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    Clinical Trial Results:
    An Open-Label, Multicenter Study Evaluating the Safety and Tolerability of Once-daily Oral Aripiprazole in Children and Adolescents with Tourette's Disorder.

    Summary
    EudraCT number
    2012-003489-42
    Trial protocol
    HU   BE   GB   ES   IT   DE   SE   NL   BG  
    Global end of trial date
    22 Sep 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    31-12-294
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01727713
    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., 001 6095246790, Eva.Kohegyi@otsuka-us.com
    Scientific contact
    Eva Kohegyi, Otsuka Pharmaceutical Development & Commercialization, Inc., 001 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
    26 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the long-term safety and tolerability of aripiprazole once-daily treatment with oral tablets in children and adolescents (7 -17 years of age) with a diagnosis of Tourette's Disorder (TD). The secondary objective was to evaluate the efficacy of once-daily aripiprazole in the suppression of tics in children and adolescents with a diagnosis of TD, as measured by change from baseline to endpoint on the total tic score (TTS) of the Yale Global Tic Severity Scale (YGTSS).
    Protection of trial subjects
    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, copies of the protocol, amendments, informed consent form (ICF), informed assent form, and subject recruitment materials were reviewed and approved by the governing institutional review board (IRB) or independent ethics committee (IEC).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Jan 2013
    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: 23
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    United States: 74
    Worldwide total number of subjects
    110
    EEA total number of subjects
    13
    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)
    52
    Adolescents (12-17 years)
    56
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A Phase 3 open-label, multicenter study evaluating the safety and tolerability of once-daily oral Aripiprazole in children and adolescents with TD. Participants who reached 18 years of age during their participation in Trial 31-12-293 (NCT01727700) were enrolled in this trial.

    Pre-assignment
    Screening details
    Participants who successfully completed the randomized, double-blind, placebo-controlled trial of once-daily Aripiprazole (protocol 31-12-293-NCT01727700) were eligible to enter this extension trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Open-label Aripiprazole
    Arm description
    All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    OPC-14597
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The once-daily aripiprazole was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability. Aripiprazole was formulated into tablets containing 2, 5, 10, and 15 mg (milligram) of aripiprazole per tablet.

    Number of subjects in period 1
    Open-label Aripiprazole
    Started
    110
    Completed
    75
    Not completed
    35
         Protocol deviation
    2
         Participant met withdrawal criteria
    5
         Adverse event, non-fatal
    10
         Consent withdrawn by subject
    13
         Lost to follow-up
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    110 110
    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)
    11.7 ± 2.9 -
    Gender categorical
    Units: Subjects
        Female
    24 24
        Male
    86 86

    End points

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    End points reporting groups
    Reporting group title
    Open-label Aripiprazole
    Reporting group description
    All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.

    Primary: Percentage of participants with adverse events.

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    End point title
    Percentage of participants with adverse events. [1]
    End point description
    An AE is defined as any untoward medical occurrence in a patient or participant enrolled in the clinical trial and which does not necessarily have to have a causal relationship with the study drug. A treatment emergent adverse event (TEAE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not considered related to have a causal relationship with the study drug. Serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires in-patient hospitalization or prolonged hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.
    End point type
    Primary
    End point timeframe
    Baseline to Follow-up period (30±3 days after the last trial visit)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Percentage of participants
    number (not applicable)
        Participants with TEAEs
    84
        Participants with severe TEAEs
    5
        Participants with serious TEAEs
    4
    No statistical analyses for this end point

    Primary: Percentage of participants with clinically significant abnormal laboratory test results.

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    End point title
    Percentage of participants with clinically significant abnormal laboratory test results. [2]
    End point description
    Laboratory tests including hematology, serum chemistry, and urinalysis were performed for all the participants. The central laboratory was used for all laboratory testing whenever possible. Any value outside the normal range was flagged for the attention of the study physician who was to indicate whether the value was clinically significant based on the pre-defined criteria for identifying laboratory values of potential clinical relevance. Percentage of participants noted with abnormal laboratory values are reported below.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Percentage of participants
    number (not applicable)
        Hematology-Eosinophils (high)
    3.7
        Hematology-Hemoglobin A1C (high)
    0.9
        Hematology-Absolute neutrophils (low)
    13
        Hematology-White blood count (low)
    4.6
        Chemistry-Total bilirubin (high)
    1.9
        Chemistry-Creatine phosphokinase (high)
    0.9
        Chemistry-Fasting glucose (high)
    3.2
        Chemistry-LDL cholesterol (high)
    3.3
        Chemistry-Triglycerides (high)
    17.4
        Chemistry-Uric acid (high)
    0.9
        Chemistry-Potassium (high)
    0.9
        Urinalysis-Urine glucose (high)
    1
        Urinalysis-Urine protein (high)
    1.9
        Prolactin (high)
    3.8
    No statistical analyses for this end point

    Primary: Percentage of participants with clinically significant abnormal vital signs.

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    End point title
    Percentage of participants with clinically significant abnormal vital signs. [3]
    End point description
    Vital sign measurements included systolic and diastolic blood pressure (BP) and heart rate, which were performed at all clinic visits. Criteria for identifying vital signs of potential clinical relevance included: Heart rate: ≥ 15 beats per minute (bpm) increase/decrease from Baseline (final visit of study 31-12-293); Systolic BP: ≥ 20 mmHg increase/decrease from Baseline; Diastolic BP: ≥ 15mmHg increase/decrease from Baseline; Orthostatic hypotension: ≥ 20 mmHg decrease in systolic BP and a ≥ 25 bpm increase in heart rate from supine to sitting/standing. Percentage of participants noted with abnormal vital sign measurements are reported below.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Percentage of participants
    number (not applicable)
        Heart rate-Supine (increase)
    0.9
        Heart rate-Supine (decrease)
    0.9
        Heart rate-Standing (increase)
    9.3
        Systolic Supine BP (decrease)
    6.5
        Systolic Standing BP (decrease)
    3.7
        Diastolic Supine BP (decrease)
    0.9
        Diastolic Standing BP (decrease)
    5.6
        Orthostatic hypotension
    2.7
    No statistical analyses for this end point

    Primary: Percentage of participants with clinically significant abnormal electrocardiogram (ECG).

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    End point title
    Percentage of participants with clinically significant abnormal electrocardiogram (ECG). [4]
    End point description
    Three 12-lead ECGs (scheduled 5 minutes apart) were recorded. Some of the pre-defined criteria for identifying ECG measurements of potential clinical relevance included: Tachycardia/sinus tachycardia: increase of ≥15 bpm from Baseline; increase in QTc of ≥10% from Baseline. The other abnormalities not present at Baseline and were present during the time of measurement were recorded. Percentage of participants noted with abnormal ECG findings are reported below.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    106
    Units: Percentage of participants
    number (not applicable)
        Tachycardia
    0.9
        Sinus Tachycardia
    0.9
        Supraventricular premature beat
    1.9
        Ventricular premature beat
    0.9
        Right bundle branch block
    1.9
        QTcB
    0.9
        QTcN
    0.9
    No statistical analyses for this end point

    Primary: Mean change from Baseline in body weight.

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    End point title
    Mean change from Baseline in body weight. [5]
    End point description
    Criteria for identifying weight of potential clinical relevance was: ≥ 7% kilogram increase/decrease from Baseline (Final visit of Trial 31-12-293 [NCT01727700]).
    End point type
    Primary
    End point timeframe
    Baseline to Weeks 12, 28, 36, 44, 52/Last visit.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    108
    Units: Kilogram
    arithmetic mean (standard deviation)
        Week 12 (N=102)
    1.8 ± 2.3
        Week 28 (N=90)
    4.8 ± 3.8
        Week 36 (N=88)
    5.8 ± 4.4
        Week 44 (N=81)
    6.8 ± 5.3
        Week 52 (N=77)
    8 ± 5.4
        Last visit (N=106)
    7.2 ± 5.8
    No statistical analyses for this end point

    Primary: Mean change from Baseline in Body Mass Index (BMI).

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    End point title
    Mean change from Baseline in Body Mass Index (BMI). [6]
    End point description
    BMI was calculated at the Baseline visit (using the Baseline height from study 31-12-293 [NCT01727700]) and at Weeks 28 and 52/ET where height measured at baseline in the current trial was used to calculate BMI.
    End point type
    Primary
    End point timeframe
    Baseline to Weeks 28, 52 and Last visit.
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    108
    Units: Kg/M^2
    arithmetic mean (standard deviation)
        Week 28 (N=90)
    3.3 ± 16.2
        Week 52 (N=77)
    1.9 ± 2.3
        Last visit (N=106)
    1.8 ± 2.3
    No statistical analyses for this end point

    Primary: Mean change from Baseline in Waist circumference.

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    End point title
    Mean change from Baseline in Waist circumference. [7]
    End point description
    Waist circumference was measured at Baseline, Weeks 12, 28, 36, 44, and the Week 52/last visit in centimeters.
    End point type
    Primary
    End point timeframe
    Baseline to Weeks 12, 28, 36, 44, and 52/last visit.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    108
    Units: Centimeter
    arithmetic mean (standard deviation)
        Week 12 (N=102)
    2.2 ± 8.3
        Week 28 (N=90)
    3.7 ± 9.7
        Week 36 (N=87)
    3.5 ± 6.5
        Week 44 (N=80)
    4.5 ± 6.7
        Week 52 (N=75)
    5.5 ± 6.5
        Last visit (N=106)
    4.6 ± 6.4
    No statistical analyses for this end point

    Primary: Change from Baseline in Abnormal Involuntary Movement Scale (AIMS) total score.

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    End point title
    Change from Baseline in Abnormal Involuntary Movement Scale (AIMS) total score. [8]
    End point description
    The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Facial and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements (item 7) were observed unobtrusively while the participant was at rest, and the investigator also made global judgments on the participant's dyskinesias (items 8 through 10). Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness/severe distress). In addition, the AIMS included 2 yes/no questions that addressed the subject’s dental status (since an edentulous state can cause lingual dyskinesias). The AIMS movement rating score (range 0 to 28) was the sum of the rating scores for facial and oral moments (ie, items 1 to 4), extremity movements (ie, items 5 and 6), and trunk movements (ie, item 7).
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=107)
    -1 ± 3
        Week 8 (N=105)
    -1.3 ± 3.4
        Week 12 (N=104)
    -1.7 ± 3.7
        Week 20 (N=100)
    -1.8 ± 3.9
        Week 28 (N=92)
    -2 ± 4.3
        Week 36 (N=88)
    -2.2 ± 4.5
        Week 44 (N=82)
    -2.3 ± 4.6
        Week 52 (N=77)
    -2.3 ± 4.7
        Last vist (N=109)
    -1.8 ± 4.3
    No statistical analyses for this end point

    Primary: Change from Baseline in Simpson-Angus Scale (SAS) total score.

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    End point title
    Change from Baseline in Simpson-Angus Scale (SAS) total score. [9]
    End point description
    The SAS consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Each item was rated on a 5-point scale, with a score of 1 representing absence of symptoms, and a score of 5 representing a severe condition. The SAS total score (range 10 to 50) was the sum of the rating scores for 10 items from the SAS panel.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=107)
    0 ± 0.9
        Week 8 (N=104)
    0 ± 0.9
        Week 12 (N=104)
    0 ± 0.9
        Week 20 (N=100)
    -0.1 ± 0.7
        Week 28 (N=92)
    -0.2 ± 0.8
        Week 36 (N=88)
    -0.2 ± 0.8
        Week 44 (N=82)
    -0.2 ± 0.8
        Week 52 (N=77)
    -0.1 ± 0.8
        Last vist (N=109)
    -0.1 ± 0.7
    No statistical analyses for this end point

    Primary: Change from Baseline in Barnes Akathisia Rating Scale (BARS) total score.

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    End point title
    Change from Baseline in Barnes Akathisia Rating Scale (BARS) total score. [10]
    End point description
    The BARS consists of 4 items related to akathisia: objective observation of akathisia by the investigator, subjective feelings of restlessness by the participant, participant distress due to akathisia, and global evaluation of akathisia. The first 3 items were rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation was made on a 6-point scale, with 0 representing absence of symptoms and a score of 5 representing severe akathisia. To complete this scale, participants were observed while they were seated and then standing for a minimum of 2 minutes in each position. The BARS global score (range 0 to 5) was derived from the global clinical assessment of akathisia from the BARS panel.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=107)
    0 ± 0.4
        Week 8 (N=105)
    0 ± 0.4
        Week 12 (N=104)
    0 ± 0.3
        Week 20 (N=100)
    -0.1 ± 0.3
        Week 28 (N=92)
    -0.1 ± 0.3
        Week 36 (N=88)
    -0.1 ± 0.3
        Week 44 (N=82)
    -0.1 ± 0.3
        Week 52 (N=77)
    -0.1 ± 0.3
        Last vist (N=109)
    0 ± 0.3
    No statistical analyses for this end point

    Primary: Change from Baseline in Suicidal Ideation Intensity Total Score based on Columbia-Suicide Severity Rating Scale (C-SSRS).

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    End point title
    Change from Baseline in Suicidal Ideation Intensity Total Score based on Columbia-Suicide Severity Rating Scale (C-SSRS). [11]
    End point description
    The C-SSRS consists of a baseline evaluation that assesses the lifetime experience of the participant with suicide events and suicidal ideation and a post baseline/“since last visit” evaluation that focuses on suicidality since the last trial visit. The C-SSRS data at Baseline and post baseline were summarized for incidence of reporting: Suicidality, Suicidal behavior (and its 4 types), Suicidal ideation (and its 5 types). The intensity score of each item ranges from 1 (least severe) to 5 (most severe), which leads to the range of the total score from 0 to 25.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 1, 2, 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N=108)
    -0.1 ± 0.7
        Week 2 (N=106)
    0 ± 0.5
        Week 4 (N=107)
    0 ± 0.8
        Week 8 (N=105)
    -0.1 ± 0.8
        Week 12 (N=104)
    0 ± 0.5
        Week 20 (N=100)
    -0.1 ± 0.5
        Week 28 (N=92)
    0.1 ± 1
        Week 36 (N=88)
    0.1 ± 1.3
        Week 44 (N=82)
    0 ± 0
        Week 52 (N=77)
    0.2 ± 1.3
        Last vist (N=110)
    0 ± 1.3
    No statistical analyses for this end point

    Primary: Change from Baseline in average score of attention deficit disorder/attention-deficit hyperactivity disorder (ADD/ADHD) of Swanson, Nolan, and Pelham-IV Rating Scale (SNAP-IV).

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    End point title
    Change from Baseline in average score of attention deficit disorder/attention-deficit hyperactivity disorder (ADD/ADHD) of Swanson, Nolan, and Pelham-IV Rating Scale (SNAP-IV). [12]
    End point description
    The SNAP-IV Rating Scale is a revision of the SNAP Questionnaire. The SNAP-IV assesses inattention and hyperactivity/impulsivity, as well as oppositional defiant disorder that are often present in children with ADD/ADHD. The SNAP-IV was administered as a semi-structured interview with the participant and caregiver. The SNAP-IV is based on a 0 to 3 rating scale: not at all = 0, just a little = 1, quite a bit = 2, and very much = 3. The ADD/ADHD subscale includes items 1 through 19 (items 1–9 measure inattention, items 11–19 measure hyperactivity/ impulsivity, and item 10 for inattention domain), items 4, 8, 11, 31, and 32 measure inattention/overactivity, and items 21, 23, 29, 34, and 35 measure aggression/defiance. Items 4, 8, 11, 21, 32, 33, 36, 37, 38, and 39 form the Conners Index.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=107)
    -0.2 ± 0.4
        Week 8 (N=105)
    -0.2 ± 0.4
        Week 12 (N=104)
    -0.3 ± 0.4
        Week 20 (N=100)
    -0.2 ± 0.4
        Week 28 (N=92)
    -0.2 ± 0.4
        Week 36 (N=88)
    -0.2 ± 0.4
        Week 44 (N=82)
    -0.2 ± 0.4
        Week 52 (N=77)
    -0.2 ± 0.4
        Last vist (N=109)
    -0.2 ± 0.5
    No statistical analyses for this end point

    Primary: Change from Baseline in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS).

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    End point title
    Change from Baseline in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). [13]
    End point description
    The CY-BOCS is a semi-structured interview used with children and adolescents aged 6 to 17 years to rate the severity and type of symptoms in participants with obsessive compulsive disorder. In general, the items depend on the participant's report; however, the final rating is based on the clinical judgment of the interviewer and should include additional information supplied by others. Nineteen items are rated in the CY-BOCS, but only items 1 through 10 (excluding items 1b and 6b) are used to determine the total score. The total CY-BOCS score is the sum of items 1 through 10 (excluding lb and 6b), whereas the obsession and compulsion subtotals are the sums of items 1 through 5 (excluding lb) and 6 through 10 (excluding 6b), respectively.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=107)
    -0.2 ± 2.6
        Week 8 (N=105)
    -0.1 ± 3
        Week 12 (N=104)
    -0.5 ± 2.7
        Week 20 (N=100)
    -0.6 ± 3
        Week 28 (N=92)
    -0.5 ± 3.3
        Week 36 (N=88)
    -0.7 ± 3.4
        Week 44 (N=82)
    -0.8 ± 3.7
        Week 52 (N=77)
    -0.9 ± 3.9
        Last vist (N=109)
    -0.7 ± 3.4
    No statistical analyses for this end point

    Primary: Change from Baseline in Children’s Depression Rating Scale - Revised (CDRS-R).

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    End point title
    Change from Baseline in Children’s Depression Rating Scale - Revised (CDRS-R). [14]
    End point description
    Modeled after the Hamilton Rating Scale for Depression, the CDRS-R has long been used to diagnose depression and determine its severity. The CDRS-R is a brief rating scale based on a semi-structured interview with the child and an adult informant who knows the child well. Designed for 6- to 12-year-old children, and successfully used with adolescents, it can be administered in 15 to 20 minutes. The interviewer rates 17 symptom areas (including those that serve as Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria for a diagnosis of depression): impaired schoolwork, difficulty having fun, social withdrawal, appetite disturbance, sleep disturbance, excessive fatigue, physical complaints, irritability, excessive guilt, low self-esteem, depressed feelings, morbid ideas, suicidal ideas, excessive weeping, depressed facial affect, listless speech, and hypoactivity.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    109
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=104)
    -0.4 ± 4.4
        Week 8 (N=100)
    -0.4 ± 3.8
        Week 12 (N=100)
    -0.3 ± 3.2
        Week 20 (N=97)
    -0.1 ± 4.2
        Week 28 (N=91)
    0.2 ± 5
        Week 36 (N=87)
    0.4 ± 4.4
        Week 44 (N=82)
    -0.3 ± 3.3
        Week 52 (N=77)
    0.6 ± 3.8
        Last vist (N=107)
    0.7 ± 4.5
    No statistical analyses for this end point

    Primary: Change from Baseline in Pediatric Anxiety Rating Scale (PARS).

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    End point title
    Change from Baseline in Pediatric Anxiety Rating Scale (PARS). [15]
    End point description
    The PARS is used to rate the severity of anxiety in children and adolescents, aged 6 to 17 years. The PARS has 2 sections: the symptom checklist and the severity items. The symptom checklist is used to determine the child’s repertoire of symptoms during the past week. The 7-item severity list is used to determine severity of symptoms and the PARS total score. The time frame for the PARS is the past week. Only those symptoms endorsed for the past week are included in the symptom checklist and rated on the severity items. The PARS total severity score was the sum of items 2, 3, 5, 6, and 7. Codes “8” (Not applicable) and “9” (Does not know) are equivalent to 0 in the summation. The total severity score ranged from 0 to 25.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 20, 28, 36, 44, 52, and Last visit
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not performed
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=107)
    -0.3 ± 3
        Week 8 (N=105)
    -0.3 ± 3.6
        Week 12 (N=104)
    -0.5 ± 2.6
        Week 20 (N=100)
    -0.4 ± 2.9
        Week 28 (N=91)
    -0.2 ± 3.1
        Week 36 (N=88)
    -0.7 ± 3
        Week 44 (N=82)
    -0.5 ± 2.7
        Week 52 (N=77)
    -0.4 ± 3.5
        Last vist (N=109)
    -0.4 ± 3.5
    No statistical analyses for this end point

    Secondary: Change from Baseline to endpoint on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS).

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    End point title
    Change from Baseline to endpoint on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS).
    End point description
    The YGTSS is a semi-structured clinical interview designed to measure current tic severity. This scale consists of a tic inventory, with 5 separate ratings to assess the number, intensity, frequency, complexity and interference of tics, plus an overall impairment/disability score. The YGTSS is a validated measurement that has been widely used in clinical trials, has been demonstrated to be sensitive to treatment effects, and represents the “reference standard” in paediatric tic assessment. 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 secondary outcome measure in this trial. The YGTSS ranking of impairment, with a maximum of 50 points, is based on the impact of the tic disorder on areas of self-esteem, family life, social acceptance, and school scores.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 52 (N=77)
    -8.6 ± 10.2
        Last visit (N=109)
    -6.6 ± 10.9
    No statistical analyses for this end point

    Secondary: Mean Clinical Global Impressions for Tourette’s Syndrome (CGI-TS) change score at endpoint.

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    End point title
    Mean Clinical Global Impressions for Tourette’s Syndrome (CGI-TS) change score at endpoint.
    End point description
    The CGI is a 7-point Likert scale used in a multitude of clinical trials as a clinical global measure to assess the severity and change in disease symptomatology (ie, tics). The CGI was included as a secondary scale to provide a more complete assessment of clinical efficacy. The CGI-TS change score obtained from CGI-TS improvement scale assessment. The CGI-TS improvement scale was rated in reference to the participant's baseline condition at the time of entry into the open-label study rather than the CGI-TS baseline condition at the time the participant enrolled into the parent trial. Response choices were 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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 52 (N=77)
    2.5 ± 1.6
        Last visit (N=109)
    2.5 ± 1.6
    No statistical analyses for this end point

    Secondary: Change from Baseline to endpoint in CGI-TS severity of illness score.

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    End point title
    Change from Baseline to endpoint in CGI-TS severity of illness score.
    End point description
    The CGI is a 7-point Likert scale used in a multitude of clinical trials as a clinical global measure to assess the severity and change in disease symptomatology (ie, tics). The CGI was included as a secondary scale to provide a more complete assessment of clinical efficacy.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 52 (N=77)
    -0.9 ± 1.2
        Last visit (N=109)
    -0.7 ± 1.3
    No statistical analyses for this end point

    Secondary: Mean change from Baseline to endpoint in Total YGTSS score.

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    End point title
    Mean change from Baseline to endpoint 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) for motor and vocal tics, and an impairment ranking. The YGTSS TTS is the summation of the severity scores of motor and vocal tics (range of 0 to 50). The total YGTSS score is the summation of the severity scores of motor and vocal tics and the ranking of impairment (total score range of 0 to 100).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 52 (N=77)
    -18 ± 23.7
        Last visit (N=109)
    -14 ± 24.3
    No statistical analyses for this end point

    Secondary: Percentage of participants with response (response rate).

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    End point title
    Percentage of participants with response (response rate).
    End point description
    Clinical response was defined as > 25% improvement from Baseline to endpoint in YGTSS TTS or a CGI-TS change score of 1 (very much improved) or 2 (much improved) at endpoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 20, 28, 36, 44 and 52
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Percentage of participants with response
    number (not applicable)
        Week 4 (N=107)
    80.4
        Week 8 (N=105)
    81.9
        Week 12 (N=104)
    82.7
        Week 20 (N=100)
    75
        Week 28 (N=92)
    77.2
        Week 36 (N=88)
    75
        Week 44 (N=81)
    75.3
        Week 52 (N=77)
    67.5
    No statistical analyses for this end point

    Secondary: Percentage of participants with treatment discontinuation (treatment discontinuation rate).

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    End point title
    Percentage of participants with treatment discontinuation (treatment discontinuation rate).
    End point description
    The treatment discontinuation rate was calculated as the number of discontinued participants (ie, those withdrawn from the study without completing the Week 52 visit) divided by the number of all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Open-label Aripiprazole
    Number of subjects analysed
    110
    Units: Percentage of discontinued participants
        number (not applicable)
    31.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 0 (Baseline) until Follow-up 30 Days (±3 days) after the last trial visit.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Open-label Aripiprazole
    Reporting group description
    All participants in this open-label extension trial were assigned to once-daily aripiprazole, which was flexibly dosed at the discretion of the investigator on the basis of treatment response and medication tolerability.

    Serious adverse events
    Open-label Aripiprazole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 110 (3.64%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Tourette's disorder
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Open-label Aripiprazole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    84 / 110 (76.36%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Immune system disorders
    House dust allergy
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Multiple allergies
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Seasonal allergy
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    12
    Influenza like illness
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Irritability
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    3
    Malaise
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    7 / 110 (6.36%)
         occurrences all number
    8
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    4
    Agitation
         subjects affected / exposed
    4 / 110 (3.64%)
         occurrences all number
    6
    Anger
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Anxiety
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    6
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    5 / 110 (4.55%)
         occurrences all number
    6
    Blunted affect
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Bruxism
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    3
    Depressed mood
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Emotional disorder
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Emotional poverty
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Flat affect
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Head banging
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Initial insomnia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    3
    Mood altered
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Obsessive-compulsive disorder
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Restlessness
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Somnambulism
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Suicidal ideation
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    3
    TIC
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    9
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Excoriation
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Hand fracture
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Patella fracture
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Investigations
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Protein urine present
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    26 / 110 (23.64%)
         occurrences all number
    27
    White blood cell count decreased
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    4
    Hiccups
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    3
    Rhinitis allergic
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    4
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Vocal cord disorder
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    3
    Cognitive disorder
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    5 / 110 (4.55%)
         occurrences all number
    6
    Dyskinesia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Dystonia
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    12
    Migraine
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Migraine with aura
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Paresthesia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Sedation
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    6
    Somnolence
         subjects affected / exposed
    13 / 110 (11.82%)
         occurrences all number
    14
    Syncope
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Eye disorders
    Excessive eye blinking
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Eye inflammation
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Strabismus
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Middle ear effusion
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Aphthous stomatitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    3
    Dry mouth
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Eructation
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    2
    Flatulence
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    8 / 110 (7.27%)
         occurrences all number
    9
    Retching
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Salivary hypersecretion
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    10 / 110 (9.09%)
         occurrences all number
    12
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Urinary hesitation
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Urinary retention
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Hyperinsulinaemia
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Increased appetite
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    6
    Insulin resistance
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Infections and infestations
    Ear infection
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    5 / 110 (4.55%)
         occurrences all number
    5
    Gastroenteritis viral
         subjects affected / exposed
    4 / 110 (3.64%)
         occurrences all number
    5
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    4
    Localised infection
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    12
    Otitis media
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Pneumonia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    5 / 110 (4.55%)
         occurrences all number
    5
    Tonsillitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 110 (3.64%)
         occurrences all number
    4
    Viral infection
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences all number
    2
    Viral rash
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Oct 2012
    A summary of the single amendment to the protocol is provided below: Added dose groups to match Trial 31-12-293; Removed Gilles de la Tourette Syndrome Quality of Life Scale assessments; Specified the entire SNAP-IV Rating Scale was to be used, rather than only the ADHD subscales; Changed the titration schedule; Clarified guidelines on the concomitant use of benzodiazepines; Added an inclusion criterion that only subjects who completed Trial 31-12-293 could be enrolled.

    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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