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    Clinical Trial Results:
    12-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study to investigate the efficacy, pharmacodynamic and safety of two doses of alfuzosin (0.1 mg/kg/day; 0.2 mg/kg/day) in the treatment of children and adolescents 2 – 16 years of age with elevated detrusor leak point pressure of neuropathic etiology followed by a 40-week open-label extension

    Summary
    EudraCT number
    		 2004-002397-38
    Trial protocol
    		 FR   PT   DE   ES   PL   EE   SK   BG  
    Global end of trial date
    09 Dec 2009

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Apr 2016
    First version publication date
    06 Dec 2014
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor correction to non-serious adverse events data (number of occurrences)

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC5722
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00549939
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin , France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jan 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Alfuzosin in comparison to Placebo on the detrusor Leak Point Pressure (LPP) in children and adolescents 2-16 years of age with elevated detrusor LPP of neuropathic etiology and detrusor LPP greater than or equal to (≥) 40 centimeter of water (cm H2O).
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Oct 2007
    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
    France: 7
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Slovakia: 14
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Serbia: 17
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Russian Federation: 19
    Country: Number of subjects enrolled
    India: 20
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Germany: 5
    Worldwide total number of subjects
    172
    EEA total number of subjects
    81
    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)
    127
    Adolescents (12-17 years)
    45
    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
    		 The study was conducted at 55 sites in 18 countries. A total of 261 subjects were screened between September 2007 and November 2008.

    Pre-assignment
    Screening details
    		 172/261 subjects were randomized in the 12-week double blind phase. 89/261 subjects were not randomized for the following reasons: - Adverse event (1 subject*), - Inclusion/Exclusion criteria not met (69 subjects*), - Subject's request (11 subjects*), - Other (13 subjects*). '*' Subjects could have several reasons.

    Period 1
    Period 1 title
    12-week efficacy phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Subjects were randomized to either Alfuzosin 0.1 milligram per kilogram per Day (mg/kg/Day) or matching placebo 0.1 mg/kg/Day or Alfuzosin 0.2 mg/kg/Day or matching placebo 0.2 mg/kg/Day. Each placebo treatment matched the active drug treatment (tablet or solution) and was indistinguishable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo - 12 weeks
    Arm description
    		 Placebo (for Alfuzosin 0.1 mg/kg/Day) or placebo (for Alfuzosin 0.2 mg/kg/Day) for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Either solution or tablet formulation depending on age; The daily dose with solution was divided in 3 doses given at breakfast, lunch and dinner. The daily dose with tablets was divided in 2 doses given at breakfast and dinner.

    Arm title
    		 Alfuzosin 0.1 mg/kg/Day - 12 weeks
    Arm description
    		 Alfuzosin 0.1 mg/kg/Day for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alfuzosin
    Investigational medicinal product code
    SL770499
    Other name
    Pharmaceutical forms
    Tablet, Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Either solution or tablet formulation depending on age; The daily dose with solution was divided in 3 doses given at breakfast, lunch and dinner. The daily dose with tablet was divided in 2 doses given at breakfast and dinner.

    Arm title
    		 Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Arm description
    		 Alfuzosin, 0.2 mg/kg/Day for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alfuzosin
    Investigational medicinal product code
    SL770499
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Either solution or tablet formulation depending on age; The daily dose with solution was divided in 3 doses given at breakfast, lunch and dinner. The daily dose with tablet was divided in 2 doses given at breakfast and dinner.

    Number of subjects in period 1
    		Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Started
    57
    57
    58
    Treated
    57
    57
    58
    Completed
    56
    55
    56
    Not completed
    1
    2
    2
         Adverse Event
    1
    1
    2
         'Too many blood draws '
    -
    1
    -
    Period 2
    Period 2 title
    40-week safety extension phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alfuzosin 0.1 mg/kg/Day - 40 weeks extension
    Arm description
    		 Alfuzosin 0.1 mg/kg/Day for 40 additional weeks open-label to subjects on Alfuzosin, 0.1 mg/kg/Day or on Placebo (for Alfuzosin, 0.1 mg/kg/Day) during the efficacy phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alfuzosin
    Investigational medicinal product code
    SL770499
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Same dosage and administration details as for the period 1.

    Arm title
    		 Alfuzosin 0.2 mg/kg/Day - 40 weeks extension
    Arm description
    		 Alfuzosin 0.2 mg/kg/Day for 40 additional weeks open-label to subjects on Alfuzosin, 0.2 mg/kg/Day or on Placebo (for Alfuzosin, 0.2 mg/kg/Day) during the efficacy phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alfuzosin
    Investigational medicinal product code
    SL770499
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Same dosage and administration details as for the period 1.

    Number of subjects in period 2 [1]
    		Alfuzosin 0.1 mg/kg/Day - 40 weeks extension Alfuzosin 0.2 mg/kg/Day - 40 weeks extension
    Started
    80
    83
    Completed
    75
    78
    Not completed
    5
    5
         Adverse Event
    2
    1
         Other
    1
    4
         Protocol Violation
    1
    -
         Lack of efficacy
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who completed the 12-week double-blind period had the possibility to continue in the 40-week open-label extension period or to stop. -54/56 subjects in the placebo group switched to Alfuzosin 0.1 mg/kg/Day (26 subjects) or 0.2 mg/kg/Day (28 subjects) according to initial randomization; -54/55 subjects in the Alfuzosin 0.1 mg/kg/Day continued; - 55/56 subjects in the Alfuzosin 0.2 mg/kg/Day continued.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo - 12 weeks
    Reporting group description
    		 Placebo (for Alfuzosin 0.1 mg/kg/Day) or placebo (for Alfuzosin 0.2 mg/kg/Day) for 12 weeks.

    Reporting group title
    Alfuzosin 0.1 mg/kg/Day - 12 weeks
    Reporting group description
    		 Alfuzosin 0.1 mg/kg/Day for 12 weeks.

    Reporting group title
    Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Reporting group description
    		 Alfuzosin, 0.2 mg/kg/Day for 12 weeks.

    Reporting group values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks Total
    Number of subjects
    		 57 57 58 172
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
        Not recorded
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.3 ± 4.4 7.9 ± 3.9 8.7 ± 3.9 -
    Gender categorical
    Units: Subjects
        Female
    		 28 27 30 85
        Male
    		 29 30 28 87
    Urinary Tract Infection (UTI) history in the last 3 months
    Units: Subjects
        No UTI episode
    		 48 50 40 138
        One UTI episode
    		 8 5 16 29
        Two UTI episodes
    		 1 2 2 5
    Study drug formulation
    Units: Subjects
        Solution (2-7 years)
    		 28 28 28 84
        Solution (8-16 years)
    		 8 10 9 27
        Tablets (8-16 years)
    		 21 19 21 61

    End points

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    End points reporting groups
    Reporting group title
    Placebo - 12 weeks
    Reporting group description
    		 Placebo (for Alfuzosin 0.1 mg/kg/Day) or placebo (for Alfuzosin 0.2 mg/kg/Day) for 12 weeks.

    Reporting group title
    Alfuzosin 0.1 mg/kg/Day - 12 weeks
    Reporting group description
    		 Alfuzosin 0.1 mg/kg/Day for 12 weeks.

    Reporting group title
    Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Reporting group description
    		 Alfuzosin, 0.2 mg/kg/Day for 12 weeks.
    Reporting group title
    Alfuzosin 0.1 mg/kg/Day - 40 weeks extension
    Reporting group description
    		 Alfuzosin 0.1 mg/kg/Day for 40 additional weeks open-label to subjects on Alfuzosin, 0.1 mg/kg/Day or on Placebo (for Alfuzosin, 0.1 mg/kg/Day) during the efficacy phase.

    Reporting group title
    Alfuzosin 0.2 mg/kg/Day - 40 weeks extension
    Reporting group description
    		 Alfuzosin 0.2 mg/kg/Day for 40 additional weeks open-label to subjects on Alfuzosin, 0.2 mg/kg/Day or on Placebo (for Alfuzosin, 0.2 mg/kg/Day) during the efficacy phase

    Subject analysis set title
    Subjects Exposed to Alfuzosin 0.1 mg/kg/Day
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of Alfuzosin 0.1 mg/kg/Day during the overall study period (efficacy phase and/or safety extension phase) and regardless of the amount of treatment received.

    Subject analysis set title
    Subjects Exposed to Alfuzosin 0.2 mg/kg/Day
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of Alfuzosin 0.2 mg/kg/Day during the overall study period (efficacy phase and/or safety extension phase) and regardless of the amount of treatment received.

    Primary: Number of Subjects With Detrusor LPP Less Than (<) 40 cm H2O at 12 Weeks

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    End point title
    		 Number of Subjects With Detrusor LPP Less Than (<) 40 cm H2O at 12 Weeks
    End point description
    Detrusor LPP was measured by cystometry. For each measure, 2 or 3 cystometries were carried out depending on the difference between the 2 first LPP values (if the difference >=20 cm H2O, a third cystometry was done). The lowest value was retained. Investigators reading was then consolidated by the review of all cystometry data by 2 external "Expert Reviewers", who were blinded for the study treatment. The analysis was performed on consolidated investigators data (that is, endorsed by the Investigator taking into account reviewers opinion). The Intent-to-treat (ITT) population was used for the analysis. All randomized subjects were included in the analysis in the treatment group to which they were allocated as per randomization.
    End point type
    Primary
    End point timeframe
    12 weeks (double blind treatment period)
    End point values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects analysed
    57
    57
    58
    Units: subject
        < 40 cmH2O ("Success")
    23
    23
    28
        ≥ 40 cmH2O or missing ("Failure")
    34
    34
    30
    Statistical analysis title
    		 Alfuzosin 0.1 mg/kg/Day vs. Placebo
    Comparison groups
    Placebo - 12 weeks v Alfuzosin 0.1 mg/kg/Day - 12 weeks
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [1]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - P-value was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 Alfuzosin 0.2 mg/kg/Day vs. Placebo
    Comparison groups
    Placebo - 12 weeks v Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - P-value was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.

    Secondary: Detrusor LPP at Baseline and 12 Weeks

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    End point title
    		 Detrusor LPP at Baseline and 12 Weeks
    End point description
    Detrusor LPP was assessed at baseline and 12 weeks as described for the primary outcome measure. The analysis was performed on the ITT population excluding the subjects who didn't have baseline and/or post-baseline LPP values. Subjects were included in the treatment group to which they were allocated as per randomization.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects analysed
    54
    53
    56
    Units: cmH2O
    arithmetic mean (standard deviation)
        Baseline
    54.2 ± 12.6
    53.3 ± 13.4
    50.9 ± 10
        12 Weeks
    48.2 ± 23.4
    41.6 ± 18.2
    39.4 ± 19.5
    No statistical analyses for this end point

    Secondary: Absolute Change in Detrusor LPP at 12 Weeks

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    End point title
    		 Absolute Change in Detrusor LPP at 12 Weeks
    End point description
    Absolute change = Detrusor LPP at 12 weeks - Detrusor LPP at baseline. LS Means were estimated using a 3-way analysis of covariance (ANCOVA) with treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo), age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets) and anticholinergic/antimuscarinic use (yes or no) as fixed effects, and centered baseline detrusor LPP as covariate. The analysis was performed on the ITT population excluding the subjects who didn't have baseline and/or post-baseline value).
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects analysed
    54
    53
    56
    Units: cm H2O
        least squares mean (standard error)
    -5.4 ± 2.8
    -11.7 ± 2.8
    -12.5 ± 2.8
    Statistical analysis title
    		 Alfuzosin 0.1 mg/kg/Day vs. Placebo
    Comparison groups
    Alfuzosin 0.1 mg/kg/Day - 12 weeks v Placebo - 12 weeks
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.104 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference versus Placebo
    Point estimate
    -6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.72
         upper limit
    		 1.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.8
    Notes
    [3] - Change in detrusor LPP was analyzed using a three-way analysis of covariance (ANCOVA) including 3 variables as fixed effects: - Treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo), - Age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets), - Anticholinergic/antimuscarinic use (yes or no), and using centered baseline detrusor LPP as covariate.
    [4] - P-value was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 Alfuzosin 0.2 mg/kg/Day vs. Placebo
    Comparison groups
    Placebo - 12 weeks v Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.104 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference versus Placebo
    Point estimate
    -7.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.51
         upper limit
    		 0.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.77
    Notes
    [5] - P-value was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.

    Secondary: Relative Change in Detrusor LPP at 12 Weeks

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    End point title
    		 Relative Change in Detrusor LPP at 12 Weeks
    End point description
    Relative change = 100 * (Detrusor LPP at 12 weeks - Detrusor LPP at baseline) / Detrusor LPP at baseline. LS Means were estimated using the same ANCOVA model as for Absolute Change in Detrusor LPP. The analysis was performed on the ITT population excluding the subjects who didn't have baseline and/or post-baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects analysed
    54
    53
    56
    Units: percentage of cmH2O
        least squares mean (standard error)
    -9.2 ± 5.53
    -20.6 ± 5.56
    -23.5 ± 5.51
    Statistical analysis title
    		 Alfuzosin 0.1 mg/kg/Day vs. Placebo
    Comparison groups
    Placebo - 12 weeks v Alfuzosin 0.1 mg/kg/Day - 12 weeks
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.1338 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference versus Placebo
    Point estimate
    -11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.27
         upper limit
    		 3.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.54
    Notes
    [6] - Change in detrusor LPP was analyzed using a three-way analysis of covariance (ANCOVA) including 3 variables as fixed effects: - Treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo), - Age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets), - Anticholinergic/antimuscarinic use (yes or no), and using centered baseline detrusor LPP as covariate.
    [7] - P-values was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 Alfuzosin 0.2 mg/kg/Day vs. Placebo
    Comparison groups
    Placebo - 12 weeks v Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1152 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference versus Placebo
    Point estimate
    -14.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.1
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.48
    Notes
    [8] - P-value was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.

    Secondary: Detrusor Compliance at Baseline and at 12 Weeks

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    End point title
    		 Detrusor Compliance at Baseline and at 12 Weeks
    End point description
    Detrusor compliance is defined as the relationship between change in detrusor volume and change in detrusor pressure. It was calculated by dividing the volume change (ΔV) by the change in detrusor pressure (Δpdet) during that change in detrusor volume at leak point (C= ΔV/Δpdet). The analysis was performed on the ITT population excluding the subjects who didn't have baseline and/or post baseline detrusor compliance values. Subjects were included in the treatment group to which they were allocated as per randomization.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects analysed
    54
    52
    55
    Units: mL/cmH20
    arithmetic mean (standard deviation)
        Baseline
    3.4 ± 2.8
    3.4 ± 2.8
    3.3 ± 2.5
        12 weeks
    4.8 ± 5
    5.3 ± 4.9
    5.8 ± 5.9
    No statistical analyses for this end point

    Secondary: Relative Change in Detrusor Compliance at 12 Weeks

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    End point title
    		 Relative Change in Detrusor Compliance at 12 Weeks
    End point description
    Relative change = 100 * (Detrusor compliance at 12 weeks - Detrusor compliance at baseline) / Detrusor compliance at baseline LS means were estimated using a 3-way analysis of covariance (ANCOVA) including treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo), age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets), anticholinergic/antimuscarinic use (yes or no) as fixed effects and centered baseline detrusor compliance as covariate. The analysis was performed on the ITT population excluding the subjects who didn't have baseline and/or post-baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects analysed
    54
    52
    55
    Units: percentage of mL/cmH2O
        least squares mean (standard error)
    113.6 ± 35.26
    126.6 ± 35.76
    98.6 ± 35.24
    Statistical analysis title
    		 Alfuzosin 0.1 mg/kg/Day vs. Placebo
    Statistical analysis description
    Change in detrusor compliance was analyzed using a three-way analysis of covariance (ANCOVA) including 3 variables as fixed effects: - Treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo), - Age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets), - Anticholinergic/antimuscarinic use (yes or no), and using centered baseline detrusor compliance as covariate.
    Comparison groups
    Alfuzosin 0.1 mg/kg/Day - 12 weeks v Placebo - 12 weeks
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7889 [9]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [9] - P-value was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 Alfuzosin 0.2 mg/kg/Day vs. Placebo
    Comparison groups
    Placebo - 12 weeks v Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7889 [10]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [10] - P-value was adjusted for multiplicity using the Hochberg procedure. The a priori threshold for statistical significance was 0.05.

    Secondary: Number of Subjects With Symptomatic UTI Episodes During the First 12 Weeks

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    End point title
    		 Number of Subjects With Symptomatic UTI Episodes During the First 12 Weeks
    End point description
    When a subject presented with symptoms such as pain, fever or hematuria (discretion of the Investigator), an urinalysis was performed including a dipstick and a quantitative urine culture. A symptomatic UTI was defined as the presence of symptoms and a positive culture with > 100 000 Colony Forming Units (CFUs) with a single organism.
    End point type
    Secondary
    End point timeframe
    12 weeks (double blind treatment period)
    End point values
    		 Placebo - 12 weeks Alfuzosin 0.1 mg/kg/Day - 12 weeks Alfuzosin 0.2 mg/kg/Day - 12 weeks
    Number of subjects analysed
    57
    57
    58
    Units: subjects
        No symptomatic UTI
    50
    53
    51
        One symptomatic UTI
    5
    3
    6
        Two symptomatic UTI
    2
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Symptomatic UTI Episodes During the Overall Study Period

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    End point title
    		 Number of Subjects With Symptomatic UTI Episodes During the Overall Study Period
    End point description
    The analysis was performed on the safety population (that is, all subjects who received at least one dose of Alfuzosin regardless of the amount of treatment received). It included 3 + 3 subjects treated during the 1st treatment period only, 26 + 28 subjects treated during the 2nd treatment period only and 54 + 55 subjects treated during both periods.
    End point type
    Secondary
    End point timeframe
    52 weeks (12 plus 40 weeks)
    End point values
    		 Subjects Exposed to Alfuzosin 0.1 mg/kg/Day Subjects Exposed to Alfuzosin 0.2 mg/kg/Day
    Number of subjects analysed
    83
    86
    Units: Subjects
        No symptomatic UTI
    66
    70
        One symptomatic UTI
    12
    13
        Two symptomatic UTI
    3
    0
        Three symptomatic UTI
    1
    1
        Four symptomatic UTI
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 52) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent AEs that is AEs that developed/worsened during the ‘on treatment period’ (time from first dose of alfuzosin [study Day 1 for subjects who took alfuzosin during the double-blind phase and Week 12 for subjects who took placebo during the double-blind phase] to last dose of alfuzosin plus 48 hours [5 half lives]).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Alfuzosin 0.1 mg/kg/Day
    Reporting group description
    		 Alfuzosin 0.1 mg/kg/Day tablet or solution orally for 52 weeks.

    Reporting group title
    Alfuzosin 0.2 mg/kg/Day
    Reporting group description
    		 Alfuzosin 0.2 mg/kg/Day tablet or solution orally for 52 weeks.

    Serious adverse events
    		 Alfuzosin 0.1 mg/kg/Day Alfuzosin 0.2 mg/kg/Day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 83 (12.05%)
    7 / 86 (8.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventriculoperitoneal Shunt Malfunction
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arnold-Chiari Malformation
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (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
    Epilepsy
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tethered Cord Syndrome
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory Failure
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar Hypertrophy
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (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
    Decubitus Ulcer
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Impairment
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral Haemorrhage
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lobar Pneumonia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 86 (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
    		 Alfuzosin 0.1 mg/kg/Day Alfuzosin 0.2 mg/kg/Day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 83 (44.58%)
    43 / 86 (50.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 83 (8.43%)
    10 / 86 (11.63%)
         occurrences all number
    9
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 83 (9.64%)
    10 / 86 (11.63%)
         occurrences all number
    14
    13
    Vomiting
         subjects affected / exposed
    4 / 83 (4.82%)
    6 / 86 (6.98%)
         occurrences all number
    6
    6
    Infections and infestations
    Cystitis
         subjects affected / exposed
    5 / 83 (6.02%)
    9 / 86 (10.47%)
         occurrences all number
    5
    18
    Nasopharyngitis
         subjects affected / exposed
    6 / 83 (7.23%)
    12 / 86 (13.95%)
         occurrences all number
    8
    17
    Pharyngitis
         subjects affected / exposed
    8 / 83 (9.64%)
    5 / 86 (5.81%)
         occurrences all number
    12
    7
    Respiratory Tract Infection
         subjects affected / exposed
    7 / 83 (8.43%)
    5 / 86 (5.81%)
         occurrences all number
    9
    8
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 83 (4.82%)
    5 / 86 (5.81%)
         occurrences all number
    6
    10
    Urinary Tract Infection
         subjects affected / exposed
    9 / 83 (10.84%)
    6 / 86 (6.98%)
         occurrences all number
    14
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Sep 2007
    Modification of several aspects of the original protocol in order to define an exclusion criterion related to the study drug more precisely, to provide more details on the formulations used in the study, to change the PK sampling schedule, to better characterize the assessment of vital signs, and to revise the time window for cystometry.
    06 Oct 2008
    Modifications of the PK sampling schedule for subjects randomized after 31 August 2008, revision of the temporary treatment discontinuation procedure and characterization of the collection of laboratory results in more detail.

    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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