Study of OnabotulinumtoxinA (BOTOX®) for Urinary Incontinence Due to Neurogenic Detrusor Overactivity in Pediatric Patients

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01852045
• Collaborator: (none)
• Enrollment: 114
• Locations: 31
• Arms: 3
• Actual Duration (Months): 63.3
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will evaluate the 3 doses of onabotulinumtoxinA (botulinum toxin Type A) for the treatment of urinary incontinence due to neurogenic detrusor overactivity in pediatric participants between the ages of 5 to 17 years to determine if 1 or more doses were safe and effective.

Condition or Disease	Intervention/Treatment	Phase
Urinary Incontinence	Biological: OnabotulinumtoxinA	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 114 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor Overactivity in Patients 5 to 17 Years of Age
• Actual Study Start Date: Jul 2, 2013
• Actual Primary Completion Date: Oct 11, 2018
• Actual Study Completion Date: Oct 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OnabotulinumtoxinA 50 U OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	Biological: OnabotulinumtoxinA; OnabotulinumtoxinA injected into the detrusor wall on Day 1.; Other Names: BOTOX® botulinum toxin Type A
Experimental: OnabotulinumtoxinA 100 U OnabotulinumtoxinA (botulinum toxin Type A) 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	Biological: OnabotulinumtoxinA; OnabotulinumtoxinA injected into the detrusor wall on Day 1.; Other Names: BOTOX® botulinum toxin Type A
Experimental: OnabotulinumtoxinA 200 U OnabotulinumtoxinA (botulinum toxin Type A) 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	Biological: OnabotulinumtoxinA; OnabotulinumtoxinA injected into the detrusor wall on Day 1.; Other Names: BOTOX® botulinum toxin Type A

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Daily Average Frequency of Daytime Urinary Incontinence Episodes [Baseline (Day -28 to Day -1) to 2 consecutive days prior to Week 6]

   Urinary incontinence was defined as involuntary loss of urine as recorded by the participant in a bladder diary during the 2 consecutive days (normalized to a 12-hour daytime period) prior to the study visit. Daytime was defined as the time between waking up to start the day and first morning catheterization and going to bed to sleep for the night. The number of incontinence episodes were averaged daily during this period. A negative change from Baseline indicates improvement. Least squares estimates were based on an Analysis of Covariance (ANCOVA) model.

Secondary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (TEAE) [First study treatment to 12 weeks after last treatment (Up to 48 weeks after first study injection)]

   An adverse event is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and 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 TEAE is defined as any new adverse event or worsening of an existing condition after initiation of treatment.

2. Change From Baseline in Average Urine Volume at First Morning Catheterization [Baseline (Day -28 to Day -1) to 2 consecutive days prior to Week 6]

   The change in urine volume at first morning catherization was recorded by the participant in a bladder diary in the 2 consecutive days during the week prior to the study visit. A positive change from Baseline indicates improvement. Least squares estimates were based on an ANCOVA model.

3. Percentage of Participants With Night Time Urinary Incontinence [Baseline (Day -28 to Day -1), Week 6]

   Urinary incontinence was defined as involuntary loss of urine and the presence or absence of night time urinary incontinence was recorded by the participant in a bladder diary in the 2 consecutive days (normalized to a 12-hour daytime period) during the week prior to the study visit. Night time was defined as the time between going to bed to sleep for the night and waking up to start the day. The percentage of participants with night time urinary incontinence is presented in categories (0, 1, 2 nights).

4. Change From Baseline in Maximum Cystometric Capacity (MCC) [Baseline (Day -28 to Day -1) to Week 6]

   The MCC was defined by urodynamics, as the volume infused before the participant felt they could no longer delay micturition (has a strong desire to void), had a leakage, or 500 mL was instilled. A positive change from Baseline indicates improvement (increase) in the maximum volume of urine the bladder holds. Least squares estimates were based on an ANCOVA model.

5. Percentage of Participants With Involuntary Detrusor Contractions (IDC) [Baseline (Day -28 to -1) and Week 6]

   Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the presence of involuntary detrusor contractions upon filling. A reduction in IDCs from Baseline to Week 6 indicates improvement.

6. Change From Baseline in Maximum Detrusor Pressure During the First IDC (PdetMax1stIDC) in Participants With IDC [Baseline (Day-28 to Day-1) to Week 6]

   Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the pressure inside of the bladder to see how well the bladder was working. A negative change from Baseline indicates improvement. Least squares estimates were based on an ANCOVA model.

7. Change From Baseline in Maximum Detrusor Pressure (PdetMax) During the Storage Phase [Baseline (Day 1) to Week 6]

   Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the pressure inside of the bladder to see how well the bladder was working. A negative change from Baseline indicates improvement. Least squares estimates were based on an ANCOVA model.

8. Change From Baseline in Detrusor Leak Point Pressure (DLPP) During the Storage Phase [Baseline (Day -28 to -1) to Week 6]

   DLPP was defined as the lowest detrusor pressure at which urine leakage occurs in the absence of either a detrusor contraction or increased intra-abdominal pressure. Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the pressure inside of the bladder to see how well the bladder was working. A negative change from Baseline indicates improvement. Least squares estimates are based on an ANCOVA model.

9. Time to Participant Request for Retreatment [48 weeks]

   Time from treatment on Day 1 to request for retreatment was estimated. For those participants who did not request retreatment, their data was censored using the date of their last study visit.

10. Time to Participant Qualification for Retreatment [48 weeks]

    In order to qualify for retreatment, the criteria listed below must be fulfilled at the qualification for retreatment visit: Participant/parent/caregiver requests retreatment, participant has a total of at least 2 daytime urinary incontinence episodes over the 2-day bladder diary collection period, at least 12 weeks has elapsed since treatment 1 and participant has not experienced a serious treatment-related adverse event at any time.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Urinary incontinence due to neurogenic detrusor overactivity

• Regularly using clean intermittent catheterization to empty the bladder

Exclusion Criteria:

• Surgery of the spinal cord within 6 months

• Diagnosis of cerebral palsy

• Current or planned use of a baclofen pump

• Current or planned use of an electrostimulation/neuromodulation device for urinary incontinence

• Use of an indwelling catheter for urinary incontinence instead of using clean intermittent catheterization to empty the bladder

• Previous or current use of botulinum toxin therapy of any serotype for any urological condition, or treatment with botulinum toxin of any serotype within 3 months for any other condition or use

• Myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
3	Children's Hospital of Orange County	Orange	California	United States	92868
4	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
5	Riley Hospital for Children	Indianapolis	Indiana	United States	46032
6	William Beaumont Hospital Research Institute	Royal Oak	Michigan	United States	48073
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Pediatric Urology Associates, PC	Tarrytown	New York	United States	10591
9	McKay Urology Carolinas Medical Center	Charlotte	North Carolina	United States	28207
10	Duke University Health System	Durham	North Carolina	United States	27710
11	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
12	Oklahoma Childrens Hospital	Oklahoma City	Oklahoma	United States	73104
13	Medical University of South Carolina	Charleston	South Carolina	United States	29425
14	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
15	UZ Antwerpen	Antwerpen		Belgium	2650
16	UZ Gent , Urology	Gent		Belgium	9000
17	UZ Leuven	Leuven		Belgium	3000
18	McMaster University Medical Centre	Hamilton	Ontario	Canada	L8N 3Z5
19	CHU Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
20	Fakultni nemocnice Hradec Kralove	Hradec Králové		Czechia	50005
21	Fakultni nemocnice Olomouc	Olomouc		Czechia	77520
22	Hopital Pellegrin - Enfants	Bordeaux		France	33076
23	CHU de Limoges - Hopital Mere et l'Enfant	Limoges		France	87000
24	Hopital Trousseau	Paris		France	75012
25	Necker Enfants Malades Hospital	Paris		France	75015
26	Seconda Università di Napoli	Caserta		Italy	80138
27	IRCCS Ospedale Pediatrico Bambino Gesu	Roma		Italy	00165
28	Copernicus Podmiot Leczniczy Sp. z o. o., Kliniczny Oddzial Chirurgii i Urologii Dzieci i Mlodziezy GUMed	Gdansk		Poland	80-803
29	Specjalistyczny Gabinet Lekarski	Poznan		Poland	61-512
30	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw		Poland	50-369
31	Ankara University Medical Faculty Cebeci Hospital	Ankara		Turkey	6100

Sponsors and Collaborators

• Allergan

Investigators

• Study Director: Margarita Furmanov, Allergan

Study Documents (Full-Text)

• Statistical Analysis Plan - Nov 12, 2018
• Study Protocol - Sep 27, 2017

More Information

Additional Information:

• Additional information on study locations near you may be found at AllerganClinicalTrials.com. For any study not on AllerganClinicalTrials.com, please contact [e-mail] for assistance.

Publications

None provided.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT01852045
• Other Study ID Numbers: 191622-120; 2012-004877-26
• First Posted: May 13, 2013
• Last Update Posted: Nov 21, 2019
• Last Verified: Nov 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Urinary Incontinence; Enuresis; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA

Study Results

Participant Flow

Pre-assignment Detail	114 patients were enrolled and randomized into the study; 113 received study treatment.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Period Title: Overall Study
STARTED	39	45	30
mITT Population	38	45	30
Safety Population	38	45	30
COMPLETED	33	41	26
NOT COMPLETED	6	4	4

Baseline Characteristics

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U	Total
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	Total of all reporting groups
Overall Participants	39	45	30	114
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.4 (3.45)	10.8 (3.26)	11.9 (3.13)	11.3 (3.29)
Sex: Female, Male (Count of Participants)
Female	19 48.7%	15 33.3%	15 50%	49 43%
Male	20 51.3%	30 66.7%	15 50%	65 57%
Race/Ethnicity, Customized (Count of Participants)
White	29 74.4%	34 75.6%	22 73.3%	85 74.6%
Black or African American	6 15.4%	3 6.7%	2 6.7%	11 9.6%
Asian	1 2.6%	2 4.4%	1 3.3%	4 3.5%
Hispanic	1 2.6%	3 6.7%	3 10%	7 6.1%
Other	2 5.1%	3 6.7%	2 6.7%	7 6.1%
Daily Daytime Average Frequency of Urinary Incontinence Episodes (urinary incontinence episodes per day) [Mean (Full Range) ]
Mean (Full Range) [urinary incontinence episodes per day]	2.81	2.99	3.68	3.16

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Daily Average Frequency of Daytime Urinary Incontinence Episodes
Description	Urinary incontinence was defined as involuntary loss of urine as recorded by the participant in a bladder diary during the 2 consecutive days (normalized to a 12-hour daytime period) prior to the study visit. Daytime was defined as the time between waking up to start the day and first morning catheterization and going to bed to sleep for the night. The number of incontinence episodes were averaged daily during this period. A negative change from Baseline indicates improvement. Least squares estimates were based on an Analysis of Covariance (ANCOVA) model.
Time Frame	Baseline (Day -28 to Day -1) to 2 consecutive days prior to Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Missing data are imputed up to Week 6 using Last Observation Carried Forward (LOCF) method.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	38	45	30
Least Squares Mean (Standard Error) [urinary incontinence episodes per day]	-1.30 (0.205)	-1.30 (0.189)	-1.34 (0.245)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 100 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9949
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.549 to 0.545
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.276
	Estimation Comments	Least squares estimates and contrast t-test were based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 200 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9123
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.673 to 0.602
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.321
	Estimation Comments	Least squares estimates and contrast t-test were based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

2. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAE)
Description	An adverse event is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and 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 TEAE is defined as any new adverse event or worsening of an existing condition after initiation of treatment.
Time Frame	First study treatment to 12 weeks after last treatment (Up to 48 weeks after first study injection)

Outcome Measure Data

Analysis Population Description

Safety population included participants who underwent treatment procedure and received study drug on randomization/Day 1, except those who received less dose due to 6 U/kg weight cap, were allocated to nearest dose group based on the actual dose received.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	38	45	30
Count of Participants [Participants]	27 69.2%	33 73.3%	23 76.7%

3. Secondary Outcome

Title	Change From Baseline in Average Urine Volume at First Morning Catheterization
Description	The change in urine volume at first morning catherization was recorded by the participant in a bladder diary in the 2 consecutive days during the week prior to the study visit. A positive change from Baseline indicates improvement. Least squares estimates were based on an ANCOVA model.
Time Frame	Baseline (Day -28 to Day -1) to 2 consecutive days prior to Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analyzed is number of participants with non-missing values at the specified Visit.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	36	43	27
Least Squares Mean (Standard Error) [milliliters (mL)]	21.93 (14.676)	34.90 (13.580)	87.49 (17.808)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 100 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5117
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	12.97
	Confidence Interval	(2-Sided) 95%; -26.120 to 52.064
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.694
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 200 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0055
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	65.57
	Confidence Interval	(2-Sided) 95%; 19.711 to 111.421
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.101
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

4. Secondary Outcome

Title	Percentage of Participants With Night Time Urinary Incontinence
Description	Urinary incontinence was defined as involuntary loss of urine and the presence or absence of night time urinary incontinence was recorded by the participant in a bladder diary in the 2 consecutive days (normalized to a 12-hour daytime period) during the week prior to the study visit. Night time was defined as the time between going to bed to sleep for the night and waking up to start the day. The percentage of participants with night time urinary incontinence is presented in categories (0, 1, 2 nights).
Time Frame	Baseline (Day -28 to Day -1), Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analyzed is number of participants with non-missing values at the specified Visit.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	38	45	28
Baseline (BL): 0 nights of incontinence	0.0 0%	13.3 29.6%	3.6 12%
BL: 1 night of incontinence	13.2 33.8%	2.2 4.9%	14.3 47.7%
BL: 2 nights of incontinence	86.8 222.6%	84.4 187.6%	82.1 273.7%
Week 6: 0 nights of incontinence	30.6 78.5%	32.6 72.4%	28.6 95.3%
Week 6: 1 night of incontinence	16.7 42.8%	16.3 36.2%	28.6 95.3%
Week 6: 2 nights of incontinence	52.8 135.4%	51.2 113.8%	42.9 143%

5. Secondary Outcome

Title	Change From Baseline in Maximum Cystometric Capacity (MCC)
Description	The MCC was defined by urodynamics, as the volume infused before the participant felt they could no longer delay micturition (has a strong desire to void), had a leakage, or 500 mL was instilled. A positive change from Baseline indicates improvement (increase) in the maximum volume of urine the bladder holds. Least squares estimates were based on an ANCOVA model.
Time Frame	Baseline (Day -28 to Day -1) to Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analyzed is number of participants with non-missing values at the specified Visit.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	34	38	28
Least Squares Mean (Standard Error) [mL]	62.06 (14.339)	48.57 (13.549)	63.55 (17.363)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 100 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4948
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-13.49
	Confidence Interval	(2-Sided) 95%; -52.605 to 25.626
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.673
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 200 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9471
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; -43.012 to 45.991
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.382
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

6. Secondary Outcome

Title	Percentage of Participants With Involuntary Detrusor Contractions (IDC)
Description	Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the presence of involuntary detrusor contractions upon filling. A reduction in IDCs from Baseline to Week 6 indicates improvement.
Time Frame	Baseline (Day -28 to -1) and Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analyzed is number of participants with non-missing values at the specified Visit.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	38	45	30
Baseline	94.4 242.1%	88.1 195.8%	92.6 308.7%
Week 6	61.8 158.5%	44.7 99.3%	46.4 154.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 100 U
	Comments	Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2027
	Comments	P-values for pairwise comparisons are obtained from 2-sided CMH test, stratified by age (<12 years or >=12 years), baseline daytime urinary incontinence episodes (<=6 or >6) and anticholinergic therapy (yes/no).
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 200 U
	Comments	Week 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1564
	Comments	P-values for pairwise comparisons are obtained from a 2-sided CMH test, stratified by age (< 12 years or >= 12 years), baseline daytime urinary incontinence episodes (<= 6 or > 6) and anticholinergic therapy (yes/no).
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.40 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Maximum Detrusor Pressure During the First IDC (PdetMax1stIDC) in Participants With IDC
Description	Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the pressure inside of the bladder to see how well the bladder was working. A negative change from Baseline indicates improvement. Least squares estimates were based on an ANCOVA model.
Time Frame	Baseline (Day-28 to Day-1) to Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Only participants who experienced an IDC are included in the analysis.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	21	17	12
Least Squares Mean (Standard Error) [centimeters of water (cm H2O)]	-7.64 (5.301)	-12.13 (5.573)	-5.46 (8.267)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 100 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5524
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.49
	Confidence Interval	(2-Sided) 95%; -19.648 to 10.669
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.488
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 200 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8313
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.18
	Confidence Interval	(2-Sided) 95%; -18.427 to 22.795
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.181
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

8. Secondary Outcome

Title	Change From Baseline in Maximum Detrusor Pressure (PdetMax) During the Storage Phase
Description	Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the pressure inside of the bladder to see how well the bladder was working. A negative change from Baseline indicates improvement. Least squares estimates were based on an ANCOVA model.
Time Frame	Baseline (Day 1) to Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analyzed is number of participants with non-missing values at the specified Visit.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	34	38	28
Least Squares Mean (Standard Error) [cm H2O]	-12.88 (3.793)	-20.09 (3.632)	-27.31 (4.557)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 100 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1737
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-7.21
	Confidence Interval	(2-Sided) 95%; -17.653 to 3.238
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.253
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OnabotulinumtoxinA 50 U, OnabotulinumtoxinA 200 U
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0157
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-14.43
	Confidence Interval	(2-Sided) 95%; -26.061 to -2.793
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.850
	Estimation Comments	Least squares estimates and contrast t-test are based on ANCOVA model with baseline value as covariate and treatment group, age, baseline daytime urinary incontinence episodes, anticholinergic therapy at baseline as factors.

9. Secondary Outcome

Title	Change From Baseline in Detrusor Leak Point Pressure (DLPP) During the Storage Phase
Description	DLPP was defined as the lowest detrusor pressure at which urine leakage occurs in the absence of either a detrusor contraction or increased intra-abdominal pressure. Urodynamic tests were performed by site personnel qualified for performing pressure/flow cystometry. The results were verified by an independent central reviewer. Cystometry was used to measures the pressure inside of the bladder to see how well the bladder was working. A negative change from Baseline indicates improvement. Least squares estimates are based on an ANCOVA model.
Time Frame	Baseline (Day -28 to -1) to Week 6

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Only participants who experienced a leak during urodynamics are included in the analysis.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	2	1	1
Mean (Standard Deviation) [cm H2O]	9.50 (2.121)	-39.00 (0.000)	12.00 (0.000)

10. Secondary Outcome

Title	Time to Participant Request for Retreatment
Description	Time from treatment on Day 1 to request for retreatment was estimated. For those participants who did not request retreatment, their data was censored using the date of their last study visit.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analyzed is number of participants with non-missing values at the specified Visit.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	27	35	23
Median (95% Confidence Interval) [weeks]	30.6	24.1	29.6

11. Secondary Outcome

Title	Time to Participant Qualification for Retreatment
Description	In order to qualify for retreatment, the criteria listed below must be fulfilled at the qualification for retreatment visit: Participant/parent/caregiver requests retreatment, participant has a total of at least 2 daytime urinary incontinence episodes over the 2-day bladder diary collection period, at least 12 weeks has elapsed since treatment 1 and participant has not experienced a serious treatment-related adverse event at any time.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

mITT population included participants who received study drug on Day 1, analyzed on as-randomized basis, except those who received less than their randomized dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analyzed is number of participants with non-missing values at the specified Visit.

Arm/Group Title	OnabotulinumtoxinA 50 U	OnabotulinumtoxinA 100 U	OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.	OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.	OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
Measure Participants	27	35	23
Median (95% Confidence Interval) [weeks]	35.0	25.0	29.6

Adverse Events

Time Frame	First study treatment to 12 weeks after last treatment (Up to 48 weeks after first study injection)
Adverse Event Reporting Description	Safety population included participants who underwent treatment procedure and received study drug on randomization/Day 1, except those who received less dose due to 6 U/kg weight cap, were allocated to nearest dose group based on the actual dose received.
Arm/Group Title	OnabotulinumtoxinA 50 U		OnabotulinumtoxinA 100 U		OnabotulinumtoxinA 200 U
Arm/Group Description	OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (NCT01852058) if qualified.		OnabotulinumtoxinA 100 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.		OnabotulinumtoxinA 200 U (not to exceed 6 U/kg) injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 if qualified.
All Cause Mortality
	OnabotulinumtoxinA 50 U		OnabotulinumtoxinA 100 U		OnabotulinumtoxinA 200 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/45 (0%)		0/30 (0%)
Serious Adverse Events
	OnabotulinumtoxinA 50 U		OnabotulinumtoxinA 100 U		OnabotulinumtoxinA 200 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/38 (10.5%)		3/45 (6.7%)		2/30 (6.7%)
Infections and infestations
Urinary tract infection	2/38 (5.3%)		2/45 (4.4%)		0/30 (0%)
Cystitis	1/38 (2.6%)		0/45 (0%)		0/30 (0%)
Postoperative wound infection	1/38 (2.6%)		0/45 (0%)		0/30 (0%)
Encephalitis viral	0/38 (0%)		1/45 (2.2%)		0/30 (0%)
Epididymitis	0/38 (0%)		0/45 (0%)		1/30 (3.3%)
Orchitis	0/38 (0%)		0/45 (0%)		1/30 (3.3%)
Injury, poisoning and procedural complications
Arteriovenous fistula thrombosis	1/38 (2.6%)		0/45 (0%)		0/30 (0%)
Nervous system disorders
Hydrocephalus	0/38 (0%)		1/45 (2.2%)		0/30 (0%)
Vascular disorders
Hypertension	0/38 (0%)		0/45 (0%)		1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	OnabotulinumtoxinA 50 U		OnabotulinumtoxinA 100 U		OnabotulinumtoxinA 200 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/38 (71.1%)		33/45 (73.3%)		23/30 (76.7%)
Gastrointestinal disorders
Diarrhoea	1/38 (2.6%)		3/45 (6.7%)		2/30 (6.7%)
Abdominal pain	2/38 (5.3%)		1/45 (2.2%)		1/30 (3.3%)
Vomiting	1/38 (2.6%)		3/45 (6.7%)		0/30 (0%)
General disorders
Pyrexia	2/38 (5.3%)		4/45 (8.9%)		0/30 (0%)
Suprapubic pain	2/38 (5.3%)		0/45 (0%)		1/30 (3.3%)
Infections and infestations
Urinary tract infection	9/38 (23.7%)		13/45 (28.9%)		7/30 (23.3%)
Bacteriuria	6/38 (15.8%)		7/45 (15.6%)		6/30 (20%)
Pharyngitis	3/38 (7.9%)		3/45 (6.7%)		0/30 (0%)
Gastroenteritis	2/38 (5.3%)		3/45 (6.7%)		1/30 (3.3%)
Nasopharyngitis	0/38 (0%)		1/45 (2.2%)		4/30 (13.3%)
Upper respiratory tract infection	0/38 (0%)		3/45 (6.7%)		1/30 (3.3%)
Sinusitis	2/38 (5.3%)		0/45 (0%)		1/30 (3.3%)
Injury, poisoning and procedural complications
Limb injury	0/38 (0%)		1/45 (2.2%)		2/30 (6.7%)
Nervous system disorders
Headache	1/38 (2.6%)		7/45 (15.6%)		2/30 (6.7%)
Renal and urinary disorders
Leukocyturia	1/38 (2.6%)		3/45 (6.7%)		4/30 (13.3%)
Hydronephrosis	2/38 (5.3%)		1/45 (2.2%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/38 (5.3%)		1/45 (2.2%)		0/30 (0%)
Skin and subcutaneous tissue disorders
Acne	2/38 (5.3%)		1/45 (2.2%)		1/30 (3.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.