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    Clinical Trial Results:
    BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor Overactivity in Patients 5 to 17 Years of Age

    Summary
    EudraCT number
    		 2012-004877-26
    Trial protocol
    		 BE   CZ   AT   IT   DE   PL   FR  
    Global end of trial date
    11 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2019
    First version publication date
    27 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    191622-120
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01852045
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergan
    Sponsor organisation address
    1st Floor, Marlow International, The Parkway, Marlow, Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@allergan.com
    Scientific contact
    Therapeutic Area, Head, Allergan plc, 001 862-261-7000, IR-CTRegistration@Allergan.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    11 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to evaluate 3 doses of onabotulinumtoxinA (botulinum toxin Type 2) 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.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    114
    EEA total number of subjects
    65
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    59
    Adolescents (12-17 years)
    55
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 114 patients were enrolled and randomised into the study; 113 received study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OnabotulinumtoxinA 50 U
    Arm description
    		 OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OnabotulinumtoxinA
    Investigational medicinal product code
    Other name
    BOTOX® botulinum toxin Type A
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    OnabotulinumtoxinA 50 U injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (2012-004898-30) if qualified.

    Arm title
    		 OnabotulinumtoxinA 100 U
    Arm description
    		 OnabotulinumtoxinA 100 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OnabotulinumtoxinA
    Investigational medicinal product code
    Other name
    BOTOX® botulinum toxin Type A
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    OnabotulinumtoxinA 100 U injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (2012-004898-30) if qualified.

    Arm title
    		 OnabotulinumtoxinA 200 U
    Arm description
    		 OnabotulinumtoxinA 200 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OnabotulinumtoxinA
    Investigational medicinal product code
    Other name
    BOTOX® botulinum toxin Type A
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    OnabotulinumtoxinA 200 U injected into the detrusor wall on Day 1. Participants were eligible for retreatment in study 191622-121 (2012-004898-30) if qualified.

    Number of subjects in period 1
    		OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Started
    39
    45
    30
    mITT Population
    38
    45
    30
    Safety Population: Received treatment
    38
    45
    30
    Completed
    33
    41
    26
    Not completed
    6
    4
    4
         Adverse Event
    1
    -
    -
         Withdrawal by Subject
    1
    -
    1
         Other Miscellaneous Reasons
    1
    3
    2
         Lost to follow-up
    -
    1
    1
         Lack of efficacy
    3
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OnabotulinumtoxinA 50 U
    Reporting group description
    		 OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Reporting group title
    OnabotulinumtoxinA 100 U
    Reporting group description
    		 OnabotulinumtoxinA 100 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Reporting group title
    OnabotulinumtoxinA 200 U
    Reporting group description
    		 OnabotulinumtoxinA 200 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Reporting group values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U Total
    Number of subjects
    		 39 45 30 114
    Age categorical
    Units: Subjects
        5-11 years
    		 21 26 12 59
        12-17 years
    		 18 19 18 55
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.4 ± 3.45 10.8 ± 3.26 11.9 ± 3.13 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 19 15 15 49
        Male
    		 20 30 15 65
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 29 34 22 85
        Black or African American
    		 6 3 2 11
        Asian
    		 1 2 1 4
        Hispanic
    		 1 3 3 7
        Other
    		 2 3 2 7
    Daily Daytime Average Frequency of Urinary Incontinence Episodes
    Urinary incontinence was defined as involuntary loss of urine as recorded by the participant in a bladder diary during the 2 consecutive days (normalised 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 catheterisation and going to bed to sleep for the night. The number of incontinence episodes were averaged daily during this period.
    Units: urinary incontinence episodes per day
        arithmetic mean (full range (min-max))
    		 2.81 (0.8 to 6.7) 2.99 (1.3 to 6.1) 3.68 (0.5 to 29.5) -

    End points

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    End points reporting groups
    Reporting group title
    OnabotulinumtoxinA 50 U
    Reporting group description
    		 OnabotulinumtoxinA (botulinum toxin Type A) 50 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Reporting group title
    OnabotulinumtoxinA 100 U
    Reporting group description
    		 OnabotulinumtoxinA 100 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Reporting group title
    OnabotulinumtoxinA 200 U
    Reporting group description
    		 OnabotulinumtoxinA 200 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Primary: Change from Baseline in Daily Average Frequency of Daytime Urinary Incontinence Episodes

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    End point title
    		 Change from Baseline in Daily Average Frequency of Daytime Urinary Incontinence Episodes
    End point description
    Urinary incontinence was defined as involuntary loss of urine as recorded by the participant in a bladder diary during the 2 consecutive days (normalised 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 catheterisation 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. mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised 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.
    End point type
    Primary
    End point timeframe
    Baseline (Day -28 to Day -1) to 2 consecutive days prior to Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    38
    45
    30
    Units: urinary incontinence episodes per day
        least squares mean (standard error)
    -1.30 ± 0.205
    -1.30 ± 0.189
    -1.34 ± 0.245
    Statistical analysis title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 100U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 100 U
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.9949
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.549
         upper limit
    		 0.545
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.276
    Notes
    [1] - 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 title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 200U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 200 U
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.9123
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.673
         upper limit
    		 0.602
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.321
    Notes
    [2] - 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.

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAE)
    End point 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. Safety population included participants who underwent treatment procedure and received study drug on randomisation/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.
    End point type
    Secondary
    End point timeframe
    First study treatment to 12 weeks after last treatment (Up to 48 weeks after first study injection)
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    38
    45
    30
    Units: participants
    27
    33
    23
    No statistical analyses for this end point

    Secondary: Change from Baseline in Average Urine Volume at First Morning Catheterisation

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    End point title
    		 Change from Baseline in Average Urine Volume at First Morning Catheterisation
    End point description
    The change in urine volume at first morning catherisation 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. mITT population included participants who received study drug on Day 1, analyzed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1) to 2 consecutive days prior to Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    36
    43
    27
    Units: milliliters (mL)
        least squares mean (standard error)
    21.93 ± 14.676
    34.90 ± 13.580
    87.49 ± 17.808
    Statistical analysis title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 100U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 100 U
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.5117
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    12.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.12
         upper limit
    		 52.064
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.694
    Notes
    [3] - 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 title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 200U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 200 U
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0055
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    65.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.711
         upper limit
    		 111.421
    Variability estimate
    Standard error of the mean
    Dispersion value
    23.101
    Notes
    [4] - 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.

    Secondary: Percentage of Participants with Night Time Urinary Incontinence

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    End point title
    		 Percentage of Participants with Night Time Urinary Incontinence
    End point 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 (normalised 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. Percentage of participants with night time urinary incontinence were assessed and represented as categories (0, 1, 2 nights). mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1), Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    38
    45
    28
    Units: percentage of participants
    number (not applicable)
        Baseline (BL): 0 nights of incontinence
    0.0
    13.3
    3.6
        BL: 1 night of incontinence
    13.2
    2.2
    14.3
        BL: 2 nights of incontinence
    86.8
    84.4
    82.1
        Week 6: 0 nights of incontinence
    30.6
    32.6
    28.6
        Week 6: 1 night of incontinence
    16.7
    16.3
    28.6
        Week 6: 2 nights of incontinence
    52.8
    51.2
    42.9
    No statistical analyses for this end point

    Secondary: Change from Baseline in Maximum Cystometric Capacity (MCC)

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    End point title
    		 Change from Baseline in Maximum Cystometric Capacity (MCC)
    End point description
    The MCC was defined by urodynamics, as the volume infused before the participants 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. mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to Day -1) to Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    34
    38
    28
    Units: mL
        least squares mean (standard error)
    62.06 ± 14.339
    48.57 ± 13.549
    63.55 ± 17.363
    Statistical analysis title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 100U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 100 U
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.4948
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -13.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.605
         upper limit
    		 25.626
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.673
    Notes
    [5] - 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 title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 200U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 200 U
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.9471
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.012
         upper limit
    		 45.991
    Variability estimate
    Standard error of the mean
    Dispersion value
    22.382
    Notes
    [6] - 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.

    Secondary: Percentage of Participants with Involuntary Detrusor Contractions (IDC)

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    End point title
    		 Percentage of Participants with Involuntary Detrusor Contractions (IDC)
    End point description
    mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    34
    38
    28
    Units: percentage of participants
        number (confidence interval 95%)
    61.8 (43.56 to 77.83)
    44.7 (28.62 to 61.70)
    46.4 (27.51 to 66.13)
    Statistical analysis title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 100U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 100 U
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2027 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.14
    Notes
    [7] - 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).
    Statistical analysis title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 200U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 200 U
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1564 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.21
    Notes
    [8] - 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).

    Secondary: Change from Baseline in Maximum Detrusor Pressure During the First IDC (PdetMax1stIDC) in Participants with IDC

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    End point title
    		 Change from Baseline in Maximum Detrusor Pressure During the First IDC (PdetMax1stIDC) in Participants with IDC
    End point 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 measure 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. mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-28 to Day-1) to Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    21
    17
    12
    Units: centimeters of water (cm H2O)
        least squares mean (standard error)
    -7.64 ± 5.301
    -12.13 ± 5.573
    -5.46 ± 8.267
    Statistical analysis title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 100U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 100 U
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.5524
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.648
         upper limit
    		 10.669
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.488
    Notes
    [9] - 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 title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 200U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 200 U
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.8313
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.427
         upper limit
    		 22.795
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.181
    Notes
    [10] - 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.

    Secondary: Change from Baseline in Maximum Detrusor Pressure (PdetMax) During the Storage Phase

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    End point title
    		 Change from Baseline in Maximum Detrusor Pressure (PdetMax) During the Storage Phase
    End point 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. mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    34
    38
    28
    Units: cm H2O
        least squares mean (standard error)
    -12.88 ± 3.793
    -20.09 ± 3.632
    -27.31 ± 4.557
    Statistical analysis title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 100U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 100 U
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.1737
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -7.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.653
         upper limit
    		 3.238
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.253
    Notes
    [11] - 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 title
    		 OnabotulinumtoxinA 50U vs OnabotulinumtoxinA 200U
    Comparison groups
    OnabotulinumtoxinA 50 U v OnabotulinumtoxinA 200 U
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.0157
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -14.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.061
         upper limit
    		 -2.793
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.85
    Notes
    [12] - 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.

    Secondary: Change from Baseline in Detrusor Leak Point Pressure (DLPP) During the Storage Phase

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    End point title
    		 Change from Baseline in Detrusor Leak Point Pressure (DLPP) During the Storage Phase
    End point 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. mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -28 to -1) to Week 6
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    2
    1
    1
    Units: cm H2O
        arithmetic mean (standard deviation)
    9.50 ± 2.121
    -39.00 ± 0.000
    12.00 ± 0.000
    No statistical analyses for this end point

    Secondary: Time to Participant Request for Retreatment

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    End point title
    		 Time to Participant Request for Retreatment
    End point 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. mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    27
    35
    23
    Units: weeks
        median (confidence interval 95%)
    30.6 (23.10 to 39.10)
    24.1 (18.10 to 27.60)
    29.6 (16.30 to 37.30)
    No statistical analyses for this end point

    Secondary: Time to Participant Qualification for Retreatment

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    End point title
    		 Time to Participant Qualification for Retreatment
    End point 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. mITT population included participants who received study drug on Day 1, analysed on as-randomised basis, except those who received less than their randomised dose due to weight and dose limit of 6 U/kg, allocated to nearest dose group based on dose received. Number analysed is number of participants with non-missing values at the specified Visit.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 100 U OnabotulinumtoxinA 200 U
    Number of subjects analysed
    27
    35
    23
    Units: weeks
        median (confidence interval 95%)
    35.0 (23.10 to 39.10)
    25.0 (20.00 to 32.10)
    29.6 (16.30 to 38.00)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First study treatment to 12 weeks after last treatment (Up to 48 weeks after first study injection)
    Adverse event reporting additional description
    Safety population included participants who underwent treatment procedure and received study drug on randomisation/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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    OnabotulinumtoxinA 50 U
    Reporting group description
    		 OnabotulinumtoxinA 50 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Reporting group title
    OnabotulinumtoxinA 200 U
    Reporting group description
    		 OnabotulinumtoxinA 200 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Reporting group title
    OnabotulinumtoxinA 100 U
    Reporting group description
    		 OnabotulinumtoxinA 100 U (not to exceed 6U/kg) injected into the detrusor wall on Day 1.

    Serious adverse events
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 200 U OnabotulinumtoxinA 100 U
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 30 (6.67%)
    3 / 45 (6.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 30 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 30 (3.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hydrocephalus
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 30 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 30 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 30 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 30 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis viral
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 30 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 30 (3.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 30 (3.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 OnabotulinumtoxinA 50 U OnabotulinumtoxinA 200 U OnabotulinumtoxinA 100 U
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 38 (71.05%)
    23 / 30 (76.67%)
    33 / 45 (73.33%)
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 30 (6.67%)
    1 / 45 (2.22%)
         occurrences all number
    0
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 30 (6.67%)
    7 / 45 (15.56%)
         occurrences all number
    1
    4
    14
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 30 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    2
    0
    10
    Suprapubic pain
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 30 (3.33%)
    0 / 45 (0.00%)
         occurrences all number
    2
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 30 (6.67%)
    3 / 45 (6.67%)
         occurrences all number
    2
    2
    8
    Abdominal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 30 (3.33%)
    1 / 45 (2.22%)
         occurrences all number
    2
    2
    1
    Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 30 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    3
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 30 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    3
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 30 (3.33%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 30 (13.33%)
    3 / 45 (6.67%)
         occurrences all number
    2
    5
    3
    Hydronephrosis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 30 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    2
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    9 / 38 (23.68%)
    7 / 30 (23.33%)
    13 / 45 (28.89%)
         occurrences all number
    11
    9
    21
    Bacteriuria
         subjects affected / exposed
    6 / 38 (15.79%)
    6 / 30 (20.00%)
    7 / 45 (15.56%)
         occurrences all number
    11
    11
    12
    Pharyngitis
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 30 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    3
    0
    3
    Gastroenteritis
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 30 (3.33%)
    3 / 45 (6.67%)
         occurrences all number
    3
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 30 (13.33%)
    1 / 45 (2.22%)
         occurrences all number
    0
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 30 (3.33%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    4
    Sinusitis
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 30 (3.33%)
    0 / 45 (0.00%)
         occurrences all number
    2
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2013
    The following changes were implemented with Amendment 1: Provided clarifications and guidance to investigators regarding entry criteria, study procedures and concomitant medications/procedures. In addition, the following procedures were added to the protocol: Collection of an immunogenicity sample at week 12, measurement of bladder wall thickness by ultrasound at the screening visit, an addition of renal function assessment (eGFR) volume at first IDC to be measured and recorded during urodynamics.
    14 Apr 2016
    The following changes were implemented with Amendment 2: Changed the minimum age to 5 years old from 8 years old and to include dosing information for a younger participant population. The FDA requested that, Allergan document the ‘opinion of the investigator’ that was used to justify treatment of UTI by each investigator. In addition, the investigator was required to describe the criteria used for qualifying ‘leukocyturia’ as an AE.
    27 Sep 2017
    The following changes were implemented with Amendment 3: The proposed sample size was reduced from N=132 to N=102 due to enrollment challenges.

    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
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