Clinical Trial Results:
An Openlabel, Baselinecontrolled, Multicenter, Phase 3 Dosetitration Study Followed by a Fixeddose 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
Summary


EudraCT number 
201500287625 
Trial protocol 
DK LT NO BE SK RO LV HR 
Global end of trial date 
06 May 2019

Results information


Results version number 
v2(current) 
This version publication date 
26 Aug 2020

First version publication date 
14 Nov 2019

Other versions 
v1 
Version creation reason 
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
178CL206A


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT02751931  
WHO universal trial number (UTN) 
  
Other trial identifiers 
Acronym: Crocodile Study  
Sponsors


Sponsor organisation name 
Astellas Pharma Europe B.V.


Sponsor organisation address 
Sylviusweg 62, Leiden, Netherlands, 2333 BE


Public contact 
Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com


Scientific contact 
Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
Yes


EMA paediatric investigation plan number(s) 
EMEA000597PIP0315  
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
Yes


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
06 May 2019


Is this the analysis of the primary completion data? 
No


Global end of trial reached? 
Yes


Global end of trial date 
06 May 2019


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
The primary objective of this study was to evaluate the efficacy of mirabegron after multipledose administration in the pediatric population.


Protection of trial subjects 
This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
17 Jun 2016


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
Yes


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
Australia: 1


Country: Number of subjects enrolled 
Belgium: 3


Country: Number of subjects enrolled 
Croatia: 7


Country: Number of subjects enrolled 
Denmark: 2


Country: Number of subjects enrolled 
Israel: 1


Country: Number of subjects enrolled 
Jordan: 3


Country: Number of subjects enrolled 
Latvia: 2


Country: Number of subjects enrolled 
Lithuania: 7


Country: Number of subjects enrolled 
Malaysia: 4


Country: Number of subjects enrolled 
Mexico: 3


Country: Number of subjects enrolled 
Norway: 5


Country: Number of subjects enrolled 
Philippines: 10


Country: Number of subjects enrolled 
Poland: 17


Country: Number of subjects enrolled 
Romania: 6


Country: Number of subjects enrolled 
Serbia: 4


Country: Number of subjects enrolled 
Slovakia: 3


Country: Number of subjects enrolled 
Korea, Republic of: 6


Country: Number of subjects enrolled 
Taiwan: 1


Country: Number of subjects enrolled 
Turkey: 6


Worldwide total number of subjects 
91


EEA total number of subjects 
52


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
56


Adolescents (1217 years) 
35


Adults (1864 years) 
0


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
Pediatric participants consisting of male and female children from 3 to <12 and adolescents from 12 to <18 years of age, with a body weight of ≥11 kg, with NDO on clean intermittent catheterization (CIC) were enrolled in this study.  
Preassignment


Screening details 
Eligible participants who met inclusion and none of the exclusion criteria were enrolled. Participants who received oral drug to manage their NDO completed a 2 week washout period. A total of 113 pediatric patients were screened, 22 of whom were screening failures.  
Period 1


Period 1 title 
Overall Study (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Nonrandomised  controlled


Blinding used 
Not blinded  
Arms


Are arms mutually exclusive 
Yes


Arm title

Children (3 to < 12 Years)  
Arm description 
Children age 3 to < 12 received an initial dose of 25 mg of mirabegron (pediatric equivalent dose [PED25]), orally once daily. Initial dose was uptitrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (pediatric equivalent dose [PED50]). After week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  
Arm type 
Experimental  
Investigational medicinal product name 
Mirabegron Tablets


Investigational medicinal product code 
YM178


Other name 
Myrbetriq, Betmiga


Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were uptitrated 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. At week 24, participants on mirabegron oral suspension could switch to tablets if the body weight became ≥35 kg. Participants who received mirabegron oral suspension could switch to mirabegron tablets for acceptability reasons after sponsor’s prior approval and on a casebycase basis.


Investigational medicinal product name 
Mirabegron Oral Suspension


Investigational medicinal product code 
YM178


Other name 
Myrbetriq, Betmiga


Pharmaceutical forms 
Oral suspension


Routes of administration 
Oral use


Dosage and administration details 
Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were uptitrated 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 oral suspension. For participants with a body weight ≥35 kg who did not want to or were unable to take tablets, the oral suspension could have been supplied. Participants who received mirabegron tablets could switch to mirabegron oral suspension for acceptability reasons after sponsor’s prior approval and on a casebycase basis. Mirabegron extendedrelease 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.


Arm title

Adolescents (12 to < 18 Years)  
Arm description 
Adolescents age 12 to < 18 received an initial dose of 25 mg of mirabegron (PED25), orally once daily. Initial dose was uptitrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (PED50). After week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  
Arm type 
Experimental  
Investigational medicinal product name 
Mirabegron Tablets


Investigational medicinal product code 
YM178


Other name 
Myrbetriq, Betmiga


Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were uptitrated 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. At week 24, participants on mirabegron oral suspension could switch to tablets if the body weight became ≥35 kg. Participants who received mirabegron oral suspension could switch to mirabegron tablets for acceptability reasons after sponsor’s prior approval and on a casebycase basis.


Investigational medicinal product name 
Mirabegron Oral Suspension


Investigational medicinal product code 
YM178


Other name 
Myrbetriq, Betmiga


Pharmaceutical forms 
Oral suspension


Routes of administration 
Oral use


Dosage and administration details 
Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were uptitrated 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 oral suspension. For participants with a body weight ≥35 kg who did not want to or were unable to take tablets, the oral suspension could have been supplied. Participants who received mirabegron tablets could switch to mirabegron oral suspension for acceptability reasons after sponsor’s prior approval and on a casebycase basis. Mirabegron extendedrelease 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.





Baseline characteristics reporting groups


Reporting group title 
Children (3 to < 12 Years)


Reporting group description 
Children age 3 to < 12 received an initial dose of 25 mg of mirabegron (pediatric equivalent dose [PED25]), orally once daily. Initial dose was uptitrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (pediatric equivalent dose [PED50]). After week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  
Reporting group title 
Adolescents (12 to < 18 Years)


Reporting group description 
Adolescents age 12 to < 18 received an initial dose of 25 mg of mirabegron (PED25), orally once daily. Initial dose was uptitrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (PED50). After week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  



End points reporting groups


Reporting group title 
Children (3 to < 12 Years)


Reporting group description 
Children age 3 to < 12 received an initial dose of 25 mg of mirabegron (pediatric equivalent dose [PED25]), orally once daily. Initial dose was uptitrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (pediatric equivalent dose [PED50]). After week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  
Reporting group title 
Adolescents (12 to < 18 Years)


Reporting group description 
Adolescents age 12 to < 18 received an initial dose of 25 mg of mirabegron (PED25), orally once daily. Initial dose was uptitrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (PED50). After week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  
Subject analysis set title 
Children PED25 (PKAS)


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Participants aged 3 to < 12 years who received pediatric equivalent dose of 25 mg at the time of PK sampling.


Subject analysis set title 
Adolescents PED25 (PKAS)


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Participants aged 12 to < 18 years who received pediatric equivalent dose of 25 mg at the time of PK sampling.


Subject analysis set title 
Children PED50 (PKAS)


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Participants aged 3 to < 12 years who received pediatric equivalent dose of 50 mg at the time of PK sampling.


Subject analysis set title 
Adolescents PED50 (PKAS)


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Participants aged 12 to < 18 years who received pediatric equivalent dose of 50 mg at the time of PK sampling.



End point title 
Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24  
End point description 
Change from baseline in MCC was based on filling urodynamics, volume at the end of filling. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the full analysis set (FAS) which consisted of all participants who took ≥ 1 dose of study drug and provided both valid (as by the central reviewer’s assessment) nonmissing MCC measurements at baseline and at a postbaseline visit for the primary efficacy endpoint. Missing MCC observations at week 24 were imputed using last observation carried forward (LOCF).


End point type 
Primary


End point timeframe 
Baseline and week 24




Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in MCC in children at week 24. The number of participants included in this analysis was 43.


Comparison groups 
Adolescents (12 to < 18 Years) v Children (3 to < 12 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[1]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
72.09


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
45.28  
upper limit 
98.89  
Notes [1]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in MCC in adolescents at week 24. The number of participants included in this analysis was 25.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[2]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
113.21


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
78.95  
upper limit 
147.47  
Notes [2]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in MCC at Week 4  
End point description 
Change from baseline in MCC was based on filling urodynamics (volume at the end of filling). During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.


End point type 
Secondary


End point timeframe 
Baseline and week 4




Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in MCC in children at week 4. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
64


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[3]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
41.36


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
18.75  
upper limit 
63.97  
Notes [3]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in MCC in adolescents at week 4. The number of participants included in this analysis was 25.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
64


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[4]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
80.78


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
39.2  
upper limit 
122.36  
Notes [4]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Bladder Compliance (ΔV/ΔP)  
End point description 
Change from baseline in bladder compliance (change in volume/change in pressure) was assessed by the independent central reviewers and reported as annotations on the urodynamic trace and in an external database. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 4 and 24




Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in ΔV/ΔP in children at week 4. The number of participants included in this analysis was 39.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.618 ^{[5]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
4.09


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
20.55  
upper limit 
12.38  
Notes [5]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in ΔV/ΔP in adolescents at week 4. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.005 ^{[6]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
15.16


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.1  
upper limit 
25.22  
Notes [6]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in ΔV/ΔP in children at week 24. The number of participants included in this analysis was 33.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.055 ^{[7]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
14.62


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.31  
upper limit 
29.54  
Notes [7]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in ΔV/ΔP in adolescents at week 24. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[8]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
13.59


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.75  
upper limit 
20.42  
Notes [8]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling  
End point description 
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 4 and 24




Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in number of overactive detrusor contractions in children at week 4. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.632 ^{[9]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.44


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.4  
upper limit 
2.28  
Notes [9]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in number of overactive detrusor contractionsin adolescents at week 4. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.321 ^{[10]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.64


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.94  
upper limit 
0.67  
Notes [10]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in number of overactive detrusor contractions in children at week 24. The number of participants included in this analysis was 36.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.011 ^{[11]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.86


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.27  
upper limit 
0.45  
Notes [11]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in number of overactive detrusor contractions in adolescents at week 24. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.359 ^{[12]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.77


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.49  
upper limit 
0.94  
Notes [12]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Detrusor Pressure at End of Filling  
End point description 
Filling was stopped (end of filling) when the detrusor pressure exceeded 100 cm H2O or was considered dangerously high by the investigator or urodynamicist (for instance, a prolonged passive detrusor pressure > 40 cm H2O). During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 4 and 24




Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in detrusor pressure in children at week 4. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[13]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
12.38


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
18.56  
upper limit 
6.21  
Notes [13]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in detrusor pressure in adolescents at week 4. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.334 ^{[14]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
6.48


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
20.09  
upper limit 
7.13  
Notes [14]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in detrusor pressure in children at week 24. The number of participants included in this analysis was 36.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[15]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
18.11


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
24.87  
upper limit 
11.35  
Notes [15]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in detrusor pressure in adolescents at week 24. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.005 ^{[16]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
13.19


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
22.02  
upper limit 
4.36  
Notes [16]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)  
End point description 
Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity.


End point type 
Secondary


End point timeframe 
Baseline and weeks 4 and 24




Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in filling bladder volume until first overactive detrusor contraction in children at week 4. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[17]}  
Method 
Wilcoxon signedrank test  
Confidence interval 

Notes [17]  From a Wilcoxon signedrank test, testing the null hypothesis that week 24 median is equal to baseline median. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in filling bladder volume until first overactive detrusor contraction in adolescents at week 4. The number of participants included in this analysis was 8.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.148 ^{[18]}  
Method 
Wilcoxon signedrank test  
Confidence interval 

Notes [18]  From a Wilcoxon signedrank test, testing the null hypothesis that week 24 median is equal to baseline median. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in filling bladder volume until first overactive detrusor contraction in children at week 24. The number of participants included in this analysis was 13.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[19]}  
Method 
Wilcoxon signedrank test  
Confidence interval 

Notes [19]  From a Wilcoxon signedrank test, testing the null hypothesis that week 24 median is equal to baseline median. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in filling bladder volume until first overactive detrusor contraction in adolescents at week 24. The number of participants included in this analysis was 8.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.039 ^{[20]}  
Method 
Wilcoxon signedrank test  
Confidence interval 

Notes [20]  From a Wilcoxon signedrank test, testing the null hypothesis that week 24 median is equal to baseline median. 


End point title 
Change From Baseline in Average Catheterized Volume Per Catheterization  
End point description 
For each participant, the average catheterized volume per catheterization was calculated as the sum of all available/nonmissing catheterized volumes recorded over 2 measuring days in the weekend diary, whether or not the 2 days were consecutive divided by the number of catheterizations with nonmissing volumes. If volumes were recorded on 1 single day of the weekend diary, the average catheterized volume per catheterization was calculated using all available/nonmissing catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend diary, the average catheterized volume per catheterization was missing. A valid bladder diary day in the weekend diary was any ediary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 2, 4, 8, 12, 24, 36, and 52




Statistical analysis title 
Change From Baseline at Week 2  Children  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in children at week 2. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.035 ^{[21]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
14.58


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1  
upper limit 
28.1  
Notes [21]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 2  Adolescents  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in adolescents at week 2. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.003 ^{[22]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
35.99


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
13.1  
upper limit 
58.9  
Notes [22]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in children at week 4. The number of participants included in this analysis was 42.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[23]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
30.08


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
14.7  
upper limit 
45.5  
Notes [23]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in adolescents at week 4. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[24]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
51.96


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
24.6  
upper limit 
79.3  
Notes [24]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Children  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in children at week 8. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[25]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
36.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
22.7  
upper limit 
51.1  
Notes [25]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Adolescents  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in adolescents at week 8. The number of participants included in this analysis was 2.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[26]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
45.1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
21.3  
upper limit 
68.9  
Notes [26]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Children  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in children at week 12. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[27]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
32.25


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
18.2  
upper limit 
46.3  
Notes [27]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Adolescents  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in adolescents at week 12. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.001 ^{[28]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
43.94


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
19.2  
upper limit 
68.6  
Notes [28]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in children at week 24. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[29]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
41.63


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
23.3  
upper limit 
60  
Notes [29]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in adolescents at week 24. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[30]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
59.31


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
23.8  
upper limit 
94.9  
Notes [30]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Children  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in children at week 36. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[31]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
53.87


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
24.5  
upper limit 
83.2  
Notes [31]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Adolescents  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in adolescents at week 36. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[32]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
52.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
20.5  
upper limit 
83.8  
Notes [32]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in children at week 52. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[33]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
42.84


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
22  
upper limit 
63.7  
Notes [33]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in average catheterized volume per catheterization in adolescents at week 52. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.008 ^{[34]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
42.4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
12.5  
upper limit 
72.3  
Notes [34]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Maximum Catheterized Volume  
End point description 
For each participant, the maximum catheterized volume per day was calculated using all available/nonmissing catheterized volumes recorded for the 2 measuring days in the weekend ediary, whether or not these 2 days were consecutive. Maximum value was calculated separately for each measuring day & the mean of the two values was used. If volumes recorded on 1 single day of the weekend ediary, the maximum catheterized volume per day was calculated using all available/nonzero catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend ediary, the maximum catheterized volume per day was missing. A valid bladder diary day in the weekend diary was any ediary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 2, 4, 8, 12, 24, 36, and 52




Statistical analysis title 
Change From Baseline at Week 2  Children  
Statistical analysis description 
Change from baseline in maximum catheterized volume in children at week 2. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.126 ^{[35]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
17.5


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.1  
upper limit 
40.1  
Notes [35]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 2  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized volume in adolescents at week 2. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.014 ^{[36]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
42.38


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
9.3  
upper limit 
75.4  
Notes [36]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in maximum catheterized volume in children at week 4. The number of participants included in this analysis was 42.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[37]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
46.69


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
21.7  
upper limit 
71.7  
Notes [37]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized volume in adolescents at week 4. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[38]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
73.25


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
29.3  
upper limit 
117.2  
Notes [38]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Children  
Statistical analysis description 
Change from baseline in maximum catheterized volume in children at week 8. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[39]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
45.27


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
22.1  
upper limit 
68.4  
Notes [39]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized volume in adolescents at week 8. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.02  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
42.86


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.4  
upper limit 
78.3  
Statistical analysis title 
Change From Baseline at Week 12  Children  
Statistical analysis description 
Change from baseline in maximum catheterized volume in children at week 12. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.003 ^{[40]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
33.23


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
12.2  
upper limit 
54.3  
Notes [40]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized volume in adolescents at week 12. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.003 ^{[41]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
47.29


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
17.8  
upper limit 
76.8  
Notes [41]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in maximum catheterized volume in children at week 24. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.004 ^{[42]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
49.88


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
17.1  
upper limit 
82.6  
Notes [42]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized volume in adolescents at week 24. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.003 ^{[43]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
84.39


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
31.6  
upper limit 
137.1  
Notes [43]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Children  
Statistical analysis description 
Change from baseline in maximum catheterized volume in children at week 36. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.003 ^{[44]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
60.09


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
21.2  
upper limit 
99  
Notes [44]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized volume in adolescents at week 36. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.017 ^{[45]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
54.78


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
10.6  
upper limit 
98.9  
Notes [45]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in maximum catheterized volume in children at week 52. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.001 ^{[46]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
53.51


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
22.6  
upper limit 
84.4  
Notes [46]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized volume in adolescents at week 52. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.021 ^{[47]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
54.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
9  
upper limit 
99.6  
Notes [47]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Maximum Catheterized Daytime Volume (MCDV)  
End point description 
For each participant, the MCDV was calculated using all available/nonmissing catheterized daytime volumes for the 2 measuring days in the weekend ediary, whether or not the 2 days were consecutive. Maximum value was calculated separately for each measuring day & the mean of the 2 values was used. If volumes were recorded on 1 single day of the weekend ediary, the MCDV was calculated using all available/nonzero catheterized daytime volumes recorded that day. If no volumes were recorded on any day of the weekend ediary, the MCDV was missing. Daytime was defined as the time between wakeup time (minus 30 min) & time to sleep (plus 29 min) recorded in the ediary. A valid bladder diary day in the weekend diary was any ediary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 2, 4, 8, 12, 24, 36, and 52




Statistical analysis title 
Change From Baseline at Week 2  Children  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in children at week 2. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.113 ^{[48]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
18.13


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.5  
upper limit 
40.7  
Notes [48]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 2  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in adolescents at week 2. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.056 ^{[49]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
35.58


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.1  
upper limit 
72.2  
Notes [49]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in children at week 4. The number of participants included in this analysis was 42.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.005 ^{[50]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
37.71


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
11.7  
upper limit 
63.7  
Notes [50]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in adolescents at week 4. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.006 ^{[51]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
70.35


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
22.2  
upper limit 
118.5  
Notes [51]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Children  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in children at week 8. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[52]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
43.91


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
21  
upper limit 
66.8  
Notes [52]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in adolescents at week 8. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.063 ^{[53]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
38.11


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.2  
upper limit 
78.4  
Notes [53]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Children  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in children at week 12. The number of participants included in this analysis was 43.


Comparison groups 
Adolescents (12 to < 18 Years) v Children (3 to < 12 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.008 ^{[54]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
29.05


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
8.2  
upper limit 
49.9  
Notes [54]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in adolescents at week 12. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.009 ^{[55]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
43.04


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
11.9  
upper limit 
74.2  
Notes [55]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in children at week 24. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.006 ^{[56]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
44.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
13.2  
upper limit 
75.2  
Notes [56]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in adolescents at week 24. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.003 ^{[57]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
81.37


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
30.4  
upper limit 
132.3  
Notes [57]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Children  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in children at week 36. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.004 ^{[58]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
58.49


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
19.8  
upper limit 
97.2  
Notes [58]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in adolescents at week 36. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.039 ^{[59]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
50.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.7  
upper limit 
99.1  
Notes [59]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in children at week 52. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[60]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
53.76


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
21.7  
upper limit 
85.8  
Notes [60]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in maximum catheterized daytime volume in adolescents at week 52. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.057 ^{[61]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
49.13


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.6  
upper limit 
99.8  
Notes [61]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Average Morning Catheterized Volume  
End point description 
The first morning catheterized volume was the first recorded nonzero volume within or after the hour of the wakeup time on a volumemeasuring day in the ediary. The average first morning catheterized volume was calculated as the average of the available first morning catheterized volumes recorded for the 2 measuring days in the weekend ediary, whether or not these 2 days were consecutive. If the first morning catheterized volume was recorded on 1 single day of the weekend ediary, the average morning catheterized is the first morning catheterized that day. If no first morning catheterized volumes are recorded on any day of the weekend ediary, the average first morning catheterized volume was missing. A valid bladder diary day in the weekend diary was any ediary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 2, 4, 8, 12, 24, 36, and 52




Statistical analysis title 
Change From Baseline at Week 2  Children  
Statistical analysis description 
Change from baseline in average morning catheterized volume in children at week 2. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.617 ^{[62]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
7.98


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
24  
upper limit 
40  
Notes [62]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 2  Adolescents  
Statistical analysis description 
Change from baseline in average morning catheterized volume in adolescents at week 2. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.035 ^{[63]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
39.52


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3  
upper limit 
76  
Notes [63]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in average morning catheterized volume in children at week 4. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.167 ^{[64]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
19.81


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
8.7  
upper limit 
48.3  
Notes [64]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in average morning catheterized volume in adolescents at week 4. The number of participants included in this analysis was 20.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.005 ^{[65]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
75.25


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
25.8  
upper limit 
124.7  
Notes [65]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Children  
Statistical analysis description 
Change from baseline in average morning catheterized volume in children at week 8. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.02 ^{[66]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
34.01


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.7  
upper limit 
62.3  
Notes [66]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Adolescents  
Statistical analysis description 
Change from baseline in average morning catheterized volume in adolescents at week 8. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.033 ^{[67]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
44.43


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.9  
upper limit 
84.9  
Notes [67]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Children  
Statistical analysis description 
Change from baseline in average morning catheterized volume in children at week 12. The number of participants included in this analysis was 39.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.503 ^{[68]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
8.68


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
17.3  
upper limit 
34.7  
Notes [68]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Adolescents  
Statistical analysis description 
Change from baseline in average morning catheterized volume in adolescents at week 12. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.016 ^{[69]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
38.23


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.8  
upper limit 
68.6  
Notes [69]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in average morning catheterized volume in children at week 24. The number of participants included in this analysis was 36.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.043 ^{[70]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
40.76


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.4  
upper limit 
80.2  
Notes [70]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in average morning catheterized volume in adolescents at week 24. The number of participants included in this analysis was 20.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[71]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
86.66


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
41.5  
upper limit 
131.8  
Notes [71]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Children  
Statistical analysis description 
Change from baseline in average morning catheterized volume in children at week 36. The number of participants included in this analysis was 37.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.203 ^{[72]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
31.08


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
17.5  
upper limit 
79.6  
Notes [72]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Adolescents  
Statistical analysis description 
Change from baseline in average morning catheterized volume in adolescents at week 36. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.019 ^{[73]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
68.47


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
12.7  
upper limit 
124.2  
Notes [73]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in average morning catheterized volume in children at week 52. The number of participants included in this analysis was 39.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.042 ^{[74]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
31.83


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.3  
upper limit 
62.4  
Notes [74]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in average morning catheterized volume in adolescents at week 52. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.121 ^{[75]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
38.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
11  
upper limit 
87.3  
Notes [75]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Mean Number of Leakage Episodes per Day  
End point description 
For each participant, the mean number of leakage episodes per day (during day & night time) was calculated using all available/nonmissing number of leakage episodes for the 2 measuring days in the weekend diary during day & night time. If the number of leakage episodes was recorded on 1 single day in the 7day diary during day & night time, the mean number of leakage episodes per day during day & night time is equal to the total number of leakage episodes recorded that day during day & night time. If no leakage episodes were recorded on any day of the weekend diary during day & night time, the mean number of leakage episodes per day was zero. Participants who did not report any leakage episode during the visit were imputed with a '0' for that visit. A valid bladder diary day in the weekend diary was any ediary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of FAS population with available data.


End point type 
Secondary


End point timeframe 
Baseline and weeks 2, 4, 8, 12, 24, 36, and 52




Statistical analysis title 
Change From Baseline at Week 2  Children  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in children at week 2. The number of participants included in this analysis was 38.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.818 ^{[76]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.35


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.7  
upper limit 
3.4  
Notes [76]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 2  Adolescents  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in adolescents at week 2. The number of participants included in this analysis was 15.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.114 ^{[77]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.53


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.2  
upper limit 
0.1  
Notes [77]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in children at week 4. The number of participants included in this analysis was 35.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.052 ^{[78]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.3  
upper limit 
0  
Notes [78]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in adolescents at week 4. The number of participants included in this analysis was 13.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.066 ^{[79]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.87


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.8  
upper limit 
0.1  
Notes [79]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Children  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in children at week 8. The number of participants included in this analysis was 34.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.674 ^{[80]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.16


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.4  
upper limit 
6.7  
Notes [80]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Adolescents  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in adolescents at week 8. The number of participants included in this analysis was 9.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.278 ^{[81]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.65


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.9  
upper limit 
0.6  
Notes [81]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Children  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in children at week 12. The number of participants included in this analysis was 32.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.871 ^{[82]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.37


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.2  
upper limit 
5  
Notes [82]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Adolescents  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in adolescents at week 12. The number of participants included in this analysis was 12.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.153 ^{[83]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.65


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.6  
upper limit 
0.3  
Notes [83]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in children at week 24. The number of participants included in this analysis was 31.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.922 ^{[84]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.18


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.5  
upper limit 
3.9  
Notes [84]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in adolescents at week 24. The number of participants included in this analysis was 13.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.047 ^{[85]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.75


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.5  
upper limit 
0  
Notes [85]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Children  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in children at week 36. The number of participants included in this analysis was 28.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.018 ^{[86]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.98


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.6  
upper limit 
0.4  
Notes [86]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Adolescents  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in adolescents at week 36. The number of participants included in this analysis was 12.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.07 ^{[87]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.81


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.7  
upper limit 
0.1  
Notes [87]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in children at week 52. The number of participants included in this analysis was 27.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.083 ^{[88]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.94


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2  
upper limit 
0.1  
Notes [88]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in mean number of leakage episodes per day in adolescents at week 52. The number of participants included in this analysis was 13.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.064 ^{[89]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.12


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.3  
upper limit 
0.1  
Notes [89]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Number of Dry Days per 7 Days (Day and Night Time)  
End point description 
Dry days were defined as leakagefree days, this included day and night time. Participants recorded dry days in the 7day diary. Dry days were calculated as follows: Ddry was the number of valid diary days where the response to the question ‘Did you leak between this catheterization and the last one’ was ‘No’ each time a new catheterization was entered in the ediary during the day & night time period. Dwet was the number of valid diary days where the response to the question ‘Did you leak between this catheterization and the last one’ was ‘Yes’ for at least one catheterization entered during the day & night time period. If (Ddry + Dwet) > 3, the number of dry days per 7 days was calculated as Ddry/(Ddry + Dwet) x 7, otherwise the value was missing. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 2, 4, 8, 12, 24, 36, and 52




Statistical analysis title 
Change From Baseline at Week 2  Children  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in children at week 2. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.018 ^{[90]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.34


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.6  
Notes [90]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 2  Adolescents  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 2. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.045 ^{[91]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.82


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
1.6  
Notes [91]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Children  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in children at week 4. The number of participants included in this analysis was 42.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.013 ^{[92]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.68


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
1.2  
Notes [92]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 4  Adolescents  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 4. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[93]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.36


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6  
upper limit 
2.2  
Notes [93]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Children  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in children at week 8. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.001 ^{[94]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5  
upper limit 
1.8  
Notes [94]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 8  Adolescents  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 8. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[95]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
2.26


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.2  
upper limit 
3.3  
Notes [95]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Children  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in children at week 12. The number of participants included in this analysis was 43.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.001 ^{[96]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.31


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5  
upper limit 
2.1  
Notes [96]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 12  Adolescents  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 12. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[97]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.93


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.9  
upper limit 
3  
Notes [97]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in children at week 24. The number of participants included in this analysis was 41.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[98]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.34


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7  
upper limit 
2  
Notes [98]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 24. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[99]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
2.17


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.2  
upper limit 
3.2  
Notes [99]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Children  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in children at week 36. The number of participants included in this analysis was 39.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[100]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.33


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5  
upper limit 
2.1  
Notes [100]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 36  Adolescents  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 36. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[101]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.88


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1  
upper limit 
2.8  
Notes [101]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in children at week 52. The number of participants included in this analysis was 40.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.002 ^{[102]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.38


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.5  
upper limit 
2.2  
Notes [102]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 52. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
< 0.001 ^{[103]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
2.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.1  
upper limit 
3.2  
Notes [103]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Pediatric Incontinence Questionnaire (PINQ) Score  
End point description 
PINQ measured quality of life via an ediary. Total score ranged from 0/no effect to 80/worst effect; decrease in score indicated improvement. Total score was 20x average of individual PinQ items, the 20 Likert scales were converted to a score: Items 6 & 17; 0: “No” to 4: “Definitely” was used; & For the other 18 items; 0: “No” to 4: “All the time” was used. Expectation that questionnaires had limited missing values; if answers >2 questions were missing, total score was not calculated & was missing. Individual item scores were directly imputed. Change from baseline to each postbaseline visit in the total score was postbaseline visit value minus baseline value. If either baseline or postbaseline visit value was missing, change from baseline was missing. If change was: <0, improvement between 2 timepoints; =0, no change between 2 time points; >0, worsening between 2 time points. FAS population. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 24 and 52




Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in PINQ score in children at week 24. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.352 ^{[104]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
2.04


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.4  
upper limit 
6.49  
Notes [104]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in PINQ score in adolescents at week 24. The number of participants included in this analysis was 21.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.127 ^{[105]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
4.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
11.34  
upper limit 
1.53  
Notes [105]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in PINQ score in children at week 52. The number of participants included in this analysis was 23.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.613 ^{[106]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
1.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.96  
upper limit 
6.57  
Notes [106]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in PINQ score in adolescents at week 52. The number of participants included in this analysis was 19.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.056 ^{[107]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
6.79


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
13.78  
upper limit 
0.2  
Notes [107]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Change From Baseline in Patient Global Impression of Severity Scale (PGIS)  
End point description 
The PGIS is an answer to the question: “How did you feel about your bladder condition during the past 3 days?” Participants evaluated their recent condition as “Really Bad”(0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). An increase indicated improvement. The change from baseline to each postbaseline visit in the PGIS score is the value at the postbaseline visit minus the value at the baseline visit. If either the baseline or the postbaseline visit value is missing, the change from baseline was missing. A positive change indicated an improvement while a negative change indicated a worsening. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Baseline and weeks 24 and 52




Statistical analysis title 
Change From Baseline at Week 24  Children  
Statistical analysis description 
Change from baseline in PGIS in children at week 24. The number of participants included in this analysis was 25.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.153 ^{[108]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.36


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.14  
upper limit 
0.86  
Notes [108]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 24  Adolescents  
Statistical analysis description 
Change from baseline in PGIS in adolescents at week 24. The number of participants included in this analysis was 22.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.007 ^{[109]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.64


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.19  
upper limit 
1.08  
Notes [109]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Children  
Statistical analysis description 
Change from baseline in PGIS in children at week 52. The number of participants included in this analysis was 24.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.106 ^{[110]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.42


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
0.93  
Notes [110]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 

Statistical analysis title 
Change From Baseline at Week 52  Adolescents  
Statistical analysis description 
Change from baseline in PGIS in adolescents at week 52. The number of participants included in this analysis was 19.


Comparison groups 
Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)


Number of subjects included in analysis 
68


Analysis specification 
Prespecified


Analysis type 
other  
Pvalue 
= 0.003 ^{[111]}  
Method 
Paired ttest  
Parameter type 
Mean difference (net)  
Point estimate 
0.95


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.38  
upper limit 
1.51  
Notes [111]  From a 2sided paired ttest, testing the null hypothesis that change from baseline is equal to 0. 


End point title 
Clinician Global Impression of Change (CGIC)  
End point description 
The Clinician Global Impression of Change (CGIC) is a 7 point scale that requires the clinician to assess how much the participant’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). Analysis population consisted of the FAS. N is the number of participants with available data at each time point.


End point type 
Secondary


End point timeframe 
Weeks 24 and 52




No statistical analyses for this end point 


End point title 
Study Drug Acceptability for Tablets at Week 4  
End point description 
Participants evaluated the taste of the study medication/tablets by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the swallow of the study medication/tablets by ticking one of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) and “Really Easy” (4). Analysis population consisted of the FAS (participants on tablets with available data at week 4).


End point type 
Secondary


End point timeframe 
Week 4




No statistical analyses for this end point 


End point title 
Study Drug Acceptability for Oral Suspension at Week 4  
End point description 
Participants evaluated the taste of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the smell of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the consumption and the preparation of the study medication/oral suspension by ticking 1 of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) & “Really Easy” (4). Analysis population consisted of the FAS (participants on oral suspension with available data at week 4).


End point type 
Secondary


End point timeframe 
Week 4




No statistical analyses for this end point 


End point title 
Study Drug Acceptability for Tablets at Week 24  
End point description 
Participants evaluated the taste of the study medication/tablets by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the swallow of the study medication/tablets by ticking one of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) and “Really Easy” (4). Analysis population consisted of the FAS (participants on tablets with available data at week 24).


End point type 
Secondary


End point timeframe 
Week 24




No statistical analyses for this end point 


End point title 
Study Drug Acceptability for Oral Suspension at Week 24  
End point description 
Participants evaluated the taste of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the smell of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the consumption and the preparation of the study medication/oral suspension by ticking 1 of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) & “Really Easy” (4). Analysis population consisted of the FAS (participants on oral suspension with available data at week 24).


End point type 
Secondary


End point timeframe 
Week 24




No statistical analyses for this end point 


End point title 
Study Drug Acceptability for Tablets at Week 52  
End point description 
Participants evaluated the taste of the study medication/tablets by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the swallow of the study medication/tablets by ticking one of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) and “Really Easy” (4). Analysis population consisted of the FAS (participants on tablets with available data at week 52).


End point type 
Secondary


End point timeframe 
Week 52




No statistical analyses for this end point 


End point title 
Study Drug Acceptability for Oral Suspension at Week 52  
End point description 
Participants evaluated the taste of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the smell of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the consumption and the preparation of the study medication/oral suspension by ticking 1 of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) & “Really Easy” (4). Analysis population consisted of the FAS (participants on oral suspension with available data at week 52).


End point type 
Secondary


End point timeframe 
Week 52




No statistical analyses for this end point 


End point title 
Number of Participants with Adverse Events (AEs)  
End point description 
An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. An AE could 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. A treatmentemergent adverse event (TEAE) was defined as any AE with date of onset occurring on or after the first dose of study medication and up to the end of study. The analysis population consisted of the safety analysis set (SAF), which consisted of all participants who took at least 1 dose of study drug.


End point type 
Secondary


End point timeframe 
From the first dose of study drug administration up to endoftreatment (EoT) (week 52).




No statistical analyses for this end point 


End point title 
Pharmacokinetics (PK) of Maximum Plasma Mirabegron Concentration (Cmax)  
End point description 
The analysis population consisted of the pharmacokinetic analysis set (PKAS), which consisted of the subset of the SAF for whom plasma concentration data were available to facilitate derivation of ≥ 1 pharmacokinetic parameter and for whom the time of the last dose prior to sampling was known. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.


End point type 
Secondary


End point timeframe 
A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 25 hours postdose more than 1 hour apart.




No statistical analyses for this end point 


End point title 
Time to Reach Maximum Plasma Concentration of Mirabegron Following Drug Administration (Tmax)  
End point description 
The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.


End point type 
Secondary


End point timeframe 
A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 25 hours postdose more than 1 hour apart.




No statistical analyses for this end point 


End point title 
Area Under the Plasma ConcentrationTime Curve From Time Zero to 24 Hours (AUC24) for Mirabegron  
End point description 
The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.


End point type 
Secondary


End point timeframe 
A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 25 hours postdose more than 1 hour apart.




No statistical analyses for this end point 


End point title 
Plasma Concentration of Mirabegron at the End of a Dosing interval at Steady State (Ctrough)  
End point description 
The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.


End point type 
Secondary


End point timeframe 
A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 25 hours postdose more than 1 hour apart.




No statistical analyses for this end point 


End point title 
Apparent Total Clearance of Mirabegron From Plasma After Oral Administration (CL/F)  
End point description 
The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.


End point type 
Secondary


End point timeframe 
A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 25 hours postdose more than 1 hour apart.




No statistical analyses for this end point 


End point title 
Apparent Volume of Distribution After Nonintravenous Administration (Vz/F) of Mirabegron  
End point description 
The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.


End point type 
Secondary


End point timeframe 
A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 25 hours postdose more than 1 hour apart.




No statistical analyses for this end point 


Adverse events information


Timeframe for reporting adverse events 
From the first dose of study drug administration up to endoftreatment (EoT) (week 52).


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
16


Reporting groups


Reporting group title 
Children (3 to < 12 Years)


Reporting group description 
Children age 3 to < 12 received initial dose of mirabegron based on weight (pediatric equivalent dose [PED25]) on day 1. At weeks 2, 4 or 8, participant's were uptitrated to the pediatric equivalent dose of 50 mg in adults (PED50) based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  
Reporting group title 
Adolescents (12 to < 18 Years)


Reporting group description 
Adolescents age 12 to < 18 received initial dose of mirabegron based on weight (pediatric equivalent dose [PED25]) on day 1. At weeks 2, 4 or 8, participant's were uptitrated to the pediatric equivalent dose of 50 mg in adults (PED50) based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 endofstudy (EOS) or endoftreatment (EOT).  


Frequency threshold for reporting nonserious adverse events: 5%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

02 Nov 2016 
The changes included:
● The age range of the patients was updated to include children from 3 to < 18 years of age. This study is targeted to fulfill both the EMA and FDA requirements related to the conduct of pediatric studies. A Written Request received from the FDA included a stipulation to decrease the lower limit of the age range from 5 to 3 years of age.
● Mirabegron oral suspension (8 mg/mL) was added to the protocol as a second study drug formulation to enable dosing of the younger patients.
● The weight range for inclusion of patients in the study was lowered to ≥ 11 kg.
● Additional SBPM were included at weeks 1 and 2 after the start of dosing and after a dose escalation to satisfy EMA and FDA comments.
● Nonsubstantial changes corrected administrativetype information.
These protocol changes were implemented after enrollment of 38 patients 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
None reported 