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    Clinical Trial Results:
    A Phase 3, Double-blind, Randomized, Multicenter, Parallel Group, Placebo-controlled Sequential Dose Titration Study to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Pediatric Subjects From 5 to < 18 Years of Age With Overactive Bladder

    Summary
    EudraCT number
    2016-001767-37
    Trial protocol
    DE   NL   BE   NO   FR   DK   PL   IT   ES  
    Global end of trial date
    24 Jul 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Dec 2023
    First version publication date
    28 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    178-CL-204
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04641975
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc. (APGD)
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical Transparency, Astellas Pharma Global Development, Inc. (APGD), 60062 8008887704, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Transparency, Astellas Pharma Global Development, Inc. (APGD), 60062 8008887704, 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-PIP02-10
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    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
    24 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Main objective of the trial was to evaluate the efficacy of mirabegron in children (5 to < 12 years of age) with overactive bladder (OAB).
    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
    15 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Malaysia: 1
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Philippines: 7
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Türkiye: 1
    Country: Number of subjects enrolled
    Ukraine: 3
    Worldwide total number of subjects
    26
    EEA total number of subjects
    8
    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)
    23
    Adolescents (12-17 years)
    3
    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
    Participants who had received 4 weeks of urotherapy prior to randomization were enrolled in the study. Specific interventions included various forms of pelvic floor training, behavioral modification, electrical stimulation, catherization and biofeedback and elements of cognitive behavioral therapy.

    Pre-assignment
    Screening details
    Standard urotherapy included information on demystification of voiding function and dysfunction, instruction on voiding habits, lifestyle advice regarding fluid intake, prevention of constipation, recording of symptoms and voiding habits in bladder diaries and support via regular follow-up.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Mirabegron (5 to<12 years)
    Arm description
    Participants aged 5 to < 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.
    Arm type
    Experimental

    Investigational medicinal product name
    Mirabegron
    Investigational medicinal product code
    YM178
    Other name
    Betanis Betmiga Myrbetriq
    Pharmaceutical forms
    Coated tablet, Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants aged 5 to < 12 years received initial dose of 25 milligram (mg) of mirabegron orally once daily based on weight (pediatric equivalent dose of 25 mg [PED25]) on day 1. Participants with a body weight ≥ 35 kilogram (kg) received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the pediatric equivalent dose of 50 mg [PED50] based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Arm title
    Placebo (5 to < 12 years)
    Arm description
    Participants aged 12 to < 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet, Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants aged 5 to < 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Arm title
    Mirabegron(12 to<18 years)
    Arm description
    Participants aged 5 to < 12 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.
    Arm type
    Experimental

    Investigational medicinal product name
    Mirabegron
    Investigational medicinal product code
    YM178
    Other name
    Betanis Betmiga Myrbetriq
    Pharmaceutical forms
    Concentrate for oral suspension, Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants aged 12 to < 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Arm title
    Placebo (12 to < 18 years)
    Arm description
    Participants aged 12 to < 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet, Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants aged 12 to < 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Number of subjects in period 1
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years) Mirabegron(12 to<18 years) Placebo (12 to < 18 years)
    Started
    11
    12
    2
    1
    Completed
    9
    10
    1
    0
    Not completed
    2
    2
    1
    1
         Consent withdrawn by subject
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    1
    1
         Protocol deviation
    1
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mirabegron (5 to<12 years)
    Reporting group description
    Participants aged 5 to < 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Placebo (5 to < 12 years)
    Reporting group description
    Participants aged 12 to < 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Mirabegron(12 to<18 years)
    Reporting group description
    Participants aged 5 to < 12 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Placebo (12 to < 18 years)
    Reporting group description
    Participants aged 12 to < 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years) Mirabegron(12 to<18 years) Placebo (12 to < 18 years) Total
    Number of subjects
    11 12 2 1
    Age categorical
    Units: Subjects
    Age
    Here "99999"denotes that data was not analyzed since there was only 1 evaluable participant.
    Units: years
        arithmetic mean (standard deviation)
    8.4 ± 1.9 7.7 ± 1.7 16 ± 1.4 12 ± 99999 -
    Sex
    Units: Subjects
        Female
    2 7 2 0 11
        Male
    9 5 0 1 15
    Analysis Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0
        Asian
    2 6 1 1 10
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    0 0 0 0 0
        White
    7 6 1 0 14
        More than one race
    0 0 0 0 0
        Unknown or Not Reported
    2 0 0 0 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 1 0 0 1
        Unknown or Not Reported
    2 0 0 0 2
        Not Hispanic or Latino
    9 11 2 1 23
    Mean Number of Micturitions per 24 hours
    A micturition was defined as any voluntary act of passing urine (excluding incontinence only episodes). The mean number of micturitions per 24 hours was calculated as the average number of times a participant urinated per day during the 7-day micturition diary period. Participants in the SAF with available data were analyzed. Here "99999"denotes that data was not analyzed since there was only 1 evaluable participant.
    Units: Micturitions per 24 hours
        arithmetic mean (standard deviation)
    9.48 ± 4.53 9.72 ± 4.95 19.43 ± 3.16 9.29 ± 99999 -

    End points

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    End points reporting groups
    Reporting group title
    Mirabegron (5 to<12 years)
    Reporting group description
    Participants aged 5 to < 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Placebo (5 to < 12 years)
    Reporting group description
    Participants aged 12 to < 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Mirabegron(12 to<18 years)
    Reporting group description
    Participants aged 5 to < 12 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Placebo (12 to < 18 years)
    Reporting group description
    Participants aged 12 to < 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Primary: Change from baseline to week 12/EoT in mean number of micturitions per 24 hours for age group 5 to <12 years

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    End point title
    Change from baseline to week 12/EoT in mean number of micturitions per 24 hours for age group 5 to <12 years [1]
    End point description
    A micturition was defined as any voluntary act of passing urine (excluding incontinence only episodes). The mean number of micturitions per 24 hours was calculated as the average number of times a participant urinated per day during the 7-day micturition diary period. The analysis was performed with imputation of missing visit 7/week 12 data using the last observation carried forward (LOCF) method. Full Analysis set: All participants who were randomized and received at least 1 dose of study drug and had at least 1 post baseline measurement for mean number of micturitions per 24 hours.
    End point type
    Primary
    End point timeframe
    Baseline, week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for 5 to <12 years of age only.
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years)
    Number of subjects analysed
    9
    10
    Units: Micturitions per 24 hours
        least squares mean (standard error)
    -1.62 ± 0.89
    -3.84 ± 0.89
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Analysis of Covariance (ANCOVA) was performed with change from baseline at week 12 Last Observation Carried Forward (LOCF) as response, treatment group, sex and geographical region as fixed effects and the mean number of micturitions per 24 hours at baseline as covariate.
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.121
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    2.22
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    4.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.34

    Secondary: Change from baseline to week 12/EoT in mean volume voided per 24 hours for age group 5 to <12 years

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    End point title
    Change from baseline to week 12/EoT in mean volume voided per 24 hours for age group 5 to <12 years [2]
    End point description
    Mean volume voided was derived from “Pee Volume” of the 2-day Weekend Episodic Diary. Mean volume voided per day was calculated as the sum of the volumes voided on that (valid diary) day divided by the number of times a volume was recorded on that day in the 2-day Weekend Episodic Diary. The analysis was performed with LOCF and without LOCF method. Full Analysis Set with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for 5 to <12 years of age only.
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years)
    Number of subjects analysed
    8
    8
    Units: milliliter (mL)/24 hours
    arithmetic mean (standard deviation)
        Week 12 (without LOCF)
    18.38 ± 33.67
    24.55 ± 32.32
        Week 12 (with LOCF)
    18.38 ± 33.67
    24.55 ± 32.32
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Week 12 LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.43
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -15.51
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -49.47
         upper limit
    18.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.91
    Notes
    [3] - ANCOVA was performed with change from baseline at week 12 with LOCF as response, treatment group, sex and geographical region as fixed effects and the mean volume voided per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Week 12 without LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.43
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -15.51
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -49.47
         upper limit
    18.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.91
    Notes
    [4] - ANCOVA was performed with change from baseline at week 12 without LOCF as response, treatment group, sex and geographical region as fixed effects and the mean volume voided per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.

    Secondary: Change from baseline to week 12/EoT in maximum volume voided (MVV) for age group 5 to <12 years

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    End point title
    Change from baseline to week 12/EoT in maximum volume voided (MVV) for age group 5 to <12 years [5]
    End point description
    MVV data was derived from “Pee Volume” of the 2-day Weekend Episodic Diary. The MVV was the largest (non-zero) volume recorded over both of the 2 (valid) measuring days in the diary. The analysis was performed with LOCF and without LOCF method. Full Analysis Set with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for 5 to <12 years of age only.
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years)
    Number of subjects analysed
    8
    8
    Units: mL
    arithmetic mean (standard deviation)
        Week 12 (without LOCF)
    26.00 ± 51.46
    26.38 ± 60.75
        Week 12 (With LOCF)
    26.00 ± 51.46
    26.38 ± 60.75
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Week 12 without LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.935
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2.58
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -53.23
         upper limit
    58.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    31.08
    Notes
    [6] - ANCOVA was performed with change from baseline at week 12 without LOCF as response, treatment group, sex and geographical region as fixed effects and the max volume voided at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Week 12 LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.935
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2.58
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -53.23
         upper limit
    58.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    31.08
    Notes
    [7] - ANCOVA was performed with change from baseline at week 12 with LOCF as response, treatment group, sex and geographical region as fixed effects and the max volume voided at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.

    Secondary: Change from baseline to week 12/EoT in mean number of daytime incontinence episodes per 24 hours for age group 5 to <12 years

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    End point title
    Change from baseline to week 12/EoT in mean number of daytime incontinence episodes per 24 hours for age group 5 to <12 years [8]
    End point description
    A daytime incontinence episode was defined as the complaint of any involuntary leakage of urine during daytime hours. Daytime was defined as time between waking up in the morning and going to sleep later the same day or next day. The mean number of daytime incontinence episodes per 24 hours was calculated by taking the sum of all daytime urinary incontinence episodes recorded in the participant diary, divided by the number of valid diary days. The analysis was performed with LOCF and without LOCF method. Full Analysis Set with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for 5 to <12 years of age only.
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years)
    Number of subjects analysed
    8
    9
    Units: incontinence episodes per 24 hours
    arithmetic mean (standard deviation)
        Week 12 (without LOCF)
    -1.29 ± 1.04
    -1.28 ± 1.73
        Week 12 (with LOCF)
    -1.20 ± 1.02
    1.09 ± 1.74
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Week 12 without LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.073
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.04
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.99
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.53
    Notes
    [9] - ANCOVA as performed with change from baseline at week 12 without LOCF as response, treatment group, sex and geographical region as fixed effects and the mean number of daytime incontinence episodes per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Week 12 LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.044
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45
    Notes
    [10] - ANCOVA as performed with change from baseline at week 12 with LOCF as response, treatment group, sex and geographical region as fixed effects and the mean number of daytime incontinence episodes per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.

    Secondary: Change from baseline to week 12/EoT in mean number of nighttime incontinence episodes per 24 hours for age group 5 to <12 years

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    End point title
    Change from baseline to week 12/EoT in mean number of nighttime incontinence episodes per 24 hours for age group 5 to <12 years [11]
    End point description
    A nighttime incontinence episode was defined as the complaint of any involuntary leakage of urine during nighttime hours. Nighttime was defined as time between between going to sleep on a day and waking up on the same or next day. The mean number of nighttime incontinence episodes per 24 hours was calculated by taking the sum of all nighttime urinary incontinence episodes recorded in the participant diary, divided by the number of valid diary days. The analysis was performed with LOCF and without LOCF method. Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for 5 to <12 years of age only.
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years)
    Number of subjects analysed
    9
    10
    Units: incontinence episodes per 24 hours
    arithmetic mean (standard deviation)
        Week 12 (without LOCF)
    -0.64 ± 0.55
    -1.34 ± 1.51
        Week 12 (with LOCF)
    -0.64 ± 0.55
    -1.34 ± 1.51
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 12 without LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.91
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [12] - ANCOVA as performed with change from baseline at week 12 without LOCF as response, treatment group, sex and geographical region as fixed effects and the mean number of daytime incontinence episodes per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 12 with LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.91
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [13] - ANCOVA as performed with change from baseline at week 12 with LOCF as response, treatment group, sex and geographical region as fixed effects and the mean number of daytime incontinence episodes per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.

    Secondary: Change from baseline to week 12/EoT in mean number of daytime micturitions per 24 hours for age group 5 to <12 years

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    End point title
    Change from baseline to week 12/EoT in mean number of daytime micturitions per 24 hours for age group 5 to <12 years [14]
    End point description
    For a week day the daytime micturitions was derived from “Number of Times using the Toilet During the Day” was entered into the 5-day Week Diary. For a weekend day the daytime micturitions was derived from the number of times a “Pee in Toilet” or a “Pee in Toilet and Leakage” was entered into the 2-day Weekend Episodic Diary between the time the participant woke-up (exclusive). The total number of micturitions per weekend day was equal to the total number of times, in the diary, an amount of pee was recorded during daytime for that day. For each participant, the mean number of daytime micturitions was calculated as:Sum of the Number of Daytime Micturitions (per day) over the Valid Diary Days prior to Visit/Number of Valid Diary Days" The analysis was performed with LOCF and without LOCF method. Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for 5 to <12 years of age only.
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years)
    Number of subjects analysed
    9
    10
    Units: micturitions per 24 hours
    arithmetic mean (standard deviation)
        Week 12 (without LOCF)
    -0.85 ± 2.67
    -3.21 ± 6.65
        Week 12 (with LOCF)
    -0.85 ± 2.67
    -3.21 ± 6.27
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Week 12 without LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.012
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2.48
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    3.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85
    Notes
    [15] - ANCOVA was performed with change from baseline at week 12 without LOCF as response, treatment group, sex and geographical region as fixed effects and the mean number of daytime micturitions per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Week 12 LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    P-value
    = 0.007
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2.46
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    3.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77
    Notes
    [16] - ANCOVA was performed with change from baseline at week 12 with LOCF as response, treatment group, sex and geographical region as fixed effects and the mean number of daytime micturitions per 24 hours at baseline as covariate. Statistically significant treatment difference at 0.10 level for mirabegron vs placebo.

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    An AE was any untoward medical occurrence in a participant administered a study drug and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug whether or not considered related to the study drug. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted a congenital anomaly/birth defect or other medically important event. A TEAE was defined as an AE observed after starting administration of the study drug until 30 days after last dose. SAF.
    End point type
    Secondary
    End point timeframe
    From first dose up to week 14
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years) Mirabegron(12 to<18 years) Placebo (12 to < 18 years)
    Number of subjects analysed
    11
    12
    2
    1
    Units: Participants
    number (not applicable)
        Treatment emergent adverse events
    5
    7
    1
    1
        Serious treatment emergent adverse events
    0
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline to week 12/EoT in Number of dry (incontinence-free) days per 7 days for age group 5 to <12 years

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    End point title
    Change From Baseline to week 12/EoT in Number of dry (incontinence-free) days per 7 days for age group 5 to <12 years [17]
    End point description
    A dry (incontinence free) day was defined as a day where the response is "Dry" to the question "How was your Day" and to "How was your Night". For a weekend day a "Dry (incontinence free) Day" was defined a day where no "New pee or leakage" was reported. Let Ddry be the number of valid diary days where the response to both questions was "Dry". Let Dwet be the number of valid diary days where the response to one of the two questions or to both questions was "Wet". If (Ddry + Dwet) > 3, the number of dry days per 7 days was calculated as Ddry/(Ddry + Dwet)* 7, otherwise the value was missing. The analysis was performed with LOCF and without LOCF method. Full Analysis Set with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for 5 to <12 years of age only.
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years)
    Number of subjects analysed
    9
    9
    Units: incontinence-free days
    arithmetic mean (standard deviation)
        Week 12 (without LOCF) (n= 8, 7)
    3.12 ± 3.36
    1.45 ± 2.33
        Week 12 (with LOCF) (n= 9, 9)
    2.94 ± 3.47
    1.46 ± 2.18
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 12 with LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.111 [18]
    Method
    Binomial regression
    Parameter type
    Rate ratio
    Point estimate
    0.22
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    1.05
    Notes
    [18] - From a negative binomial regression model including treatment group, sex and region as factors and the log baseline rate of number of dry days (the log of the ratio of dry days at baseline and number of diary days at baseline) as covariate.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 12 Without LOCF
    Comparison groups
    Mirabegron (5 to<12 years) v Placebo (5 to < 12 years)
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 105 [19]
    Method
    Binomial regression
    Parameter type
    Rate ratio
    Point estimate
    0.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    1.02
    Notes
    [19] - From a negative binomial regression model including treatment group, sex and region as factors and the log baseline rate of number of dry days (the log of the ratio of dry days at baseline and number of diary days at baseline) as covariate.

    Secondary: Change from baseline in post void residual (PVR) volume

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    End point title
    Change from baseline in post void residual (PVR) volume
    End point description
    PVR was assessed by ultrasonography. Here "99999"denotes that data is not available as there were no participants or only 1 participant was analyzed. SAF with available data was analyzed
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 4, 12, 14
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years) Mirabegron(12 to<18 years) Placebo (12 to < 18 years)
    Number of subjects analysed
    10
    10
    2
    1
    Units: mL
    arithmetic mean (standard deviation)
        Week 4 (n=2, 9, 0, 10)
    -0.56 ± 11.59
    8.80 ± 29.90
    -3.00 ± 9.90
    99999 ± 99999
        Week 12 (n=1, 8, 1, 7)
    1.63 ± 4.27
    5.43 ± 12.79
    5.00 ± 99999
    0.00 ± 99999
        Week 14 (n=2,10, 1, 10)
    2.20 ± 8.44
    11.00 ± 33.60
    4.50 ± 0.71
    0.00 ± 99999
    No statistical analyses for this end point

    Secondary: Number of Participants With Study Drug Acceptability and Palatability for Tablets

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    End point title
    Number of Participants With Study Drug Acceptability and Palatability for Tablets
    End point description
    Participants evaluated the taste of the study drug/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 drug/tablets by ticking one of the following categories: "Really Difficult" (0), "Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) and "Really Easy" (4). SAF with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years) Mirabegron(12 to<18 years) Placebo (12 to < 18 years)
    Number of subjects analysed
    3
    1
    2
    0 [20]
    Units: Participants
    number (not applicable)
        Taste: Really bad
    0
    0
    0
        Taste: Bad
    1
    0
    0
        Taste: Not Bad, Not Good
    1
    1
    2
        Taste: Good
    1
    0
    0
        Taste: Really Good
    0
    0
    0
        Swallow: Really Difficult
    0
    0
    0
        Swallow: Difficult
    0
    0
    0
        Swallow: Not Difficult, Not Easy
    0
    0
    1
        Swallow: Easy
    2
    0
    0
        Swallow: Really Easy
    1
    1
    1
    Notes
    [20] - No participants was analyzed.
    No statistical analyses for this end point

    Secondary: Number of Participants With Study Drug Acceptability and Palatability for Oral Suspension

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    End point title
    Number of Participants With Study Drug Acceptability and Palatability for Oral Suspension
    End point description
    Participants evaluated the taste of the study drug/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 drug/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 of the study drug/oral suspension by ticking 1 of the following categories: "Really Difficult" (0),"Difficult" (1), "Not Difficult, Not Easy" (2), "Easy" (3) & "Really Easy" (4). Participants evaluated the preparation of the study drug/oral suspension by ticking 1 of the following categories: “Really Difficult” (0), “Difficult” (1), “Not Difficult, Not Easy” (2), “Easy” (3) & “Really Easy” (4). SAF with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Mirabegron (5 to<12 years) Placebo (5 to < 12 years) Mirabegron(12 to<18 years) Placebo (12 to < 18 years)
    Number of subjects analysed
    6
    7
    0 [21]
    0 [22]
    Units: Participants
    number (not applicable)
        Taste: Really Bad
    0
    0
        Taste: Bad
    0
    0
        Taste: Not Bad, Not Good
    4
    6
        Taste: Good
    1
    1
        Taste: Really Good
    1
    0
        Smell: Really Bad
    0
    0
        Smell: Bad
    0
    0
        Smell: Not Bad, Not Good
    3
    4
        Smell: Good
    0
    2
        Smell: Really Good
    3
    1
        Taking: Really Difficult
    0
    0
        Taking: Difficult
    0
    0
        Taking: Not Difficult, Not Easy
    0
    1
        Taking: Easy
    4
    5
        Taking: Really Easy
    2
    1
        Preparing: Really Difficult
    0
    0
        Preparing: Difficult
    0
    0
        Preparing: Not Difficult, Not Easy
    0
    2
        Preparing: Easy
    4
    5
        Preparing: Really Easy
    2
    0
    Notes
    [21] - No participants was analyzed.
    [22] - No participants was analyzed.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) of mirabegron in plasma: Maximum concentration (Cmax)

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    End point title
    Pharmacokinetic (PK) of mirabegron in plasma: Maximum concentration (Cmax) [23]
    End point description
    Maximum observed plasma concentration (Cmax). PK parameter calculation was not possible due to low number of samples collected.
    End point type
    Secondary
    End point timeframe
    Predose (1 hour prior) at weeks 4 and 12
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for mirabegron arms (5 to <12 years and 12<18 years).
    End point values
    Mirabegron (5 to<12 years) Mirabegron(12 to<18 years)
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [24] - No participant was analyzed.
    [25] - No participant was analyzed.
    No statistical analyses for this end point

    Secondary: PK of mirabegron in plasma: Apparent total clearance (CL/F)

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    End point title
    PK of mirabegron in plasma: Apparent total clearance (CL/F) [26]
    End point description
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. PK parameter calculation was not possible due to low number of samples collected.
    End point type
    Secondary
    End point timeframe
    Predose (1 hour prior) at weeks 4 and 12
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for mirabegron arms (5 to <12 years and 12<18 years).
    End point values
    Mirabegron (5 to<12 years) Mirabegron(12 to<18 years)
    Number of subjects analysed
    0 [27]
    0 [28]
    Units: Liter/hour
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [27] - No participant was analyzed.
    [28] - No participant was analyzed.
    No statistical analyses for this end point

    Secondary: PK of mirabegron in plasma: Concentration immediately prior to dosing (Ctrough)

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    End point title
    PK of mirabegron in plasma: Concentration immediately prior to dosing (Ctrough) [29]
    End point description
    Trough level or trough concentration (Ctrough) in the concentration reached by the drug immediately before the next dose is administered. Here "99999"denotes that data is not available as there were no participants were analyzed
    End point type
    Secondary
    End point timeframe
    Predose (1 hour prior) at weeks 4 and 12
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for mirabegron arms (5 to <12 years and 12<18 years).
    End point values
    Mirabegron (5 to<12 years) Mirabegron(12 to<18 years)
    Number of subjects analysed
    8
    1
    Units: nanograms/mL (ng/mL)
    arithmetic mean (standard deviation)
        Week 4 (n= 1, 7)
    3.18 ± 1.01
    0.00 ± 99999
        Week 12 (n= 0, 8)
    12.68 ± 21.33
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Time of the maximum concentration (Tmax)

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    End point title
    Time of the maximum concentration (Tmax) [30]
    End point description
    Time taken to reach Cmax (Tmax). PK parameter calculation was not possible due to low number of samples collected.
    End point type
    Secondary
    End point timeframe
    Predose (1 hour prior) at weeks 4 and 12
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for mirabegron arms (5 to <12 years and 12<18 years).
    End point values
    Mirabegron (5 to<12 years) Mirabegron(12 to<18 years)
    Number of subjects analysed
    0 [31]
    0 [32]
    Units: hours
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [31] - No participant was analyzed.
    [32] - No participant was analyzed.
    No statistical analyses for this end point

    Secondary: PK of mirabegron in plasma: PK of mirabegron in plasma: Area under concentration-time curve over dosing interval (AUCtau)

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    End point title
    PK of mirabegron in plasma: PK of mirabegron in plasma: Area under concentration-time curve over dosing interval (AUCtau) [33]
    End point description
    AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption. PK parameter calculation was not possible due to low number of samples collected.
    End point type
    Secondary
    End point timeframe
    Predose (1 hour prior) at weeks 4 and 12
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for mirabegron arms (5 to <12 years and 12<18 years).
    End point values
    Mirabegron (5 to<12 years) Mirabegron(12 to<18 years)
    Number of subjects analysed
    0 [34]
    0 [35]
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [34] - No participant was analyzed.
    [35] - No participant was analyzed.
    No statistical analyses for this end point

    Secondary: PK of mirabegron in plasma: Apparent volume of distribution (Vz/F)

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    End point title
    PK of mirabegron in plasma: Apparent volume of distribution (Vz/F) [36]
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed. PK parameter calculation was not possible due to low number of samples collected.
    End point type
    Secondary
    End point timeframe
    Predose (1 hour prior) at weeks 4 and 12
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was intended to report data for mirabegron arms (5 to <12 years and 12<18 years).
    End point values
    Mirabegron (5 to<12 years) Mirabegron(12 to<18 years)
    Number of subjects analysed
    0 [37]
    0 [38]
    Units: Liters
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [37] - No participant was analyzed.
    [38] - No participant was analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to week 14
    Adverse event reporting additional description
    SAF
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    v25.0
    Reporting groups
    Reporting group title
    Mirabegron(5 to<12 years)
    Reporting group description
    Participants aged 5 to < 12 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Placebo (5 to < 12 years)
    Reporting group description
    Participants aged 5 to < 12 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Mirabegron (12 to<18 years)
    Reporting group description
    Participants aged 12 to < 18 years received initial dose of 25 mg of mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Reporting group title
    Placebo (12 to < 18 years)
    Reporting group description
    Participants aged 12 to < 18 years received placebo matched to mirabegron orally once daily based on weight PED25 on day 1. Participants with a body weight ≥ 35 kg received tablet and participants with a body weight< 35 kg or those who could not be dosed with the tablet received an oral suspension. At week 4, participants were up-titrated to the PED50 based on the given dose titration criteria up to week 12. Urotherapy continued throughout the study treatment period until week 12.

    Serious adverse events
    Mirabegron(5 to<12 years) Placebo (5 to < 12 years) Mirabegron (12 to<18 years) Placebo (12 to < 18 years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Diffuse axonal injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Mirabegron(5 to<12 years) Placebo (5 to < 12 years) Mirabegron (12 to<18 years) Placebo (12 to < 18 years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 11 (45.45%)
    7 / 12 (58.33%)
    1 / 2 (50.00%)
    1 / 1 (100.00%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eyelid abrasion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Medical device pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Genital erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Mood swings
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Viral infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 12 (16.67%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 12 (8.33%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2021
    The schedule of assessments is updated with the following changes: • Physical examination is added to visit 5 (week 4). • Height and body weight measurement is added to visit 7 (week 12). • Clinical Laboratory Tests (Hematology and Biochemistry) footnote is removed from visit 5 (week 4) • Self-blood pressure measurement (SBPM) is added visit 2 (week -2) and removed from visit 8 (week 14). • Pregnancy tests are added to visit 3 (week 0), visit 5 (week 4) and visit 7 (week 12). • Additional text is added to footnote h to explain that the SBPM should be done during the weekend preceding the study visit. • Footnote i is revised to remove visit 5 (week 4). Footnote j is revised to clarify that urine pregnancy tests will be performed for females of childbearing potential at all on-site visits. • The minimum weight of subjects is changed from 11 kg to 13 kg. This is updated in the dose rationale and Inclusion Criterion #4. • A criterion (#11) that subjects must have a pulse of > 99th percentile for age at Screening is deleted • Text is added to allow the option that the subject is currently taking medication known to prolong the QT interval. • The criterion is updated to exclude subjects who use moderate or strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers.
    01 Feb 2023
    • The following secondary endpoint is removed: “mean number of nighttime incontinence episodes per 24 hours” • The following inclusion criterion is removed: “16 Subject must have at least 1 daytime incontinence episode (on average) per day, during the 7 day period before visit 3/baseline, as recorded in the bladder e diary.” • The following exclusion criteria are removed: “1. Subject has extraordinary daytime only urinary frequency according to the ICCS definition. o This applies to a toilet-trained child who has the frequent need to void that is associated with small micturition volumes solely during the day. o The daytime voiding frequency is at least once per hour with an average voided volume of < 50% of expected bladder capacity (EBC) (typically 10% to 15%). o Incontinence is rare and nocturia is absent.” “26. Subject has extraordinary daytime only urinary frequency according to the ICCS definition based on the bladder e diary.” • The following exclusion criteria are removed: “3. Subject has monosymptomatic enuresis.” “27. Subject has monosymptomatic enuresis confirmed by the bladder e-diary.” • Exclusion criterion no. 2 is updated to: “flow indices as a predictor” of pathology other than OAB • The following text is added to exclusion criteria nos. 7 and 32: “Note: subjects with microhematuria without gross proteinuria are eligible.” • The following new exclusion criteria at ‘Visit 1/Week -4 (Screening)’ are added after exclusion criterion no. 25: “36. Subject has a current or previous history of epilepsy. 37. Subject with neuropsychiatric diagnoses (e.g., ADHD, anxiety, severe depression, autism, bipolar disorder)” • Exclusion criterion no. 30 and footnote m in Table 1 is updated to: “> 30 mL (average of 2 lowest PVR volume results) as measured by a bladder ultrasound device that gives images in 3 planes.” • Text in Sections 1.3 (Table 1, Footnote m) and 7.2.5 is updated to: “a bladder ultrasound device that gives images in 3 planes.”
    01 Feb 2023
    • The following text is updated from: “Subject with (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mmHg.” To: “Blood pressure at or above the stage II HTN threshold (≥ 95th percentile + 12 mmHg, or ≥ 140/90 mmHg [whichever is lower]) [Flynn et al, 2017]” • The interim analysis is updated from: “blinded” To: “comparative” • The uroflow assessment is removed from the screening visit and added to visit 3 (baseline). • The following text is added: • “Subjects with previously normal or pre HTN BPs will have a timely in-clinic visit, either scheduled or unscheduled, within 2 weeks of any home SBPM measurements that are at, or above, the stage l HTN threshold to measure, document and confirm BP increases. At this timely in person visit, BP measurements intended to confirm home SBPM measurements will be taken by trained healthcare personnel. • Subjects will have an expedited in-clinic visit, either scheduled or unscheduled, within 1 week of any home SBPM measurement that are at, or above, the stage II HTN threshold, and/or a pulse rate above the 99th percentile compared to age-related pulse rate norms and ≥ 15 bpm change from baseline, to measure, document and confirm BP and/or pulse rate increases. At this expedited in clinic visit, BP measurements will be taken by trained healthcare personnel.” • The statistical methodology is updated From: In general, all data will be summarized with descriptive statistics frequency and percentage for categorical data. Data will be summarized by age group, treatment group and visit unless otherwise stated. To: In general, continuous data will be summarized descriptively including the number of subjects (n), mean, standard deviation (SD), median, minimum and maximum. Categorical data will be summarized by frequencies and percentages.
    01 Feb 2023
    • The following bolded text is added to the age group details for the analysis of vital signs: “Descriptive statistics will be used to summarize vital sign results and changes from baseline by treatment group and within treatment group and across age group. In addition to the presentation by age groups for 5 to < 12 years of age and 12 to < 18 years of age and overall, vital signs will also be presented for age groups 5 to < 8 years of age and 8 to < 12 years of age.”

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Jul 2023
    Termination due to operational futility.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the small number of subjects, a proper assessment of the efficacy endpoints was not possible, and observed results were inconclusive and efficacy could not be determined due to early termination of the study.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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