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    Clinical Trial Results:
    An Open-label, Baseline-controlled, Multicenter, Phase 3 Dose-titration Study Followed by a Fixed-dose Observation Period to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Children and Adolescents From 3 to Less Than 18 Years of Age with Neurogenic Detrusor Overactivity (NDO) on Clean Intermittent Catheterization

    Summary
    EudraCT number
    2015-002876-25
    Trial protocol
    DK   LT   NO   BE   SK   RO   LV   HR  
    Global end of trial date
    06 May 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    26 Aug 2020
    First version publication date
    14 Nov 2019
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    178-CL-206A
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02751931
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Acronym: Crocodile Study
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe B.V.
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000597-PIP03-15
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of mirabegron after multiple-dose administration in the pediatric population.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Jordan: 3
    Country: Number of subjects enrolled
    Latvia: 2
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Philippines: 10
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Turkey: 6
    Worldwide total number of subjects
    91
    EEA total number of subjects
    52
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    56
    Adolescents (12-17 years)
    35
    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
    Pediatric participants consisting of male and female children from 3 to <12 and adolescents from 12 to <18 years of age, with a body weight of ≥11 kg, with NDO on clean intermittent catheterization (CIC) were enrolled in this study.

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

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Children (3 to < 12 Years)
    Arm description
    Children age 3 to < 12 received an initial dose of 25 mg of mirabegron (pediatric equivalent dose [PED25]), orally once daily. Initial dose was up-titrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (pediatric equivalent dose [PED50]). After week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT).
    Arm type
    Experimental

    Investigational medicinal product name
    Mirabegron Tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq, Betmiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were up-titrated to PED50 based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT. Participants with a body weight ≥35 kg received mirabegron tablets. At week 24, participants on mirabegron oral suspension could switch to tablets if the body weight became ≥35 kg. Participants who received mirabegron oral suspension could switch to mirabegron tablets for acceptability reasons after sponsor’s prior approval and on a case-by-case basis.

    Investigational medicinal product name
    Mirabegron Oral Suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq, Betmiga
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were up-titrated to PED50 based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT. Participants with a body weight <35 kg received mirabegron oral suspension. For participants with a body weight ≥35 kg who did not want to or were unable to take tablets, the oral suspension could have been supplied. Participants who received mirabegron tablets could switch to mirabegron oral suspension for acceptability reasons after sponsor’s prior approval and on a case-by-case basis. Mirabegron extended-release granules were reconstituted with water to prepare a mirabegron oral suspension of 8 mg/mL. Administration was via an oral syringe with a sip of water afterwards.

    Arm title
    Adolescents (12 to < 18 Years)
    Arm description
    Adolescents age 12 to < 18 received an initial dose of 25 mg of mirabegron (PED25), orally once daily. Initial dose was up-titrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (PED50). After week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT).
    Arm type
    Experimental

    Investigational medicinal product name
    Mirabegron Tablets
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq, Betmiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were up-titrated to PED50 based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT. Participants with a body weight ≥35 kg received mirabegron tablets. At week 24, participants on mirabegron oral suspension could switch to tablets if the body weight became ≥35 kg. Participants who received mirabegron oral suspension could switch to mirabegron tablets for acceptability reasons after sponsor’s prior approval and on a case-by-case basis.

    Investigational medicinal product name
    Mirabegron Oral Suspension
    Investigational medicinal product code
    YM178
    Other name
    Myrbetriq, Betmiga
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received initial dose of 25 mg of mirabegron PED25 orally once daily. At weeks 2, 4 or 8, participants were up-titrated to PED50 based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 EOS or EOT. Participants with a body weight <35 kg received mirabegron oral suspension. For participants with a body weight ≥35 kg who did not want to or were unable to take tablets, the oral suspension could have been supplied. Participants who received mirabegron tablets could switch to mirabegron oral suspension for acceptability reasons after sponsor’s prior approval and on a case-by-case basis. Mirabegron extended-release granules were reconstituted with water to prepare a mirabegron oral suspension of 8 mg/mL. Administration was via an oral syringe with a sip of water afterwards.

    Number of subjects in period 1
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Started
    56
    35
    Received Study Drug
    55
    31
    Completed
    43
    27
    Not completed
    13
    8
         Miscellaneous
    10
    8
         Adverse Event
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Children (3 to < 12 Years)
    Reporting group description
    Children age 3 to < 12 received an initial dose of 25 mg of mirabegron (pediatric equivalent dose [PED25]), orally once daily. Initial dose was up-titrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (pediatric equivalent dose [PED50]). After week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT).

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

    Reporting group values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years) Total
    Number of subjects
    56 35
    Age categorical
    Units: Subjects
    Age continuous
    The baseline characteristics analysis population consisted of the all enrolled/all allocated set (total of 91 participants).
    Units: years
        arithmetic mean (standard deviation)
    7.9 ± 2.5 13.9 ± 1.6 -
    Gender categorical
    The baseline characteristics analysis population consisted of the all enrolled/all allocated set (total of 91 participants).
    Units: Subjects
        M
    23 20 43
        F
    33 15 48
    Analysis Race
    The baseline characteristics analysis population consisted of the all enrolled/all allocated set (total of 91 participants).
    Units: Subjects
        White
    41 25 66
        Asian
    13 8 21
        American Indian/Alaska Native
    0 1 1
        Other
    2 1 3
    Ethnicity
    The baseline characteristics analysis population consisted of the all enrolled/all allocated set (total of 91 participants).
    Units: Subjects
        NOT HISPANIC OR LATINO
    55 33 88
        HISPANIC OR LATINO
    1 2 3
    Maximum Cystometric Capacity (MCC) (mL)
    The study specific baseline characteristics analysis population consisted of the all enrolled/all allocated set with MCC baseline data collected (total of 86 participants).
    Units: Year
        arithmetic mean (standard deviation)
    167.35 ± 100 242.42 ± 100.64 -

    End points

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    End points reporting groups
    Reporting group title
    Children (3 to < 12 Years)
    Reporting group description
    Children age 3 to < 12 received an initial dose of 25 mg of mirabegron (pediatric equivalent dose [PED25]), orally once daily. Initial dose was up-titrated at weeks 2, 4 or 8 up to 50 mg of mirabegron (pediatric equivalent dose [PED50]). After week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT).

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

    Subject analysis set title
    Children PED25 (PKAS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants aged 3 to < 12 years who received pediatric equivalent dose of 25 mg at the time of PK sampling.

    Subject analysis set title
    Adolescents PED25 (PKAS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants aged 12 to < 18 years who received pediatric equivalent dose of 25 mg at the time of PK sampling.

    Subject analysis set title
    Children PED50 (PKAS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants aged 3 to < 12 years who received pediatric equivalent dose of 50 mg at the time of PK sampling.

    Subject analysis set title
    Adolescents PED50 (PKAS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants aged 12 to < 18 years who received pediatric equivalent dose of 50 mg at the time of PK sampling.

    Primary: Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24

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    End point title
    Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 24
    End point description
    Change from baseline in MCC was based on filling urodynamics, volume at the end of filling. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the full analysis set (FAS) which consisted of all participants who took ≥ 1 dose of study drug and provided both valid (as by the central reviewer’s assessment) nonmissing MCC measurements at baseline and at a postbaseline visit for the primary efficacy endpoint. Missing MCC observations at week 24 were imputed using last observation carried forward (LOCF).
    End point type
    Primary
    End point timeframe
    Baseline and week 24
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: mL
        arithmetic mean (standard deviation)
    72.09 ± 87.09
    113.21 ± 82.99
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in MCC in children at week 24. The number of participants included in this analysis was 43.
    Comparison groups
    Adolescents (12 to < 18 Years) v Children (3 to < 12 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [1]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    72.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    45.28
         upper limit
    98.89
    Notes
    [1] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in MCC in adolescents at week 24. The number of participants included in this analysis was 25.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [2]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    113.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    78.95
         upper limit
    147.47
    Notes
    [2] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in MCC at Week 4

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    End point title
    Change From Baseline in MCC at Week 4
    End point description
    Change from baseline in MCC was based on filling urodynamics (volume at the end of filling). During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. Here, Overall Number of participants analyzed signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and week 4
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    41
    23
    Units: mL
        arithmetic mean (standard deviation)
    41.36 ± 71.64
    80.78 ± 96.15
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in MCC in children at week 4. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [3]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    41.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.75
         upper limit
    63.97
    Notes
    [3] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in MCC in adolescents at week 4. The number of participants included in this analysis was 25.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [4]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    80.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    39.2
         upper limit
    122.36
    Notes
    [4] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Bladder Compliance (ΔV/ΔP)

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    End point title
    Change From Baseline in Bladder Compliance (ΔV/ΔP)
    End point description
    Change from baseline in bladder compliance (change in volume/change in pressure) was assessed by the independent central reviewers and reported as annotations on the urodynamic trace and in an external database. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4 and 24
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: mL/cm H2O
    arithmetic mean (standard deviation)
        Week 4 (N=39, 22)
    -4.09 ± 50.78
    15.16 ± 22.69
        Week 24 (N=33, 21)
    14.62 ± 42.09
    13.59 ± 15.02
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in ΔV/ΔP in children at week 4. The number of participants included in this analysis was 39.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.618 [5]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -4.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.55
         upper limit
    12.38
    Notes
    [5] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in ΔV/ΔP in adolescents at week 4. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.005 [6]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    15.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.1
         upper limit
    25.22
    Notes
    [6] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in ΔV/ΔP in children at week 24. The number of participants included in this analysis was 33.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.055 [7]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    14.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    29.54
    Notes
    [7] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in ΔV/ΔP in adolescents at week 24. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [8]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    13.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.75
         upper limit
    20.42
    Notes
    [8] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling

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    End point title
    Change From Baseline in Number of Overactive Detrusor Contractions (> 15 cm H20) Until End of Filling
    End point description
    Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4 and 24
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: overactive detrusor contractions
    arithmetic mean (standard deviation)
        Week 4 (N=41, 22)
    0.44 ± 5.82
    -0.64 ± 2.94
        Week 24 (N=36, 22)
    -1.86 ± 4.16
    -0.77 ± 3.87
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in number of overactive detrusor contractions in children at week 4. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.632 [9]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    2.28
    Notes
    [9] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in number of overactive detrusor contractionsin adolescents at week 4. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.321 [10]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.94
         upper limit
    0.67
    Notes
    [10] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in number of overactive detrusor contractions in children at week 24. The number of participants included in this analysis was 36.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.011 [11]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.27
         upper limit
    -0.45
    Notes
    [11] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in number of overactive detrusor contractions in adolescents at week 24. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.359 [12]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.49
         upper limit
    0.94
    Notes
    [12] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Detrusor Pressure at End of Filling

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    End point title
    Change From Baseline in Detrusor Pressure at End of Filling
    End point description
    Filling was stopped (end of filling) when the detrusor pressure exceeded 100 cm H2O or was considered dangerously high by the investigator or urodynamicist (for instance, a prolonged passive detrusor pressure > 40 cm H2O). During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4 and 24
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: cm H2O
    arithmetic mean (standard deviation)
        Week 4 (N=41, 22)
    -12.38 ± 19.56
    -6.48 ± 30.70
        Week 24 (N=36, 22)
    -18.11 ± 19.97
    -13.19 ± 19.91
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in detrusor pressure in children at week 4. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [13]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -12.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.56
         upper limit
    -6.21
    Notes
    [13] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in detrusor pressure in adolescents at week 4. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.334 [14]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -6.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.09
         upper limit
    7.13
    Notes
    [14] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in detrusor pressure in children at week 24. The number of participants included in this analysis was 36.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [15]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -18.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.87
         upper limit
    -11.35
    Notes
    [15] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in detrusor pressure in adolescents at week 24. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.005 [16]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -13.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.02
         upper limit
    -4.36
    Notes
    [16] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)

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    End point title
    Change From Baseline in Filling Bladder Volume Until First Overactive Detrusor Contraction (> 15 cm H20)
    End point description
    Detrusor overactivity is the occurrence of involuntary detrusor contractions during filling cystometry. During urodynamic assessments, the bladder was filled until voiding/leakage began, or until the participant experienced pain or discomfort, or because dangerous high detrusor pressure, or 135% of maximum catheterized volume for age had been reached. A valid urodynamic assessment was confirmed valid by the central reviewers. The analysis population consisted of the FAS. N is the number of participants with available data at each time point. If no detrusor contraction of > 15 cm H2O occurred, the bladder volume was imputed with maximum cystometric capacity.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4 and 24
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: mL
    median (inter-quartile range (Q1-Q3))
        Week 4 (N=21, 8)
    54.00 (13.00 to 105.30)
    41.15 (3.00 to 62.50)
        Week 24 (N=13, 8)
    68.00 (32.00 to 110.0)
    62.00 (4.00 to 95.15)
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in filling bladder volume until first overactive detrusor contraction in children at week 4. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [17]
    Method
    Wilcoxon signed-rank test
    Confidence interval
    Notes
    [17] - From a Wilcoxon signed-rank test, testing the null hypothesis that week 24 median is equal to baseline median.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in filling bladder volume until first overactive detrusor contraction in adolescents at week 4. The number of participants included in this analysis was 8.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.148 [18]
    Method
    Wilcoxon signed-rank test
    Confidence interval
    Notes
    [18] - From a Wilcoxon signed-rank test, testing the null hypothesis that week 24 median is equal to baseline median.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in filling bladder volume until first overactive detrusor contraction in children at week 24. The number of participants included in this analysis was 13.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [19]
    Method
    Wilcoxon signed-rank test
    Confidence interval
    Notes
    [19] - From a Wilcoxon signed-rank test, testing the null hypothesis that week 24 median is equal to baseline median.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in filling bladder volume until first overactive detrusor contraction in adolescents at week 24. The number of participants included in this analysis was 8.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.039 [20]
    Method
    Wilcoxon signed-rank test
    Confidence interval
    Notes
    [20] - From a Wilcoxon signed-rank test, testing the null hypothesis that week 24 median is equal to baseline median.

    Secondary: Change From Baseline in Average Catheterized Volume Per Catheterization

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    End point title
    Change From Baseline in Average Catheterized Volume Per Catheterization
    End point description
    For each participant, the average catheterized volume per catheterization was calculated as the sum of all available/non-missing catheterized volumes recorded over 2 measuring days in the weekend diary, whether or not the 2 days were consecutive divided by the number of catheterizations with non-missing volumes. If volumes were recorded on 1 single day of the weekend diary, the average catheterized volume per catheterization was calculated using all available/non-missing catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend diary, the average catheterized volume per catheterization was missing. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: mL
    arithmetic mean (standard deviation)
        Week 2 (N=43, 24)
    14.58 ± 43.98
    35.99 ± 54.19
        Week 4 (N=42, 24)
    30.08 ± 49.50
    51.96 ± 64.71
        Week 8 (N=43, 22)
    36.90 ± 46.05
    45.10 ± 53.77
        Week 12 (N=43, 24)
    32.25 ± 45.51
    43.94 ± 58.49
        Week 24 (N=41, 23)
    41.63 ± 58.03
    59.31 ± 82.22
        Week 36 (N=40, 24)
    53.87 ± 91.74
    52.14 ± 74.90
        Week 52 (N=40, 23)
    42.84 ± 65.31
    42.40 ± 69.25
    Statistical analysis title
    Change From Baseline at Week 2 - Children
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in children at week 2. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.035 [21]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    14.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    28.1
    Notes
    [21] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 2 - Adolescents
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in adolescents at week 2. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.003 [22]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    35.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.1
         upper limit
    58.9
    Notes
    [22] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in children at week 4. The number of participants included in this analysis was 42.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [23]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    30.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.7
         upper limit
    45.5
    Notes
    [23] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in adolescents at week 4. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [24]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    51.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.6
         upper limit
    79.3
    Notes
    [24] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Children
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in children at week 8. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [25]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    36.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.7
         upper limit
    51.1
    Notes
    [25] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Adolescents
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in adolescents at week 8. The number of participants included in this analysis was 2.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [26]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    45.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.3
         upper limit
    68.9
    Notes
    [26] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Children
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in children at week 12. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [27]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    32.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.2
         upper limit
    46.3
    Notes
    [27] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Adolescents
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in adolescents at week 12. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.001 [28]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    43.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.2
         upper limit
    68.6
    Notes
    [28] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in children at week 24. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [29]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    41.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.3
         upper limit
    60
    Notes
    [29] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in adolescents at week 24. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [30]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    59.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.8
         upper limit
    94.9
    Notes
    [30] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Children
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in children at week 36. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [31]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    53.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.5
         upper limit
    83.2
    Notes
    [31] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Adolescents
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in adolescents at week 36. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [32]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    52.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.5
         upper limit
    83.8
    Notes
    [32] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in children at week 52. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [33]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    42.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22
         upper limit
    63.7
    Notes
    [33] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in average catheterized volume per catheterization in adolescents at week 52. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.008 [34]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    42.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.5
         upper limit
    72.3
    Notes
    [34] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Maximum Catheterized Volume

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    End point title
    Change From Baseline in Maximum Catheterized Volume
    End point description
    For each participant, the maximum catheterized volume per day was calculated using all available/non-missing catheterized volumes recorded for the 2 measuring days in the weekend e-diary, whether or not these 2 days were consecutive. Maximum value was calculated separately for each measuring day & the mean of the two values was used. If volumes recorded on 1 single day of the weekend e-diary, the maximum catheterized volume per day was calculated using all available/non-zero catheterized volumes recorded that day. If no volumes were recorded on any day of the weekend e-diary, the maximum catheterized volume per day was missing. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: mL
    arithmetic mean (standard deviation)
        Week 2 (N=43, 24)
    17.50 ± 73.58
    42.38 ± 78.23
        Week 4 (N=42, 24)
    46.69 ± 80.29
    73.25 ± 103.98
        Week 8 (N=43, 22)
    45.27 ± 75.22
    42.86 ± 79.97
        Week 12 (N=43, 24)
    33.23 ± 68.31
    47.29 ± 69.83
        Week 24 (N=41, 23)
    49.88 ± 103.70
    84.39 ± 121.98
        Week 36 (N=40, 24)
    60.09 ± 121.66
    54.78 ± 104.54
        Week 52 (N=40, 23)
    53.51 ± 96.72
    54.30 ± 104.74
    Statistical analysis title
    Change From Baseline at Week 2 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized volume in children at week 2. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.126 [35]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    17.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.1
         upper limit
    40.1
    Notes
    [35] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 2 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized volume in adolescents at week 2. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.014 [36]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    42.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.3
         upper limit
    75.4
    Notes
    [36] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized volume in children at week 4. The number of participants included in this analysis was 42.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [37]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    46.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.7
         upper limit
    71.7
    Notes
    [37] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized volume in adolescents at week 4. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [38]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    73.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    29.3
         upper limit
    117.2
    Notes
    [38] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized volume in children at week 8. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [39]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    45.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.1
         upper limit
    68.4
    Notes
    [39] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized volume in adolescents at week 8. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.02
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    42.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.4
         upper limit
    78.3
    Statistical analysis title
    Change From Baseline at Week 12 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized volume in children at week 12. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.003 [40]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    33.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.2
         upper limit
    54.3
    Notes
    [40] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized volume in adolescents at week 12. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.003 [41]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    47.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.8
         upper limit
    76.8
    Notes
    [41] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized volume in children at week 24. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004 [42]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    49.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.1
         upper limit
    82.6
    Notes
    [42] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized volume in adolescents at week 24. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.003 [43]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    84.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.6
         upper limit
    137.1
    Notes
    [43] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized volume in children at week 36. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.003 [44]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    60.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.2
         upper limit
    99
    Notes
    [44] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized volume in adolescents at week 36. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.017 [45]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    54.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.6
         upper limit
    98.9
    Notes
    [45] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized volume in children at week 52. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.001 [46]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    53.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.6
         upper limit
    84.4
    Notes
    [46] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized volume in adolescents at week 52. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.021 [47]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    54.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9
         upper limit
    99.6
    Notes
    [47] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Maximum Catheterized Daytime Volume (MCDV)

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    End point title
    Change From Baseline in Maximum Catheterized Daytime Volume (MCDV)
    End point description
    For each participant, the MCDV was calculated using all available/non-missing catheterized daytime volumes for the 2 measuring days in the weekend e-diary, whether or not the 2 days were consecutive. Maximum value was calculated separately for each measuring day & the mean of the 2 values was used. If volumes were recorded on 1 single day of the weekend e-diary, the MCDV was calculated using all available/non-zero catheterized daytime volumes recorded that day. If no volumes were recorded on any day of the weekend e-diary, the MCDV was missing. Daytime was defined as the time between wake-up time (minus 30 min) & time to sleep (plus 29 min) recorded in the e-diary. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: mL
    arithmetic mean (standard deviation)
        Week 2 (N=43, 24)
    18.13 ± 73.38
    35.58 ± 86.78
        Week 4 (N=42, 24)
    37.71 ± 83.33
    70.35 ± 113.98
        Week 8 (N=43, 22)
    43.91 ± 74.44
    38.11 ± 90.88
        Week 12 (N=43, 24)
    29.05 ± 67.86
    43.04 ± 73.82
        Week 24 (N=41, 23)
    44.20 ± 98.31
    81.37 ± 117.77
        Week 36 (N=40, 24)
    58.49 ± 121.12
    50.90 ± 114.05
        Week 52 (N=40, 23)
    53.76 ± 100.24
    49.13 ± 117.23
    Statistical analysis title
    Change From Baseline at Week 2 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in children at week 2. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.113 [48]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    18.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.5
         upper limit
    40.7
    Notes
    [48] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 2 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in adolescents at week 2. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.056 [49]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    35.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    72.2
    Notes
    [49] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in children at week 4. The number of participants included in this analysis was 42.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.005 [50]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    37.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.7
         upper limit
    63.7
    Notes
    [50] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in adolescents at week 4. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.006 [51]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    70.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.2
         upper limit
    118.5
    Notes
    [51] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in children at week 8. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [52]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    43.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21
         upper limit
    66.8
    Notes
    [52] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in adolescents at week 8. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.063 [53]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    38.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    78.4
    Notes
    [53] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in children at week 12. The number of participants included in this analysis was 43.
    Comparison groups
    Adolescents (12 to < 18 Years) v Children (3 to < 12 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.008 [54]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    29.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.2
         upper limit
    49.9
    Notes
    [54] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in adolescents at week 12. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.009 [55]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    43.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.9
         upper limit
    74.2
    Notes
    [55] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in children at week 24. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.006 [56]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    44.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.2
         upper limit
    75.2
    Notes
    [56] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in adolescents at week 24. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.003 [57]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    81.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    30.4
         upper limit
    132.3
    Notes
    [57] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in children at week 36. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004 [58]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    58.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.8
         upper limit
    97.2
    Notes
    [58] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in adolescents at week 36. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.039 [59]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    50.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.7
         upper limit
    99.1
    Notes
    [59] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in children at week 52. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [60]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    53.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.7
         upper limit
    85.8
    Notes
    [60] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in maximum catheterized daytime volume in adolescents at week 52. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.057 [61]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    49.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    99.8
    Notes
    [61] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Average Morning Catheterized Volume

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    End point title
    Change From Baseline in Average Morning Catheterized Volume
    End point description
    The first morning catheterized volume was the first recorded non-zero volume within or after the hour of the wake-up time on a volume-measuring day in the e-diary. The average first morning catheterized volume was calculated as the average of the available first morning catheterized volumes recorded for the 2 measuring days in the weekend e-diary, whether or not these 2 days were consecutive. If the first morning catheterized volume was recorded on 1 single day of the weekend e-diary, the average morning catheterized is the first morning catheterized that day. If no first morning catheterized volumes are recorded on any day of the weekend e-diary, the average first morning catheterized volume was missing. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: mL
    arithmetic mean (standard deviation)
        Week 2 (N=41, 21)
    7.98 ± 101.36
    39.52 ± 80.24
        Week 4 (N=40, 20)
    19.81 ± 89.04
    75.25 ± 105.72
        Week 8 (N=41, 21)
    34.01 ± 89.53
    44.43 ± 89.01
        Week 12 (N=39, 21)
    8.68 ± 80.16
    38.23 ± 66.80
        Week 24 (N=36, 20)
    40.76 ± 116.41
    86.66 ± 96.55
        Week 36 (N=37, 21)
    31.08 ± 145.63
    68.47 ± 122.43
        Week 52 (N=39, 21)
    31.83 ± 94.25
    38.14 ± 108.06
    Statistical analysis title
    Change From Baseline at Week 2 - Children
    Statistical analysis description
    Change from baseline in average morning catheterized volume in children at week 2. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.617 [62]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    7.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24
         upper limit
    40
    Notes
    [62] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 2 - Adolescents
    Statistical analysis description
    Change from baseline in average morning catheterized volume in adolescents at week 2. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.035 [63]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    39.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3
         upper limit
    76
    Notes
    [63] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in average morning catheterized volume in children at week 4. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.167 [64]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    19.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    48.3
    Notes
    [64] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in average morning catheterized volume in adolescents at week 4. The number of participants included in this analysis was 20.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.005 [65]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    75.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    25.8
         upper limit
    124.7
    Notes
    [65] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Children
    Statistical analysis description
    Change from baseline in average morning catheterized volume in children at week 8. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.02 [66]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    34.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.7
         upper limit
    62.3
    Notes
    [66] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Adolescents
    Statistical analysis description
    Change from baseline in average morning catheterized volume in adolescents at week 8. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.033 [67]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    44.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.9
         upper limit
    84.9
    Notes
    [67] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Children
    Statistical analysis description
    Change from baseline in average morning catheterized volume in children at week 12. The number of participants included in this analysis was 39.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.503 [68]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    8.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.3
         upper limit
    34.7
    Notes
    [68] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Adolescents
    Statistical analysis description
    Change from baseline in average morning catheterized volume in adolescents at week 12. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.016 [69]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    38.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.8
         upper limit
    68.6
    Notes
    [69] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in average morning catheterized volume in children at week 24. The number of participants included in this analysis was 36.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.043 [70]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    40.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.4
         upper limit
    80.2
    Notes
    [70] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in average morning catheterized volume in adolescents at week 24. The number of participants included in this analysis was 20.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [71]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    86.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    41.5
         upper limit
    131.8
    Notes
    [71] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Children
    Statistical analysis description
    Change from baseline in average morning catheterized volume in children at week 36. The number of participants included in this analysis was 37.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.203 [72]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    31.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.5
         upper limit
    79.6
    Notes
    [72] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Adolescents
    Statistical analysis description
    Change from baseline in average morning catheterized volume in adolescents at week 36. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.019 [73]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    68.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.7
         upper limit
    124.2
    Notes
    [73] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in average morning catheterized volume in children at week 52. The number of participants included in this analysis was 39.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.042 [74]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    31.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    62.4
    Notes
    [74] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in average morning catheterized volume in adolescents at week 52. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.121 [75]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    38.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11
         upper limit
    87.3
    Notes
    [75] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Mean Number of Leakage Episodes per Day

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    End point title
    Change From Baseline in Mean Number of Leakage Episodes per Day
    End point description
    For each participant, the mean number of leakage episodes per day (during day & night time) was calculated using all available/non-missing number of leakage episodes for the 2 measuring days in the weekend diary during day & night time. If the number of leakage episodes was recorded on 1 single day in the 7-day diary during day & night time, the mean number of leakage episodes per day during day & night time is equal to the total number of leakage episodes recorded that day during day & night time. If no leakage episodes were recorded on any day of the weekend diary during day & night time, the mean number of leakage episodes per day was zero. Participants who did not report any leakage episode during the visit were imputed with a '0' for that visit. A valid bladder diary day in the weekend diary was any e-diary day for which ≥1 catheterized volume >0 mL was recorded with complete date and time. Analysis population consisted of FAS population with available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: leakage episodes per day
    arithmetic mean (standard deviation)
        Week 2 (N=39, 17)
    0.35 ± 9.35
    -0.53 ± 1.30
        Week 4 (N=36, 15)
    -1.14 ± 3.39
    -0.87 ± 1.68
        Week 8 (N=35, 10)
    1.16 ± 16.11
    -0.65 ± 1.78
        Week 12 (N=33, 13)
    0.37 ± 13.03
    -0.65 ± 1.55
        Week 24 (N=31, 14)
    0.18 ± 10.05
    -0.75 ± 1.28
        Week 36 (N=30, 13)
    -1.98 ± 4.33
    -0.81 ± 1.47
        Week 52 (N=32, 13)
    -0.94 ± 2.96
    -1.12 ± 1.97
    Statistical analysis title
    Change From Baseline at Week 2 - Children
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in children at week 2. The number of participants included in this analysis was 38.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.818 [76]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    3.4
    Notes
    [76] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 2 - Adolescents
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in adolescents at week 2. The number of participants included in this analysis was 15.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.114 [77]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.1
    Notes
    [77] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in children at week 4. The number of participants included in this analysis was 35.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.052 [78]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    0
    Notes
    [78] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in adolescents at week 4. The number of participants included in this analysis was 13.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.066 [79]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    0.1
    Notes
    [79] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Children
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in children at week 8. The number of participants included in this analysis was 34.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.674 [80]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.4
         upper limit
    6.7
    Notes
    [80] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Adolescents
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in adolescents at week 8. The number of participants included in this analysis was 9.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.278 [81]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    0.6
    Notes
    [81] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Children
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in children at week 12. The number of participants included in this analysis was 32.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.871 [82]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.2
         upper limit
    5
    Notes
    [82] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Adolescents
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in adolescents at week 12. The number of participants included in this analysis was 12.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.153 [83]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    0.3
    Notes
    [83] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in children at week 24. The number of participants included in this analysis was 31.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.922 [84]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    3.9
    Notes
    [84] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in adolescents at week 24. The number of participants included in this analysis was 13.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.047 [85]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0
    Notes
    [85] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Children
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in children at week 36. The number of participants included in this analysis was 28.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.018 [86]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -1.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    -0.4
    Notes
    [86] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Adolescents
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in adolescents at week 36. The number of participants included in this analysis was 12.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.07 [87]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    0.1
    Notes
    [87] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in children at week 52. The number of participants included in this analysis was 27.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.083 [88]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    0.1
    Notes
    [88] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in mean number of leakage episodes per day in adolescents at week 52. The number of participants included in this analysis was 13.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.064 [89]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    0.1
    Notes
    [89] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Number of Dry Days per 7 Days (Day and Night Time)

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    End point title
    Change From Baseline in Number of Dry Days per 7 Days (Day and Night Time)
    End point description
    Dry days were defined as leakage-free days, this included day and night time. Participants recorded dry days in the 7-day diary. Dry days were calculated as follows: Ddry was the number of valid diary days where the response to the question ‘Did you leak between this catheterization and the last one’ was ‘No’ each time a new catheterization was entered in the e-diary during the day & night time period. Dwet was the number of valid diary days where the response to the question ‘Did you leak between this catheterization and the last one’ was ‘Yes’ for at least one catheterization entered during the day & night time period. If (Ddry + Dwet) > 3, the number of dry days per 7 days was calculated as Ddry/(Ddry + Dwet) x 7, otherwise the value was missing. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: number of dry days per 7 days
    arithmetic mean (standard deviation)
        Week 2 (N=43, 24)
    0.34 ± 0.91
    0.82 ± 1.90
        Week 4 (N=42, 24)
    0.68 ± 1.69
    1.36 ± 1.91
        Week 8 (N=43, 23)
    1.14 ± 2.15
    2.26 ± 2.48
        Week 12 (N=43, 24)
    1.31 ± 2.50
    1.93 ± 2.46
        Week 24 (N=41, 24)
    1.34 ± 2.18
    2.17 ± 2.38
        Week 36 (N=39, 24)
    1.33 ± 2.43
    1.88 ± 2.13
        Week 52 (N=40, 24)
    1.38 ± 2.65
    2.14 ± 2.51
    Statistical analysis title
    Change From Baseline at Week 2 - Children
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in children at week 2. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.018 [90]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.6
    Notes
    [90] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 2 - Adolescents
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 2. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.045 [91]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1.6
    Notes
    [91] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Children
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in children at week 4. The number of participants included in this analysis was 42.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.013 [92]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    1.2
    Notes
    [92] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 4 - Adolescents
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 4. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [93]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    2.2
    Notes
    [93] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Children
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in children at week 8. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.001 [94]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    1.8
    Notes
    [94] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 8 - Adolescents
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 8. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [95]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    2.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    3.3
    Notes
    [95] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Children
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in children at week 12. The number of participants included in this analysis was 43.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.001 [96]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    2.1
    Notes
    [96] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 12 - Adolescents
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 12. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [97]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    3
    Notes
    [97] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in children at week 24. The number of participants included in this analysis was 41.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [98]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    2
    Notes
    [98] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 24. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [99]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    2.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    3.2
    Notes
    [99] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Children
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in children at week 36. The number of participants included in this analysis was 39.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [100]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    2.1
    Notes
    [100] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 36 - Adolescents
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 36. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [101]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    2.8
    Notes
    [101] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in children at week 52. The number of participants included in this analysis was 40.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [102]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    2.2
    Notes
    [102] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in number of dry days per 7 days (day and night time) in adolescents at week 52. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [103]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    2.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    3.2
    Notes
    [103] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Pediatric Incontinence Questionnaire (PIN-Q) Score

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    End point title
    Change From Baseline in Pediatric Incontinence Questionnaire (PIN-Q) Score
    End point description
    PIN-Q measured quality of life via an e-diary. Total score ranged from 0/no effect to 80/worst effect; decrease in score indicated improvement. Total score was 20x average of individual PinQ items, the 20 Likert scales were converted to a score: Items 6 & 17; 0: “No” to 4: “Definitely” was used; & For the other 18 items; 0: “No” to 4: “All the time” was used. Expectation that questionnaires had limited missing values; if answers >2 questions were missing, total score was not calculated & was missing. Individual item scores were directly imputed. Change from baseline to each post-baseline visit in the total score was post-baseline visit value minus baseline value. If either baseline or post-baseline visit value was missing, change from baseline was missing. If change was: <0, improvement between 2 time-points; =0, no change between 2 time points; >0, worsening between 2 time points. FAS population. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 24 and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 24 (N=24, 21)
    2.04 ± 10.53
    -4.90 ± 14.13
        Week 52 (N=23, 19)
    1.30 ± 12.17
    -6.79 ± 14.50
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in PIN-Q score in children at week 24. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.352 [104]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    2.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    6.49
    Notes
    [104] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in PIN-Q score in adolescents at week 24. The number of participants included in this analysis was 21.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.127 [105]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -4.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.34
         upper limit
    1.53
    Notes
    [105] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in PIN-Q score in children at week 52. The number of participants included in this analysis was 23.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.613 [106]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.96
         upper limit
    6.57
    Notes
    [106] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in PIN-Q score in adolescents at week 52. The number of participants included in this analysis was 19.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.056 [107]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    -6.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.78
         upper limit
    0.2
    Notes
    [107] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Change From Baseline in Patient Global Impression of Severity Scale (PGI-S)

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    End point title
    Change From Baseline in Patient Global Impression of Severity Scale (PGI-S)
    End point description
    The PGI-S is an answer to the question: “How did you feel about your bladder condition during the past 3 days?” Participants evaluated their recent condition as “Really Bad”(0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). An increase indicated improvement. The change from baseline to each postbaseline visit in the PGI-S score is the value at the post-baseline visit minus the value at the baseline visit. If either the baseline or the post-baseline visit value is missing, the change from baseline was missing. A positive change indicated an improvement while a negative change indicated a worsening. Analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 24 and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 24 (N=25, 22)
    0.36 ± 1.22
    0.64 ± 1.00
        Week 52 (N=24, 19)
    0.42 ± 1.21
    0.95 ± 1.18
    Statistical analysis title
    Change From Baseline at Week 24 - Children
    Statistical analysis description
    Change from baseline in PGI-S in children at week 24. The number of participants included in this analysis was 25.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.153 [108]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.86
    Notes
    [108] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 24 - Adolescents
    Statistical analysis description
    Change from baseline in PGI-S in adolescents at week 24. The number of participants included in this analysis was 22.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.007 [109]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    1.08
    Notes
    [109] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Children
    Statistical analysis description
    Change from baseline in PGI-S in children at week 52. The number of participants included in this analysis was 24.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.106 [110]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.93
    Notes
    [110] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.
    Statistical analysis title
    Change From Baseline at Week 52 - Adolescents
    Statistical analysis description
    Change from baseline in PGI-S in adolescents at week 52. The number of participants included in this analysis was 19.
    Comparison groups
    Children (3 to < 12 Years) v Adolescents (12 to < 18 Years)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.003 [111]
    Method
    Paired t-test
    Parameter type
    Mean difference (net)
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    1.51
    Notes
    [111] - From a 2-sided paired t-test, testing the null hypothesis that change from baseline is equal to 0.

    Secondary: Clinician Global Impression of Change (CGI-C)

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    End point title
    Clinician Global Impression of Change (CGI-C)
    End point description
    The Clinician Global Impression of Change (CGI-C) is a 7 point scale that requires the clinician to assess how much the participant’s overall bladder symptoms since the start of the study on day 1 has improved or worsened and rated as: very much improved (1); much improved (2); minimally improved (3); no change (4); minimally worse (5); much worse (6); or very much worse (7). Analysis population consisted of the FAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Weeks 24 and 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    43
    25
    Units: participants
        Week 24 - Very Much Improved (N=41, 24)
    6
    10
        Week 24 - Much Improved (N=41, 24)
    24
    7
        Week 24 - Minimally Improved (N=41, 24)
    6
    5
        Week 24 - No Change (N=41, 24)
    4
    1
        Week 24 - Minimally Worse (N=41, 24)
    1
    1
        Week 24 - Much Worse (N=41, 24)
    0
    0
        Week 24 - Very Much Worse (N=41, 24)
    0
    0
        Week 52 - Very Much Improved (N=38, 23)
    8
    9
        Week 52 - Much Improved (N=38, 23)
    23
    12
        Week 52 - Minimally Improved (N=38, 23)
    5
    1
        Week 52 - No Change (N=38, 23)
    2
    0
        Week 52 - Minimally Worse (N=38, 23)
    0
    0
        Week 52 - Much Worse (N=38, 23)
    0
    1
        Week 52 - Very Much Worse (N=38, 23)
    0
    0
    No statistical analyses for this end point

    Secondary: Study Drug Acceptability for Tablets at Week 4

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    End point title
    Study Drug Acceptability for Tablets at Week 4
    End point description
    Participants evaluated the taste of the study medication/tablets by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the swallow of the study medication/tablets by ticking one of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) and “Really Easy” (4). Analysis population consisted of the FAS (participants on tablets with available data at week 4).
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    9
    12
    Units: participants
        Taste - Really bad
    0
    0
        Taste - Bad
    0
    0
        Taste - Not bad, not good
    5
    7
        Taste - Good
    3
    4
        Taste - Really good
    1
    1
        Swallow - Really difficult
    0
    0
        Swallow - Difficult
    0
    0
        Swallow - Not difficult, not easy
    1
    0
        Swallow - Easy
    3
    7
        Swallow - Really easy
    5
    5
    No statistical analyses for this end point

    Secondary: Study Drug Acceptability for Oral Suspension at Week 4

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    End point title
    Study Drug Acceptability for Oral Suspension at Week 4
    End point description
    Participants evaluated the taste of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the smell of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the consumption and the preparation of the study medication/oral suspension by ticking 1 of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) & “Really Easy” (4). Analysis population consisted of the FAS (participants on oral suspension with available data at week 4).
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    22
    2
    Units: participants
        Taste - Really bad
    1
    0
        Taste - Bad
    3
    0
        Taste - Not bad, not good
    4
    2
        Taste - Good
    11
    0
        Taste - Really good
    3
    0
        Smell - Really bad
    0
    0
        Smell - Bad
    1
    0
        Smell - Not bad, not good
    8
    1
        Smell - Good
    12
    1
        Smell - Really good
    1
    0
        Take - Really difficult
    0
    0
        Take - Difficult
    0
    0
        Take - Not difficult, not easy
    4
    0
        Take - Easy
    7
    1
        Take - Really Easy
    11
    1
        Prepare - Really difficult
    0
    0
        Prepare - Difficult
    0
    0
        Prepare - Not difficult, not easy
    2
    0
        Prepare - Easy
    12
    0
        Prepare - Really Easy
    8
    2
    No statistical analyses for this end point

    Secondary: Study Drug Acceptability for Tablets at Week 24

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    End point title
    Study Drug Acceptability for Tablets at Week 24
    End point description
    Participants evaluated the taste of the study medication/tablets by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the swallow of the study medication/tablets by ticking one of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) and “Really Easy” (4). Analysis population consisted of the FAS (participants on tablets with available data at week 24).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    17
    23
    Units: participants
        Taste - Really bad
    1
    0
        Taste - Bad
    2
    0
        Taste - Not bad, not good
    6
    15
        Taste - Good
    4
    6
        Taste - Really good
    4
    2
        Swallow - Really difficult
    0
    0
        Swallow - Difficult
    0
    0
        Swallow - Not difficult, not easy
    2
    2
        Swallow - Easy
    3
    10
        Swallow - Really easy
    12
    11
    No statistical analyses for this end point

    Secondary: Study Drug Acceptability for Oral Suspension at Week 24

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    End point title
    Study Drug Acceptability for Oral Suspension at Week 24
    End point description
    Participants evaluated the taste of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the smell of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the consumption and the preparation of the study medication/oral suspension by ticking 1 of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) & “Really Easy” (4). Analysis population consisted of the FAS (participants on oral suspension with available data at week 24).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    23
    2
    Units: participants
        Taste - Really bad
    3
    0
        Taste - Bad
    1
    0
        Taste - Not bad, not good
    3
    2
        Taste - Good
    10
    0
        Taste - Really good
    6
    0
        Smell - Really bad
    2
    0
        Smell - Bad
    0
    0
        Smell - Not bad, not good
    8
    2
        Smell - Good
    11
    0
        Smell - Really good
    2
    0
        Take - Really difficult
    0
    0
        Take - Difficult
    2
    0
        Take - Not difficult, not easy
    2
    0
        Take - Easy
    6
    0
        Take - Really Easy
    13
    2
        Prepare - Really difficult
    0
    0
        Prepare - Difficult
    1
    0
        Prepare - Not difficult, not easy
    3
    0
        Prepare - Easy
    10
    2
        Prepare - Really Easy
    9
    0
    No statistical analyses for this end point

    Secondary: Study Drug Acceptability for Tablets at Week 52

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    End point title
    Study Drug Acceptability for Tablets at Week 52
    End point description
    Participants evaluated the taste of the study medication/tablets by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the swallow of the study medication/tablets by ticking one of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) and “Really Easy” (4). Analysis population consisted of the FAS (participants on tablets with available data at week 52).
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    17
    20
    Units: participants
        Taste - Really bad
    0
    0
        Taste - Bad
    0
    0
        Taste - Not bad, not good
    8
    16
        Taste - Good
    6
    2
        Taste - Really good
    3
    2
        Swallow - Really difficult
    0
    0
        Swallow - Difficult
    0
    0
        Swallow - Not difficult, not easy
    2
    2
        Swallow - Easy
    4
    7
        Swallow - Really easy
    11
    11
    No statistical analyses for this end point

    Secondary: Study Drug Acceptability for Oral Suspension at Week 52

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    End point title
    Study Drug Acceptability for Oral Suspension at Week 52
    End point description
    Participants evaluated the taste of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the smell of the study medication/oral suspension by ticking 1 of the following categories: “Really Bad” (0), “Bad” (1), “Not Bad, Not Good” (2), “Good” (3) & “Really Good” (4). Participants evaluated the consumption and the preparation of the study medication/oral suspension by ticking 1 of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) & “Really Easy” (4). Analysis population consisted of the FAS (participants on oral suspension with available data at week 52).
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    22
    2
    Units: participants
        Taste - Really bad
    1
    0
        Taste - Bad
    2
    0
        Taste - Not bad, not good
    5
    2
        Taste - Good
    8
    0
        Taste - Really good
    6
    0
        Smell - Really bad
    2
    0
        Smell - Bad
    1
    0
        Smell - Not bad, not good
    5
    1
        Smell - Good
    12
    1
        Smell - Really good
    2
    0
        Take - Really difficult
    0
    0
        Take - Difficult
    1
    0
        Take - Not difficult, not easy
    3
    0
        Take - Easy
    7
    0
        Take - Really Easy
    11
    2
        Prepare - Really difficult
    0
    0
        Prepare - Difficult
    0
    0
        Prepare - Not difficult, not easy
    3
    0
        Prepare - Easy
    9
    2
        Prepare - Really Easy
    10
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    Number of Participants with Adverse Events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A treatment-emergent adverse event (TEAE) was defined as any AE with date of onset occurring on or after the first dose of study medication and up to the end of study. The analysis population consisted of the safety analysis set (SAF), which consisted of all participants who took at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug administration up to end-of-treatment (EoT) (week 52).
    End point values
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Number of subjects analysed
    55
    31
    Units: participants
        TEAE
    33
    18
        Drug-related TEAE
    8
    6
        Serious TEAE
    9
    5
        Drug-related Serious TEAE
    0
    0
        TEAE Leading to Death
    0
    0
        Drug-related TEAE Leading to Death
    0
    0
        TEAE Leading to Permanent Discontinuation
    3
    0
        Drug-related TEAE Leading to Permanent Disc.
    2
    0
        Death
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) of Maximum Plasma Mirabegron Concentration (Cmax)

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    End point title
    Pharmacokinetics (PK) of Maximum Plasma Mirabegron Concentration (Cmax)
    End point description
    The analysis population consisted of the pharmacokinetic analysis set (PKAS), which consisted of the subset of the SAF for whom plasma concentration data were available to facilitate derivation of ≥ 1 pharmacokinetic parameter and for whom the time of the last dose prior to sampling was known. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.
    End point type
    Secondary
    End point timeframe
    A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 2-5 hours postdose more than 1 hour apart.
    End point values
    Children PED25 (PKAS) Adolescents PED25 (PKAS) Children PED50 (PKAS) Adolescents PED50 (PKAS)
    Number of subjects analysed
    1
    3
    43
    24
    Units: ng/mL
        arithmetic mean (standard deviation)
    9.386 ± 99999
    9.044 ± 5.407
    20.55 ± 13.63
    18.40 ± 12.45
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Plasma Concentration of Mirabegron Following Drug Administration (Tmax)

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    End point title
    Time to Reach Maximum Plasma Concentration of Mirabegron Following Drug Administration (Tmax)
    End point description
    The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.
    End point type
    Secondary
    End point timeframe
    A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 2-5 hours postdose more than 1 hour apart.
    End point values
    Children PED25 (PKAS) Adolescents PED25 (PKAS) Children PED50 (PKAS) Adolescents PED50 (PKAS)
    Number of subjects analysed
    1
    3
    43
    24
    Units: hour
        arithmetic mean (standard deviation)
    3.000 ± 99999
    3.500 ± 0.433
    3.419 ± 0.6608
    3.635 ± 1.101
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) for Mirabegron

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    End point title
    Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC24) for Mirabegron
    End point description
    The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.
    End point type
    Secondary
    End point timeframe
    A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 2-5 hours postdose more than 1 hour apart.
    End point values
    Children PED25 (PKAS) Adolescents PED25 (PKAS) Children PED50 (PKAS) Adolescents PED50 (PKAS)
    Number of subjects analysed
    1
    3
    43
    24
    Units: ng*hr/mL
        arithmetic mean (standard deviation)
    166.3 ± 99999
    137.8 ± 53.07
    310.1 ± 163.1
    291.6 ± 171.8
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Mirabegron at the End of a Dosing interval at Steady State (Ctrough)

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    End point title
    Plasma Concentration of Mirabegron at the End of a Dosing interval at Steady State (Ctrough)
    End point description
    The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.
    End point type
    Secondary
    End point timeframe
    A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 2-5 hours postdose more than 1 hour apart.
    End point values
    Children PED25 (PKAS) Adolescents PED25 (PKAS) Children PED50 (PKAS) Adolescents PED50 (PKAS)
    Number of subjects analysed
    1
    3
    43
    24
    Units: ng/mL
        arithmetic mean (standard deviation)
    5.312 ± 99999
    4.114 ± 1.186
    9.024 ± 5.149
    8.888 ± 5.588
    No statistical analyses for this end point

    Secondary: Apparent Total Clearance of Mirabegron From Plasma After Oral Administration (CL/F)

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    End point title
    Apparent Total Clearance of Mirabegron From Plasma After Oral Administration (CL/F)
    End point description
    The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.
    End point type
    Secondary
    End point timeframe
    A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 2-5 hours postdose more than 1 hour apart.
    End point values
    Children PED25 (PKAS) Adolescents PED25 (PKAS) Children PED50 (PKAS) Adolescents PED50 (PKAS)
    Number of subjects analysed
    1
    3
    43
    24
    Units: L/hr
        arithmetic mean (standard deviation)
    192.5 ± 99999
    202.3 ± 83.05
    230.9 ± 162
    279.6 ± 294.2
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution After Non-intravenous Administration (Vz/F) of Mirabegron

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    End point title
    Apparent Volume of Distribution After Non-intravenous Administration (Vz/F) of Mirabegron
    End point description
    The analysis population consisted of the PKAS. The population of the pharmacokinetic analysis included all participants (n=71) that contributed at least one measurable PK sample. This included 5 partcipants who were excluded from the PKAS dataset (n=66) because PK samples were collected outside the protocol specified time window for collection. Due to the low number of participants, data could not be calculated and is denoted as "99999" as applicable.
    End point type
    Secondary
    End point timeframe
    A total of 4 samples were collected over 2 sampling days at 2 separate visits at any of weeks 4, 8, 12, 24, 36, or 52, at the following time points: Sampling day 1, predose; Sampling day 2, predose and 2 samples 2-5 hours postdose more than 1 hour apart.
    End point values
    Children PED25 (PKAS) Adolescents PED25 (PKAS) Children PED50 (PKAS) Adolescents PED50 (PKAS)
    Number of subjects analysed
    1
    3
    43
    24
    Units: Liter
        arithmetic mean (standard deviation)
    14450 ± 99999
    15380 ± 6524
    12150 ± 5630
    14770 ± 6792
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug administration up to end-of-treatment (EoT) (week 52).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    Children (3 to < 12 Years)
    Reporting group description
    Children age 3 to < 12 received initial dose of mirabegron based on weight (pediatric equivalent dose [PED25]) on day 1. At weeks 2, 4 or 8, participant's were up-titrated to the pediatric equivalent dose of 50 mg in adults (PED50) based on the given dose titration criteria. Following week 24, participants stayed on their individual dose level until week 52 end-of-study (EOS) or end-of-treatment (EOT).

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

    Serious adverse events
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 55 (16.36%)
    5 / 31 (16.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Shunt malfunction
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Talipes correction
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of skin
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Talipes
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Epididymitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral perforation
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash generalised
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Children (3 to < 12 Years) Adolescents (12 to < 18 Years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 55 (30.91%)
    9 / 31 (29.03%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 55 (3.64%)
    2 / 31 (6.45%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 31 (3.23%)
         occurrences all number
    3
    1
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 31 (16.13%)
         occurrences all number
    5
    6
    Nasopharyngitis
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 31 (6.45%)
         occurrences all number
    3
    2
    Respiratory tract infection viral
         subjects affected / exposed
    4 / 55 (7.27%)
    0 / 31 (0.00%)
         occurrences all number
    6
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 31 (9.68%)
         occurrences all number
    1
    6
    Urinary tract infection
         subjects affected / exposed
    4 / 55 (7.27%)
    0 / 31 (0.00%)
         occurrences all number
    5
    0
    Urinary tract infection bacterial
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 31 (3.23%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)

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

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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