2005.
Available from: https://www.nhlbi.nih.gov/files/docs/resources/heart/hbp_ped.pdf


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10
APPENDICES
10.1
Appendix 1: Inclusion and Exclusion Criteria
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.
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 is exclusively using CIC (no voluntary voiding), starting 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:
○
Clearly premenarchal or in the judgment of the Investigator is premenarchal,
○
Documented surgically sterile,
●
Or, if of childbearing potential:
○
Agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration, 
○
And have a negative pregnancy test at visit 1/screening and at baseline,
○
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.  


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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 are NOT allowed.
Exclusion Criteria:
Subject are 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 or during the pre-
treatment period
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 higher
than 5 mmHg above the 99th percentile (stage 2 hypertension) or subject has a systolic or 
diastolic blood pressure that ranges from the 95th percentile to 5mmHg above the 99th


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percentile (stage 1 hypertension) which is not well-controlled. Percentiles are determined 
by sex, age, and height [The Fourth Report, 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.
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 
individually dose-titrated, 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 are NOT allowed.  






Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 95 of 160
10.4
Appendix 4:  Questionnaires
Appendix 4.1 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












Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 101 of 160
10.5
Appendix 5
Centiles of heart rate for normal children from 
birth to 18 years of age [Fleming et al, 2011]


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 102 of 160
10.6
Appendix 6  CDC Data Table of Stature-for-age Chart for Males


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 103 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 104 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 105 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 106 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 107 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 108 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 109 of 160
10.7
Appendix 7  CDC Data Table of Stature-for-age Chart for Females


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 110 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 111 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 112 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 113 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 114 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 115 of 160


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 116 of 160
10.8
Appendix 8  CDC Data Table of Weight-for-age Chart for Males
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
24
10.38209
10.64009
11.05266
11.78598
12.67076
13.63692
14.5834
15.18777
15.59648
24.5
10.44144
10.70051
11.1149
11.85182
12.74154
13.71386
14.66716
15.2763
15.68841
25.5
10.55847
10.81958
11.23747
11.98142
12.88102
13.8659
14.83332
15.45242
15.8717
26.5
10.6738
10.93681
11.35806
12.10889
13.01842
14.01623
14.99848
15.62819
16.05514
27.5
10.78798
11.0528
11.47728
12.23491
13.1545
14.16567
15.16351
15.8045
16.23967
28.5
10.90147
11.16803
11.59567
12.36007
13.2899
14.31493
15.32917
15.98214
16.42609
29.5
11.01466
11.28293
11.71368
12.4849
13.42519
14.46462
15.4961
16.16177
16.61508
30.5
11.12787
11.39782
11.8317
12.60983
13.56088
14.61527
15.66485
16.34395
16.8072
31.5
11.24135
11.513
11.95005
12.73523
13.69738
14.76732
15.83588
16.52915
17.00291
32.5
11.3553
11.62869
12.069
12.86144
13.83505
14.92117
16.00958
16.71773
17.2026
33.5
11.46988
11.74508
12.18875
12.9887
13.97418
15.07711
16.18624
16.91
17.40654
34.5
11.58521
11.8623
12.30948
13.11723
14.11503
15.23541
16.36612
17.10619
17.61495
35.5
11.70137
11.98046
12.43132
13.24721
14.2578
15.39628
16.5494
17.30646
17.82797
36.5
11.81842
12.09962
12.55436
13.37875
14.40263
15.55987
16.73623
17.51093
18.0457
37.5
11.93639
12.21984
12.67868
13.51197
14.54965
15.7263
16.9267
17.71965
18.26818
38.5
12.05529
12.34115
12.80431
13.64693
14.69893
15.89565
17.12085
17.93265
18.49539
39.5
12.17512
12.46354
12.93128
13.78366
14.85054
16.06797
17.3187
18.14992
18.72731
40.5
12.29587
12.58701
13.05959
13.92218
15.00449
16.24326
17.52025
18.37141
18.96385
41.5
12.41751
12.71154
13.18923
14.0625
15.16078
16.42153
17.72545
18.59705
19.20492
42.5
12.54001
12.8371
13.32017
14.20458
15.3194
16.60273
17.93424
18.82675
19.45041
43.5
12.66334
12.96366
13.45238
14.3484
15.4803
16.78682
18.14654
19.06041
19.70017
44.5
12.78746
13.09119
13.58581
14.49391
15.64343
16.97373
18.36226
19.29789
19.95407
45.5
12.91234
13.21963
13.72043
14.64105
15.80873
17.16336
18.58128
19.53907
20.21195
46.5
13.03792
13.34895
13.85618
14.78977
15.9761
17.35564
18.80348
19.78381
20.47366
47.5
13.16419
13.47911
13.99301
14.93998
16.14548
17.55044
19.02875
20.03197
20.73903
48.5
13.29111
13.61006
14.13086
15.09163
16.31677
17.74767
19.25695
20.28339
21.00793
49.5
13.41864
13.74176
14.26968
15.24463
16.48986
17.9472
19.48794
20.53795
21.28018
50.5
13.54675
13.87418
14.40943
15.39892
16.66468
18.14892
19.7216
20.79548
21.55565
51.5
13.67543
14.00727
14.55004
15.55441
16.8411
18.3527
19.95779
21.05586
21.83419
52.5
13.80466
14.14102
14.69148
15.71103
17.01904
18.55842
20.19637
21.31896
22.11568
53.5
13.93441
14.2754
14.8337
15.86872
17.19839
18.76598
20.43722
21.58464
22.39999
54.5
14.06467
14.41037
14.97666
16.0274
17.37906
18.97524
20.68022
21.8528
22.68702
55.5
14.19544
14.54593
15.12032
16.18701
17.56096
19.1861
20.92526
22.12331
22.97667
56.5
14.32672
14.68205
15.26465
16.34748
17.744
19.39846
21.17222
22.3961
23.26885
57.5
14.4585
14.81872
15.40962
16.50877
17.92809
19.6122
21.421
22.67106
23.56349
58.5
14.59079
14.95595
15.55521
16.67081
18.11316
19.82724
21.67152
22.94813
23.86054


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 117 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
59.5
14.72359
15.09371
15.70139
16.83356
18.29912
20.04348
21.92369
23.22723
24.15995
60.5
14.85692
15.23202
15.84814
16.99698
18.48592
20.26086
22.17744
23.50833
24.46169
61.5
14.99078
15.37087
15.99546
17.16103
18.6735
20.47929
22.4327
23.79136
24.76575
62.5
15.1252
15.51027
16.14334
17.32567
18.8618
20.69871
22.68943
24.07632
25.07212
63.5
15.26018
15.65023
16.29176
17.49088
19.05077
20.91907
22.94758
24.36317
25.38081
64.5
15.39575
15.79076
16.44074
17.65664
19.24037
21.14031
23.20712
24.65192
25.69185
65.5
15.53193
15.93186
16.59026
17.82293
19.43058
21.36242
23.46802
24.94257
26.00527
66.5
15.66872
16.07356
16.74033
17.98974
19.62136
21.58534
23.73029
25.23514
26.32111
67.5
15.80617
16.21586
16.89096
18.15706
19.8127
21.80908
23.99391
25.52965
26.63944
68.5
15.94427
16.35879
17.04215
18.32489
20.00459
22.0336
24.2589
25.82615
26.96033
69.5
16.08306
16.50235
17.19393
18.49324
20.19703
22.25893
24.52527
26.12468
27.28386
70.5
16.22255
16.64657
17.34629
18.66211
20.39002
22.48505
24.79305
26.4253
27.6101
71.5
16.36276
16.79146
17.49926
18.83151
20.58357
22.712
25.06229
26.72807
27.93916
72.5
16.5037
16.93704
17.65285
19.00147
20.7777
22.93978
25.33302
27.03308
28.27115
73.5
16.64539
17.08332
17.80708
19.17199
20.97243
23.16845
25.6053
27.34039
28.60616
74.5
16.78785
17.23031
17.96197
19.34311
21.16779
23.39803
25.87919
27.6501
28.94432
75.5
16.93107
17.37804
18.11754
19.51485
21.36383
23.62858
26.15477
27.9623
29.28574
76.5
17.07507
17.52651
18.2738
19.68724
21.56058
23.86016
26.4321
28.27709
29.63055
77.5
17.21986
17.67574
18.43077
19.86032
21.75811
24.09284
26.71128
28.59457
29.97888
78.5
17.36543
17.82572
18.58848
20.03413
21.95645
24.32667
26.99239
28.91486
30.33083
79.5
17.5118
17.97649
18.74695
20.20871
22.15567
24.56175
27.27553
29.23806
30.68656
80.5
17.65895
18.12803
18.9062
20.38409
22.35584
24.79815
27.56081
29.56428
31.04617
81.5
17.80689
18.28036
19.06624
20.56032
22.55702
25.03598
27.84832
29.89365
31.4098
82.5
17.9556
18.43348
19.2271
20.73745
22.7593
25.27531
28.13817
30.22628
31.77756
83.5
18.10509
18.5874
19.3888
20.91553
22.96273
25.51626
28.43049
30.56228
32.14959
84.5
18.25535
18.74211
19.55136
21.0946
23.16742
25.75894
28.72538
30.90178
32.52599
85.5
18.40637
18.89763
19.71479
21.27471
23.37343
26.00344
29.02298
31.24489
32.90689
86.5
18.55813
19.05395
19.87913
21.45592
23.58086
26.24988
29.3234
31.59174
33.29238
87.5
18.71062
19.21107
20.04438
21.63828
23.78979
26.49839
29.62676
31.94243
33.68257
88.5
18.86385
19.369
20.21057
21.82185
24.00031
26.74907
29.9332
32.29708
34.07755
89.5
19.01778
19.52773
20.37771
22.00666
24.21251
27.00204
30.24283
32.65581
34.47742
90.5
19.17243
19.68727
20.54584
22.19278
24.42648
27.25743
30.55579
33.01871
34.88226
91.5
19.32776
19.84762
20.71496
22.38027
24.64231
27.51535
30.8722
33.38591
35.29215
92.5
19.48379
20.00878
20.88511
22.56917
24.8601
27.77593
31.19218
33.75749
35.70715
93.5
19.6405
20.17076
21.05629
22.75955
25.07992
28.03928
31.51586
34.13355
36.12732
94.5
19.79788
20.33357
21.22855
22.95145
25.30189
28.30554
31.84335
34.5142
36.55271
95.5
19.95594
20.4972
21.4019
23.14493
25.52607
28.5748
32.17478
34.8995
36.98338


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 118 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
96.5
20.11467
20.66168
21.57637
23.34005
25.75257
28.84718
32.51025
35.28955
37.41935
97.5
20.27408
20.82702
21.75198
23.53686
25.98146
29.12281
32.84988
35.68443
37.86065
98.5
20.43418
20.99322
21.92878
23.73542
26.21284
29.40179
33.19377
36.08419
38.30731
99.5
20.59497
21.16032
22.10678
23.93579
26.44679
29.68422
33.54202
36.4889
38.75932
100.5
20.75647
21.32832
22.28602
24.13801
26.68339
29.97021
33.89472
36.89862
39.2167
101.5
20.91869
21.49726
22.46654
24.34216
26.92273
30.25986
34.25197
37.3134
39.67943
102.5
21.08166
21.66716
22.64838
24.54828
27.16489
30.55326
34.61384
37.73327
40.14749
103.5
21.2454
21.83805
22.83157
24.75645
27.40995
30.85051
34.98041
38.15826
40.62087
104.5
21.40994
22.00997
23.01617
24.9667
27.65797
31.15169
35.35176
38.58841
41.09952
105.5
21.57532
22.18296
23.20222
25.17912
27.90904
31.45689
35.72793
39.02372
41.5834
106.5
21.74156
22.35705
23.38976
25.39375
28.16324
31.76618
36.10899
39.46421
42.07247
107.5
21.90873
22.5323
23.57885
25.61067
28.42064
32.07964
36.49499
39.90987
42.56665
108.5
22.07685
22.70876
23.76955
25.82993
28.6813
32.39734
36.88596
40.36069
43.06589
109.5
22.24599
22.88648
23.96192
26.05161
28.9453
32.71933
37.28193
40.81665
43.5701
110.5
22.4162
23.06551
24.15601
26.27576
29.21271
33.04569
37.68294
41.27773
44.0792
111.5
22.58754
23.24593
24.35189
26.50246
29.48359
33.37646
38.08898
41.74388
44.5931
112.5
22.76008
23.42779
24.54962
26.73177
29.758
33.7117
38.50008
42.21507
45.11169
113.5
22.93388
23.61117
24.74929
26.96376
30.03602
34.05144
38.91622
42.69124
45.63487
114.5
23.10902
23.79613
24.95096
27.19851
30.3177
34.39573
39.33741
43.17232
46.16253
115.5
23.28558
23.98277
25.1547
27.43609
30.60311
34.7446
39.76363
43.65825
46.69454
116.5
23.46364
24.17115
25.3606
27.67657
30.8923
35.09808
40.19484
44.14895
47.23077
117.5
23.64329
24.36137
25.56874
27.92001
31.18533
35.4562
40.63103
44.64432
47.77109
118.5
23.8246
24.55351
25.77921
28.16651
31.48225
35.81896
41.07214
45.14428
48.31536
119.5
24.00769
24.74766
25.99208
28.41613
31.78312
36.1864
41.51813
45.64872
48.86343
120.5
24.19264
24.94392
26.20745
28.66894
32.08799
36.55851
41.96894
46.15753
49.41515
121.5
24.37956
25.14238
26.42541
28.92502
32.3969
36.93529
42.42452
46.6706
49.97037
122.5
24.56855
25.34314
26.64604
29.18446
32.70991
37.31675
42.88478
47.1878
50.52892
123.5
24.75971
25.54631
26.86945
29.44731
33.02704
37.70287
43.34967
47.70901
51.09064
124.5
24.95315
25.75198
27.09573
29.71365
33.34835
38.09365
43.81908
48.23408
51.65537
125.5
25.14898
25.96027
27.32496
29.98357
33.67387
38.48906
44.29292
48.76288
52.22293
126.5
25.34731
26.17126
27.55726
30.25713
34.00363
38.88907
44.77111
49.29526
52.79314
127.5
25.54826
26.38509
27.7927
30.53439
34.33766
39.29366
45.25354
49.83107
53.36584
128.5
25.75195
26.60184
28.0314
30.81543
34.67599
39.7028
45.7401
50.37016
53.94084
129.5
25.95847
26.82163
28.27343
31.10032
35.01864
40.11642
46.23066
50.91236
54.51797
130.5
26.16796
27.04457
28.51891
31.38912
35.36562
40.5345
46.72512
51.45752
55.09704
131.5
26.38051
27.27076
28.76791
31.68189
35.71695
40.95697
47.22334
52.00546
55.67787
132.5
26.59626
27.50031
29.02052
31.97868
36.07263
41.38377
47.72519
52.55602
56.26029


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 119 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
133.5
26.81531
27.73332
29.27685
32.27955
36.43266
41.81484
48.23054
53.10903
56.84411
134.5
27.03777
27.96989
29.53696
32.58454
36.79704
42.2501
48.73924
53.66432
57.42915
135.5
27.26376
28.21013
29.80095
32.89371
37.16577
42.68947
49.25114
54.22171
58.01524
136.5
27.49337
28.45412
30.06888
33.20709
37.53881
43.13287
49.76611
54.78102
58.60219
137.5
27.72672
28.70197
30.34084
33.52472
37.91616
43.5802
50.28397
55.34208
59.18983
138.5
27.9639
28.95376
30.61689
33.84662
38.29777
44.03137
50.80458
55.9047
59.77799
139.5
28.20501
29.20958
30.8971
34.17281
38.68361
44.48627
51.32778
56.46873
60.3665
140.5
28.45015
29.4695
31.18151
34.5033
39.07364
44.94478
51.85339
57.03397
60.95519
141.5
28.69939
29.7336
31.4702
34.83811
39.46781
45.40679
52.38125
57.60024
61.5439
142.5
28.95283
30.00195
31.76319
35.17724
39.86604
45.87218
52.91119
58.16739
62.13246
143.5
29.21053
30.2746
32.06052
35.52066
40.26828
46.3408
53.44304
58.73522
62.72072
144.5
29.47257
30.55162
32.36224
35.86837
40.67444
46.81253
53.97661
59.30357
63.30853
145.5
29.739
30.83304
32.66834
36.22034
41.08443
47.28721
54.51174
59.87226
63.89573
146.5
30.00988
31.11891
32.97885
36.57653
41.49817
47.7647
55.04825
60.44112
64.48219
147.5
30.28525
31.40925
33.29378
36.9369
41.91555
48.24483
55.58594
61.00999
65.06776
148.5
30.56516
31.70409
33.6131
37.30138
42.33644
48.72744
56.12464
61.57871
65.65231
149.5
30.84962
32.00343
33.93681
37.66991
42.76073
49.21236
56.66416
62.1471
66.2357
150.5
31.13865
32.30727
34.26488
38.04241
43.18828
49.6994
57.20431
62.715
66.81782
151.5
31.43227
32.61561
34.59726
38.4188
43.61896
50.18839
57.74492
63.28226
67.39854
152.5
31.73046
32.92842
34.93391
38.79897
44.05259
50.67913
58.28578
63.84873
67.97776
153.5
32.03321
33.24567
35.27477
39.18281
44.48903
51.17143
58.82671
64.41424
68.55535
154.5
32.3405
33.56731
35.61976
39.5702
44.92809
51.66508
59.36752
64.97865
69.13122
155.5
32.65229
33.89329
35.96879
39.96099
45.3696
52.15987
59.90801
65.54182
69.70526
156.5
32.96852
34.22353
36.32176
40.35506
45.81336
52.65558
60.448
66.10359
70.27738
157.5
33.28913
34.55796
36.67857
40.75222
46.25917
53.152
60.98729
66.66382
70.84748
158.5
33.61404
34.89647
37.03908
41.15232
46.70681
53.64889
61.52569
67.22238
71.41549
159.5
33.94317
35.23896
37.40317
41.55516
47.15606
54.14603
62.063
67.77913
71.98133
160.5
34.27642
35.58531
37.77067
41.96056
47.60669
54.64318
62.59903
68.33393
72.5449
161.5
34.61365
35.93538
38.14143
42.3683
48.05847
55.1401
63.13359
68.88665
73.10614
162.5
34.95475
36.28902
38.51526
42.77818
48.51113
55.63653
63.66648
69.43717
73.66498
163.5
35.29956
36.64606
38.89198
43.18995
48.96443
56.13224
64.1975
69.98535
74.22134
164.5
35.64794
37.00634
39.27138
43.60337
49.4181
56.62696
64.72647
70.53106
74.77517
165.5
35.99969
37.36965
39.65325
44.01821
49.87187
57.12044
65.25318
71.07419
75.32641
166.5
36.35464
37.7358
40.03736
44.43419
50.32546
57.61241
65.77745
71.61461
75.87498
167.5
36.71259
38.10456
40.42347
44.85104
50.77859
58.10262
66.29907
72.15219
76.42083
168.5
37.07331
38.47571
40.81133
45.26849
51.23096
58.5908
66.81785
72.68681
76.9639
169.5
37.43658
38.849
41.20067
45.68625
51.68229
59.07667
67.33359
73.21836
77.50413


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 120 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
170.5
37.80215
39.22417
41.59121
46.10402
52.13226
59.55998
67.84611
73.7467
78.04146
171.5
38.16976
39.60097
41.98269
46.52151
52.58059
60.04046
68.3552
74.27172
78.57582
172.5
38.53916
39.97909
42.37479
46.9384
53.02696
60.51782
68.86067
74.7933
79.10716
173.5
38.91004
40.35826
42.76722
47.35437
53.47107
60.99182
69.36233
75.3113
79.63542
174.5
39.28212
40.73817
43.15967
47.76912
53.91261
61.46217
69.85999
75.82561
80.1605
175.5
39.65509
41.11851
43.55182
48.18232
54.35128
61.92862
70.35345
76.3361
80.68236
176.5
40.02863
41.49895
43.94334
48.59365
54.78677
62.3909
70.84252
76.84263
81.2009
177.5
40.40241
41.87917
44.3339
49.00279
55.21878
62.84876
71.32701
77.34509
81.71605
178.5
40.77608
42.25882
44.72317
49.40941
55.64701
63.30195
71.80674
77.84332
82.2277
179.5
41.14932
42.63757
45.1108
49.81318
56.07116
63.75019
72.2815
78.3372
82.73579
180.5
41.52175
43.01506
45.49646
50.21378
56.49096
64.19328
72.75113
78.82659
83.24017
181.5
41.89302
43.39093
45.8798
50.61091
56.90611
64.63096
73.21544
79.31134
83.74075
182.5
42.26275
43.76482
46.26048
51.00423
57.31634
65.063
73.67424
79.7913
84.23741
183.5
42.63058
44.13638
46.63815
51.39346
57.72139
65.48919
74.12736
80.26632
84.73
184.5
42.99612
44.50523
47.01247
51.77827
58.121
65.90932
74.57462
80.73625
85.21839
185.5
43.35899
44.87102
47.3831
52.15839
58.51492
66.32318
75.01586
81.20093
85.70242
186.5
43.71882
45.23338
47.74972
52.53352
58.90293
66.73059
75.4509
81.66019
86.18192
187.5
44.07523
45.59196
48.11199
52.90339
59.2848
67.13136
75.87959
82.11386
86.65673
188.5
44.42784
45.9464
48.46959
53.26773
59.66033
67.52534
76.30176
82.56177
87.12663
189.5
44.77629
46.29635
48.82222
53.6263
60.02932
67.91236
76.71726
83.00375
87.59143
190.5
45.1202
46.64147
49.16956
53.97886
60.39159
68.29229
77.12595
83.43962
88.05093
191.5
45.45922
46.98144
49.51134
54.32518
60.74699
68.665
77.52768
83.8692
88.50487
192.5
45.79301
47.31593
49.84727
54.66505
61.09537
69.03038
77.92233
84.29229
88.95303
193.5
46.12122
47.64464
50.17709
54.99828
61.4366
69.38833
78.30977
84.70871
89.39516
194.5
46.44354
47.96727
50.50055
55.3247
61.77057
69.73878
78.68987
85.11828
89.83098
195.5
46.75967
48.28356
50.81743
55.64414
62.09719
70.08164
79.06252
85.5208
90.26024
196.5
47.06932
48.59325
51.12752
55.95647
62.41639
70.41688
79.42763
85.91607
90.68264
197.5
47.37223
48.89609
51.43062
56.26158
62.72809
70.74445
79.78509
86.30392
91.0979
198.5
47.66815
49.19189
51.72656
56.55935
63.03228
71.06433
80.13483
86.68415
91.50571
199.5
47.95687
49.48044
52.0152
56.84971
63.32892
71.37652
80.47676
87.05657
91.90578
200.5
48.23819
49.76158
52.29642
57.13261
63.61802
71.68103
80.81082
87.42099
92.29779
201.5
48.51195
50.03518
52.57011
57.408
63.89959
71.97788
81.13696
87.77725
92.68144
202.5
48.778
50.30112
52.8362
57.67589
64.17367
72.26711
81.45512
88.12516
93.05643
203.5
49.03625
50.55931
53.09465
57.93627
64.44032
72.54879
81.76528
88.46456
93.42244
204.5
49.28662
50.80971
53.34544
58.18918
64.69961
72.82297
82.06741
88.79528
93.77917
205.5
49.52905
51.05229
53.58858
58.43468
64.95165
73.08975
82.3615
89.11718
94.12633
206.5
49.76354
51.28706
53.82409
58.67285
65.19653
73.34922
82.64755
89.43011
94.46364


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 121 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
207.5
49.9901
51.51404
54.05205
58.9038
65.4344
73.60152
82.92558
89.73396
94.79081
208.5
50.2088
51.73333
54.27255
59.12764
65.6654
73.84675
83.1956
90.02861
95.10761
209.5
50.4197
51.94499
54.4857
59.34454
65.8897
74.08507
83.45768
90.31396
95.41379
210.5
50.62293
52.14918
54.69165
59.55466
66.10749
74.31664
83.71185
90.58994
95.70913
211.5
50.81862
52.34603
54.89058
59.75819
66.31897
74.54164
83.9582
90.85649
95.99346
212.5
51.00695
52.53572
55.08267
59.95536
66.52437
74.76024
84.19682
91.11358
96.26661
213.5
51.18811
52.71847
55.26814
60.14639
66.7239
74.97267
84.42781
91.3612
96.52847
214.5
51.36232
52.8945
55.44723
60.33153
66.91784
75.17912
84.6513
91.59938
96.77894
215.5
51.52982
53.06406
55.6202
60.51105
67.10642
75.37983
84.86744
91.82817
97.01799
216.5
51.69086
53.2274
55.78731
60.68521
67.28993
75.57503
85.0764
92.04765
97.24564
217.5
51.84574
53.38481
55.94884
60.85431
67.46863
75.76499
85.27837
92.25795
97.46194
218.5
51.99472
53.53657
56.10508
61.01862
67.64281
75.94994
85.47356
92.45925
97.66704
219.5
52.13808
53.68296
56.25633
61.17846
67.81277
76.13018
85.66221
92.65175
97.86111
220.5
52.27612
53.82428
56.40286
61.33409
67.97877
76.30597
85.8446
92.83572
98.04443
221.5
52.40911
53.96079
56.54495
61.4858
68.14111
76.47759
86.02101
93.01148
98.21733
222.5
52.53731
54.09278
56.68288
61.63386
68.30005
76.64533
86.19177
93.17941
98.38026
223.5
52.66098
54.22046
56.81689
61.77851
68.45585
76.80948
86.35725
93.33994
98.53375
224.5
52.78032
54.34408
56.94719
61.91997
68.60872
76.97031
86.51781
93.49361
98.67844
225.5
52.89553
54.46381
57.07396
62.05842
68.75889
77.12809
86.6739
93.64099
98.81509
226.5
53.00674
54.57977
57.19732
62.19399
68.90653
77.2831
86.82597
93.78276
98.94455
227.5
53.11402
54.69205
57.31737
62.32678
69.05176
77.4356
86.97452
93.91968
99.06786
228.5
53.21739
54.80066
57.43409
62.4568
69.19467
77.5858
87.12008
94.05261
99.18615
229.5
53.31679
54.90552
57.54742
62.58399
69.33527
77.73392
87.26324
94.18252
99.30075
230.5
53.41207
55.00648
57.6572
62.70822
69.47351
77.88014
87.40462
94.31046
99.41315
231.5
53.50297
55.10328
57.76315
62.82922
69.60926
78.02461
87.54488
94.43765
99.52501
232.5
53.58913
55.19552
57.86488
62.94664
69.74228
78.16742
87.68474
94.5654
99.63819
233.5
53.67003
55.2827
57.96187
63.06
69.87224
78.30863
87.82495
94.69517
99.75477
234.5
53.74501
55.36413
58.05343
63.16863
69.99869
78.44824
87.96634
94.82857
99.87706
235.5
53.81325
55.43897
58.13869
63.27175
70.12104
78.58618
88.10976
94.96735
100.0076
236.5
53.87373
55.50617
58.21662
63.36835
70.23857
78.72234
88.25614
95.11344
100.1492
237.5
53.92519
55.56447
58.28594
63.45727
70.3504
78.8565
88.40645
95.26894
100.3048
238.5
53.96614
55.61236
58.34515
63.53709
70.45546
78.98839
88.56175
95.43613
100.4779
239.5
53.99482
55.64807
58.39247
63.60618
70.55252
79.11762
88.72311
95.61749
100.6721
240
54.00392
55.66071
58.41105
63.63611
70.59761
79.18111
88.80644
95.71431
100.7784


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 122 of 160
10.9
Appendix 9  CDC Data Table of Weight-for-age Chart for Females
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
24
9.985668
10.21027
10.57373
11.23357
12.05504
12.98667
13.93766
14.56636
15.00156
24.5
10.04881
10.27483
10.64076
11.30567
12.13456
13.07613
14.03902
14.67659
15.11839
25.5
10.17173
10.40066
10.77167
11.44697
12.29102
13.25293
14.24017
14.89587
15.35122
26.5
10.29079
10.52274
10.89899
11.58501
12.44469
13.42753
14.43984
15.11428
15.58363
27.5
10.40664
10.64171
11.02338
11.72047
12.59622
13.60059
14.63873
15.33249
15.81632
28.5
10.5199
10.75819
11.14545
11.85392
12.74621
13.77271
14.83743
15.55113
16.0499
29.5
10.63112
10.87273
11.26575
11.98592
12.89517
13.9444
15.03646
15.7707
16.28491
30.5
10.74078
10.98581
11.38474
12.11692
13.04357
14.11611
15.23626
15.99164
16.52176
31.5
10.84935
11.09789
11.50288
12.24735
13.19181
14.28823
15.43719
16.21432
16.76085
32.5
10.95722
11.20934
11.62054
12.37757
13.34023
14.46106
15.63957
16.43904
17.00245
33.5
11.06475
11.32054
11.73806
12.50791
13.48913
14.63491
15.84365
16.66605
17.24681
34.5
11.17225
11.43177
11.85574
12.63865
13.63877
14.80998
16.04963
16.89553
17.49412
35.5
11.28
11.54332
11.97384
12.77001
13.78937
14.98647
16.25767
17.12762
17.7445
36.5
11.38824
11.65542
12.09259
12.90222
13.94108
15.16452
16.46789
17.36244
17.99807
37.5
11.49718
11.76826
12.21216
13.03542
14.09407
15.34425
16.68038
17.60006
18.25487
38.5
11.607
11.88202
12.33273
13.16977
14.24844
15.52574
16.89519
17.8405
18.51494
39.5
11.71783
11.99685
12.45442
13.30538
14.40429
15.70905
17.11235
18.08377
18.77826
40.5
11.82981
12.11284
12.57735
13.44234
14.56168
15.89422
17.33186
18.32988
19.04483
41.5
11.94304
12.23011
12.70158
13.58071
14.72064
16.08126
17.55371
18.57877
19.31458
42.5
12.05757
12.34871
12.8272
13.72054
14.88121
16.27016
17.77788
18.83042
19.58748
43.5
12.17348
12.4687
12.95423
13.86186
15.04341
16.46093
18.00432
19.08475
19.86343
44.5
12.2908
12.59011
13.08271
14.00469
15.20721
16.65353
18.23298
19.34169
20.14237
45.5
12.40954
12.71297
13.21265
14.14902
15.37263
16.84793
18.46379
19.60118
20.4242
46.5
12.52972
12.83726
13.34405
14.29485
15.53962
17.04408
18.69671
19.86313
20.70884
47.5
12.65132
12.96298
13.47689
14.44217
15.70817
17.24195
18.93166
20.12746
20.99619
48.5
12.77432
13.09012
13.61116
14.59093
15.87824
17.44149
19.16858
20.39409
21.28616
49.5
12.89869
13.21864
13.74682
14.74112
16.04978
17.64265
19.40739
20.66293
21.57866
50.5
13.02441
13.3485
13.88384
14.89269
16.22277
17.84537
19.64805
20.93393
21.8736
51.5
13.15141
13.47966
14.02217
15.0456
16.39715
18.04961
19.89048
21.20699
22.1709
52.5
13.27965
13.61206
14.16176
15.19981
16.57289
18.25533
20.13464
21.48207
22.4705
53.5
13.40907
13.74566
14.30257
15.35527
16.74994
18.46249
20.38048
21.7591
22.77232
54.5
13.53962
13.8804
14.44453
15.51193
16.92827
18.67105
20.62795
22.03803
23.07631
55.5
13.67121
14.01621
14.5876
15.66975
17.10783
18.88097
20.87704
22.31884
23.38243
56.5
13.80381
14.15303
14.73172
15.82868
17.28859
19.09224
21.1277
22.60148
23.69063
57.5
13.93732
14.29081
14.87683
15.98868
17.47052
19.30483
21.37993
22.88594
24.0009
58.5
14.0717
14.42947
15.02287
16.14971
17.65361
19.51874
21.63373
23.17222
24.31322


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 123 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
59.5
14.20687
14.56897
15.16981
16.31173
17.83782
19.73395
21.88909
23.46031
24.62758
60.5
14.34277
14.70924
15.31758
16.47471
18.02314
19.95048
22.14604
23.75024
24.94401
61.5
14.47934
14.85022
15.46614
16.63861
18.20956
20.16834
22.4046
24.04202
25.26252
62.5
14.61652
14.99186
15.61545
16.80342
18.39709
20.38753
22.6648
24.3357
25.58315
63.5
14.75426
15.13412
15.76547
16.9691
18.58571
20.6081
22.92668
24.63133
25.90595
64.5
14.8925
15.27694
15.91616
17.13565
18.77545
20.83007
23.19031
24.92897
26.23096
65.5
15.03119
15.42029
16.06749
17.30305
18.96631
21.05349
23.45574
25.22868
26.55827
66.5
15.1703
15.56413
16.21943
17.4713
19.15831
21.2784
23.72305
25.53055
26.88796
67.5
15.30978
15.70843
16.37197
17.6404
19.35149
21.50486
23.99232
25.83467
27.2201
68.5
15.44961
15.85316
16.52509
17.81035
19.54588
21.73294
24.26364
26.14113
27.55481
69.5
15.58975
15.99831
16.67878
17.98118
19.74151
21.96271
24.5371
26.45005
27.8922
70.5
15.73018
16.14385
16.83304
18.15288
19.93843
22.19425
24.81282
26.76154
28.23237
71.5
15.87089
16.28977
16.98787
18.32549
20.1367
22.42763
25.09089
27.07573
28.57547
72.5
16.01186
16.43608
17.14327
18.49904
20.33636
22.66294
25.37145
27.39274
28.92162
73.5
16.1531
16.58277
17.29926
18.67356
20.53748
22.90029
25.65461
27.71272
29.27096
74.5
16.2946
16.72986
17.45586
18.84908
20.74013
23.13976
25.94051
28.0358
29.62364
75.5
16.43638
16.87736
17.61309
19.02566
20.94438
23.38146
26.22926
28.36213
29.97981
76.5
16.57843
17.02528
17.77097
19.20334
21.1503
23.6255
26.52102
28.69185
30.33962
77.5
16.7208
17.17365
17.92956
19.38217
21.35797
23.87199
26.81591
29.02513
30.70323
78.5
16.86349
17.3225
18.08887
19.56221
21.56748
24.12103
27.11407
29.36212
31.0708
79.5
17.00654
17.47187
18.24897
19.74353
21.77891
24.37274
27.41566
29.70296
31.44249
80.5
17.14998
17.6218
18.40989
19.9262
21.99235
24.62725
27.7208
30.04782
31.81846
81.5
17.29386
17.77232
18.5717
20.11027
22.20789
24.88466
28.02965
30.39685
32.19887
82.5
17.43821
17.9235
18.73445
20.29582
22.42562
25.14509
28.34233
30.75021
32.58389
83.5
17.5831
18.07539
18.89819
20.48293
22.64564
25.40866
28.659
31.10804
32.97366
84.5
17.72858
18.22805
19.063
20.67168
22.86804
25.67549
28.97979
31.47049
33.36833
85.5
17.8747
18.38153
19.22895
20.86215
23.09293
25.94569
29.30484
31.83771
33.76807
86.5
18.02152
18.53591
19.3961
21.05441
23.32039
26.21937
29.63426
32.20984
34.17302
87.5
18.16912
18.69124
19.56453
21.24855
23.55052
26.49666
29.9682
32.58701
34.5833
88.5
18.31757
18.84762
19.73432
21.44467
23.78342
26.77764
30.30677
32.96935
34.99906
89.5
18.46693
19.00511
19.90554
21.64283
24.01918
27.06244
30.65008
33.35698
35.42042
90.5
18.61729
19.16378
20.07828
21.84313
24.25789
27.35114
30.99825
33.75001
35.8475
91.5
18.76871
19.32373
20.25261
22.04564
24.49965
27.64385
31.35137
34.14856
36.2804
92.5
18.92129
19.48502
20.42863
22.25047
24.74454
27.94066
31.70954
34.55271
36.71922
93.5
19.07511
19.64775
20.6064
22.45768
24.99264
28.24165
32.07286
34.96256
37.16406
94.5
19.23024
19.81199
20.78601
22.66736
25.24403
28.54689
32.44138
35.37818
37.61498
95.5
19.38678
19.97783
20.96755
22.8796
25.4988
28.85648
32.8152
35.79964
38.07207


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 124 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
96.5
19.54481
20.14535
21.15111
23.09446
25.75702
29.17046
33.19435
36.22699
38.53537
97.5
19.70442
20.31464
21.33675
23.31203
26.01874
29.4889
33.5789
36.66029
39.00492
98.5
19.86568
20.48579
21.52456
23.53237
26.28404
29.81185
33.96887
37.09956
39.48077
99.5
20.0287
20.65887
21.71462
23.75556
26.55298
30.13934
34.36431
37.54482
39.96292
100.5
20.19355
20.83397
21.907
23.98166
26.82559
30.47142
34.76522
37.99609
40.45138
101.5
20.36032
21.01117
22.10179
24.21073
27.10193
30.80811
35.17161
38.45335
40.94614
102.5
20.5291
21.19055
22.29905
24.44283
27.38203
31.14942
35.58347
38.91658
41.44718
103.5
20.69997
21.37219
22.49884
24.67802
27.66593
31.49536
36.00078
39.38577
41.95447
104.5
20.873
21.55616
22.70125
24.91634
27.95365
31.84592
36.42352
39.86086
42.46794
105.5
21.04828
21.74253
22.90633
25.15783
28.24521
32.20108
36.85164
40.34179
42.98755
106.5
21.22589
21.93138
23.11413
25.40252
28.5406
32.56084
37.28507
40.82849
43.5132
107.5
21.40589
22.12277
23.32471
25.65046
28.83984
32.92513
37.72376
41.32088
44.0448
108.5
21.58837
22.31677
23.53813
25.90167
29.14291
33.29393
38.16762
41.81885
44.58226
109.5
21.77338
22.51343
23.75442
26.15616
29.4498
33.66717
38.61656
42.32229
45.12543
110.5
21.96099
22.71282
23.97364
26.41394
29.76048
34.04479
39.07046
42.83107
45.67419
111.5
22.15126
22.91497
24.19581
26.67503
30.07493
34.4267
39.52921
43.34505
46.22839
112.5
22.34426
23.11994
24.42096
26.93942
30.39308
34.81282
39.99268
43.86408
46.78786
113.5
22.54002
23.32778
24.64912
27.20709
30.7149
35.20305
40.46071
44.38798
47.35242
114.5
22.73861
23.53851
24.88031
27.47805
31.04032
35.59726
40.93316
44.91658
47.92187
115.5
22.94006
23.75217
25.11454
27.75225
31.36928
35.99535
41.40984
45.44968
48.49603
116.5
23.14441
23.96879
25.35181
28.02968
31.70168
36.39717
41.89057
45.98708
49.07465
117.5
23.3517
24.18838
25.59214
28.31029
32.03745
36.80259
42.37517
46.52854
49.65753
118.5
23.56195
24.41097
25.83551
28.59403
32.37649
37.21144
42.86342
47.07385
50.2444
119.5
23.77519
24.63656
26.08191
28.88087
32.71868
37.62356
43.35511
47.62276
50.83502
120.5
23.99143
24.86516
26.33132
29.17072
33.06392
38.03878
43.85001
48.17501
51.42913
121.5
24.21068
25.09677
26.58372
29.46353
33.41208
38.45691
44.34788
48.73033
52.02644
122.5
24.43296
25.33137
26.83907
29.75922
33.76303
38.87775
44.84847
49.28846
52.62666
123.5
24.65826
25.56895
27.09734
30.0577
34.11663
39.30111
45.35152
49.84911
53.22951
124.5
24.88657
25.80949
27.35848
30.35888
34.47272
39.72676
45.85676
50.41198
53.83467
125.5
25.11788
26.05297
27.62244
30.66267
34.83116
40.15449
46.36392
50.97677
54.44183
126.5
25.35217
26.29934
27.88915
30.96895
35.19176
40.58407
46.87271
51.54317
55.05067
127.5
25.58941
26.54856
28.15856
31.27762
35.55437
41.01526
47.38283
52.11086
55.66086
128.5
25.82958
26.8006
28.43059
31.58856
35.9188
41.44782
47.894
52.67951
56.27207
129.5
26.07263
27.05539
28.70516
31.90163
36.28486
41.88148
48.40589
53.2488
56.88395
130.5
26.31852
27.31287
28.98218
32.21671
36.65236
42.316
48.9182
53.81837
57.49615
131.5
26.56719
27.57298
29.26156
32.53364
37.02111
42.75111
49.43061
54.3879
58.10833
132.5
26.81859
27.83564
29.54321
32.8523
37.39089
43.18655
49.9428
54.95703
58.72013


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 125 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
133.5
27.07265
28.10077
29.827
33.17252
37.76149
43.62203
50.45443
55.52542
59.33118
134.5
27.3293
28.36829
30.11285
33.49415
38.1327
44.05728
50.96519
56.09271
59.94114
135.5
27.58846
28.63809
30.40062
33.81701
38.5043
44.49201
51.47473
56.65855
60.54964
136.5
27.85004
28.91009
30.69019
34.14096
38.87605
44.92595
51.98272
57.22257
61.15631
137.5
28.11395
29.18417
30.98143
34.4658
39.24775
45.3588
52.48882
57.78443
61.7608
138.5
28.38009
29.46022
31.27421
34.79137
39.61914
45.79028
52.9927
58.34376
62.36274
139.5
28.64837
29.73813
31.56838
35.11747
39.99
46.22009
53.49402
58.90022
62.96178
140.5
28.91866
30.01776
31.86381
35.44394
40.36009
46.64794
53.99244
59.45344
63.55756
141.5
29.19086
30.299
32.16034
35.77056
40.72918
47.07354
54.48762
60.00308
64.14972
142.5
29.46484
30.5817
32.45781
36.09716
41.09701
47.49661
54.97925
60.54878
64.73791
143.5
29.74046
30.86573
32.75608
36.42354
41.46336
47.91684
55.46697
61.0902
65.32179
144.5
30.0176
31.15094
33.05496
36.7495
41.82798
48.33396
55.95048
61.62701
65.90103
145.5
30.29612
31.43718
33.3543
37.07485
42.19063
48.74767
56.42944
62.15887
66.47528
146.5
30.57588
31.7243
33.65394
37.39937
42.55108
49.15771
56.90354
62.68544
67.04422
147.5
30.85671
32.01214
33.95368
37.72288
42.90909
49.56378
57.37247
63.20642
67.60754
148.5
31.13848
32.30053
34.25336
38.04517
43.26442
49.96562
57.83593
63.72148
68.16491
149.5
31.42101
32.58932
34.55281
38.36604
43.61683
50.36297
58.29361
64.23032
68.71605
150.5
31.70415
32.87832
34.85183
38.68529
43.96612
50.75555
58.74524
64.73264
69.26067
151.5
31.98774
33.16738
35.15025
39.00272
44.31204
51.14313
59.19053
65.22816
69.79847
152.5
32.27159
33.4563
35.44789
39.31812
44.65437
51.52544
59.62921
65.71661
70.32919
153.5
32.55554
33.74492
35.74455
39.63131
44.99291
51.90225
60.06103
66.19771
70.85258
154.5
32.8394
34.03306
36.04006
39.94209
45.32745
52.27334
60.48572
66.67121
71.36839
155.5
33.12301
34.32053
36.33424
40.25026
45.65777
52.63847
60.90306
67.13688
71.87638
156.5
33.40617
34.60715
36.62688
40.55564
45.98369
52.99745
61.31281
67.59448
72.37633
157.5
33.6887
34.89274
36.91782
40.85805
46.30501
53.35007
61.71477
68.04379
72.86804
158.5
33.97042
35.17711
37.20687
41.15729
46.62155
53.69614
62.10874
68.48463
73.35131
159.5
34.25114
35.46007
37.49385
41.45321
46.93314
54.03549
62.49452
68.91679
73.82597
160.5
34.53066
35.74145
37.77858
41.74562
47.23962
54.36794
62.87195
69.34011
74.29185
161.5
34.80881
36.02105
38.06087
42.03435
47.54083
54.69335
63.24088
69.75442
74.7488
162.5
35.08539
36.2987
38.34057
42.31926
47.83661
55.01159
63.60115
70.1596
75.19669
163.5
35.36022
36.57421
38.61748
42.60018
48.12685
55.32252
63.95264
70.5555
75.6354
164.5
35.63309
36.84739
38.89145
42.87697
48.41141
55.62603
64.29525
70.94203
76.06483
165.5
35.90384
37.11808
39.16232
43.14949
48.69018
55.92203
64.62889
71.31908
76.48488
166.5
36.17227
37.3861
39.42991
43.4176
48.96305
56.21044
64.95347
71.68659
76.89549
167.5
36.4382
37.65127
39.69408
43.68119
49.22993
56.49119
65.26895
72.04449
77.2966
168.5
36.70144
37.91342
39.95467
43.94012
49.49075
56.76423
65.57527
72.39275
77.68817
169.5
36.96182
38.17238
40.21154
44.1943
49.74544
57.02954
65.87243
72.73133
78.07017


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 126 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
170.5
37.21916
38.428
40.46454
44.44363
49.99394
57.28708
66.16042
73.06023
78.44259
171.5
37.4733
38.68012
40.71356
44.688
50.23621
57.53687
66.43925
73.37946
78.80544
172.5
37.72405
38.92858
40.95845
44.92735
50.47222
57.77893
66.70897
73.68906
79.15873
173.5
37.97127
39.17324
41.19909
45.1616
50.70196
58.01327
66.96961
73.98906
79.50251
174.5
38.21478
39.41396
41.43538
45.39069
50.92541
58.23994
67.22127
74.27953
79.83682
175.5
38.45445
39.6506
41.66721
45.61455
51.14259
58.45903
67.46402
74.56056
80.16173
176.5
38.69012
39.88303
41.89448
45.83316
51.35353
58.67061
67.69798
74.83223
80.4773
177.5
38.92165
40.11114
42.1171
46.04647
51.55825
58.87477
67.92327
75.09468
80.78364
178.5
39.14891
40.3348
42.33498
46.25446
51.75681
59.07164
68.14006
75.34802
81.08083
179.5
39.37177
40.55392
42.54806
46.45712
51.94926
59.26135
68.3485
75.59243
81.36901
180.5
39.59012
40.76839
42.75627
46.65445
52.13568
59.44404
68.54877
75.82805
81.6483
181.5
39.80385
40.97812
42.95955
46.84646
52.31616
59.61988
68.74109
76.05507
81.91883
182.5
40.01284
41.18304
43.15786
47.03316
52.4908
59.78905
68.92566
76.2737
82.18076
183.5
40.21702
41.38308
43.35116
47.21458
52.6597
59.95173
69.10273
76.48415
82.43425
184.5
40.4163
41.57816
43.53942
47.39077
52.82299
60.10814
69.27255
76.68664
82.67946
185.5
40.6106
41.76824
43.72263
47.56176
52.98079
60.2585
69.43538
76.88142
82.91657
186.5
40.79986
41.95328
43.90078
47.72763
53.13327
60.40303
69.59151
77.06875
83.14578
187.5
40.98403
42.13324
44.07388
47.88844
53.28056
60.54199
69.74124
77.2489
83.36727
188.5
41.16306
42.3081
44.24193
48.04426
53.42284
60.67562
69.88487
77.42214
83.58126
189.5
41.33692
42.47785
44.40496
48.1952
53.56028
60.8042
70.02272
77.58878
83.78795
190.5
41.50559
42.64249
44.563
48.34134
53.69307
60.928
70.15513
77.74911
83.98755
191.5
41.66907
42.80203
44.71609
48.48279
53.82138
61.04731
70.28244
77.90345
84.18029
192.5
41.82734
42.95649
44.8643
48.61968
53.94544
61.16241
70.40499
78.05211
84.36639
193.5
41.98043
43.1059
45.00768
48.75212
54.06543
61.2736
70.52314
78.19542
84.54608
194.5
42.12835
43.25031
45.14631
48.88026
54.18158
61.3812
70.63725
78.33372
84.7196
195.5
42.27115
43.38976
45.28027
49.00422
54.29411
61.48549
70.7477
78.46734
84.88718
196.5
42.40886
43.52432
45.40964
49.12417
54.40324
61.58681
70.85484
78.59661
85.04905
197.5
42.54155
43.65406
45.53455
49.24026
54.50921
61.68546
70.95905
78.72189
85.20546
198.5
42.66928
43.77907
45.65509
49.35265
54.61224
61.78176
71.06071
78.84351
85.35663
199.5
42.79212
43.89944
45.77138
49.46152
54.71257
61.87602
71.16017
78.96181
85.50282
200.5
42.91017
44.01527
45.88355
49.56702
54.81044
61.96856
71.2578
79.07713
85.64425
201.5
43.02352
44.12666
45.99174
49.66936
54.9061
62.05968
71.35395
79.18979
85.78117
202.5
43.13227
44.23375
46.09608
49.7687
54.99978
62.1497
71.44899
79.30012
85.91379
203.5
43.23654
44.33665
46.19672
49.86524
55.09172
62.23891
71.54326
79.40845
86.04235
204.5
43.33646
44.4355
46.29382
49.95916
55.18217
62.32761
71.63707
79.51506
86.16706
205.5
43.43215
44.53044
46.38753
50.05066
55.27135
62.41609
71.73076
79.62027
86.28815
206.5
43.52374
44.62161
46.47801
50.13993
55.35951
62.50462
71.82463
79.72434
86.40583


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 127 of 160
Age (in 
months)
3rd 
Percentile 
Weight (in 
kilograms)
5th 
Percentile 
Weight (in 
kilograms)
10th 
Percentile 
Weight (in 
kilograms)
25th 
Percentile 
Weight (in 
kilograms)
50th 
Percentile 
Weight (in 
kilograms)
75th 
Percentile 
Weight (in 
kilograms)
90th 
Percentile 
Weight (in 
kilograms)
95th 
Percentile 
Weight (in 
kilograms)
97th 
Percentile 
Weight (in 
kilograms)
207.5
43.61137
44.70917
46.56543
50.22716
55.44686
62.59347
71.91896
79.82755
86.52029
208.5
43.69521
44.79326
46.64995
50.31253
55.53362
62.68289
72.01403
79.93015
86.63173
209.5
43.77538
44.87405
46.73174
50.39624
55.62001
62.77311
72.11008
80.03235
86.74034
210.5
43.85205
44.95168
46.81097
50.47847
55.70624
62.86437
72.20733
80.13439
86.84629
211.5
43.92537
45.02633
46.8878
50.5594
55.79248
62.95684
72.306
80.23643
86.94976
212.5
43.9955
45.09815
46.9624
50.63919
55.87892
63.05073
72.40626
80.33866
87.05088
213.5
44.06258
45.16729
47.03493
50.71802
55.96573
63.1462
72.50825
80.4412
87.14981
214.5
44.12679
45.23391
47.10554
50.79603
56.05305
63.24336
72.61209
80.54417
87.24667
215.5
44.18826
45.29817
47.17437
50.87336
56.141
63.34234
72.71787
80.64766
87.34157
216.5
44.24715
45.3602
47.24158
50.95014
56.2297
63.4432
72.82563
80.75172
87.43462
217.5
44.3036
45.42015
47.30728
51.02649
56.31922
63.546
72.9354
80.85638
87.5259
218.5
44.35775
45.47815
47.3716
51.10249
56.40963
63.65074
73.04714
80.96163
87.61548
219.5
44.40973
45.53431
47.43464
51.17823
56.50096
63.7574
73.1608
81.06744
87.70342
220.5
44.45965
45.58875
47.4965
51.25375
56.5932
63.86593
73.27626
81.17373
87.78975
221.5
44.50764
45.64157
47.55724
51.32908
56.68633
63.9762
73.39338
81.28039
87.87449
222.5
44.55377
45.69284
47.61693
51.40422
56.78026
64.08808
73.51197
81.3873
87.95764
223.5
44.59815
45.74262
47.67559
51.47916
56.8749
64.20136
73.63178
81.49427
88.03918
224.5
44.64082
45.79097
47.73323
51.55381
56.9701
64.3158
73.75253
81.60109
88.11907
225.5
44.68185
45.8379
47.78983
51.6281
57.06565
64.4311
73.87389
81.70752
88.19726
226.5
44.72126
45.88343
47.84535
51.70189
57.16132
64.54692
73.99546
81.81326
88.27366
227.5
44.75906
45.92751
47.89972
51.77499
57.2568
64.66283
74.1168
81.91801
88.34817
228.5
44.79521
45.97009
47.9528
51.8472
57.35176
64.77838
74.23744
82.02139
88.42066
229.5
44.82969
46.0111
48.00447
51.91825
57.44578
64.89303
74.35682
82.12303
88.491
230.5
44.8624
46.0504
48.05453
51.98781
57.5384
65.00619
74.47435
82.22248
88.55903
231.5
44.89324
46.08784
48.10274
52.05553
57.6291
65.1172
74.58939
82.31928
88.62455
232.5
44.92205
46.12322
48.14882
52.12097
57.71728
65.22534
74.70121
82.41292
88.68734
233.5
44.94866
46.1563
48.19244
52.18364
57.80227
65.32981
74.80907
82.50285
88.74718
234.5
44.97281
46.18678
48.23321
52.243
57.88334
65.42974
74.91215
82.58851
88.80382
235.5
44.99424
46.21432
48.27069
52.29842
57.95967
65.52419
75.00958
82.66927
88.85697
236.5
45.0126
46.23851
48.30438
52.34921
58.0304
65.61215
75.10041
82.74448
88.90635
237.5
45.02752
46.25891
48.3337
52.3946
58.09453
65.69252
75.18367
82.81345
88.95164
238.5
45.03852
46.27498
48.358
52.43376
58.15104
65.76413
75.25831
82.87546
88.99253
239.5
45.0451
46.28612
48.37657
52.46576
58.19877
65.82574
75.32321
82.92975
89.02867
240
45.04655
46.28963
48.38346
52.47876
58.21897
65.85238
75.35165
82.95375
89.04485


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 128 of 160
10.10
Blood Pressure Levels for Males by Age and Height Percentile
APPENDIX 10.1
Fourth (4th) Report
From Fourth (4th) Report, Males, see References
Age
(years)
BP
percentile
Systolic Blood Pressure
(mmHg)
Diastolic Blood Pressure
(mmHg)
Percentiles
Percentiles
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
3
90th
100
101
103
105
107
108
109
59
59
60
61
62
63
63
95th
104
105
107
109
110
112
113
63
63
64
65
66
67
67
99th
111
112
114
116
118
119
120
71
71
72
73
74
75
75
4
90th
102
103
105
107
109
110
111
62
63
64
65
66
66
67
95th
106
107
109
111
112
114
115
66
67
68
69
70
71
71
99th
113
114
116
118
120
121
122
74
75
76
77
78
78
79
5
90th
104
105
106
108
110
111
112
65
66
67
68
69
69
70
95th
108
109
110
112
114
115
116
69
70
71
72
73
74
74
99th
115
116
118
120
121
123
123
77
78
79
80
81
81
82
6
90th
105
106
108
110
111
113
113
68
68
69
70
71
72
72
95th
109
110
112
114
115
117
117
72
72
73
74
75
76
76
99th
116
117
119
121
123
124
125
80
80
81
82
83
84
84
7
90th
106
107
109
111
113
114
115
70
70
71
72
73
74
74
95th
110
111
113
115
117
118
119
74
74
75
76
77
78
78
99th
117
118
120
122
124
125
126
82
82
83
84
85
86
86
8
90th
107
109
110
112
114
115
116
71
72
72
73
74
75
76
95th
111
112
114
116
118
119
120
75
76
77
78
79
79
80
99th
119
120
122
123
125
127
127
83
84
85
86
87
87
88
9
90th
109
110
112
114
115
117
118
72
73
74
75
76
76
77
95th
113
114
116
118
119
121
121
76
77
78
79
80
81
81
99th
120
121
123
125
127
128
129
84
85
86
87
88
88
89
10
90th
111
112
114
115
117
119
119
73
73
74
75
76
77
78
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
99th
122
123
125
127
128
130
130
85
86
86
88
88
89
90
11
90th
113
114
115
117
119
120
121
74
74
75
76
77
78
78
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
99th
124
125
127
129
130
132
132
86
86
87
88
89
90
90
12
90th
115
116
118
120
121
123
123
74
75
75
76
77
78
79
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
99th
126
127
129
131
133
134
135
86
87
88
89
90
90
91
13
90th
117
118
120
122
124
125
126
75
75
76
77
78
79
79
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
99th
128
130
131
133
135
136
137
87
87
88
89
90
91
91
14
90th
120
121
123
125
126
128
128
75
76
77
78
79
79
80
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
99th
131
132
134
136
138
139
140
87
88
89
90
91
92
92
15
90th
122
124
125
127
129
130
131
76
77
78
79
80
80
81
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
99th
134
135
136
138
140
142
142
88
89
90
91
92
93
93
16
90th
125
126
128
130
131
133
134
78
78
79
80
81
82
82
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
99th
136
137
139
141
143
144
145
90
90
91
92
93
94
94
17
90th
127
128
130
132
134
135
136
80
80
81
82
83
84
84
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
99th
139
140
141
143
145
146
147
92
93
93
94
95
96
97


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 129 of 160
APPENDIX 10.2
2017 Clinical Practice Guidelines
From 2017 (American Academy of Pediatric) Clinical Practice Guidelines, Table 4, Males, see References
Age
(years)
BP
Percentile
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Percentiles
Percentiles
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
3
Height (cm)
92.5
93.9
96.3
99
101.8
104.3
105.8
92.5
93.9
96.3
99
101.8
104.3
105.8
90th
101
102
102
103
104
105
105
58
58
59
59
60
61
61
95th
106
106
107
107
108
109
109
60
61
61
62
63
64
64
95th+12mmHg
118
118
119
119
120
121
121
72
73
73
74
75
76
76
4
Height (cm)
98.5
100.2
102.9
105.9
108.9
111.5
113.2
98.5
100.2
102.9
105.9
108.9
111.5
113.2
90th
102
103
104
105
105
106
107
60
61
62
62
63
64
64
95th 
107
107
108
108
109
110
110
63
64
65
66
67
67
68
95th+12mmHg
119
119
120
120
121
122
122
75
76
77
78
79
79
80
5
Height (cm)
104.4
106.2
109.1
112.4
115.7
118.6
120.3
104.4
106.2
109.1
112.4
115.7
118.6
120.3
90th
103
104
105
106
107
108
108
63
64
65
65
66
67
67
95th
107
108
109
109
110
111
112
66
67
68
69
70
70
71
95th+12mmHg
119
120
121
121
122
123
124
78
79
80
81
82
82
83
6
Height (cm)
110.3
112.2
115.3
118.9
122.4
125.6
127.5
110.3
112.2
115.3
118.9
122.4
125.6
127.5
90th
105
105
106
107
109
110
110
66
66
67
68
68
69
69
95th
108
109
110
111
112
113
114
69
70
70
71
72
72
73
95th+12mmHg
120
121
122
123
124
125
126
81
82
82
83
84
84
85
7
Height (cm)
116.1
118
121.4
125.1
128.9
132.4
134.5
116.1
118
121.4
125.1
128.9
132.4
134.5
90th
106
107
108
109
110
111
111
68
68
69
70
70
71
71
95th
110
110
111
112
114
115
116
71
71
72
73
73
74
74
95th+12mmHg
122
122
123
124
126
127
128
83
83
84
85
85
86
86
8
Height (cm)
121.4
123.5
127
131
135.1
138.8
141
121.4
123.5
127
131
135.1
138.8
141
90th
107
108
109
110
111
112
112
69
70
70
71
72
72
73
95th
111
112
112
114
115
116
117
72
73
73
74
75
75
75
95th+12mmHg
123
124
124
126
127
128
129
84
85
85
86
87
87
87
9
Height (cm)
126
128.3
132.1
136.3
140.7
144.7
147.1
126
128.3
132.1
136.3
140.7
144.7
147.1
90th
107
108
109
110
112
113
114
70
71
72
73
74
74
74
95th
112
112
113
115
116
118
119
74
74
75
76
76
77
77
95th+12mmHg
124
124
125
127
128
130
131
86
86
87
88
88
89
89
10
Height (cm)
130.2
132.7
136.7
141.3
146.9
150.1
152.7
130.2
132.7
136.7
141.3
146.9
150.1
152.7
90th
108
109
111
112
113
115
116
72
73
74
74
75
75
76
95th
112
113
114
116
118
120
121
76
76
77
77
78
78
78
95th+12mmHg
124
125
126
128
130
132
133
88
88
89
89
90
90
90
11
Height (cm)
134.7
137.3
141.5
145.4
151.3
155.8
158.5
134.7
137.3
141.5
145.4
151.3
155.8
158.5
90th
110
111
112
114
116
117
118
74
74
75
75
75
76
76
95th
114
114
116
118
120
123
124
77
78
78
78
78
78
78
95th+12mmHg
126
126
128
130
132
135
136
89
90
90
90
90
90
90
12
Height (cm)
140.3
143
147.5
152.7
157.9
162.6
165.5
140.3
143
147.5
152.7
157.9
152.6
165.5
90th
113
114
115
117
119
121
122
75
75
75
75
75
76
76
95th
116
117
118
121
124
126
128
78
78
78
78
78
79
79
95th+12mmHg
128
129
130
133
136
138
140
90
90
90
90
90
91
91


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 130 of 160
10.11
Blood Pressure Levels for Females by Age and Height Percentile
APPENDIX 11.1
Fourth (4th) Report
From Fourth (4th) Report, Females, see Reference.
Age
(years)
BP
percentile
Systolic Blood Pressure
(mmHg)
Diastolic Blood Pressure
(mmHg)
Percentiles
Percentiles
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
3
90th
100
100
102
103
104
106
106
61
62
62
63
64
64
65
95th
104
104
105
107
108
109
110
65
66
66
67
68
68
69
99th
111
111
113
114
115
116
117
73
73
74
74
75
76
76
4
90th
101
102
103
104
106
107
108
64
64
65
66
67
67
68
95th
105
106
107
108
110
111
112
68
68
69
70
71
71
72
99th
112
113
114
115
117
118
119
76
76
76
77
78
79
79
5
90th
103
103
105
106
107
109
109
66
67
67
68
69
69
70
95th
107
107
108
110
111
112
113
70
71
71
72
73
73
74
99th
114
114
116
117
118
120
120
78
78
79
79
80
81
81
6
90th
104
105
106
108
109
110
111
68
68
69
70
70
71
72
95th
108
109
110
111
113
114
115
72
72
73
74
74
75
76
99th
115
116
117
119
120
121
122
80
80
80
81
82
83
83
7
90th
106
107
108
109
111
112
113
69
70
70
71
72
72
73
95th
110
111
112
113
115
116
116
73
74
74
75
76
76
77
99th
117
118
119
120
122
123
124
81
81
82
82
83
84
84
8
90th
108
109
110
111
113
114
114
71
71
71
72
73
74
74
95th
112
112
114
115
116
118
118
75
75
75
76
77
78
78
99th
119
120
121
122
123
125
125
82
82
83
83
84
85
86
9
90th
110
110
112
113
114
116
116
72
72
72
73
74
75
75
95th
114
114
115
117
118
119
120
76
76
76
77
78
79
79
99th
121
121
123
124
125
127
127
83
83
84
84
85
86
87
10
90th
112
112
114
115
116
118
118
73
73
73
74
75
76
76
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
99th
123
123
125
126
127
129
129
84
84
85
86
86
87
88
11
90th
114
114
116
117
118
119
120
74
74
74
75
76
77
77
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
99th
125
125
126
128
129
130
131
85
85
86
87
87
88
89
12
90th
116
116
117
119
120
121
122
75
75
75
76
77
78
78
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
99th
127
127
128
130
131
132
133
86
86
87
88
88
89
90
13
90th
117
118
119
121
122
123
124
76
76
76
77
78
79
79
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
99th
128
129
130
132
133
134
135
87
87
88
89
89
90
91
14
90th
119
120
121
122
124
125
125
77
77
77
78
79
80
80
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
99th
130
131
132
133
135
136
136
88
88
89
90
90
91
92
15
90th
120
121
122
123
125
126
127
78
78
78
79
80
81
81
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
99th
131
132
133
134
136
137
138
89
89
90
91
91
92
93
16
90th
121
122
123
124
126
127
128
78
78
79
80
81
81
82
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
99th
132
133
134
135
137
138
139
90
90
90
91
92
93
93
17
90th
122
122
123
125
126
127
128
78
79
79
80
81
81
82
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
99th
133
133
134
136
137
138
139
90
90
91
91
92
93
93


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 131 of 160
APPENDIX 11.2
2017 Clinical Practice Guidelines
From 2017 (American Academy of Pediatric) Clinical Practice Guidelines, Table 5, Females, see Reference
Age
(years)
BP
Percentile
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Percentiles
Percentiles
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
3
Height (cm)
91
92.4
94.9
97.6
100.5
103.1
104.6
91
92.4
94.9
97.6
100.5
103.1
104.6
90th
102
103
104
104
105
106
107
60
61
61
62
63
64
65
95th
106
106
107
108
109
110
110
64
65
65
66
67
68
69
95th+12mmHg
118
118
119
120
121
122
122
76
77
77
78
79
80
81
4
Height (cm)
97.2
98.8
101.4
104.5
107.6
110.5
112.2
97.2
98.8
101.4
104.5
107.6
110.5
112.2
90th
103
104
105
106
107
108
108
62
63
64
65
66
67
67
95th 
107
108
109
109
110
111
112
66
67
68
69
70
70
71
95th+12mmHg
119
120
121
121
122
123
124
78
79
80
81
82
82
83
5
Height (cm)
103.6
105.3
108.2
111.5
114.9
118.1
120
103.6
105.3
108.2
111.5
114.9
118.1
120
90th
104
105
106
107
108
109
110
64
65
66
67
68
69
70
95th
108
109
109
110
111
112
113
68
69
70
71
72
73
73
95th+12mmHg
120
121
121
122
123
124
125
80
81
82
83
84
85
85
6
Height (cm)
110
111.8
114.9
118.4
122.1
125.6
127.7
110
111.8
114.9
118.4
122.1
125.6
127.7
90th
105
106
107
108
109
110
111
67
67
68
69
70
71
71
95th
109
109
110
111
112
113
114
70
71
72
72
73
74
74
95th+12mmHg
121
121
122
123
124
125
126
82
83
84
84
85
86
86
7
Height (cm)
115.9
117.8
121.1
124.9
128.8
132.5
134.7
115.9
117.8
121.1
124.9
128.8
132.5
134.7
90th
106
106
107
109
110
111
112
68
68
69
70
71
72
72
95th
109
110
111
112
113
114
115
72
72
73
73
74
74
75
95th+12mmHg
121
122
123
124
125
126
127
84
84
85
85
86
86
87
8
Height (cm)
121
123
126.5
130.6
134.7
138.5
140.9
121
123
126.5
130.6
134.7
138.5
140.9
90th
107
107
108
110
111
112
113
69
70
71
72
72
73
73
95th
110
111
112
113
115
116
117
72
73
74
74
75
75
75
95th+12mmHg
122
123
124
125
127
128
129
84
85
86
86
87
87
87
9
Height (cm)
125.3
127.6
131.3
135.6
140.1
144.1
146.6
125.3
127.6
131.3
135.6
140.1
144.1
146.6
90th
108
108
109
111
112
113
114
71
71
72
73
73
73
73
95th
112
112
113
114
116
117
118
74
74
75
75
75
75
75
95th+12mmHg
124
124
125
126
128
129
130
86
86
87
87
87
87
87
10
Height (cm)
129.7
132.2
136.3
141
145.8
150.2
152.8
129.7
132.2
136.3
141
145.8
150.2
152.8
90th
109
110
111
112
113
115
116
72
73
73
73
73
73
73
95th
113
114
114
116
117
119
120
75
75
76
76
76
76
76
95th+12mmHg
125
126
126
128
129
131
132
87
87
88
88
88
88
88
11
Height (cm)
135.6
138.3
142.8
147.8
152.8
157.3
160
135.6
138.3
142.8
147.8
152.8
157.3
160
90th
111
112
113
114
116
118
120
74
74
74
74
74
75
75
95th
115
116
117
118
120
123
124
76
77
77
77
77
77
77
95th+12mmHg
127
128
129
130
132
135
136
88
89
89
89
89
89
89
12
Height (cm)
142.8
145.5
149.9
154.8
159.6
163.8
166.4
142.8
145.5
149.9
154.8
159.6
163.8
166.4
90th
114
115
116
118
120
122
122
75
75
75
75
76
76
76
95th
118
119
120
122
124
125
126
78
78
78
78
79
79
79
95th+12mmHg
130
131
132
134
136
137
138
90
90
90
90
91
91
91


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 132 of 160
10.12 Appendix 12:  Calculation of Z-Scores for Height, Weight and BMI 
for Age and Sex Norms
The Centers for Disease Control and Prevention have provided growth charts that enable the 
calculation of z-scores for height, weight and BMI based on the age (in months) and sex for 
children, adolescents and young adults upto the age of 20 years [Kuczmarski et al, 2002].
On the basis that a 12-month year consists of 365.25 days, Am, the age in months of a child at 
a study visit, equals (date of visit – date of birth)/30.4375.  This age should not be rounded to 
the nearest month in the calculation of the z-score.
For each gender, separate formulae for the height, weight and BMI norms curves are supplied 
for each month in a child’s age with integer values of the age at the mid-point of each 
interval, e.g there are separate curves for 30.5-<31.5, 59.5-<60.5 months etc.
For a curve where the mid-point of the age interval is A whole months (e.g. for a child of 
30.85 or 31.36 months, A=31), the formula of the curve relies on six constants, L1, M1, S1, L2, 
M2 and S2.
For a child aged Am months, the z-score (Z) for height can be derived as follows (z-scores for 
weight and BMI follow similar steps):
●
Let r= (Am-A+0.5)
●
Let L=L1+(L2-L1)* r, M=M1+(M2-M1)* r, and S=S1+(S2-S1)* r
●
If -0.01 < L < 0.01 then













M
height
S
Z
log
1
otherwise 



















1
1
L
M
height
LS
Z
Formula are also given for if a z-score indicates a “biologically infeasible value” (BIV):
●
Let
)
)
2
1(
(
*
5.0
1
L
LS
M
M
LO



●
Let
)
)
2
1(
(
*
5.0
1
M
LS
M
HI
L 


●
If height<M then flag=(height-M)/LO, otherwise flag=(height-M)/HI
●
If flag<-5 or flag>3 then the height is a BIV.
To illustrate, a boy born on the 1st January 2001 comes for a visit on 13th January 2013 and 
his height is measured as 159 cm.  The steps for calculating Z are as follows:
●
The boy is 4395 days old at the visit, which gives Am=4395/30.4375=144.3943
●
As 144.3943 is in the interval (143.5,144.5), A=144


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●
R=144.3943-144+0.5=0.8943
●
The curve for A=144 has L1=0.416777012, M1=148.7917006, S1=0.04987865, 
L2=0.420919142, M2=149.3088178 and S2=0.049947823 (see example SAS code 
below).
●
The values of L,M and S are calculated to be L=0.420481, M=149.254, and 
S=0.0499478.
●




















1
254
.
149
159
0499478
.0
*
420481
.0
1
420481
0
Z
=1.283576
●
LO=7.23925, HI=7.67069 and, as height>M, flag=(height-M)/HI=1.27053.  This 
does not represent a BIV
Example SAS code for  the creation of the Z-Score and BIV flag is as follows:
*input dataset is called DATAIN and has at least the following variables;
*AGEMOS : Age in months;
*SEX    : 1=male, 2=female;
*HEIGHT : standing height in cm;
*WEIGHT : weight in kg;
*BMI    : BMI in kg/m^2;
**DATA FILE FOR HEIGHT-FOR-AGE;
data htcrv;
     infile cards pad;
     input sex _age _LH1 _MH1 _SH1 _LH2 _MH2 _SH2;
cards;
1 24 0.875839864 86.042792680 0.040247430 1.007208070 86.861609340 0.040395626
1 25 1.007208070 86.861609340 0.040395626 0.837251351 87.652472820 0.040577525
1 26 0.837251351 87.652472820 0.040577525 0.681492975 88.423264340 0.040723122
1 27 0.681492975 88.423264340 0.040723122 0.538779654 89.175492280 0.040833194
1 28 0.538779654 89.175492280 0.040833194 0.407697153 89.910408530 0.040909059
1 29 0.407697153 89.910408530 0.040909059 0.286762453 90.629077620 0.040952433
1 30 0.286762453 90.629077620 0.040952433 0.174489485 91.332423790 0.040965330
1 31 0.174489485 91.332423790 0.040965330 0.069444521 92.021271670 0.040949976
1 32 0.069444521 92.021271670 0.040949976 -0.029720564 92.696379460 0.040908737
1 33 -0.029720564 92.696379460 0.040908737 -0.124251789 93.358465460 0.040844062
1 34 -0.124251789 93.358465460 0.040844062 -0.215288396 94.008229230 0.040758431
1 35 -0.215288396 94.008229230 0.040758431 -0.303854340 94.646369810 0.040654312
1 36 -0.303854340 94.646369810 0.040654312 -0.390918369 95.273591060 0.040534120
1 37 -0.390918369 95.273591060 0.040534120 -0.254801167 95.914749290 0.040572876
1 38 -0.254801167 95.914749290 0.040572876 -0.125654535 96.547343280 0.040616910
1 39 -0.125654535 96.547343280 0.040616910 -0.003167350 97.171913090 0.040666414
1 40 -0.003167350 97.171913090 0.040666414 0.112912210 97.788977270 0.040721467
1 41 0.112912210 97.788977270 0.040721467 0.222754969 98.399028300 0.040782045
1 42 0.222754969 98.399028300 0.040782045 0.326530126 99.002543380 0.040848042
1 43 0.326530126 99.002543380 0.040848042 0.424361560 99.599977000 0.040919281
1 44 0.424361560 99.599977000 0.040919281 0.516353108 100.191764000 0.040995524
1 45 0.516353108 100.191764000 0.040995524 0.602595306 100.778319800 0.041076485
1 46 0.602595306 100.778319800 0.041076485 0.683170764 101.360041100 0.041161838
1 47 0.683170764 101.360041100 0.041161838 0.758158406 101.937305800 0.041251224
1 48 0.758158406 101.937305800 0.041251224 0.827636736 102.510473500 0.041344257
1 49 0.827636736 102.510473500 0.041344257 0.891686306 103.079885200 0.041440534
1 50 0.891686306 103.079885200 0.041440534 0.950391530 103.645864000 0.041539635
1 51 0.950391530 103.645864000 0.041539635 1.003830006 104.208713000 0.041641136
1 52 1.003830006 104.208713000 0.041641136 1.052135690 104.768725600 0.041744602
1 53 1.052135690 104.768725600 0.041744602 1.095366900 105.326163800 0.041849607


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1 54 1.095366900 105.326163800 0.041849607 1.133652119 105.881282300 0.041955723
1 55 1.133652119 105.881282300 0.041955723 1.167104213 106.434314600 0.042062532
1 56 1.167104213 106.434314600 0.042062532 1.195845353 106.985476900 0.042169628
1 57 1.195845353 106.985476900 0.042169628 1.220004233 107.534968000 0.042276619
1 58 1.220004233 107.534968000 0.042276619 1.239715856 108.082969500 0.042383129
1 59 1.239715856 108.082969500 0.042383129 1.255121285 108.629645700 0.042488804
1 60 1.255121285 108.629645700 0.042488804 1.266367398 109.175144100 0.042593311
1 61 1.266367398 109.175144100 0.042593311 1.273606657 109.719595400 0.042696342
1 62 1.273606657 109.719595400 0.042696342 1.276996893 110.263113600 0.042797615
1 63 1.276996893 110.263113600 0.042797615 1.276701119 110.805796700 0.042896877
1 64 1.276701119 110.805796700 0.042896877 1.272887366 111.347726500 0.042993904
1 65 1.272887366 111.347726500 0.042993904 1.265728536 111.888969400 0.043088503
1 66 1.265728536 111.888969400 0.043088503 1.255402281 112.429576100 0.043180513
1 67 1.255402281 112.429576100 0.043180513 1.242090871 112.969582700 0.043269806
1 68 1.242090871 112.969582700 0.043269806 1.225981067 113.509010800 0.043356287
1 69 1.225981067 113.509010800 0.043356287 1.207263978 114.047867800 0.043439893
1 70 1.207263978 114.047867800 0.043439893 1.186140222 114.586148600 0.043520597
1 71 1.186140222 114.586148600 0.043520597 1.162796198 115.123831500 0.043598407
1 72 1.162796198 115.123831500 0.043598407 1.137442868 115.660886200 0.043673359
1 73 1.137442868 115.660886200 0.043673359 1.110286487 116.197269100 0.043745523
1 74 1.110286487 116.197269100 0.043745523 1.081536236 116.732925000 0.043815003
1 75 1.081536236 116.732925000 0.043815003 1.051403740 117.267787900 0.043881929
1 76 1.051403740 117.267787900 0.043881929 1.020102497 117.801781900 0.043946461
1 77 1.020102497 117.801781900 0.043946461 0.987847213 118.334821500 0.044008785
1 78 0.987847213 118.334821500 0.044008785 0.954853043 118.866812300 0.044069112
1 79 0.954853043 118.866812300 0.044069112 0.921334742 119.397652000 0.044127675
1 80 0.921334742 119.397652000 0.044127675 0.887505723 119.927230900 0.044184725
1 81 0.887505723 119.927230900 0.044184725 0.853577030 120.455433000 0.044240532
1 82 0.853577030 120.455433000 0.044240532 0.819756239 120.982136200 0.044295379
1 83 0.819756239 120.982136200 0.044295379 0.786246296 121.507213600 0.044349559
1 84 0.786246296 121.507213600 0.044349559 0.753244292 122.030534200 0.044403374
1 85 0.753244292 122.030534200 0.044403374 0.720940222 122.551963400 0.044457130
1 86 0.720940222 122.551963400 0.044457130 0.689515708 123.071364500 0.044511135
1 87 0.689515708 123.071364500 0.044511135 0.659142731 123.588599000 0.044565693
1 88 0.659142731 123.588599000 0.044565693 0.629997853 124.103531200 0.044621104
1 89 0.629997853 124.103531200 0.044621104 0.602203984 124.616016100 0.044677662
1 90 0.602203984 124.616016100 0.044677662 0.575908038 125.125918200 0.044735646
1 91 0.575908038 125.125918200 0.044735646 0.551231340 125.633101200 0.044795322
1 92 0.551231340 125.633101200 0.044795322 0.528279901 126.137431900 0.044856941
1 93 0.528279901 126.137431900 0.044856941 0.507143576 126.638780400 0.044920730
1 94 0.507143576 126.638780400 0.044920730 0.487895344 127.137021700 0.044986899
1 95 0.487895344 127.137021700 0.044986899 0.470590753 127.632036200 0.045055632
1 96 0.470590753 127.632036200 0.045055632 0.455267507 128.123710400 0.045127088
1 97 0.455267507 128.123710400 0.045127088 0.441945241 128.611938300 0.045201399
1 98 0.441945241 128.611938300 0.045201399 0.430625458 129.096622000 0.045278671
1 99 0.430625458 129.096622000 0.045278671 0.421291648 129.577672300 0.045358979
1 100 0.421291648 129.577672300 0.045358979 0.413909588 130.055010100 0.045442372
1 101 0.413909588 130.055010100 0.045442372 0.408427813 130.528566900 0.045528869
1 102 0.408427813 130.528566900 0.045528869 0.404778262 130.998285700 0.045618459
1 103 0.404778262 130.998285700 0.045618459 0.402877077 131.464121800 0.045711105
1 104 0.402877077 131.464121800 0.045711105 0.402625561 131.926043900 0.045806742
1 105 0.402625561 131.926043900 0.045806742 0.403911270 132.384034800 0.045905281
1 106 0.403911270 132.384034800 0.045905281 0.406609232 132.838092000 0.046006604
1 107 0.406609232 132.838092000 0.046006604 0.410583274 133.288229100 0.046110573
1 108 0.410583274 133.288229100 0.046110573 0.415687443 133.734475900 0.046217028
1 109 0.415687443 133.734475900 0.046217028 0.421767514 134.176880100 0.046325790
1 110 0.421767514 134.176880100 0.046325790 0.428662551 134.615507600 0.046436662
1 111 0.428662551 134.615507600 0.046436662 0.436206531 135.050443300 0.046549430
1 112 0.436206531 135.050443300 0.046549430 0.444230000 135.481792500 0.046663871
1 113 0.444230000 135.481792500 0.046663871 0.452561760 135.909681300 0.046779748
1 114 0.452561760 135.909681300 0.046779748 0.461030578 136.334257700 0.046896817
1 115 0.461030578 136.334257700 0.046896817 0.469466904 136.755692300 0.047014827
1 116 0.469466904 136.755692300 0.047014827 0.477704608 137.174179400 0.047133525
1 117 0.477704608 137.174179400 0.047133525 0.485582720 137.589937800 0.047252654
1 118 0.485582720 137.589937800 0.047252654 0.492947182 138.003211400 0.047371961
1 119 0.492947182 138.003211400 0.047371961 0.499652617 138.414270300 0.047491194
1 120 0.499652617 138.414270300 0.047491194 0.505564115 138.823411400 0.047610108
1 121 0.505564115 138.823411400 0.047610108 0.510559047 139.230959200 0.047728463
1 122 0.510559047 139.230959200 0.047728463 0.514528903 139.637266300 0.047846030
1 123 0.514528903 139.637266300 0.047846030 0.517381177 140.042714000 0.047962592
1 124 0.517381177 140.042714000 0.047962592 0.519041285 140.447712700 0.048077942


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1 125 0.519041285 140.447712700 0.048077942 0.519454524 140.852702200 0.048191889
1 126 0.519454524 140.852702200 0.048191889 0.518588072 141.258151500 0.048304259
1 127 0.518588072 141.258151500 0.048304259 0.516433004 141.664559200 0.048414893
1 128 0.516433004 141.664559200 0.048414893 0.513006312 142.072452000 0.048523648
1 129 0.513006312 142.072452000 0.048523648 0.508352901 142.482385200 0.048630402
1 130 0.508352901 142.482385200 0.048630402 0.502547502 142.894940300 0.048735050
1 131 0.502547502 142.894940300 0.048735050 0.495696454 143.310724100 0.048837504
1 132 0.495696454 143.310724100 0.048837504 0.487939275 143.730366300 0.048937694
1 133 0.487939275 143.730366300 0.048937694 0.479449924 144.154516700 0.049035564
1 134 0.479449924 144.154516700 0.049035564 0.470437652 144.583841400 0.049131073
1 135 0.470437652 144.583841400 0.049131073 0.461147305 145.019019200 0.049224189
1 136 0.461147305 145.019019200 0.049224189 0.451858946 145.460735900 0.049314887
1 137 0.451858946 145.460735900 0.049314887 0.442886661 145.909678400 0.049403145
1 138 0.442886661 145.909678400 0.049403145 0.434576385 146.366527800 0.049488934
1 139 0.434576385 146.366527800 0.049488934 0.427302633 146.831951300 0.049572216
1 140 0.427302633 146.831951300 0.049572216 0.421464027 147.306592900 0.049652935
1 141 0.421464027 147.306592900 0.049652935 0.417477538 147.791063500 0.049731004
1 142 0.417477538 147.791063500 0.049731004 0.415771438 148.285929400 0.049806300
1 143 0.415771438 148.285929400 0.049806300 0.416777012 148.791700600 0.049878650
1 144 0.416777012 148.791700600 0.049878650 0.420919142 149.308817800 0.049947823
1 145 0.420919142 149.308817800 0.049947823 0.428606007 149.837639100 0.050013518
1 146 0.428606007 149.837639100 0.050013518 0.440218167 150.378426700 0.050075353
1 147 0.440218167 150.378426700 0.050075353 0.456097443 150.931333100 0.050132858
1 148 0.456097443 150.931333100 0.050132858 0.476536014 151.496388700 0.050185471
1 149 0.476536014 151.496388700 0.050185471 0.501766234 152.073489700 0.050232532
1 150 0.501766234 152.073489700 0.050232532 0.531951655 152.662387800 0.050273285
1 151 0.531951655 152.662387800 0.050273285 0.567179725 153.262681900 0.050306885
1 152 0.567179725 153.262681900 0.050306885 0.607456565 153.873812400 0.050332406
1 153 0.607456565 153.873812400 0.050332406 0.652704121 154.495058000 0.050348860
1 154 0.652704121 154.495058000 0.050348860 0.702759868 155.125536500 0.050355216
1 155 0.702759868 155.125536500 0.050355216 0.757379106 155.764208600 0.050350423
1 156 0.757379106 155.764208600 0.050350423 0.816239713 156.409885800 0.050333444
1 157 0.816239713 156.409885800 0.050333444 0.878947416 157.061241500 0.050303283
1 158 0.878947416 157.061241500 0.050303283 0.945053486 157.716828900 0.050259018
1 159 0.945053486 157.716828900 0.050259018 1.014046108 158.375092900 0.050199837
1 160 1.014046108 158.375092900 0.050199837 1.085383319 159.034399000 0.050125062
1 161 1.085383319 159.034399000 0.050125062 1.158487278 159.693050100 0.050034180
1 162 1.158487278 159.693050100 0.050034180 1.232768816 160.349316800 0.049926861
1 163 1.232768816 160.349316800 0.049926861 1.307628899 161.001458600 0.049802977
1 164 1.307628899 161.001458600 0.049802977 1.382473225 161.647751500 0.049662610
1 165 1.382473225 161.647751500 0.049662610 1.456720479 162.286511900 0.049506051
1 166 1.456720479 162.286511900 0.049506051 1.529810247 162.916120200 0.049333801
1 167 1.529810247 162.916120200 0.049333801 1.601219573 163.535045000 0.049146553
1 168 1.601219573 163.535045000 0.049146553 1.670433444 164.141848600 0.048945190
1 169 1.670433444 164.141848600 0.048945190 1.736995571 164.735219900 0.048730749
1 170 1.736995571 164.735219900 0.048730749 1.800483802 165.313975500 0.048504404
1 171 1.800483802 165.313975500 0.048504404 1.860518777 165.877071500 0.048267442
1 172 1.860518777 165.877071500 0.048267442 1.916765525 166.423608700 0.048021230
1 173 1.916765525 166.423608700 0.048021230 1.968934444 166.952835400 0.047767192
1 174 1.968934444 166.952835400 0.047767192 2.016781776 167.464146600 0.047506783
1 175 2.016781776 167.464146600 0.047506783 2.060109658 167.957081400 0.047241456
1 176 2.060109658 167.957081400 0.047241456 2.098765817 168.431317500 0.046972650
1 177 2.098765817 168.431317500 0.046972650 2.132642948 168.886664400 0.046701759
1 178 2.132642948 168.886664400 0.046701759 2.161677790 169.323054800 0.046430122
1 179 2.161677790 169.323054800 0.046430122 2.185849904 169.740535100 0.046159004
1 180 2.185849904 169.740535100 0.046159004 2.205180153 170.139255000 0.045889585
1 181 2.205180153 170.139255000 0.045889585 2.219728869 170.519456700 0.045622955
1 182 2.219728869 170.519456700 0.045622955 2.229593700 170.881464000 0.045360101
1 183 2.229593700 170.881464000 0.045360101 2.234907144 171.225671700 0.045101913
1 184 2.234907144 171.225671700 0.045101913 2.235833767 171.552534500 0.044849174
1 185 2.235833767 171.552534500 0.044849174 2.232567138 171.862557600 0.044602566
1 186 2.232567138 171.862557600 0.044602566 2.225326500 172.156286500 0.044362674
1 187 2.225326500 172.156286500 0.044362674 2.214353232 172.434298300 0.044129985
1 188 2.214353232 172.434298300 0.044129985 2.199905902 172.697193500 0.043904897
1 189 2.199905902 172.697193500 0.043904897 2.182262864 172.945589800 0.043687723
1 190 2.182262864 172.945589800 0.043687723 2.161704969 173.180112000 0.043478698
1 191 2.161704969 173.180112000 0.043478698 2.138524662 173.401389600 0.043277987
1 192 2.138524662 173.401389600 0.043277987 2.113023423 173.610051800 0.043085685
1 193 2.113023423 173.610051800 0.043085685 2.085490286 173.806717900 0.042901835
1 194 2.085490286 173.806717900 0.042901835 2.056219500 173.991999800 0.042726424
1 195 2.056219500 173.991999800 0.042726424 2.025496648 174.166495100 0.042559396


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1 196 2.025496648 174.166495100 0.042559396 1.993598182 174.330785500 0.042400652
1 197 1.993598182 174.330785500 0.042400652 1.960789092 174.485434400 0.042250063
1 198 1.960789092 174.485434400 0.042250063 1.927320937 174.630985600 0.042107465
1 199 1.927320937 174.630985600 0.042107465 1.893430240 174.767961700 0.041972676
1 200 1.893430240 174.767961700 0.041972676 1.859337259 174.896863400 0.041845488
1 201 1.859337259 174.896863400 0.041845488 1.825245107 175.018169100 0.041725679
1 202 1.825245107 175.018169100 0.041725679 1.791339209 175.132334500 0.041613015
1 203 1.791339209 175.132334500 0.041613015 1.757787065 175.239792600 0.041507249
1 204 1.757787065 175.239792600 0.041507249 1.724738292 175.340954000 0.041408129
1 205 1.724738292 175.340954000 0.041408129 1.692324905 175.436207100 0.041315398
1 206 1.692324905 175.436207100 0.041315398 1.660661815 175.525919100 0.041228796
1 207 1.660661815 175.525919100 0.041228796 1.629847495 175.610435800 0.041148060
1 208 1.629847495 175.610435800 0.041148060 1.599964788 175.690083000 0.041072931
1 209 1.599964788 175.690083000 0.041072931 1.571081817 175.765167100 0.041003150
1 210 1.571081817 175.765167100 0.041003150 1.543252982 175.835975700 0.040938463
1 211 1.543252982 175.835975700 0.040938463 1.516519998 175.902778800 0.040878617
1 212 1.516519998 175.902778800 0.040878617 1.490912963 175.965829300 0.040823368
1 213 1.490912963 175.965829300 0.040823368 1.466451429 176.025364100 0.040772475
1 214 1.466451429 176.025364100 0.040772475 1.443145460 176.081605000 0.040725706
1 215 1.443145460 176.081605000 0.040725706 1.420996665 176.134759300 0.040682834
1 216 1.420996665 176.134759300 0.040682834 1.399999187 176.185020800 0.040643640
1 217 1.399999187 176.185020800 0.040643640 1.380140651 176.232570700 0.040607913
1 218 1.380140651 176.232570700 0.040607913 1.361403047 176.277578100 0.040575448
1 219 1.361403047 176.277578100 0.040575448 1.343763564 176.320200800 0.040546051
1 220 1.343763564 176.320200800 0.040546051 1.327195355 176.360586400 0.040519532
1 221 1.327195355 176.360586400 0.040519532 1.311668242 176.398872500 0.040495713
1 222 1.311668242 176.398872500 0.040495713 1.297149359 176.435187400 0.040474421
1 223 1.297149359 176.435187400 0.040474421 1.283603728 176.469651000 0.040455493
1 224 1.283603728 176.469651000 0.040455493 1.270994782 176.502375100 0.040438773
1 225 1.270994782 176.502375100 0.040438773 1.259284830 176.533464000 0.040424111
1 226 1.259284830 176.533464000 0.040424111 1.248435461 176.563015300 0.040411366
1 227 1.248435461 176.563015300 0.040411366 1.238407910 176.591119700 0.040400405
1 228 1.238407910 176.591119700 0.040400405 1.229163362 176.617862100 0.040391101
1 229 1.229163362 176.617862100 0.040391101 1.220663228 176.643321900 0.040383334
1 230 1.220663228 176.643321900 0.040383334 1.212869374 176.667572900 0.040376990
1 231 1.212869374 176.667572900 0.040376990 1.205744310 176.690684400 0.040371962
1 232 1.205744310 176.690684400 0.040371962 1.199251356 176.712721000 0.040368149
1 233 1.199251356 176.712721000 0.040368149 1.193354770 176.733743000 0.040365456
1 234 1.193354770 176.733743000 0.040365456 1.188019859 176.753807000 0.040363795
1 235 1.188019859 176.753807000 0.040363795 1.183213059 176.772965700 0.040363080
1 236 1.183213059 176.772965700 0.040363080 1.178901998 176.791268700 0.040363233
1 237 1.178901998 176.791268700 0.040363233 1.175055543 176.808762200 0.040364179
1 238 1.175055543 176.808762200 0.040364179 1.171643828 176.825489500 0.040365850
1 239 1.171643828 176.825489500 0.040365850 1.168638270 176.841491400 0.040368180
2 24 1.093625008 84.553793340 0.040723061 1.051272912 85.397316900 0.040859727
2 25 1.051272912 85.397316900 0.040859727 1.041951175 86.290263180 0.041142161
2 26 1.041951175 86.290263180 0.041142161 1.012592236 87.157141820 0.041349399
2 27 1.012592236 87.157141820 0.041349399 0.970541909 87.996018400 0.041500428
2 28 0.970541909 87.996018400 0.041500428 0.921129988 88.805511500 0.041610508
2 29 0.921129988 88.805511500 0.041610508 0.868221392 89.584766890 0.041691761
2 30 0.868221392 89.584766890 0.041691761 0.814544130 90.333417220 0.041753680
2 31 0.814544130 90.333417220 0.041753680 0.761957977 91.051543600 0.041803562
2 32 0.761957977 91.051543600 0.041803562 0.711660228 91.739635200 0.041846882
2 33 0.711660228 91.739635200 0.041846882 0.664323379 92.398544290 0.041887626
2 34 0.664323379 92.398544290 0.041887626 0.620285102 93.029453920 0.041928568
2 35 0.620285102 93.029453920 0.041928568 0.579556310 93.633822780 0.041971514
2 36 0.579556310 93.633822780 0.041971514 0.541980940 94.213357090 0.042017509
2 37 0.541980940 94.213357090 0.042017509 0.511429832 94.796432390 0.042104522
2 38 0.511429832 94.796432390 0.042104522 0.482799937 95.373919180 0.042199507
2 39 0.482799937 95.373919180 0.042199507 0.455521041 95.946926770 0.042300333
2 40 0.455521041 95.946926770 0.042300333 0.429150288 96.516449120 0.042405225
2 41 0.429150288 96.516449120 0.042405225 0.403351725 97.083372110 0.042512706
2 42 0.403351725 97.083372110 0.042512706 0.377878239 97.648480700 0.042621565
2 43 0.377878239 97.648480700 0.042621565 0.352555862 98.212465790 0.042730809
2 44 0.352555862 98.212465790 0.042730809 0.327270297 98.775930690 0.042839638
2 45 0.327270297 98.775930690 0.042839638 0.301955463 99.339397350 0.042947412
2 46 0.301955463 99.339397350 0.042947412 0.276583851 99.903312200 0.043053626
2 47 0.276583851 99.903312200 0.043053626 0.251158446 100.468051600 0.043157889
2 48 0.251158446 100.468051600 0.043157889 0.225705996 101.033927000 0.043259907
2 49 0.225705996 101.033927000 0.043259907 0.200271450 101.601189800 0.043359463
2 50 0.200271450 101.601189800 0.043359463 0.174913356 102.170035800 0.043456406


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 137 of 160
2 51 0.174913356 102.170035800 0.043456406 0.149700081 102.740609400 0.043550638
2 52 0.149700081 102.740609400 0.043550638 0.124706710 103.313007700 0.043642107
2 53 0.124706710 103.313007700 0.043642107 0.100012514 103.887283900 0.043730791
2 54 0.100012514 103.887283900 0.043730791 0.075698881 104.463451100 0.043816701
2 55 0.075698881 104.463451100 0.043816701 0.051847635 105.041485300 0.043899867
2 56 0.051847635 105.041485300 0.043899867 0.028539670 105.621328700 0.043980337
2 57 0.028539670 105.621328700 0.043980337 0.005853853 106.202892100 0.044058171
2 58 0.005853853 106.202892100 0.044058171 -0.016133871 106.786058300 0.044133440
2 59 -0.016133871 106.786058300 0.044133440 -0.037351181 107.370684100 0.044206218
2 60 -0.037351181 107.370684100 0.044206218 -0.057729947 107.956603100 0.044276588
2 61 -0.057729947 107.956603100 0.044276588 -0.077206672 108.543627800 0.044344632
2 62 -0.077206672 108.543627800 0.044344632 -0.095722830 109.131552100 0.044410436
2 63 -0.095722830 109.131552100 0.044410436 -0.113225128 109.720153100 0.044474084
2 64 -0.113225128 109.720153100 0.044474084 -0.129665689 110.309193400 0.044535662
2 65 -0.129665689 110.309193400 0.044535662 -0.145002179 110.898422800 0.044595254
2 66 -0.145002179 110.898422800 0.044595254 -0.159197885 111.487580600 0.044652942
2 67 -0.159197885 111.487580600 0.044652942 -0.172221748 112.076396700 0.044708809
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2 69 -0.184048358 112.664594300 0.044762936 -0.194660215 113.251890200 0.044815402
2 70 -0.194660215 113.251890200 0.044815402 -0.204030559 113.838000600 0.044866288
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2 73 -0.219069129 115.005497800 0.044963636 -0.224722166 115.586308900 0.045010259
2 74 -0.224722166 115.586308900 0.045010259 -0.229140412 116.164778200 0.045055624
2 75 -0.229140412 116.164778200 0.045055624 -0.232335686 116.740622100 0.045099817
2 76 -0.232335686 116.740622100 0.045099817 -0.234324563 117.313562200 0.045142924
2 77 -0.234324563 117.313562200 0.045142924 -0.235128195 117.883325900 0.045185036
2 78 -0.235128195 117.883325900 0.045185036 -0.234772114 118.449648100 0.045226249
2 79 -0.234772114 118.449648100 0.045226249 -0.233286033 119.012272200 0.045266662
2 80 -0.233286033 119.012272200 0.045266662 -0.230703633 119.570951300 0.045306383
2 81 -0.230703633 119.570951300 0.045306383 -0.227062344 120.125449500 0.045345524
2 82 -0.227062344 120.125449500 0.045345524 -0.222403111 120.675542700 0.045384203
2 83 -0.222403111 120.675542700 0.045384203 -0.216770161 121.221020000 0.045422551
2 84 -0.216770161 121.221020000 0.045422551 -0.210210748 121.761684400 0.045460702
2 85 -0.210210748 121.761684400 0.045460702 -0.202774891 122.297354200 0.045498803
2 86 -0.202774891 122.297354200 0.045498803 -0.194515104 122.827864000 0.045537012
2 87 -0.194515104 122.827864000 0.045537012 -0.185486099 123.353065200 0.045575495
2 88 -0.185486099 123.353065200 0.045575495 -0.175744476 123.872827600 0.045614432
2 89 -0.175744476 123.872827600 0.045614432 -0.165348396 124.387040000 0.045654016
2 90 -0.165348396 124.387040000 0.045654016 -0.154357220 124.895611400 0.045694450
2 91 -0.154357220 124.895611400 0.045694450 -0.142831123 125.398472000 0.045735953
2 92 -0.142831123 125.398472000 0.045735953 -0.130830669 125.895574000 0.045778759
2 93 -0.130830669 125.895574000 0.045778759 -0.118416354 126.386892900 0.045823114
2 94 -0.118416354 126.386892900 0.045823114 -0.105648092 126.872428400 0.045869280
2 95 -0.105648092 126.872428400 0.045869280 -0.092584657 127.352205600 0.045917535
2 96 -0.092584657 127.352205600 0.045917535 -0.079283065 127.826275900 0.045968169
2 97 -0.079283065 127.826275900 0.045968169 -0.065797888 128.294718700 0.046021490
2 98 -0.065797888 128.294718700 0.046021490 -0.052180500 128.757642000 0.046077818
2 99 -0.052180500 128.757642000 0.046077818 -0.038478250 129.215183900 0.046137487
2 100 -0.038478250 129.215183900 0.046137487 -0.024733545 129.667514300 0.046200842
2 101 -0.024733545 129.667514300 0.046200842 -0.010982868 130.114835400 0.046268240
2 102 -0.010982868 130.114835400 0.046268240 0.002744306 130.557383900 0.046340046
2 103 0.002744306 130.557383900 0.046340046 0.016426655 130.995432000 0.046416629
2 104 0.016426655 130.995432000 0.046416629 0.030052231 131.429288700 0.046498361
2 105 0.030052231 131.429288700 0.046498361 0.043619747 131.859301500 0.046585611
2 106 0.043619747 131.859301500 0.046585611 0.057139880 132.285857400 0.046678741
2 107 0.057139880 132.285857400 0.046678741 0.070636605 132.709384500 0.046778099
2 108 0.070636605 132.709384500 0.046778099 0.084148480 133.130352700 0.046884010
2 109 0.084148480 133.130352700 0.046884010 0.097729873 133.549274900 0.046996769
2 110 0.097729873 133.549274900 0.046996769 0.111452039 133.966707300 0.047116633
2 111 0.111452039 133.966707300 0.047116633 0.125404005 134.383249900 0.047243801
2 112 0.125404005 134.383249900 0.047243801 0.139693160 134.799546300 0.047378413
2 113 0.139693160 134.799546300 0.047378413 0.154445482 135.216282600 0.047520521
2 114 0.154445482 135.216282600 0.047520521 0.169805275 135.634186000 0.047670085
2 115 0.169805275 135.634186000 0.047670085 0.185934346 136.054022300 0.047826946
2 116 0.185934346 136.054022300 0.047826946 0.203010488 136.476592500 0.047990810
2 117 0.203010488 136.476592500 0.047990810 0.221225200 136.902728100 0.048161228
2 118 0.221225200 136.902728100 0.048161228 0.240780542 137.333284600 0.048337570
2 119 0.240780542 137.333284600 0.048337570 0.261885086 137.769133900 0.048519011
2 120 0.261885086 137.769133900 0.048519011 0.284748919 138.211155200 0.048704503
2 121 0.284748919 138.211155200 0.048704503 0.309577733 138.660222800 0.048892759


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 138 of 160
2 122 0.309577733 138.660222800 0.048892759 0.336566048 139.117193300 0.049082239
2 123 0.336566048 139.117193300 0.049082239 0.365889711 139.582889800 0.049271137
2 124 0.365889711 139.582889800 0.049271137 0.397699038 140.058084800 0.049457371
2 125 0.397699038 140.058084800 0.049457371 0.432104409 140.543478700 0.049638596
2 126 0.432104409 140.543478700 0.049638596 0.469179930 141.039683200 0.049812203
2 127 0.469179930 141.039683200 0.049812203 0.508943272 141.547194500 0.049975355
2 128 0.508943272 141.547194500 0.049975355 0.551354277 142.066373100 0.050125012
2 129 0.551354277 142.066373100 0.050125012 0.596307363 142.597420000 0.050257992
2 130 0.596307363 142.597420000 0.050257992 0.643626542 143.140355300 0.050371024
2 131 0.643626542 143.140355300 0.050371024 0.693062173 143.694998100 0.050460835
2 132 0.693062173 143.694998100 0.050460835 0.744289752 144.260949700 0.050524236
2 133 0.744289752 144.260949700 0.050524236 0.796910980 144.837580900 0.050558224
2 134 0.796910980 144.837580900 0.050558224 0.850457280 145.424024600 0.050560083
2 135 0.850457280 145.424024600 0.050560083 0.904395871 146.019174800 0.050527494
2 136 0.904395871 146.019174800 0.050527494 0.958138449 146.621692000 0.050458634
2 137 0.958138449 146.621692000 0.050458634 1.011054559 147.230017700 0.050352269
2 138 1.011054559 147.230017700 0.050352269 1.062474568 147.842391800 0.050207825
2 139 1.062474568 147.842391800 0.050207825 1.111727029 148.456887900 0.050025434
2 140 1.111727029 148.456887900 0.050025434 1.158135105 149.071441300 0.049805967
2 141 1.158135105 149.071441300 0.049805967 1.201050821 149.683894300 0.049551023
2 142 1.201050821 149.683894300 0.049551023 1.239852328 150.292032800 0.049262895
2 143 1.239852328 150.292032800 0.049262895 1.274006058 150.893646900 0.048944504
2 144 1.274006058 150.893646900 0.048944504 1.303044695 151.486563600 0.048599314
2 145 1.303044695 151.486563600 0.048599314 1.326605954 152.068698500 0.048231224
2 146 1.326605954 152.068698500 0.048231224 1.344443447 152.638095500 0.047844442
2 147 1.344443447 152.638095500 0.047844442 1.356437773 153.192963100 0.047443362
2 148 1.356437773 153.192963100 0.047443362 1.362602695 153.731703100 0.047032430
2 149 1.362602695 153.731703100 0.047032430 1.363085725 154.252933200 0.046616026
2 150 1.363085725 154.252933200 0.046616026 1.358162799 154.755501000 0.046198356
2 151 1.358162799 154.755501000 0.046198356 1.348227142 155.238490400 0.045783350
2 152 1.348227142 155.238490400 0.045783350 1.333772923 155.701221600 0.045374597
2 153 1.333772923 155.701221600 0.045374597 1.315374704 156.143243800 0.044975281
2 154 1.315374704 156.143243800 0.044975281 1.293664024 156.564323000 0.044588148
2 155 1.293664024 156.564323000 0.044588148 1.269304678 156.964425800 0.044215488
2 156 1.269304678 156.964425800 0.044215488 1.242968236 157.343699500 0.043859135
2 157 1.242968236 157.343699500 0.043859135 1.215311270 157.702450700 0.043520480
2 158 1.215311270 157.702450700 0.043520480 1.186955477 158.041123300 0.043200497
2 159 1.186955477 158.041123300 0.043200497 1.158471522 158.360275600 0.042899776
2 160 1.158471522 158.360275600 0.042899776 1.130367088 158.660558800 0.042618565
2 161 1.130367088 158.660558800 0.042618565 1.103079209 158.942696400 0.042356812
2 162 1.103079209 158.942696400 0.042356812 1.076970655 159.207465400 0.042114211
2 163 1.076970655 159.207465400 0.042114211 1.052329922 159.455679000 0.041890247
2 164 1.052329922 159.455679000 0.041890247 1.029374161 159.688172000 0.041684240
2 165 1.029374161 159.688172000 0.041684240 1.008254396 159.905787100 0.041495379
2 166 1.008254396 159.905787100 0.041495379 0.989062282 160.109364700 0.041322765
2 167 0.989062282 160.109364700 0.041322765 0.971837799 160.299733000 0.041165437
2 168 0.971837799 160.299733000 0.041165437 0.956572150 160.477699600 0.041022401
2 169 0.956572150 160.477699600 0.041022401 0.943242280 160.644052600 0.040892651
2 170 0.943242280 160.644052600 0.040892651 0.931767062 160.799542800 0.040775193
2 171 0.931767062 160.799542800 0.040775193 0.922058291 160.944891600 0.040669052
2 172 0.922058291 160.944891600 0.040669052 0.914012643 161.080785700 0.040573288
2 173 0.914012643 161.080785700 0.040573288 0.907516917 161.207875500 0.040487005
2 174 0.907516917 161.207875500 0.040487005 0.902452436 161.326774400 0.040409354
2 175 0.902452436 161.326774400 0.040409354 0.898698641 161.438059300 0.040339537
2 176 0.898698641 161.438059300 0.040339537 0.896143482 161.542272600 0.040276811
2 177 0.896143482 161.542272600 0.040276811 0.894659668 161.639917000 0.040220488
2 178 0.894659668 161.639917000 0.040220488 0.894138920 161.731464500 0.040169932
2 179 0.894138920 161.731464500 0.040169932 0.894475371 161.817353400 0.040124562
2 180 0.894475371 161.817353400 0.040124562 0.895569834 161.897991300 0.040083845
2 181 0.895569834 161.897991300 0.040083845 0.897330209 161.973755800 0.040047295
2 182 0.897330209 161.973755800 0.040047295 0.899671635 162.044996900 0.040014473
2 183 0.899671635 162.044996900 0.040014473 0.902516442 162.112038600 0.039984980
2 184 0.902516442 162.112038600 0.039984980 0.905793969 162.175180000 0.039958458
2 185 0.905793969 162.175180000 0.039958458 0.909440266 162.234697900 0.039934584
2 186 0.909440266 162.234697900 0.039934584 0.913397733 162.290847400 0.039913066
2 187 0.913397733 162.290847400 0.039913066 0.917614710 162.343864000 0.039893644
2 188 0.917614710 162.343864000 0.039893644 0.922045055 162.393965200 0.039876087
2 189 0.922045055 162.393965200 0.039876087 0.926647697 162.441351300 0.039860185
2 190 0.926647697 162.441351300 0.039860185 0.931386217 162.486207100 0.039845754
2 191 0.931386217 162.486207100 0.039845754 0.936228420 162.528702900 0.039832629
2 192 0.936228420 162.528702900 0.039832629 0.941145943 162.568995800 0.039820663


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 139 of 160
2 193 0.941145943 162.568995800 0.039820663 0.946113880 162.607230900 0.039809725
2 194 0.946113880 162.607230900 0.039809725 0.951110430 162.643541800 0.039799700
2 195 0.951110430 162.643541800 0.039799700 0.956116576 162.678051900 0.039790485
2 196 0.956116576 162.678051900 0.039790485 0.961115792 162.710875100 0.039781991
2 197 0.961115792 162.710875100 0.039781991 0.966093766 162.742116800 0.039774136
2 198 0.966093766 162.742116800 0.039774136 0.971038162 162.771874100 0.039766850
2 199 0.971038162 162.771874100 0.039766850 0.975938391 162.800237100 0.039760070
2 200 0.975938391 162.800237100 0.039760070 0.980785418 162.827288900 0.039753741
2 201 0.980785418 162.827288900 0.039753741 0.985571579 162.853106700 0.039747815
2 202 0.985571579 162.853106700 0.039747815 0.990290420 162.877761900 0.039742249
2 203 0.990290420 162.877761900 0.039742249 0.994936555 162.901320800 0.039737004
2 204 0.994936555 162.901320800 0.039737004 0.999505539 162.923844900 0.039732048
2 205 0.999505539 162.923844900 0.039732048 1.003993753 162.945391200 0.039727352
2 206 1.003993753 162.945391200 0.039727352 1.008398300 162.966013100 0.039722890
2 207 1.008398300 162.966013100 0.039722890 1.012716921 162.985759900 0.039718640
2 208 1.012716921 162.985759900 0.039718640 1.016947912 163.004677600 0.039714581
2 209 1.016947912 163.004677600 0.039714581 1.021090055 163.022809400 0.039710697
2 210 1.021090055 163.022809400 0.039710697 1.025142554 163.040195300 0.039706971
2 211 1.025142554 163.040195300 0.039706971 1.029104983 163.056872700 0.039703391
2 212 1.029104983 163.056872700 0.039703391 1.032977233 163.072876800 0.039699945
2 213 1.032977233 163.072876800 0.039699945 1.036759475 163.088240400 0.039696623
2 214 1.036759475 163.088240400 0.039696623 1.040452117 163.102994300 0.039693415
2 215 1.040452117 163.102994300 0.039693415 1.044055774 163.117167300 0.039690313
2 216 1.044055774 163.117167300 0.039690313 1.047571238 163.130786600 0.039687311
2 217 1.047571238 163.130786600 0.039687311 1.050999451 163.143877600 0.039684402
2 218 1.050999451 163.143877600 0.039684402 1.054341482 163.156464400 0.039681581
2 219 1.054341482 163.156464400 0.039681581 1.057598512 163.168569700 0.039678842
2 220 1.057598512 163.168569700 0.039678842 1.060771808 163.180214600 0.039676182
2 221 1.060771808 163.180214600 0.039676182 1.063862715 163.191419400 0.039673596
2 222 1.063862715 163.191419400 0.039673596 1.066872639 163.202203000 0.039671082
2 223 1.066872639 163.202203000 0.039671082 1.069803036 163.212583500 0.039668635
2 224 1.069803036 163.212583500 0.039668635 1.072655401 163.222577900 0.039666254
2 225 1.072655401 163.222577900 0.039666254 1.075431258 163.232202400 0.039663936
2 226 1.075431258 163.232202400 0.039663936 1.078132156 163.241472200 0.039661679
2 227 1.078132156 163.241472200 0.039661679 1.080759655 163.250401900 0.039659481
2 228 1.080759655 163.250401900 0.039659481 1.083315329 163.259005200 0.039657339
2 229 1.083315329 163.259005200 0.039657339 1.085800751 163.267295400 0.039655252
2 230 1.085800751 163.267295400 0.039655252 1.088217496 163.275284800 0.039653218
2 231 1.088217496 163.275284800 0.039653218 1.090567133 163.282985400 0.039651237
2 232 1.090567133 163.282985400 0.039651237 1.092851222 163.290408600 0.039649306
2 233 1.092851222 163.290408600 0.039649306 1.095071313 163.297565000 0.039647424
2 234 1.095071313 163.297565000 0.039647424 1.097228939 163.304465000 0.039645591
2 235 1.097228939 163.304465000 0.039645591 1.099325619 163.311118500 0.039643804
2 236 1.099325619 163.311118500 0.039643804 1.101362852 163.317534900 0.039642063
2 237 1.101362852 163.317534900 0.039642063 1.103342119 163.323723100 0.039640367
2 238 1.103342119 163.323723100 0.039640367 1.105264876 163.329691800 0.039638715
2 239 1.105264876 163.329691800 0.039638715 1.107132561 163.335449100 0.039637105
;
run;
**DATA FILE FOR WEIGHT-FOR-AGE;
data wtcrv;
     infile cards pad;
     input sex _age _LW1 _MW1 _SW1 _LW2 _MW2 _SW2;
cards;
1 24 -0.196701960 12.599134940 0.108095077 -0.216501213 12.741543960 0.108166006
1 25 -0.216501213 12.741543960 0.108166006 -0.239790488 12.881022760 0.108274706
1 26 -0.239790488 12.881022760 0.108274706 -0.266315853 13.018423820 0.108421025
1 27 -0.266315853 13.018423820 0.108421025 -0.295754969 13.154496600 0.108604770
1 28 -0.295754969 13.154496600 0.108604770 -0.327729368 13.289896670 0.108825681
1 29 -0.327729368 13.289896670 0.108825681 -0.361817468 13.425194080 0.109083424
1 30 -0.361817468 13.425194080 0.109083424 -0.397568087 13.560881130 0.109377581
1 31 -0.397568087 13.560881130 0.109377581 -0.434520252 13.697378580 0.109707646
1 32 -0.434520252 13.697378580 0.109707646 -0.472188756 13.835046220 0.110073084
1 33 -0.472188756 13.835046220 0.110073084 -0.510116627 13.974182990 0.110473254
1 34 -0.510116627 13.974182990 0.110473254 -0.547885579 14.115032400 0.110907400
1 35 -0.547885579 14.115032400 0.110907400 -0.585070110 14.257796180 0.111374787
1 36 -0.585070110 14.257796180 0.111374787 -0.621319726 14.402627490 0.111874514
1 37 -0.621319726 14.402627490 0.111874514 -0.656295986 14.549646140 0.112405687
1 38 -0.656295986 14.549646140 0.112405687 -0.689735029 14.698933260 0.112967254
1 39 -0.689735029 14.698933260 0.112967254 -0.721410388 14.850541510 0.113558110
1 40 -0.721410388 14.850541510 0.113558110 -0.751175223 15.004491430 0.114176956


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 140 of 160
1 41 -0.751175223 15.004491430 0.114176956 -0.778904279 15.160784540 0.114822482
1 42 -0.778904279 15.160784540 0.114822482 -0.804515498 15.319402460 0.115493292
1 43 -0.804515498 15.319402460 0.115493292 -0.828003255 15.480303130 0.116187777
1 44 -0.828003255 15.480303130 0.116187777 -0.849380372 15.643433090 0.116904306
1 45 -0.849380372 15.643433090 0.116904306 -0.868699650 15.808725350 0.117641148
1 46 -0.868699650 15.808725350 0.117641148 -0.886033992 15.976104560 0.118396541
1 47 -0.886033992 15.976104560 0.118396541 -0.901507878 16.145481940 0.119168555
1 48 -0.901507878 16.145481940 0.119168555 -0.915241589 16.316767270 0.119955320
1 49 -0.915241589 16.316767270 0.119955320 -0.927377772 16.489864600 0.120754916
1 50 -0.927377772 16.489864600 0.120754916 -0.938069819 16.664675290 0.121565421
1 51 -0.938069819 16.664675290 0.121565421 -0.947477940 16.841099480 0.122384927
1 52 -0.947477940 16.841099480 0.122384927 -0.955765694 17.019037460 0.123211562
1 53 -0.955765694 17.019037460 0.123211562 -0.963096972 17.198390800 0.124043503
1 54 -0.963096972 17.198390800 0.124043503 -0.969633434 17.379063410 0.124878992
1 55 -0.969633434 17.379063410 0.124878992 -0.975532355 17.560962450 0.125716348
1 56 -0.975532355 17.560962450 0.125716348 -0.980937915 17.744000820 0.126554022
1 57 -0.980937915 17.744000820 0.126554022 -0.986006518 17.928091210 0.127390453
1 58 -0.986006518 17.928091210 0.127390453 -0.990866940 18.113156250 0.128224294
1 59 -0.990866940 18.113156250 0.128224294 -0.995644402 18.299122860 0.129054277
1 60 -0.995644402 18.299122860 0.129054277 -1.000453886 18.485924130 0.129879257
1 61 -1.000453886 18.485924130 0.129879257 -1.005399668 18.673499650 0.130698212
1 62 -1.005399668 18.673499650 0.130698212 -1.010575003 18.861795760 0.131510245
1 63 -1.010575003 18.861795760 0.131510245 -1.016061941 19.050765790 0.132314586
1 64 -1.016061941 19.050765790 0.132314586 -1.021931241 19.240370190 0.133110593
1 65 -1.021931241 19.240370190 0.133110593 -1.028242376 19.430576620 0.133897752
1 66 -1.028242376 19.430576620 0.133897752 -1.035043608 19.621360070 0.134675673
1 67 -1.035043608 19.621360070 0.134675673 -1.042372125 19.812702800 0.135444090
1 68 -1.042372125 19.812702800 0.135444090 -1.050254232 20.004594400 0.136202860
1 69 -1.050254232 20.004594400 0.136202860 -1.058705595 20.197031710 0.136951959
1 70 -1.058705595 20.197031710 0.136951959 -1.067731529 20.390018720 0.137691478
1 71 -1.067731529 20.390018720 0.137691478 -1.077321193 20.583568620 0.138421673
1 72 -1.077321193 20.583568620 0.138421673 -1.087471249 20.777695650 0.139142773
1 73 -1.087471249 20.777695650 0.139142773 -1.098152984 20.972426310 0.139855242
1 74 -1.098152984 20.972426310 0.139855242 -1.109334080 21.167791920 0.140559605
1 75 -1.109334080 21.167791920 0.140559605 -1.120974043 21.363830130 0.141256489
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1 78 -1.145431351 21.758105060 0.142630785 -1.158132499 21.956446270 0.143309898
1 79 -1.158132499 21.956446270 0.143309898 -1.171061612 22.155668420 0.143984924
1 80 -1.171061612 22.155668420 0.143984924 -1.184141975 22.355838620 0.144656953
1 81 -1.184141975 22.355838620 0.144656953 -1.197307185 22.557022680 0.145327009
1 82 -1.197307185 22.557022680 0.145327009 -1.210475099 22.759295580 0.145996289
1 83 -1.210475099 22.759295580 0.145996289 -1.223565263 22.962734400 0.146666000
1 84 -1.223565263 22.962734400 0.146666000 -1.236497304 23.167418880 0.147337375
1 85 -1.236497304 23.167418880 0.147337375 -1.249186293 23.373433410 0.148011715
1 86 -1.249186293 23.373433410 0.148011715 -1.261555446 23.580861450 0.148690256
1 87 -1.261555446 23.580861450 0.148690256 -1.273523619 23.789790960 0.149374297
1 88 -1.273523619 23.789790960 0.149374297 -1.285013783 24.000310640 0.150065107
1 89 -1.285013783 24.000310640 0.150065107 -1.295952066 24.212510280 0.150763933
1 90 -1.295952066 24.212510280 0.150763933 -1.306268473 24.426480430 0.151471982
1 91 -1.306268473 24.426480430 0.151471982 -1.315897530 24.642312000 0.152190413
1 92 -1.315897530 24.642312000 0.152190413 -1.324778843 24.860095960 0.152920322
1 93 -1.324778843 24.860095960 0.152920322 -1.332857581 25.079923030 0.153662731
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1 95 -1.340080195 25.301885840 0.154418635 -1.346412105 25.526069770 0.155188768
1 96 -1.346412105 25.526069770 0.155188768 -1.351813296 25.752565280 0.155973912
1 97 -1.351813296 25.752565280 0.155973912 -1.356253969 25.981459900 0.156774684
1 98 -1.356253969 25.981459900 0.156774684 -1.359710858 26.212839900 0.157591579
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1 100 -1.362167159 26.446790270 0.158424964 -1.363612378 26.683394570 0.159275071
1 101 -1.363612378 26.683394570 0.159275071 -1.364042106 26.922734940 0.160141995
1 102 -1.364042106 26.922734940 0.160141995 -1.363457829 27.164891990 0.161025689
1 103 -1.363457829 27.164891990 0.161025689 -1.361865669 27.409945390 0.161925976
1 104 -1.361865669 27.409945390 0.161925976 -1.359282610 27.657969780 0.162842452
1 105 -1.359282610 27.657969780 0.162842452 -1.355720571 27.909044330 0.163774719
1 106 -1.355720571 27.909044330 0.163774719 -1.351202536 28.163242640 0.164722138
1 107 -1.351202536 28.163242640 0.164722138 -1.345754408 28.420637440 0.165683945
1 108 -1.345754408 28.420637440 0.165683945 -1.339405453 28.681300050 0.166659247
1 109 -1.339405453 28.681300050 0.166659247 -1.332188093 28.945300290 0.167647017
1 110 -1.332188093 28.945300290 0.167647017 -1.324137479 29.212706450 0.168646104
1 111 -1.324137479 29.212706450 0.168646104 -1.315291073 29.483585270 0.169655235


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 141 of 160
1 112 -1.315291073 29.483585270 0.169655235 -1.305688240 29.758001980 0.170673022
1 113 -1.305688240 29.758001980 0.170673022 -1.295369867 30.036020210 0.171697970
1 114 -1.295369867 30.036020210 0.171697970 -1.284374967 30.317704170 0.172728540
1 115 -1.284374967 30.317704170 0.172728540 -1.272750864 30.603111070 0.173762961
1 116 -1.272750864 30.603111070 0.173762961 -1.260539193 30.892300720 0.174799493
1 117 -1.260539193 30.892300720 0.174799493 -1.247783611 31.185329840 0.175836284
1 118 -1.247783611 31.185329840 0.175836284 -1.234527763 31.482253150 0.176871417
1 119 -1.234527763 31.482253150 0.176871417 -1.220815047 31.783123290 0.177902912
1 120 -1.220815047 31.783123290 0.177902912 -1.206688407 32.087990620 0.178928740
1 121 -1.206688407 32.087990620 0.178928740 -1.192190150 32.396903130 0.179946830
1 122 -1.192190150 32.396903130 0.179946830 -1.177361786 32.709906200 0.180955078
1 123 -1.177361786 32.709906200 0.180955078 -1.162243894 33.027042440 0.181951361
1 124 -1.162243894 33.027042440 0.181951361 -1.146876007 33.348351480 0.182933537
1 125 -1.146876007 33.348351480 0.182933537 -1.131296524 33.673869730 0.183899465
1 126 -1.131296524 33.673869730 0.183899465 -1.115542634 34.003630170 0.184847006
1 127 -1.115542634 34.003630170 0.184847006 -1.099650267 34.337662070 0.185774041
1 128 -1.099650267 34.337662070 0.185774041 -1.083654055 34.675990760 0.186678470
1 129 -1.083654055 34.675990760 0.186678470 -1.067587314 35.018637320 0.187558229
1 130 -1.067587314 35.018637320 0.187558229 -1.051482972 35.365617370 0.188411280
1 131 -1.051482972 35.365617370 0.188411280 -1.035367321 35.716947230 0.189235738
1 132 -1.035367321 35.716947230 0.189235738 -1.019277299 36.072625690 0.190029545
1 133 -1.019277299 36.072625690 0.190029545 -1.003235326 36.432659960 0.190790973
1 134 -1.003235326 36.432659960 0.190790973 -0.987269866 36.797043920 0.191518224
1 135 -0.987269866 36.797043920 0.191518224 -0.971406609 37.165767100 0.192209619
1 136 -0.971406609 37.165767100 0.192209619 -0.955670107 37.538812680 0.192863569
1 137 -0.955670107 37.538812680 0.192863569 -0.940083834 37.916157210 0.193478582
1 138 -0.940083834 37.916157210 0.193478582 -0.924670244 38.297770300 0.194053274
1 139 -0.924670244 38.297770300 0.194053274 -0.909450843 38.683614300 0.194586368
1 140 -0.909450843 38.683614300 0.194586368 -0.894446258 39.073644010 0.195076705
1 141 -0.894446258 39.073644010 0.195076705 -0.879676305 39.467806430 0.195523246
1 142 -0.879676305 39.467806430 0.195523246 -0.865160071 39.866040440 0.195925079
1 143 -0.865160071 39.866040440 0.195925079 -0.850915987 40.268276520 0.196281418
1 144 -0.850915987 40.268276520 0.196281418 -0.836961905 40.674436580 0.196591612
1 145 -0.836961905 40.674436580 0.196591612 -0.823315176 41.084433630 0.196855140
1 146 -0.823315176 41.084433630 0.196855140 -0.809992726 41.498171640 0.197071620
1 147 -0.809992726 41.498171640 0.197071620 -0.797011132 41.915545280 0.197240806
1 148 -0.797011132 41.915545280 0.197240806 -0.784386693 42.336439780 0.197362591
1 149 -0.784386693 42.336439780 0.197362591 -0.772135506 42.760730780 0.197437004
1 150 -0.772135506 42.760730780 0.197437004 -0.760273528 43.188284190 0.197464210
1 151 -0.760273528 43.188284190 0.197464210 -0.748815968 43.618957030 0.197444522
1 152 -0.748815968 43.618957030 0.197444522 -0.737780398 44.052593100 0.197378345
1 153 -0.737780398 44.052593100 0.197378345 -0.727181568 44.489030270 0.197266263
1 154 -0.727181568 44.489030270 0.197266263 -0.717035494 44.928094830 0.197108968
1 155 -0.717035494 44.928094830 0.197108968 -0.707358338 45.369603150 0.196907274
1 156 -0.707358338 45.369603150 0.196907274 -0.698166437 45.813361720 0.196662115
1 157 -0.698166437 45.813361720 0.196662115 -0.689476327 46.259167290 0.196374538
1 158 -0.689476327 46.259167290 0.196374538 -0.681304750 46.706807010 0.196045701
1 159 -0.681304750 46.706807010 0.196045701 -0.673668658 47.156058630 0.195676862
1 160 -0.673668658 47.156058630 0.195676862 -0.666585194 47.606690740 0.195269380
1 161 -0.666585194 47.606690740 0.195269380 -0.660069969 48.058465720 0.194824730
1 162 -0.660069969 48.058465720 0.194824730 -0.654142602 48.511131380 0.194344410
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1 164 -0.648819666 48.964432240 0.193830046 -0.644118611 49.418103740 0.193283319
1 165 -0.644118611 49.418103740 0.193283319 -0.640056805 49.871874090 0.192705974
1 166 -0.640056805 49.871874090 0.192705974 -0.636651424 50.325464780 0.192099812
1 167 -0.636651424 50.325464780 0.192099812 -0.633919328 50.778591210 0.191466681
1 168 -0.633919328 50.778591210 0.191466681 -0.631876912 51.230963320 0.190808471
1 169 -0.631876912 51.230963320 0.190808471 -0.630539940 51.682286250 0.190127105
1 170 -0.630539940 51.682286250 0.190127105 -0.629923353 52.132261130 0.189424530
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Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 142 of 160
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Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 143 of 160
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Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 144 of 160
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2 149 -0.833586038 43.264415500 0.201185082 -0.841634949 43.616834020 0.200818928
2 150 -0.841634949 43.616834020 0.200818928 -0.850307441 43.966116900 0.200419208
2 151 -0.850307441 43.966116900 0.200419208 -0.859607525 44.312035790 0.199986681
2 152 -0.859607525 44.312035790 0.199986681 -0.869534339 44.654373190 0.199522233
2 153 -0.869534339 44.654373190 0.199522233 -0.880088651 44.992913560 0.199026736
2 154 -0.880088651 44.992913560 0.199026736 -0.891270585 45.327447040 0.198501096
2 155 -0.891270585 45.327447040 0.198501096 -0.903079458 45.657770130 0.197946255
2 156 -0.903079458 45.657770130 0.197946255 -0.915513542 45.983686560 0.197363191
2 157 -0.915513542 45.983686560 0.197363191 -0.928569454 46.305008580 0.196752931
2 158 -0.928569454 46.305008580 0.196752931 -0.942245864 46.621551830 0.196116472
2 159 -0.942245864 46.621551830 0.196116472 -0.956537923 46.933144040 0.195454890
2 160 -0.956537923 46.933144040 0.195454890 -0.971440492 47.239620580 0.194769279
2 161 -0.971440492 47.239620580 0.194769279 -0.986947308 47.540826040 0.194060758
2 162 -0.986947308 47.540826040 0.194060758 -1.003050887 47.836614660 0.193330477
2 163 -1.003050887 47.836614660 0.193330477 -1.019742425 48.126850820 0.192579614
2 164 -1.019742425 48.126850820 0.192579614 -1.037011698 48.411409380 0.191809374
2 165 -1.037011698 48.411409380 0.191809374 -1.054846957 48.690176130 0.191020995
2 166 -1.054846957 48.690176130 0.191020995 -1.073234825 48.963048100 0.190215739
2 167 -1.073234825 48.963048100 0.190215739 -1.092160195 49.229933910 0.189394901
2 168 -1.092160195 49.229933910 0.189394901 -1.111606122 49.490754090 0.188559804
2 169 -1.111606122 49.490754090 0.188559804 -1.131553723 49.745441320 0.187711798
2 170 -1.131553723 49.745441320 0.187711798 -1.151982079 49.993940680 0.186852266
2 171 -1.151982079 49.993940680 0.186852266 -1.172868141 50.236209850 0.185982617
2 172 -1.172868141 50.236209850 0.185982617 -1.194184620 50.472222130 0.185104331
2 173 -1.194184620 50.472222130 0.185104331 -1.215907492 50.701955810 0.184218803
2 174 -1.215907492 50.701955810 0.184218803 -1.238005268 50.925409420 0.183327556
2 175 -1.238005268 50.925409420 0.183327556 -1.260445591 51.142592290 0.182432113
2 176 -1.260445591 51.142592290 0.182432113 -1.283193626 51.353526800 0.181534018
2 177 -1.283193626 51.353526800 0.181534018 -1.306212032 51.558248310 0.180634839
2 178 -1.306212032 51.558248310 0.180634839 -1.329460945 51.756805130 0.179736168
2 179 -1.329460945 51.756805130 0.179736168 -1.352897980 51.949258410 0.178839614


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 145 of 160
2 180 -1.352897980 51.949258410 0.178839614 -1.376478254 52.135681930 0.177946804
2 181 -1.376478254 52.135681930 0.177946804 -1.400154426 52.316161970 0.177059379
2 182 -1.400154426 52.316161970 0.177059379 -1.423876772 52.490797030 0.176178990
2 183 -1.423876772 52.490797030 0.176178990 -1.447593267 52.659697570 0.175307296
2 184 -1.447593267 52.659697570 0.175307296 -1.471249702 52.822985720 0.174445958
2 185 -1.471249702 52.822985720 0.174445958 -1.494789826 52.980794900 0.173596636
2 186 -1.494789826 52.980794900 0.173596636 -1.518155513 53.133269460 0.172760982
2 187 -1.518155513 53.133269460 0.172760982 -1.541286949 53.280564250 0.171940640
2 188 -1.541286949 53.280564250 0.171940640 -1.564122852 53.422844170 0.171137232
2 189 -1.564122852 53.422844170 0.171137232 -1.586600712 53.560283700 0.170352363
2 190 -1.586600712 53.560283700 0.170352363 -1.608657054 53.693066370 0.169587605
2 191 -1.608657054 53.693066370 0.169587605 -1.630227728 53.821384220 0.168844497
2 192 -1.630227728 53.821384220 0.168844497 -1.651248208 53.945437250 0.168124538
2 193 -1.651248208 53.945437250 0.168124538 -1.671653920 54.065432780 0.167429179
2 194 -1.671653920 54.065432780 0.167429179 -1.691380583 54.181584860 0.166759816
2 195 -1.691380583 54.181584860 0.166759816 -1.710364557 54.294113560 0.166117788
2 196 -1.710364557 54.294113560 0.166117788 -1.728543207 54.403244310 0.165504365
2 197 -1.728543207 54.403244310 0.165504365 -1.745855274 54.509207170 0.164920747
2 198 -1.745855274 54.509207170 0.164920747 -1.762241248 54.612236030 0.164368054
2 199 -1.762241248 54.612236030 0.164368054 -1.777643747 54.712567870 0.163847320
2 200 -1.777643747 54.712567870 0.163847320 -1.792007891 54.810441840 0.163359491
2 201 -1.792007891 54.810441840 0.163359491 -1.805281675 54.906098420 0.162905415
2 202 -1.805281675 54.906098420 0.162905415 -1.817416335 54.999778460 0.162485839
2 203 -1.817416335 54.999778460 0.162485839 -1.828366707 55.091722170 0.162101402
2 204 -1.828366707 55.091722170 0.162101402 -1.838091576 55.182168110 0.161752634
2 205 -1.838091576 55.182168110 0.161752634 -1.846554015 55.271352000 0.161439944
2 206 -1.846554015 55.271352000 0.161439944 -1.853721704 55.359505580 0.161163623
2 207 -1.853721704 55.359505580 0.161163623 -1.859567242 55.446855310 0.160923833
2 208 -1.859567242 55.446855310 0.160923833 -1.864068443 55.533621070 0.160720609
2 209 -1.864068443 55.533621070 0.160720609 -1.867208610 55.620014640 0.160553850
2 210 -1.867208610 55.620014640 0.160553850 -1.868976800 55.706238260 0.160423319
2 211 -1.868976800 55.706238260 0.160423319 -1.869371157 55.792479390 0.160328578
2 212 -1.869371157 55.792479390 0.160328578 -1.868386498 55.878923560 0.160269232
2 213 -1.868386498 55.878923560 0.160269232 -1.866033924 55.965730220 0.160244549
2 214 -1.866033924 55.965730220 0.160244549 -1.862327775 56.053046010 0.160253714
2 215 -1.862327775 56.053046010 0.160253714 -1.857289195 56.140998820 0.160295765
2 216 -1.857289195 56.140998820 0.160295765 -1.850946286 56.229695640 0.160369590
2 217 -1.850946286 56.229695640 0.160369590 -1.843334250 56.319220300 0.160473930
2 218 -1.843334250 56.319220300 0.160473930 -1.834495505 56.409631050 0.160607377
2 219 -1.834495505 56.409631050 0.160607377 -1.824479785 56.500958110 0.160768380
2 220 -1.824479785 56.500958110 0.160768380 -1.813344222 56.593201070 0.160955249
2 221 -1.813344222 56.593201070 0.160955249 -1.801153404 56.686326190 0.161166157
2 222 -1.801153404 56.686326190 0.161166157 -1.787979408 56.780263640 0.161399151
2 223 -1.787979408 56.780263640 0.161399151 -1.773901816 56.874904650 0.161652158
2 224 -1.773901816 56.874904650 0.161652158 -1.759007704 56.970098560 0.161922998
2 225 -1.759007704 56.970098560 0.161922998 -1.743391606 57.065649890 0.162209399
2 226 -1.743391606 57.065649890 0.162209399 -1.727155460 57.161315280 0.162509006
2 227 -1.727155460 57.161315280 0.162509006 -1.710410733 57.256798210 0.162819353
2 228 -1.710410733 57.256798210 0.162819353 -1.693267093 57.351757920 0.163138124
2 229 -1.693267093 57.351757920 0.163138124 -1.675854420 57.445781720 0.163462715
2 230 -1.675854420 57.445781720 0.163462715 -1.658302847 57.538404290 0.163790683
2 231 -1.658302847 57.538404290 0.163790683 -1.640747464 57.629100940 0.164119574
2 232 -1.640747464 57.629100940 0.164119574 -1.623332891 57.717275800 0.164446997
2 233 -1.623332891 57.717275800 0.164446997 -1.606209374 57.802265530 0.164770638
2 234 -1.606209374 57.802265530 0.164770638 -1.589533346 57.883335020 0.165088289
2 235 -1.589533346 57.883335020 0.165088289 -1.573467222 57.959674580 0.165397881
2 236 -1.573467222 57.959674580 0.165397881 -1.558179166 58.030397300 0.165697507
2 237 -1.558179166 58.030397300 0.165697507 -1.543846192 58.094532090 0.165985386
2 238 -1.543846192 58.094532090 0.165985386 -1.530642461 58.151035750 0.166260109
2 239 -1.530642461 58.151035750 0.166260109 -1.518754013 58.198771400 0.166520370
;
run;
**DATA FILE FOR BMI-FOR-AGE;
data bmicrv;
     infile cards pad;
     input sex _age _LB1 _MB1 _SB1 _LB2 _MB2 _SB2;
cards;
1 24 -2.039988545 16.602280490 0.081057501 -1.982373595 16.547774870 0.080127429
1 25 -1.982373595 16.547774870 0.080127429 -1.924100169 16.494427630 0.079233994


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 146 of 160
1 26 -1.924100169 16.494427630 0.079233994 -1.865497930 16.442595520 0.078389356
1 27 -1.865497930 16.442595520 0.078389356 -1.807261899 16.392243400 0.077593501
1 28 -1.807261899 16.392243400 0.077593501 -1.750118905 16.343336540 0.076846462
1 29 -1.750118905 16.343336540 0.076846462 -1.694815840 16.295840970 0.076148308
1 30 -1.694815840 16.295840970 0.076148308 -1.642106779 16.249723710 0.075499126
1 31 -1.642106779 16.249723710 0.075499126 -1.592744414 16.204952680 0.074898994
1 32 -1.592744414 16.204952680 0.074898994 -1.547442391 16.161498710 0.074347997
1 33 -1.547442391 16.161498710 0.074347997 -1.506902601 16.119332580 0.073846139
1 34 -1.506902601 16.119332580 0.073846139 -1.471770047 16.078427580 0.073393370
1 35 -1.471770047 16.078427580 0.073393370 -1.442628957 16.038758960 0.072989551
1 36 -1.442628957 16.038758960 0.072989551 -1.419991255 16.000304010 0.072634432
1 37 -1.419991255 16.000304010 0.072634432 -1.404277619 15.963042770 0.072327649
1 38 -1.404277619 15.963042770 0.072327649 -1.395863170 15.926954180 0.072068640
1 39 -1.395863170 15.926954180 0.072068640 -1.394935252 15.892025820 0.071856805
1 40 -1.394935252 15.892025820 0.071856805 -1.401671596 15.858240930 0.071691278
1 41 -1.401671596 15.858240930 0.071691278 -1.416100312 15.825588220 0.071571093
1 42 -1.416100312 15.825588220 0.071571093 -1.438164899 15.794057280 0.071495113
1 43 -1.438164899 15.794057280 0.071495113 -1.467669032 15.763642550 0.071462106
1 44 -1.467669032 15.763642550 0.071462106 -1.504376347 15.734336680 0.071470646
1 45 -1.504376347 15.734336680 0.071470646 -1.547942838 15.706135660 0.071519218
1 46 -1.547942838 15.706135660 0.071519218 -1.597896397 15.679040620 0.071606277
1 47 -1.597896397 15.679040620 0.071606277 -1.653732283 15.653051920 0.071730167
1 48 -1.653732283 15.653051920 0.071730167 -1.714869347 15.628172690 0.071889214
1 49 -1.714869347 15.628172690 0.071889214 -1.780673181 15.604408000 0.072081737
1 50 -1.780673181 15.604408000 0.072081737 -1.850468473 15.581764580 0.072306081
1 51 -1.850468473 15.581764580 0.072306081 -1.923551865 15.560250670 0.072560637
1 52 -1.923551865 15.560250670 0.072560637 -1.999220429 15.539874600 0.072843840
1 53 -1.999220429 15.539874600 0.072843840 -2.076707178 15.520649930 0.073154324
1 54 -2.076707178 15.520649930 0.073154324 -2.155348017 15.502584270 0.073490667
1 55 -2.155348017 15.502584270 0.073490667 -2.234438552 15.485689730 0.073851672
1 56 -2.234438552 15.485689730 0.073851672 -2.313321723 15.469977180 0.074236235
1 57 -2.313321723 15.469977180 0.074236235 -2.391381273 15.455456920 0.074643374
1 58 -2.391381273 15.455456920 0.074643374 -2.468032491 15.442139610 0.075072264
1 59 -2.468032491 15.442139610 0.075072264 -2.542781541 15.430032070 0.075522104
1 60 -2.542781541 15.430032070 0.075522104 -2.615165950 15.419141630 0.075992250
1 61 -2.615165950 15.419141630 0.075992250 -2.684789516 15.409473560 0.076482128
1 62 -2.684789516 15.409473560 0.076482128 -2.751316949 15.401031390 0.076991232
1 63 -2.751316949 15.401031390 0.076991232 -2.814459450 15.393817850 0.077519149
1 64 -2.814459450 15.393817850 0.077519149 -2.874024760 15.387830940 0.078065390
1 65 -2.874024760 15.387830940 0.078065390 -2.929840480 15.383069450 0.078629592
1 66 -2.929840480 15.383069450 0.078629592 -2.981796828 15.379529580 0.079211369
1 67 -2.981796828 15.379529580 0.079211369 -3.029831343 15.377205820 0.079810334
1 68 -3.029831343 15.377205820 0.079810334 -3.073924224 15.376091070 0.080426086
1 69 -3.073924224 15.376091070 0.080426086 -3.114093476 15.376176770 0.081058206
1 70 -3.114093476 15.376176770 0.081058206 -3.150390040 15.377453040 0.081706249
1 71 -3.150390040 15.377453040 0.081706249 -3.182893018 15.379908860 0.082369741
1 72 -3.182893018 15.379908860 0.082369741 -3.211705110 15.383532170 0.083048178
1 73 -3.211705110 15.383532170 0.083048178 -3.236948340 15.388310050 0.083741021
1 74 -3.236948340 15.388310050 0.083741021 -3.258760110 15.394228830 0.084447700
1 75 -3.258760110 15.394228830 0.084447700 -3.277281546 15.401274960 0.085167651
1 76 -3.277281546 15.401274960 0.085167651 -3.292683774 15.409432520 0.085900184
1 77 -3.292683774 15.409432520 0.085900184 -3.305124073 15.418686910 0.086644667
1 78 -3.305124073 15.418686910 0.086644667 -3.314768951 15.429022730 0.087400421
1 79 -3.314768951 15.429022730 0.087400421 -3.321785992 15.440424390 0.088166744
1 80 -3.321785992 15.440424390 0.088166744 -3.326345795 15.452875810 0.088942897
1 81 -3.326345795 15.452875810 0.088942897 -3.328602731 15.466362180 0.089728202
1 82 -3.328602731 15.466362180 0.089728202 -3.328725277 15.480867040 0.090521875
1 83 -3.328725277 15.480867040 0.090521875 -3.326870180 15.496374650 0.091323162
1 84 -3.326870180 15.496374650 0.091323162 -3.323188896 15.512869360 0.092131305
1 85 -3.323188896 15.512869360 0.092131305 -3.317827016 15.530335630 0.092945544
1 86 -3.317827016 15.530335630 0.092945544 -3.310923871 15.548758070 0.093765118
1 87 -3.310923871 15.548758070 0.093765118 -3.302612272 15.568121430 0.094589270
1 88 -3.302612272 15.568121430 0.094589270 -3.293018361 15.588410650 0.095417247
1 89 -3.293018361 15.588410650 0.095417247 -3.282260813 15.609611010 0.096248301
1 90 -3.282260813 15.609611010 0.096248301 -3.270454609 15.631707350 0.097081694
1 91 -3.270454609 15.631707350 0.097081694 -3.257703616 15.654685630 0.097916698
1 92 -3.257703616 15.654685630 0.097916698 -3.244108214 15.678531390 0.098752593
1 93 -3.244108214 15.678531390 0.098752593 -3.229761713 15.703230520 0.099588675
1 94 -3.229761713 15.703230520 0.099588675 -3.214751287 15.728769110 0.100424251
1 95 -3.214751287 15.728769110 0.100424251 -3.199158184 15.755133470 0.101258643
1 96 -3.199158184 15.755133470 0.101258643 -3.183057950 15.782310070 0.102091189


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 147 of 160
1 97 -3.183057950 15.782310070 0.102091189 -3.166520664 15.810285600 0.102921245
1 98 -3.166520664 15.810285600 0.102921245 -3.149610300 15.839047080 0.103748189
1 99 -3.149610300 15.839047080 0.103748189 -3.132389637 15.868581230 0.104571386
1 100 -3.132389637 15.868581230 0.104571386 -3.114911153 15.898875620 0.105390269
1 101 -3.114911153 15.898875620 0.105390269 -3.097226399 15.929917650 0.106204258
1 102 -3.097226399 15.929917650 0.106204258 -3.079383079 15.961694810 0.107012788
1 103 -3.079383079 15.961694810 0.107012788 -3.061423765 15.994194890 0.107815327
1 104 -3.061423765 15.994194890 0.107815327 -3.043386071 16.027406070 0.108611374
1 105 -3.043386071 16.027406070 0.108611374 -3.025310003 16.061315900 0.109400388
1 106 -3.025310003 16.061315900 0.109400388 -3.007225737 16.095912920 0.110181915
1 107 -3.007225737 16.095912920 0.110181915 -2.989164598 16.131185320 0.110955478
1 108 -2.989164598 16.131185320 0.110955478 -2.971148225 16.167122340 0.111720691
1 109 -2.971148225 16.167122340 0.111720691 -2.953208047 16.203711680 0.112477059
1 110 -2.953208047 16.203711680 0.112477059 -2.935363951 16.240942390 0.113224200
1 111 -2.935363951 16.240942390 0.113224200 -2.917635157 16.278803460 0.113961734
1 112 -2.917635157 16.278803460 0.113961734 -2.900039803 16.317283850 0.114689291
1 113 -2.900039803 16.317283850 0.114689291 -2.882593796 16.356372670 0.115406523
1 114 -2.882593796 16.356372670 0.115406523 -2.865311266 16.396059160 0.116113097
1 115 -2.865311266 16.396059160 0.116113097 -2.848204697 16.436332650 0.116808702
1 116 -2.848204697 16.436332650 0.116808702 -2.831285052 16.477182560 0.117493042
1 117 -2.831285052 16.477182560 0.117493042 -2.814561890 16.518598430 0.118165840
1 118 -2.814561890 16.518598430 0.118165840 -2.798043470 16.560569870 0.118826835
1 119 -2.798043470 16.560569870 0.118826835 -2.781736856 16.603086610 0.119475785
1 120 -2.781736856 16.603086610 0.119475785 -2.765648008 16.646138440 0.120112464
1 121 -2.765648008 16.646138440 0.120112464 -2.749782197 16.689715180 0.120736656
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Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 148 of 160
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Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 149 of 160
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Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 3.0
ISN/Protocol 178-CL-206A
21-May-2019
Astellas
Page 150 of 160
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2 100 -2.547141473 15.938015450 0.120004290 -2.524635245 15.976407870 0.120935994
2 101 -2.524635245 15.976407870 0.120935994 -2.502569666 16.015464830 0.121858355
2 102 -2.502569666 16.015464830 0.121858355 -2.480951890 16.055169840 0.122770870
2 103 -2.480951890 16.055169840 0.122770870 -2.459785573 16.095506880 0.123673085
2 104 -2.459785573 16.095506880 0.123673085 -2.439080117 16.136458810 0.124564484
2 105 -2.439080117 16.136458810 0.124564484 -2.418838304 16.178009550 0.125444639
2 106 -2.418838304 16.178009550 0.125444639 -2.399063683 16.220142810 0.126313121
2 107 -2.399063683 16.220142810 0.126313121 -2.379756861 16.262842770 0.127169545
2 108 -2.379756861 16.262842770 0.127169545 -2.360920527 16.306093160 0.128013515
2 109 -2.360920527 16.306093160 0.128013515 -2.342557728 16.349877590 0.128844639
2 110 -2.342557728 16.349877590 0.128844639 -2.324663326 16.394181180 0.129662637
2 111 -2.324663326 16.394181180 0.129662637 -2.307240716 16.438987410 0.130467138
2 112 -2.307240716 16.438987410 0.130467138 -2.290287663 16.484280820 0.131257852
2 113 -2.290287663 16.484280820 0.131257852 -2.273803847 16.530045540 0.132034479
2 114 -2.273803847 16.530045540 0.132034479 -2.257782149 16.576267130 0.132796819
2 115 -2.257782149 16.576267130 0.132796819 -2.242227723 16.622928640 0.133544525
2 116 -2.242227723 16.622928640 0.133544525 -2.227132805 16.670015720 0.134277436
2 117 -2.227132805 16.670015720 0.134277436 -2.212495585 16.717512880 0.134995324
2 118 -2.212495585 16.717512880 0.134995324 -2.198312750 16.765404960 0.135697996
2 119 -2.198312750 16.765404960 0.135697996 -2.184580762 16.813676890 0.136385276
2 120 -2.184580762 16.813676890 0.136385276 -2.171295888 16.862313660 0.137057004
2 121 -2.171295888 16.862313660 0.137057004 -2.158454232 16.911300360 0.137713039
2 122 -2.158454232 16.911300360 0.137713039 -2.146051754 16.960622160 0.138353254
2 123 -2.146051754 16.960622160 0.138353254 -2.134084303 17.010264300 0.138977537
2 124 -2.134084303 17.010264300 0.138977537 -2.122547629 17.060212130 0.139585795
2 125 -2.122547629 17.060212130 0.139585795 -2.111437411 17.110451060 0.140177947
2 126 -2.111437411 17.110451060 0.140177947 -2.100749266 17.160966560 0.140753927
2 127 -2.100749266 17.160966560 0.140753927 -2.090478774 17.211744240 0.141313686
2 128 -2.090478774 17.211744240 0.141313686 -2.080621484 17.262769730 0.141857186
2 129 -2.080621484 17.262769730 0.141857186 -2.071172932 17.314028780 0.142384404
2 130 -2.071172932 17.314028780 0.142384404 -2.062128649 17.365507200 0.142895332
2 131 -2.062128649 17.365507200 0.142895332 -2.053484173 17.417190900 0.143389972
2 132 -2.053484173 17.417190900 0.143389972 -2.045235058 17.469065850 0.143868341
2 133 -2.045235058 17.469065850 0.143868341 -2.037376880 17.521118110 0.144330469
2 134 -2.037376880 17.521118110 0.144330469 -2.029906684 17.573333470 0.144776372
2 135 -2.029906684 17.573333470 0.144776372 -2.022817914 17.625698690 0.145206138
2 136 -2.022817914 17.625698690 0.145206138 -2.016107084 17.678199870 0.145619819
2 137 -2.016107084 17.678199870 0.145619819 -2.009769905 17.730823400 0.146017491
2 138 -2.009769905 17.730823400 0.146017491 -2.003802134 17.783555750 0.146399239
2 139 -2.003802134 17.783555750 0.146399239 -1.998199572 17.836383470 0.146765161
2 140 -1.998199572 17.836383470 0.146765161 -1.992958064 17.889293210 0.147115364
2 141 -1.992958064 17.889293210 0.147115364 -1.988073505 17.942271680 0.147449967
2 142 -1.988073505 17.942271680 0.147449967 -1.983541835 17.995305700 0.147769097
2 143 -1.983541835 17.995305700 0.147769097 -1.979359041 18.048382160 0.148072891
2 144 -1.979359041 18.048382160 0.148072891 -1.975521156 18.101488040 0.148361495
2 145 -1.975521156 18.101488040 0.148361495 -1.972024258 18.154610390 0.148635067
2 146 -1.972024258 18.154610390 0.148635067 -1.968864465 18.207736390 0.148893769
2 147 -1.968864465 18.207736390 0.148893769 -1.966037938 18.260853250 0.149137776
2 148 -1.966037938 18.260853250 0.149137776 -1.963540872 18.313948320 0.149367270
2 149 -1.963540872 18.313948320 0.149367270 -1.961369499 18.367009020 0.149582439
2 150 -1.961369499 18.367009020 0.149582439 -1.959520079 18.420022840 0.149783482
2 151 -1.959520079 18.420022840 0.149783482 -1.957988900 18.472977390 0.149970604
2 152 -1.957988900 18.472977390 0.149970604 -1.956772271 18.525860350 0.150144020
2 153 -1.956772271 18.525860350 0.150144020 -1.955866520 18.578659510 0.150303950
2 154 -1.955866520 18.578659510 0.150303950 -1.955267984 18.631362750 0.150450621
2 155 -1.955267984 18.631362750 0.150450621 -1.954973011 18.683958010 0.150584270
2 156 -1.954973011 18.683958010 0.150584270 -1.954977947 18.736433380 0.150705138
2 157 -1.954977947 18.736433380 0.150705138 -1.955279136 18.788777000 0.150813475
2 158 -1.955279136 18.788777000 0.150813475 -1.955872909 18.840977130 0.150909535
2 159 -1.955872909 18.840977130 0.150909535 -1.956755579 18.893022120 0.150993582
2 160 -1.956755579 18.893022120 0.150993582 -1.957923436 18.944900410 0.151065883
2 161 -1.957923436 18.944900410 0.151065883 -1.959372737 18.996600550 0.151126714
2 162 -1.959372737 18.996600550 0.151126714 -1.961099700 19.048111180 0.151176355
2 163 -1.961099700 19.048111180 0.151176355 -1.963100496 19.099421050 0.151215094
2 164 -1.963100496 19.099421050 0.151215094 -1.965371240 19.150518990 0.151243223


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21-May-2019
Astellas
Page 151 of 160
2 165 -1.965371240 19.150518990 0.151243223 -1.967907983 19.201393970 0.151261042
2 166 -1.967907983 19.201393970 0.151261042 -1.970706706 19.252035030 0.151268855
2 167 -1.970706706 19.252035030 0.151268855 -1.973763307 19.302431310 0.151266974
2 168 -1.973763307 19.302431310 0.151266974 -1.977073595 19.352572090 0.151255713
2 169 -1.977073595 19.352572090 0.151255713 -1.980633277 19.402446710 0.151235395
2 170 -1.980633277 19.402446710 0.151235395 -1.984437954 19.452044650 0.151206347
2 171 -1.984437954 19.452044650 0.151206347 -1.988483106 19.501355480 0.151168902
2 172 -1.988483106 19.501355480 0.151168902 -1.992764085 19.550368880 0.151123398
2 173 -1.992764085 19.550368880 0.151123398 -1.997276103 19.599074640 0.151070180
2 174 -1.997276103 19.599074640 0.151070180 -2.002014224 19.647462660 0.151009595
2 175 -2.002014224 19.647462660 0.151009595 -2.006973350 19.695522940 0.150942000
2 176 -2.006973350 19.695522940 0.150942000 -2.012148213 19.743245600 0.150867753
2 177 -2.012148213 19.743245600 0.150867753 -2.017533363 19.790620860 0.150787221
2 178 -2.017533363 19.790620860 0.150787221 -2.023123159 19.837639070 0.150700774
2 179 -2.023123159 19.837639070 0.150700774 -2.028911755 19.884290660 0.150608788
2 180 -2.028911755 19.884290660 0.150608788 -2.034893091 19.930566200 0.150511645
2 181 -2.034893091 19.930566200 0.150511645 -2.041060881 19.976456360 0.150409731
2 182 -2.041060881 19.976456360 0.150409731 -2.047408604 20.021951920 0.150303440
2 183 -2.047408604 20.021951920 0.150303440 -2.053929490 20.067043770 0.150193169
2 184 -2.053929490 20.067043770 0.150193169 -2.060616513 20.111722910 0.150079322
2 185 -2.060616513 20.111722910 0.150079322 -2.067462375 20.155980470 0.149962308
2 186 -2.067462375 20.155980470 0.149962308 -2.074459502 20.199807670 0.149842540
2 187 -2.074459502 20.199807670 0.149842540 -2.081600029 20.243195860 0.149720441
2 188 -2.081600029 20.243195860 0.149720441 -2.088875793 20.286136480 0.149596434
2 189 -2.088875793 20.286136480 0.149596434 -2.096278323 20.328621090 0.149470953
2 190 -2.096278323 20.328621090 0.149470953 -2.103798828 20.370641380 0.149344433
2 191 -2.103798828 20.370641380 0.149344433 -2.111428194 20.412189110 0.149217319
2 192 -2.111428194 20.412189110 0.149217319 -2.119156972 20.453256170 0.149090060
2 193 -2.119156972 20.453256170 0.149090060 -2.126975375 20.493834570 0.148963110
2 194 -2.126975375 20.493834570 0.148963110 -2.134873266 20.533916400 0.148836931
2 195 -2.134873266 20.533916400 0.148836931 -2.142840157 20.573493870 0.148711989
2 196 -2.142840157 20.573493870 0.148711989 -2.150865204 20.612559290 0.148588757
2 197 -2.150865204 20.612559290 0.148588757 -2.158937201 20.651105060 0.148467715
2 198 -2.158937201 20.651105060 0.148467715 -2.167044578 20.689123700 0.148349348
2 199 -2.167044578 20.689123700 0.148349348 -2.175176987 20.726607280 0.148234120
2 200 -2.175176987 20.726607280 0.148234120 -2.183317362 20.763550110 0.148122614
2 201 -2.183317362 20.763550110 0.148122614 -2.191457792 20.799943370 0.148015249
2 202 -2.191457792 20.799943370 0.148015249 -2.199583649 20.835780510 0.147912564
2 203 -2.199583649 20.835780510 0.147912564 -2.207681525 20.871054490 0.147815078
2 204 -2.207681525 20.871054490 0.147815078 -2.215737645 20.905758390 0.147723315
2 205 -2.215737645 20.905758390 0.147723315 -2.223739902 20.939884770 0.147637768
2 206 -2.223739902 20.939884770 0.147637768 -2.231667995 20.973428580 0.147559083
2 207 -2.231667995 20.973428580 0.147559083 -2.239511942 21.006381710 0.147487716
2 208 -2.239511942 21.006381710 0.147487716 -2.247257081 21.038737400 0.147424210
2 209 -2.247257081 21.038737400 0.147424210 -2.254885145 21.070489960 0.147369174
2 210 -2.254885145 21.070489960 0.147369174 -2.262382090 21.101632410 0.147323144
2 211 -2.262382090 21.101632410 0.147323144 -2.269731517 21.132158450 0.147286698
2 212 -2.269731517 21.132158450 0.147286698 -2.276917229 21.162061710 0.147260415
2 213 -2.276917229 21.162061710 0.147260415 -2.283925442 21.191335100 0.147244828
2 214 -2.283925442 21.191335100 0.147244828 -2.290731442 21.219974720 0.147240683
2 215 -2.290731442 21.219974720 0.147240683 -2.297324270 21.247972620 0.147248467
2 216 -2.297324270 21.247972620 0.147248467 -2.303687802 21.275322390 0.147268770
2 217 -2.303687802 21.275322390 0.147268770 -2.309799971 21.302019330 0.147302299
2 218 -2.309799971 21.302019330 0.147302299 -2.315651874 21.328054890 0.147349514
2 219 -2.315651874 21.328054890 0.147349514 -2.321217310 21.353425630 0.147411215
2 220 -2.321217310 21.353425630 0.147411215 -2.326481911 21.378124620 0.147487979
2 221 -2.326481911 21.378124620 0.147487979 -2.331428139 21.402145890 0.147580453
2 222 -2.331428139 21.402145890 0.147580453 -2.336038473 21.425483510 0.147689289
2 223 -2.336038473 21.425483510 0.147689289 -2.340295450 21.448131560 0.147815150
2 224 -2.340295450 21.448131560 0.147815150 -2.344181703 21.470084120 0.147958706
2 225 -2.344181703 21.470084120 0.147958706 -2.347680000 21.491335290 0.148120633
2 226 -2.347680000 21.491335290 0.148120633 -2.350773286 21.511879180 0.148301619
2 227 -2.350773286 21.511879180 0.148301619 -2.353444725 21.531709890 0.148502355
2 228 -2.353444725 21.531709890 0.148502355 -2.355677743 21.550821550 0.148723546
2 229 -2.355677743 21.550821550 0.148723546 -2.357456070 21.569208240 0.148965902
2 230 -2.357456070 21.569208240 0.148965902 -2.358763788 21.586864060 0.149230142
2 231 -2.358763788 21.586864060 0.149230142 -2.359585369 21.603783090 0.149516994
2 232 -2.359585369 21.603783090 0.149516994 -2.359905726 21.619959390 0.149827195
2 233 -2.359905726 21.619959390 0.149827195 -2.359710258 21.635387000 0.150161492
2 234 -2.359710258 21.635387000 0.150161492 -2.358980464 21.650061260 0.150520734
2 235 -2.358980464 21.650061260 0.150520734 -2.357714508 21.663972700 0.150905439


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2 236 -2.357714508 21.663972700 0.150905439 -2.355892424 21.677117360 0.151316531
2 237 -2.355892424 21.677117360 0.151316531 -2.353501353 21.689489350 0.151754808
2 238 -2.353501353 21.689489350 0.151754808 -2.350528726 21.701082880 0.152221086
2 239 -2.350528726 21.701082880 0.152221086 -2.346962247 21.711892250 0.152716206
;
run;
data curves;
     merge htcrv wtcrv bmicrv;
           by sex _age;
run;
data test; 
     set datain;  
     _age=int(agemos+0.5);                             *age rounded to nearest month; 
     _id=_N_;
run;
proc sort data=test out=test2; 
     by sex _age _id;
run;
data test2; 
     merge test2(in=a) curves(in=b); 
           by sex _age;
     if a;
     if height lt 45 or height gt 300 then _ht=.;      *implausible height;
     else _ht=height;
     if weight lt 10 or weight gt 150 then _wt=.;      *implausible weight;
     else wt=weight;
     if bmi lt 10 or bmi gt 45 then _bmi=.;            *implausible bmi;
     else _bmi=bmi;
     _r=(agemos-_age+0.5); 
     ***HEIGHT***;
     if _ht eq . then do;  
        _ZH=.; _BIVH=.;
     end;
     else do;
       _LH = _LH1+_r*(_LH2-_LH1);
       _MH = _MH1+_r*(_MH2-_MH1);
       _SH = _SH1+_r*(_SH2-_SH1);
       if (_LH gt -0.01 and _LH lt 0.01) then _ZH=log(_ht/_MH)/_SH;
       else _ZH=((_ht/_MH)**_LH-1)/(_LH*_SH);
       _LOH=((_MH-_MH*(1-2*_LH*_SH)**(1/_LH))/2);
       _HIH=((_MH*(1+2*_LH*_SH)**(1/_LH)-_MH)/2);
       if _ht lt _MH then flagH=(_ht-_MH)/_LOH;
       else flagH=( ht- MH)/ HIH;
       if flagH eq . then BIVH=.;
       else if flagH lt -5 then _BIVH=1;  *implausibly low value;
       else if flagH gt 3 then _BIVH=2;   *implausibly high value;
       else _BIVH=0;                      *acceptable value;
     end;
    
     ***WEIGHT***;
     if _wt eq . then do;  
        _ZW=.; _BIVW=.;
     end;
     else do;
       _LW = _LW1+_r*(_LW2-_LW1);
       _MW = _MW1+_r*(_MW2-_MW1);
       SW = SW1+ r*( SW2- SW1);
       if ( LW gt -0.01 and LW lt 0.01) then _ZW=log(_wt/_MW)/_SW;
       else ZW=(( wt/ MW)** LW-1)/( LW* SW);
       _LOW=((_MW-_MW*(1-2*_LW*_SW)**(1/_LW))/2);
       _HIW=((_MW*(1+2*_LW*_SW)**(1/_LW)-_MW)/2);
       if _wt lt _MW then flagW=(_wt-_MW)/_LOW;
       else flagW=(_wt-_MW)/_HIW;
       if flagW eq . then _BIVW=.;


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Page 153 of 160
       else if flagW lt -5 then BIVW=1;  *implausibly low value;
       else if flagW gt 5 then BIVW=2;   *implausibly high value;
       else _BIVW=0;                      *acceptable value;
    end;
   
    
    ***BMI***;
    if _bmi eq . then do;  
       _ZB=.; _BIVB=.;
    end;
    else do;
       _LB = _LB1+_r*(_LB2-_LB1);
       _MB = _MB1+_r*(_MB2-_MB1);
       SB = SB1+ r*( SB2- SB1);
       if (_LB gt -0.01 and _LB lt 0.01) then _ZB=log(_bmi/_MB)/_SB;
       else ZB=(( bmi/ MB)** LB-1)/( LB* SB);
       LOB=(( MB- MB*(1-2* LB* SB)**(1/ LB))/2);
       _HIB=((_MB*(1+2*_LB*_SB)**(1/_LB)-_MB)/2);
      if _bmi lt _MB then flagB=(_bmi-_MB)/_LOB;
      else flagB=(_bmi-_MB)/_HIB;
      if flagB eq . then _BIVB=.;
      else if flagB lt -4 then _BIVB=1;  *implausibly low value;
      else if flagB gt 5 then _BIVB=2;   *implausibly high value;
      else _BIVB=0;                      *acceptable value;
   end;
   keep _id _zh _bivh _zw _bivw _zb _bivb;
run;
*output dataset contains original data plus Z scores and BIV flags for height, weight and 
BMI;
proc sort data=test2;
     by _id;
run;
data dataout(drop=_id);
     merge test(drop=_age) test2; 
           by _id;
run;


Sponsor: Astellas Pharma Global Development, Inc.
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21-May-2019
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Page 154 of 160
10.13 Appendix 13:  ECG Abnormality Codes
ECG abnormalities are coded according to the class of the abnormality and specific type. 
Each type of abnormality is given a particular abnormality code.  The classes of abnormality 
and the form of the abnormality codes for each class are as follows:
Abnormality Class
Form of Abnormality Code
Rhythm
PR Intervals
QT Intervals
P Wave
QRS Complex
ST Segment
T Wave
Other
1xy or 1xy.z
3xy or 3xy.z
4xy or 4xy.z
6xy or 6xy.z
7xy or 7xy.z
8xy or 8xy.z
90x or 90x.y
98x or 98x.y
Specific abnormalities coded in each class are as follows:
Class: Rhythm
Abnormality Code
Abnormality Text
101
Sinus Tachycardia
102
Sinus Bradycardia
103
Atrial Tachycardia - Without Block
104
Atrial Tachycardia - With Block
105
Atrial Flutter
106
Atrial Fibrillation
106.5
Ectopic Atrial Rhythm
107
PSVT(Paroxysmal Supraventricular Tachycardia)
108
Variable Atrial Pacemaker
109
Junctional Rhythm without Aberrancy
110
Junctional Rhythm with Aberrancy
110.4
Junctional Tachycardia
110.5
Junctional Rhythm
111
Ventricular Rhythm
112
Ventricular Tachycardia
112.1
Sustained Ventricular Tachycardia
112.2
Non-sustained Ventricular Tachycardia
112.4
Torsades de Pointes


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Abnormality Code
Abnormality Text
112.5
Idioventricular Rhythm
113
Accelerated AV Conduction Pattern
113.5
Short PR Interval without Ventricular Pre-Excitation
114
Wolff - Parkinson - White Pattern
115
Supraventricular Ectopic Beats
115.2
Frequent Atrial Premature Complexes (>3)
115.3
Atrial Premature Complexes
115.4
Supraventricular Tachycardia
115.5
Ectopic Supraventricular Rhythm
116
Ventricular Ectopic Beats – Unifocal
117
Ventricular Ectopic Beats – Multifocal
118
Pacemaker Rhythm
119
Ventricular Fibrillation
119.4
Frequent Ventricular Premature Complexes (>2)
119.5
Ventricular Premature Complexes
120
Sinus Arrest
120.5
Sinus Pause
121
Sinus Arrhythmia
122
Nodal Tachycardia
123
LGL Syndrome
124
Junctional Escape Complexes
125
Sino - Atrial Block
199.4
Ectopy Other
199.5
Rhythm Other
Class: PR Intervals
Abnormality Code
Abnormality Text
301
First Degree AV Block
302
Second Degree AV Block - Mobitz I
303
Second Degree AV Block - Mobitz II
304
Complete AV Block
304.5
2:1 AV Block
399.5
Conduction Other


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Class: QT Intervals
Abnormality Code
Abnormality Text
401
Prolonged QT Interval
402
Prolonged QTc interval
Class: P Wave
Abnormality Code
Abnormality Text
601
Right Atrial Enlargement
602
Left Atrial Enlargement
602.5
Borderline Left Atrial Enlargement
603
P-Wave Abnormality
Class: QRS Complex
Abnormality Code
Abnormality Text
701
AV Dissociation
702
Left Anterior Hemiblock
703
Left Posterior Hemiblock
704
Right Bundle Branch Block
705
Incomplete Right Bundle Branch Block
706
Left Bundle Branch Block
707
Incomplete Left Bundle Branch Block
708
Nonspecific Intraventricular Conduction Delay
709
Bifascicular Block
710
Left Axis Deviation
711
Right Axis Deviation
712
Abnormal QRS Axis
712.5
Indeterminate Axis
713
Left Ventricular Hypertrophia
714
Left Ventricular Hypertrophia by Voltage Only
714.4
Left Atrial Abnormality
714.5
Left Ventricular Hypertrophy with Strain
715
Right Ventricular Hypertrophia
715.5
Right Atrial Abnormality
716
Old Myocardial Infarction: Antero Septal
716.4
Septal MI V1, V2, (V3)
716.5
Antero Septal MI V1-V4


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Abnormality Code
Abnormality Text
717
Old Myocardial Infarction: Antero Lateral
717.4
Extensive Anterior MI 1, L, V1-V6
717.5
Antero Lateral MI V3-V6
718
Old Myocardial Infarction: Infero Lateral
718.5
Anterior MI V3, V4
719
Old Myocardial Infarction: Infero Posterior
719.5
Inferior MI (2), 3, F
720
Old Myocardial Infarction: Postero Lateral
721
Old Myocardial Infarction: Lateral
721.4
Lateral MI 1, L, V5, V6
721.5
High Lateral MI 1, AVL
722
Low Voltage QRS Complex
723
Poor R-Wave Progression
724
Late R-Wave Transition
725
Early Repolarization - Normal Variant
726
Early R-Wave Transition
799.4
Morphology Other
799.5
Myocardial Infarction Other
Class: ST Segment
Abnormality Code
Abnormality Text
801
New Myocardial Infarction: Antero Septal
802
New Myocardial Infarction: Antero Lateral
803
New Myocardial Infarction: Infero Lateral
804
New Myocardial Infarction: Infero Posterior
805
New Myocardial Infarction: Postero Lateral
806
New Myocardial Infarction: Lateral
807
Myocardial Infarction - Nontransmural -Acute or Evolving
808
ST Elevation Consistent with Ischaemia: Anterior
809
ST Elevation Consistent with Ischaemia: Septal
810
ST Elevation Consistent with Ischaemia: Lateral
811
ST Elevation Consistent with Ischaemia: Inferior
812
ST Elevation Consistent with Ischaemia: Posterior
813
ST Elevation Consistent with Ischaemia: High Lateral
814
ST Elevation Consistent with Pericarditis
814.5
ST Segment Elevated
815
Non-Specific ST-T Change


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Abnormality Code
Abnormality Text
816
ST-T Changes - Consistent with Drug Effects
817
ST Depression: Anterior
818
ST Depression: Septal
819
ST Depression: Lateral
820
ST Depression: Inferior
821
ST Depression: Posterior
822
ST Depression: High Lateral
823
ST Depression - Non-Specific
823.5
ST Segment Depressed
899.5
ST Segment Other
Class: T Wave
Abnormality Code
Abnormality Text
901
T-Wave Inversion Suggestive of Non-Q-Wave MI
902
T-Wave Flattening or Inversion in Two or More Leads
902.4
T-Wave Flat
902.5
T-Wave Inverted
903
Non-Specific T-Wave Changes
904
T-Wave Inversion Suggestive of Ischaemia
905
T-Wave Peaking
905.5
T Wave Other
Class: Other
Abnormality Code
Abnormality Text
998
U-Wave Abnormality
998.5
U-Wave Other
999
Other