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

    Summary
    EudraCT number
    		 2011-000467-27
    Trial protocol
    		 HU  
    Global end of trial date
    06 Nov 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
    31-10-272
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01418339
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development &Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, Maryland 20850
    Public contact
    Eva Kohegyi, MD, Otsuka Pharmaceutical Development &Commercialization, Inc., 1 609 524-6790,
    Scientific contact
    Eva Kohegyi, MD, Otsuka Pharmaceutical Development &Commercialization, Inc., 1 609 524-6790,
    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
    28 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: 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). The primary efficacy measure is change from Baseline to endpoint (Week 8) on the Total Tic score (TTS) of the Yale Global Tic Severity Scale (YGTSS). The secondary objective was to evaluate the safety and tolerability of aripiprazole treatment with oral tablets in children and adolescents with a diagnosis of TD. Secondary efficacy measures include Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS) and Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL).
    Protection of trial subjects
    The trial was conducted in accordance with the protocol, legal and regulatory requirements, as well as the general principles set forth in Guidelines for Good Clinical Practice (GCP) (International Conference on Harmonization [ICH] 1996). In addition, the study was conducted in accordance with applicable local regulatory requirements and laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jul 2011
    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
    Canada: 23
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    135
    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)
    61
    Adolescents (12-17 years)
    74
    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
    		 A total of 152 participants were screened and 135 were randomised to treatment. The randomized participants were recruited from 45 study sites in the following 6 countries: United States (US), Hungary, Canada, Taiwan, South Korea, and Mexico. 124 participants were included in the modified intention-to-treat (mITT) population.

    Pre-assignment
    Screening details
    		 The trial consisted of a pretreatment and treatment phase. The pretreatment phase consisted of a Screening period, a washout period (when applicable), and a Baseline visit. This was followed by an 8-week treatment phase. There was also a follow-up period (30 ± 3 days) for those participants who did not roll over into the open-label study.

    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 participant had completed trial treatment and the database had been locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Aripiprazole
    Arm description
    		 Aripiprazole was administered orally once a week (QW) for 8 weeks. Participants randomised to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, according to the investigator’s discretion based on efficacy and tolerability, the dose of aripiprazole could remain at 52.5 mg QW or could be increased to 77.5 mg QW. The dose could be increased to 110 mg QW for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apipiprazole
    Investigational medicinal product code
    OPC-14597
    Other name
    Abilify
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    52.5 mg to 110 mg QW for 8 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.
    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
    Participants received matching placebo tablets in the same way as aripiprazole

    Number of subjects in period 1
    		Aripiprazole Placebo
    Started
    90
    45
    Completed
    78
    35
    Not completed
    12
    10
         Consent withdrawn by subject
    1
    2
         Adverse event
    5
    2
         Lack of efficacy
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aripiprazole
    Reporting group description
    		 Aripiprazole was administered orally once a week (QW) for 8 weeks. Participants randomised to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, according to the investigator’s discretion based on efficacy and tolerability, the dose of aripiprazole could remain at 52.5 mg QW or could be increased to 77.5 mg QW. The dose could be increased to 110 mg QW for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.

    Reporting group values
    		 Aripiprazole Placebo Total
    Number of subjects
    		 90 45 135
    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
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        Children (7-12 years)
    		 0
        Adolescents (13-17 years)
    		 0
    Age continuous
    Data are presented for the modified intention-to-treat (mITT) population. All subjects participants assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements. The mITT sample was used in place of the ITT sample, the primary dataset for all efficacy endpoints, and was analysed according to the treatment group to which subjects were randomized.
    Units: years
        arithmetic mean (standard deviation)
    		 12 ( 2.9 ) 11.5 ( 2.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 14 31
        Male
    		 73 31 104

    End points

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    End points reporting groups
    Reporting group title
    Aripiprazole
    Reporting group description
    		 Aripiprazole was administered orally once a week (QW) for 8 weeks. Participants randomised to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, according to the investigator’s discretion based on efficacy and tolerability, the dose of aripiprazole could remain at 52.5 mg QW or could be increased to 77.5 mg QW. The dose could be increased to 110 mg QW for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.

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

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    End point title
    		 Change from Baseline to Week 8 in Yale Global Tic Severity Scale (YGTSS) TTS
    End point description
    YGTSS is a semi-structured clinical interview designed to measure current (time frame of the past 1 week) tic severity. The scale consists of a tic inventory, with 5 separate rating scales to rate 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. Total tic score ranges from 0 to 50 with a higher score for more severe symptoms. The scale assesses areas of self-esteem, family life, social acceptance, and school scores. This is a fully validated scale in adults and has become a standard instrument for the evaluation of the severity of TD in children. Data are presented for the modified intention-to-treat population (mITT).
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Aripiprazole Placebo
    Number of subjects analysed
    71 [1]
    34 [2]
    Units: Units on a scale
        least squares mean (standard error)
    -12.34 ( 0.88 )
    -7.72 ( 1.23 )
    Notes
    [1] - Number of participants in the mITT with Baseline and Week 8 measurement of YGTSS-TTS.
    [2] - Number of participants in the mITT with Baseline and Week 8 measurement of YGTSS-TTS.
    Statistical analysis title
    		 Statistical analysis 1 at Week 8
    Statistical analysis description
    The objective of the primary analysis was to compare the efficacy of QW oral aripiprazole with that of placebo through the change from baseline in YGTSS TTS. The statistical comparison was performed using a mixed model repeated measures (MMRM) linear model with treatment and visit week as factors, baseline YGTSS TTS as a covariate, and treatment-by-week interactions in the model at a significance level of 0.05 (2-sided).
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.028 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -4.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.62
         upper limit
    		 -1.63
    Notes
    [3] - Derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline value as a fixed covariate, and week as the time variable for repeated measures.

    Secondary: Change in CGI-TS Score at Week 8

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    End point title
    		 Change in CGI-TS Score at Week 8
    End point description
    To CGI-TS 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. Data are presented for the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Aripiprazole Placebo
    Number of subjects analysed
    70 [4]
    33 [5]
    Units: Units on a scale
        least squares mean (standard error)
    2.29 ( 0.12 )
    2.81 ( 0.17 )
    Notes
    [4] - Number of participants in mITT with baseline CGI-TS severity and Week 8 CGI-TS change score.
    [5] - Number of participants in mITT with baseline CGI-TS severity and Week 8 CGI-TS change score.
    Statistical analysis title
    		 Statisitcal analysis at Week8
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0124 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 -0.12
    Notes
    [6] - Derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline CGI-TS severity score as a fixed covariate, and week as the time variable for repeated measures.

    Secondary: Change from Baseline to Week 8 in GTS-QOL

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    End point title
    		 Change from Baseline to Week 8 in GTS-QOL
    End point description
    The GTS-QOL is a disease-specific patient-reported scale for the measurement of health-related quality of life in patients with TD, taking into account the complexity of the clinical picture of the disease.he questionnaire consists of a 27-item, TD-specific scale with 4 subscales (psychological, physical, obsessional, and cognitive).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Aripiprazole Placebo
    Number of subjects analysed
    71 [7]
    34 [8]
    Units: Units on a scale
        least squares mean (standard error)
    10.04 ( 1.83 )
    12.04 ( 2.6 )
    Notes
    [7] - Number of participants in the mITT with baseline and Week 8 GTS-QOL Overall Score.
    [8] - Number of participants in the mITT with baseline and Week 8 GTS-QOL Overall Score.
    Statistical analysis title
    		 Statistical analysis at Week 8
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5317 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.31
         upper limit
    		 4.32
    Notes
    [9] - Derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline value as a fixed covariate, and week as the time variable for repeated measures.

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

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    End point title
    		 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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Aripiprazole Placebo
    Number of subjects analysed
    71 [10]
    34 [11]
    Units: Units on a scale
        least squares mean (standard error)
    -25.05 ( 1.9 )
    -15.61 ( 2.65 )
    Notes
    [10] - Number of participants in the mITT with baseline and Week 8 Total YGTSS Score.
    [11] - Number of participants in the mITT with baseline and Week 8 Total YGTSS Score.
    Statistical analysis title
    		 Statistical analysis at Week 8
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0046 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -9.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.92
         upper limit
    		 -2.97
    Notes
    [12] - Derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline value as a fixed covariate, and week as the time variable for repeated measures.

    Secondary: Change from Baseline to Endpoint (Week 8) in CGI-TS Severity

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    End point title
    		 Change from Baseline to Endpoint (Week 8) in CGI-TS Severity
    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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Aripiprazole Placebo
    Number of subjects analysed
    71 [13]
    34 [14]
    Units: Units on a scale
        least squares mean (standard error)
    -1.62 ( 0.12 )
    -1.01 ( 0.17 )
    Notes
    [13] - Number of participants in the mITT with baseline and Week 8 measurement of the given variable.
    [14] - Number of participants in the mITT with baseline and Week 8 measurement of the given variable.
    Statistical analysis title
    		 Statistical analysis at Week 8
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0043 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.02
         upper limit
    		 -0.19
    Notes
    [15] - Derived from a repeated measures linear model with treatment, week, and treatment by week interaction as fixed categorical effects, the baseline value as a fixed covariate, and week as the time variable for repeated measures.

    Secondary: Clinical Response

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    End point title
    		 Clinical Response
    End point description
    Clinical response was defined as > 25% improvement from baseline to endpoint (Week 8) in YGTSS TTS or a CGI-TS change score of 1 (very much improved) or 2 (much improved) at endpoint (Week 8).
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Aripiprazole Placebo
    Number of subjects analysed
    71 [16]
    34 [17]
    Units: Percentage of participants
        number (not applicable)
    81.7
    61.8
    Notes
    [16] - Number of subjects with YGTSS or CGI change score at week 8.
    [17] - Number of subjects with YGTSS or CGI change score at week 8.
    Statistical analysis title
    		 Statitical Analysis at Week 8
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0269 [18]
    Method
    		 Chi-squared
    Parameter type
    		 Response ratio
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.76
    Notes
    [18] - Response Ratio > 1 favours aripiprazole. P-value derived from Chi-square test.

    Secondary: Treatment discontinuation rate

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    End point title
    		 Treatment discontinuation rate
    End point description
    Treatment discontinuation rate was 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.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Aripiprazole Placebo
    Number of subjects analysed
    82
    42
    Units: Percentage of participants
        number (not applicable)
    14.6
    23.8
    Statistical analysis title
    		 Statitical analysis 1 at Week 8
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2056 [19]
    Method
    		 Chi-squared
    Parameter type
    		 Response ratio
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.3
    Notes
    [19] - Discontinuation ratio < 1 favours aripiprazole. P-value derived from Chi-square test.
    Statistical analysis title
    		 Statistical analysis 2 at Week 8
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2376 [20]
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.3
    Notes
    [20] - Hazard ratio < 1 favours aripiprazole. P-value derived from Cox proportional hazard regression.

    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 events reported for safety population (N=135).
    Adverse event reporting additional description
    AE is defined as any untoward medical occurrence with the use of study drug. AE was considered serious if fatal, life threatening, disabling/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
    Reporting group description
    		 Aripiprazole was administered orally once a week (QW) for 8 weeks. Participantsd to aripiprazole began on a 52.5 milligrams (mg) QW dose on Day 0. At the Week 1 visit, according to the investigator’s discretion based on efficacy and tolerability, the dose of aripiprazole could remain at 52.5 mg QW or could be increased to 77.5 mg QW. The dose could be increased to 110 mg QW for efficacy as early as Week 2. For the remainder of the trial, the dose was to be adjusted up and down among these 3 dose levels, as determined by investigator discretion. 82 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo tablets in the same way as aripiprazole. 42 participants were included in the mITT which was all participants randomly assigned to the double-blind treatment, with the exclusion of participants randomized at sites 002 and 005. These two centres were terminated from conducting this trial due to their failure to abide by GCPs and the protocol requirements.

    Serious adverse events
    		 Aripiprazole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 45 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Aripiprazole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 90 (42.22%)
    8 / 45 (17.78%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 90 (13.33%)
    2 / 45 (4.44%)
         occurrences all number
    17
    3
    Somnolence
         subjects affected / exposed
    15 / 90 (16.67%)
    3 / 45 (6.67%)
         occurrences all number
    24
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 90 (8.89%)
    0 / 45 (0.00%)
         occurrences all number
    8
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    12 / 90 (13.33%)
    4 / 45 (8.89%)
         occurrences all number
    15
    4
    Vomiting
         subjects affected / exposed
    9 / 90 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    9
    1
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    6 / 90 (6.67%)
    1 / 45 (2.22%)
         occurrences all number
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2013
    In the amendment, the protocol was modified to remove the option to allow participants who discontinued due to lack of efficacy at Week 5 to enter the open-label extension trial. To clarify the protocol, new text was added describing exclusion of participants for QTc values > 450 milliseconds and the process for breaking the blind for an individual participant. The duration of the conduct of the trial was increased, based on the then current enrolment rates, and the statistical methods were updated. Vyvanse [lisdexamphetamine] was added throughout the protocol to the list of psychostimulant medications prescribed for the treatment of symptoms of Attention-Deficit Disorder/Attention-Deficit Hyperactivity Disorder, which were permitted during the trial.

    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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