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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Fixed-dose Once-daily Oral Aripiprazole in Children and Adolescents with Tourette's Disorder

    Summary
    EudraCT number
    2012-003488-23
    Trial protocol
    HU   FI   BE   SE   ES   GB   IT   DE   NL   BG  
    Global end of trial date
    03 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Mar 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    31-12-293
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01727700
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, Maryland, United States, 20850
    Public contact
    Eva Kohegyi, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 6095246790, Eva.Kohegyi@otsuka-us.com
    Scientific contact
    Eva Kohegyi, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 6095246790, Eva.Kohegyi@otsuka-us.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of aripiprazole with placebo in the suppression of tics in children and adolescents (7-17 years) with a diagnosis of Tourette's Disorder (TD) and to evaluate the safety and tolerability of aripiprazole once-daily treatment with oral tablets in children and adolescents with a diagnosis of TD.
    Protection of trial subjects
    This study was designed and monitored in compliance with the protocol and in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline, and the applicable local laws and regulatory requirements of the countries in which the trial was conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Nov 2012
    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
    Canada: 27
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    United States: 92
    Worldwide total number of subjects
    133
    EEA total number of subjects
    14
    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)
    66
    Adolescents (12-17 years)
    67
    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
    This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in children and adolescents (aged 7-17 years) with TD. 171 participants were screened, of which 133 were randomized to treatment.

    Pre-assignment
    Screening details
    The trial consisted of a pretreatment phase and a treatment phase. Pretreatment phase consisted of a screening and washout (when applicable) period. This was followed by an 8-week treatment phase starting with the baseline visit (Day 0). Participants were randomized 1:1:1 to aripiprazole high dose, aripiprazole low dose or placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    During the trial, the treatment assignment code list was available only to an independent biostatistician. Except in cases of emergency unblinding, subjects, investigational site personnel, OPDC employees, and all other trial personnel remained blinded to the identity of the treatment assignments until every subject had completed trial treatment and the database had been locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Aripiprazole low dose
    Arm description
    For participants who weighed < 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    Abilify, OPC-14597
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants who weighed < 50 kg at baseline, low dose was one 5 mg/day plus 1 placebo tablet. For participants who weighed ≥ 50 kg at baseline, low dose was one 10 mg/day and 1 placebo tablet.

    Arm title
    Aripiprazole high dose
    Arm description
    For participants who weighed < 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    Abilify, OPC-14597
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants who weighed < 50 kg at baseline, high dose was 10 mg/day plus 1 placebo tablet. For participants who weighed ≥ 50 kg at baseline, high dose was two 10 mg/day plus no placebo tablet.

    Arm title
    Placebo
    Arm description
    Participants received matching placebo tablets in the same way as aripiprazole.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets in the same way as aripiprazole.

    Number of subjects in period 1
    Aripiprazole low dose Aripiprazole high dose Placebo
    Started
    44
    45
    44
    Completed
    42
    35
    42
    Not completed
    2
    10
    2
         Protocol Violation
    2
    -
    -
         Consent withdrawn by subject
    -
    3
    1
         Adverse Event
    -
    7
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aripiprazole low dose
    Reporting group description
    For participants who weighed < 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.

    Reporting group title
    Aripiprazole high dose
    Reporting group description
    For participants who weighed < 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo tablets in the same way as aripiprazole.

    Reporting group values
    Aripiprazole low dose Aripiprazole high dose Placebo Total
    Number of subjects
    44 45 44 133
    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
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.1 ± 3.1 11.8 ± 2.8 11.6 ± 2.8 -
    Gender categorical
    Units: Subjects
        Female
    8 10 11 29
        Male
    36 35 33 104

    End points

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    End points reporting groups
    Reporting group title
    Aripiprazole low dose
    Reporting group description
    For participants who weighed < 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.

    Reporting group title
    Aripiprazole high dose
    Reporting group description
    For participants who weighed < 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo tablets in the same way as aripiprazole.

    Primary: Change from Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)

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    End point title
    Change from Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)
    End point description
    The YGTSS is a semi-structured clinical interview designed to measure current (time frame of the past 1 week) tic severity. This scale consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms, and an impairment ranking. Ratings are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each, including number, frequency, intensity, complexity, and interference. Summation of these 10 scores (ie, 0-50) provides a TTS that was the primary outcome measure in this trial. The YGTSS ranking of impairment score rated on a 50-point scale anchored from 0 (no impairment) to 50 (severe impairment) to assess impairment experienced in areas of self-esteem, family life, social acceptance, and school scores. Intent-to-Treat (ITT) Population: All participants randomly assigned to the double-blind treatment. Ns are number of participants with Baseline and a Week-8 assessment of the given variable.
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    Aripiprazole low dose Aripiprazole high dose Placebo
    Number of subjects analysed
    42
    35
    42
    Units: Units on a scale
        least squares mean (standard error)
    -13.35 ± 1.59
    -16.94 ± 1.61
    -7.09 ± 1.55
    Statistical analysis title
    Statistical analysis 1 at Week 8
    Statistical analysis description
    Assuming 5% of participants may drop out of the trial without a post-baseline efficacy evaluation, a total of 126 participants were required to provide at least 80% power to detect a treatment difference of -5 (common standard deviation [SD] of 8.5) between at least 1 of 2 aripiprazole dose levels and placebo in the primary outcome.
    Comparison groups
    Aripiprazole low dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [1]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -6.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.18
         upper limit
    -2.34
    Notes
    [1] - The Hochberg procedure was used to adjust for multiplicity.
    Statistical analysis title
    Statistical analysis 2 at Week 8
    Statistical analysis description
    Assuming 5% of participants may drop out of the trial without a post-baseline efficacy evaluation, a total of 126 participants were required to provide at least 80% power to detect a treatment difference of -5 (common standard SD of 8.5) between at least 1 of 2 aripiprazole dose levels and placebo in the primary outcome.
    Comparison groups
    Placebo v Aripiprazole high dose
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -9.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.84
         upper limit
    -5.86
    Notes
    [2] - The Hochberg procedure was used to adjust for multiplicity.

    Secondary: Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8

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    End point title
    Change in Clinical Global Impressions Scale-Tourette's Syndrome (CGI-TS) Score at Week 8
    End point description
    To assess CGI-TS severity, the rater or physician answered the following question: “Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?” The change score was obtained from CGI-TS improvement scale assessment: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Aripiprazole low dose Aripiprazole high dose Placebo
    Number of subjects analysed
    42
    35
    42
    Units: Units on a scale
        least squares mean (standard error)
    2.12 ± 0.21
    2.13 ± 0.21
    3.15 ± 0.2
    Statistical analysis title
    Statistical analysis 1 at Week 8
    Comparison groups
    Aripiprazole low dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [3]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.54
         upper limit
    -0.52
    Notes
    [3] - The Hochberg procedure was used to adjust for multiplicity.
    Statistical analysis title
    Statistical analysis 2 at Week 8
    Comparison groups
    Aripiprazole high dose v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [4]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.54
         upper limit
    -0.49
    Notes
    [4] - The Hochberg procedure was used to adjust for multiplicity.

    Secondary: Mean change from Baseline to Endpoint (Week 8) in Total YGTSS Score

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    End point title
    Mean change from Baseline to Endpoint (Week 8) in Total YGTSS Score
    End point description
    The YGTSS consists of a tic inventory, with 5 separate rating scales to rate the severity of symptoms (on a scale of 0 to 5 for 5 different dimensions, including number, frequency, intensity, complexity, and interference) of motor and vocal tics, and an impairment ranking. The Total YGTSS score is the summation of the severity scores of motor and vocal tics and also the ranking of impairment (range of 0 to 100). A missing value of a YGTSS item scale could result in a missing Total YGTSS score. A reduction in Total YGTSS score from baseline represents an improvement in symptoms. ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    Aripiprazole low dose Aripiprazole high dose Placebo
    Number of subjects analysed
    42
    35
    42
    Units: Units on a scale
        least squares mean (standard error)
    -26.69 ± 3.34
    -32.8 ± 3.39
    -13.43 ± 3.27
    Statistical analysis title
    Statistical analysis 1 at Week 8
    Comparison groups
    Aripiprazole low dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017 [5]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -13.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.43
         upper limit
    -5.08
    Notes
    [5] - Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
    Statistical analysis title
    Statistical analysis 2 at Week 8
    Comparison groups
    Aripiprazole high dose v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -19.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.7
         upper limit
    -11.04
    Notes
    [6] - Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.

    Secondary: Mean change from Baseline to Endpoint (Week 8) in CGI-TS Severity Score

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    End point title
    Mean change from Baseline to Endpoint (Week 8) in CGI-TS Severity Score
    End point description
    The CGI-TS Severity scale (range 0-7) is a single-item rating score, with higher scores representing greater severity or less improvement. A response of 0 (not assessed) is considered and handled as missing data. ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    Aripiprazole low dose Aripiprazole high dose Placebo
    Number of subjects analysed
    42
    35
    42
    Units: Units on a scale
        least squares mean (standard error)
    -1.35 ± 0.19
    -1.47 ± 0.19
    -0.55 ± 0.19
    Statistical analysis title
    Statistiscal analysis 1 at Week 8
    Comparison groups
    Aripiprazole low dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [7]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.27
         upper limit
    -0.33
    Notes
    [7] - Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.
    Statistical analysis title
    Statistical analysis 2 at Week 8
    Comparison groups
    Aripiprazole high dose v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [8]
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.41
         upper limit
    -0.44
    Notes
    [8] - Treatment, week, treatment by week interaction, region, and weight group were fixed categorical effects; baseline value as a fixed covariate.

    Secondary: Response Rate

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    End point title
    Response Rate
    End point description
    Clinical response is defined as > 25% improvement from baseline to Week 8 in YGTSS TTS or a CGI-TS Change score of 1 [very much improved] or 2 [much improved] at Week 8. Response will be considered as missing only if both YGTSS TTS and CGI-TS change score are missing. As long as one of them is non-missing, response outcome will be determined based on the non-missing score. ITT Population: All participants randomly assigned to the double-blind treatment. At Week 8, data were available for 42 participants in the low dose, 35 in the high dose and 42 in the placebo group.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Aripiprazole low dose Aripiprazole high dose Placebo
    Number of subjects analysed
    42
    35
    42
    Units: Percentage of participants
        number (not applicable)
    73.8
    88.6
    54.8
    Statistical analysis title
    Statistical analysis 1 at Week 8
    Comparison groups
    Aripiprazole low dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0835 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Response ratio
    Point estimate
    1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.88
    Notes
    [9] - P-value derived from Cochran-Mantel-Haenszel (CMH) General Association Test adjusting for region and weight group. The response ratio >1 favours aripiprazole.
    Statistical analysis title
    Statistical analysis 2 at Week 8
    Comparison groups
    Aripiprazole high dose v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Response ratio
    Point estimate
    1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    2.16
    Notes
    [10] - P-value derived from CMH General Association Test adjusting for region and weight group. The response ratio >1 favours aripiprazole.

    Secondary: Treatment discontinuation rate

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    End point title
    Treatment discontinuation rate
    End point description
    Treatment discontinuation rate will be calculated as the number of discontinued participants (ie, those who were withdrawn from the trial without completing the Week 8 visit) over the number of all randomized participants. ITT Population: All participants randomly assigned to the double-blind treatment.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Aripiprazole low dose Aripiprazole high dose Placebo
    Number of subjects analysed
    44
    45
    44
    Units: Percentage of participants
        number (not applicable)
    4.5
    22.5
    4.5
    Statistical analysis title
    Statistical analysis 1 at Week 8
    Comparison groups
    Placebo v Aripiprazole low dose
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9187 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Discontinuation ratio
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    7.05
    Notes
    [11] - Discontinuation ratio < 1 favors aripiprazole. P-value derived from CMH General Association Test adjusting for region and weight group.
    Statistical analysis title
    Statistical analysis 2 at Week 8
    Comparison groups
    Placebo v Aripiprazole low dose
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9576 [12]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    7.05
    Notes
    [12] - Hazard ratio < 1 favors aripiprazole. P-value derived from Cox proportional hazard regression adjusting for region and weight group.
    Statistical analysis title
    Statistical analysis 3 at Week 8
    Comparison groups
    Aripiprazole high dose v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0132 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Discontinuation ratio
    Point estimate
    4.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    14.95
    Notes
    [13] - Discontinuation ratio < 1 favors aripiprazole. P-value derived from CMH General Association Test adjusting for region and weight group.
    Statistical analysis title
    Statistical analysis 4 at Week 8
    Comparison groups
    Placebo v Aripiprazole high dose
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0278 [14]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    5.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    14.95
    Notes
    [14] - Hazard ratio < 1 favors aripiprazole. P-value derived from Cox proportional hazard regression adjusting for region and weight group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from the time of signing the informed consent up to 30 days after the last trial visit.
    Adverse event reporting additional description
    An AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling or incapacitating, required in participant hospitalization or prolonged hospitalization, congenital anomaly/birth defect or other medically significant event.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Aripiprazole low dose
    Reporting group description
    For participants who weighed < 50 kg at baseline, low dose was 5 mg/day. For participants who weighed ≥ 50 kg at baseline, low dose was 10 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was titrated to achieve the randomized dose. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.

    Reporting group title
    Aripiprazole high dose
    Reporting group description
    For participants who weighed < 50 kg at baseline, high dose was 10 mg/day. For participants who weighed ≥ 50 kg at baseline, high dose was 20 mg/day. All participants randomized to aripiprazole began treatment at 2 mg/day, with the dose titrated to 5 mg/day after 2 days. The dose was then titrated weekly until the randomized dose was achieved. All participants were to have reached their randomized dose by Week 3 (Day 21) and were to remain on that dose.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo tablets in the same way as aripiprazole.

    Serious adverse events
    Aripiprazole low dose Aripiprazole high dose Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Aripiprazole low dose Aripiprazole high dose Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 44 (47.73%)
    29 / 45 (64.44%)
    8 / 44 (18.18%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 45 (6.67%)
    0 / 44 (0.00%)
         occurrences all number
    0
    3
    0
    Headache
         subjects affected / exposed
    3 / 44 (6.82%)
    4 / 45 (8.89%)
    1 / 44 (2.27%)
         occurrences all number
    3
    4
    1
    Lethargy
         subjects affected / exposed
    0 / 44 (0.00%)
    5 / 45 (11.11%)
    0 / 44 (0.00%)
         occurrences all number
    0
    5
    0
    Sedation
         subjects affected / exposed
    8 / 44 (18.18%)
    4 / 45 (8.89%)
    1 / 44 (2.27%)
         occurrences all number
    8
    5
    1
    Somnolence
         subjects affected / exposed
    5 / 44 (11.36%)
    7 / 45 (15.56%)
    1 / 44 (2.27%)
         occurrences all number
    5
    7
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 44 (6.82%)
    7 / 45 (15.56%)
    0 / 44 (0.00%)
         occurrences all number
    3
    7
    0
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 45 (6.67%)
    1 / 44 (2.27%)
         occurrences all number
    0
    3
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 44 (6.82%)
    4 / 45 (8.89%)
    1 / 44 (2.27%)
         occurrences all number
    3
    4
    1
    Vomiting
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 45 (6.67%)
    2 / 44 (4.55%)
         occurrences all number
    2
    4
    2
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 45 (6.67%)
    1 / 44 (2.27%)
         occurrences all number
    4
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 44 (6.82%)
    4 / 45 (8.89%)
    0 / 44 (0.00%)
         occurrences all number
    3
    4
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 45 (2.22%)
    3 / 44 (6.82%)
         occurrences all number
    1
    1
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2012
    Protocol amendment 1 clarified the concomitant use of benzodiazepines, changed the titration scheme, specified the entire Swanson, Nolan and Pelham-IV (SNAP-IV) rating scale, rather than the attention-deficit/hyperactivity disorder (ADHD) subscales; removed the Gilles de la Tourette Syndrome-Quality of Life scale assessments; added weight-based dosing stratification.

    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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