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    Clinical Trial Results:
    A Long-term, Multicenter, Open-Label Study to Evaluate the Safety and Tolerability of Flexible-Dose Oral Aripiprazole (OPC-14597) as Maintenance Treatment in Adolescent Patients with Schizophrenia or Child and Adolescent Patients with Bipolar I Disorder, Manic or Mixed Episode with or without Psychotic Features

    Summary
    EudraCT number
    2010-018911-13
    Trial protocol
    PL   BG   HU  
    Global end of trial date
    07 Sep 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    09 Apr 2016
    First version publication date
    12 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • New data added to full data set
    New data added to full data set.

    Trial information

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    Trial identification
    Sponsor protocol code
    31-09-267
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01122927
    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
    Dorota Plewicka , Covance CAPS Ltd, 47 578213 25, dorota.plewicka@covance.com
    Scientific contact
    Dorota Plewicka , Covance CAPS Ltd, 47 578213 25, dorota.plewicka@covance.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000235-PIP02-10
    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
    27 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this trial was to further characterize the long-term safety and tolerability of aripiprazole in adolescent subjects with schizophrenia and child and adolescent subjects with bipolar I disorder, manic or mixed episode, with or without psychotic features.
    Protection of trial subjects
    The trial was conducted in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH-GCP), and applicable local laws and regulatory requirements. Written informed consent was obtained from each participant's legally acceptable representative as applicable for local laws, and informed assent was obtained from all participants, as applicable for local laws. Informed consent/assent, as applicable for local laws, was obtained and documented prior to initiation of any procedures that were performed solely for the purpose of determining eligibility for this trial, including withdrawal from current medications. All participants received copies of their signed and dated Informed consent forms (ICFs).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Aug 2010
    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
    Taiwan: 1
    Country: Number of subjects enrolled
    Ukraine: 98
    Country: Number of subjects enrolled
    United States: 105
    Country: Number of subjects enrolled
    Bulgaria: 70
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    India: 93
    Country: Number of subjects enrolled
    Philippines: 12
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Russian Federation: 73
    Country: Number of subjects enrolled
    Serbia: 12
    Worldwide total number of subjects
    524
    EEA total number of subjects
    130
    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)
    18
    Adolescents (12-17 years)
    493
    Adults (18-64 years)
    13
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This trial was conducted in 524 participants at 118 trial sites in 13 countries.

    Pre-assignment
    Screening details
    524 participants entered this trial (297 participants in the conversion phase and 510 participants in the open-label treatment phase). In the latter, 362 were de novo participants (280 participants entered into the conversion phase) and 148 rolled over from Trial 2010-020987-39. 416 participants had schizophrenia and 94 had bipolar disorder.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable for this open-label trial.

    Arms
    Arm title
    All Participants
    Arm description
    Data for all the participants were analyzed.
    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
    Participants were administered oral aripiprazole titrated from 10 to 30 milligram per day (mg/day), with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Number of subjects in period 1
    All Participants
    Started
    524
    Completed
    198
    Not completed
    326
         Protocol deviation
    1
         Physician decision
    14
         Lack of efficacy
    7
         Consent withdrawn by subject
    72
         Met Withdrawal Criteria
    10
         Adverse Event
    36
         Lost to follow-up
    21
         Sponsor Discontinued Trial
    165

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Participants
    Reporting group description
    Data for all the participants were analyzed.

    Reporting group values
    All Participants Total
    Number of subjects
    524 524
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    18 18
        Adolescents (12-17 years)
    493 493
        Adults (18-64 years)
    13 13
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    15.2 ± 1.6 -
    Gender categorical
    Units: Subjects
        Female
    208 208
        Male
    316 316

    End points

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    End points reporting groups
    Reporting group title
    All Participants
    Reporting group description
    Data for all the participants were analyzed.

    Subject analysis set title
    Open-label Treatment Phase
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were administered oral aripiprazole titrated from 10 to 30 milligram per day (mg/day), with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Subject analysis set title
    Tanner score at Baseline of 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants who entered this phase had received oral aripiprazole titrated from 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Subject analysis set title
    Tanner score at Baseline of 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants who entered this phase had received oral aripiprazole titrated from 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Subject analysis set title
    Tanner score at Baseline of 3
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants who entered this phase had received oral aripiprazole titrated from 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Subject analysis set title
    Tanner score of Baseline of 4
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Subject analysis set title
    Tanner score of Baseline of 5
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants who entered this phase had received oral aripiprazole titrated from 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Primary: Number of participants with adverse events (AEs)

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    End point title
    Number of participants with adverse events (AEs) [1]
    End point description
    An AE was defined as any untoward medical occurrence in a participant or participant enrolled in a clinical trial and which did not necessarily have a causal relationship with the study medication. A treatment emergent adverse event (TEAE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study medication, whether or not considered to have a causal relationship with the study medication. A serious-AE or reaction was any untoward occurrence that, at any dose, was fatal, life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was any other medically significant event that, based on appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above.
    End point type
    Primary
    End point timeframe
    Adverse events were recorded from the time of the informed consent was signed until the follow-up visit 30 (± 3) days after the end of trial.
    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: No statistical analysis provided for Number of participants with adverse events (AEs).
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Participants
        Participants with TEAEs
    349
        Participants with serious TEAEs
    49
        Participants with severe TEAEs
    33
        Discontinued due to AEs
    32
    No statistical analyses for this end point

    Secondary: Incidence of laboratory values of potential clinical relevance

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    End point title
    Incidence of laboratory values of potential clinical relevance
    End point description
    The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria. Abnormal laboratory values in participants were reported as SAE/AEs and are reported in the SAE/non-serious AE section of this report.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Participants
        Chemistry-Alanine transaminase
    11
        Chemistry-Aspartate transaminase
    8
        Chemistry-Bilirubin, total
    20
        Chemistry-Calcium
    30
        Chemistry-Chloride
    158
        Chemistry-Cholesterol, total, fasting
    68
        Chemistry-Creatine phosphokinase, total
    40
        Chemistry-Glutamyl transferase
    78
        Chemistry-HDL cholesterol, fasting
    128
        Chemistry-LDL cholesterol, calculation
    2
        Chemistry-Phosphorus inorganic
    135
        Chemistry-Protein, total serum
    81
        Chemistry-Triglycerides, fasting
    46
        Hematology-Eosinophils
    19
        Hematology-Hemoglobin
    14
        Hematology-White blood cell count
    9
        Urinalysis-Protein, urine
    348
        Urinalysis-Specific gravity
    188
        Others-Insulin
    49
        Others-Insulin, fasting
    78
        Others-Prolactin
    324
    No statistical analyses for this end point

    Secondary: Incidence of physical examination findings of potential clinical relevance

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    End point title
    Incidence of physical examination findings of potential clinical relevance
    End point description
    The physical examination evaluation was one of the parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in the following body systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Participants
    0
    No statistical analyses for this end point

    Secondary: Incidence of vital signs of potential clinical relevance

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    End point title
    Incidence of vital signs of potential clinical relevance
    End point description
    Vital signs are taken at Baseline, Weeks 1, 2, 3, 4, 6, 8, and Months 3, 4, 6, 9, 12, 15, 18, 21, 24 of Phase 2 (Visits beyond Month 12 only for de novo subjects). Assessments included orthostatic (supine and standing) blood pressure (BP) measured as millimeter of mercury [mmhg]), heart rate and body temperature. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate (measured as beats per minutes [bpm]), systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria. Abnormal vital signs in participants were reported as SAE/AEs and are reported in the SAE/non-serious AE section of this report.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Participants
        Heart rate supine-Increase ≥15 bpm
    1
        Heart rate supine-Decrease ≥15 bpm
    1
        Heart rate standing-Increase ≥15 bpm
    4
        Heart rate standing-Decrease ≥15 bpm
    0
        Systolic supine BP-Increase ≥20 mmHg
    36
        Systolic supine BP-Decrease ≥20 mmHg
    31
        Systolic standing BP-Increase ≥20mmHg
    38
        Systolic standing BP-Decrease ≥20mmHg
    40
        Diastolic supine BP-Increase ≥15 mmHg
    41
        Diastolic supine BP-Decrease ≥15mmHg
    19
        Diastolic standing BP-Increase ≥15mmHg
    53
        Diastolic standing BP-Decrease ≥15mmHg
    13
        Weight gain ≥7%
    195
        Weight loss ≥7%
    45
    No statistical analyses for this end point

    Secondary: Mean change from Baseline by Week in Abnormal Involuntary Movement Scale (AIMS)

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    End point title
    Mean change from Baseline by Week in Abnormal Involuntary Movement Scale (AIMS)
    End point description
    The AIMS Scale was an extrapyramidal symptoms (EPS) rating scale. The AIMS is a 12 item scale. The first 10 items e.g. facial and oral movements (items 1-4), extremity movements (items 5 and 6), trunk movements (item 7), investigators global assessment of dyskinesia (items 8 to 10). The first 10 items are rated from 0 to 4 (0=best, 4=worst). Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N=486)
    -0.02 ± 0.24
        Week 2 (N=507)
    -0.01 ± 0.25
        Week 3 (N=507)
    0.01 ± 0.36
        Week 4 (N=507)
    -0.01 ± 0.27
        Week 6 (N=507)
    0.02 ± 0.56
        Week 8 (N=507)
    -0.02 ± 0.28
        Month 3 (N=507)
    0 ± 0.31
        Month 6 (N=507)
    -0.02 ± 0.4
        Month 9 (N=506)
    0.01 ± 0.55
        Month 12 (N=507)
    -0.02 ± 0.41
        Month 15 (N=360)
    -0.01 ± 0.43
        Month 18 (N=360)
    -0.04 ± 0.35
        Month 21 (N=360)
    -0.01 ± 0.52
        Month 24 (N=360)
    -0.04 ± 0.34
    No statistical analyses for this end point

    Secondary: Mean change from Baseline by Week in Simpson-Angus Scale (SAS) total score

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    End point title
    Mean change from Baseline by Week in Simpson-Angus Scale (SAS) total score
    End point description
    The SAS is a rating scale used to measure EPS. The SAS scale 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), with each item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is sum of ratings for all 10 items, with possible Total scores from 0 to 40.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N=486)
    -0.08 ± 0.89
        Week 2 (N=507)
    -0.11 ± 1.22
        Week 3 (N=507)
    -0.08 ± 1.23
        Week 4 (N=507)
    -0.18 ± 1.37
        Week 6 (N=507)
    -0.12 ± 1.49
        Week 8 (N=507)
    -0.21 ± 1.34
        Month 3 (N=507)
    -0.23 ± 1.56
        Month 6 (N=507)
    -0.31 ± 1.48
        Month 9 (N=506)
    -0.35 ± 1.5
        Month 12 (N=507)
    -0.36 ± 1.51
        Month 15 (N=360)
    -0.43 ± 1.78
        Month 18 (N=360)
    -0.48 ± 1.74
        Month 21 (N=360)
    -0.49 ± 1.82
        Month 24 (N=360)
    -0.53 ± 1.81
    No statistical analyses for this end point

    Secondary: Mean change from Baseline by Week in Barnes Akathisia Rating Scale (BARS) score

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    End point title
    Mean change from Baseline by Week in Barnes Akathisia Rating Scale (BARS) score
    End point description
    The BARS was an EPS rating scale. The BARS was used to assess the presence and severity of akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical Assessment of Akathisia, was evaluated in this trial. This item is rated on a 6 point scale, with 0 being best (absent) and 5 being worst (severe akathisia).
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N=487)
    -0.02 ± 0.26
        Week 2 (N=507)
    -0.02 ± 0.35
        Week 3 (N=507)
    -0.02 ± 0.35
        Week 4 (N=507)
    -0.03 ± 0.33
        Week 6 (N=507)
    -0.03 ± 0.36
        Week 8 (N=507)
    -0.02 ± 0.41
        Month 3 (N=507)
    0 ± 0.45
        Month 6 (N=507)
    -0.03 ± 0.44
        Month 9 (N=506)
    -0.04 ± 0.43
        Month 12 (N=507)
    -0.04 ± 0.42
        Month 15 (N=360)
    -0.02 ± 0.47
        Month 18 (N=360)
    -0.05 ± 0.48
        Month 21 (N=360)
    -0.04 ± 0.5
        Month 24 (N=360)
    -0.05 ± 0.47
    No statistical analyses for this end point

    Secondary: Number of participants with cognitive impairment for each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)

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    End point title
    Number of participants with cognitive impairment for each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)
    End point description
    The NY-AACENT is not a validated scale. It was included in this trial because of concerns that regulatory authorities (the European Committee for Medicinal Products for Human Use [CHMP] and the Paediatric Sub-Committee of the European Medicinal Agency [PDCO]) had regarding drug induced cognitive impairment. No validated scale addressing these issues was available at the time of the trial. The NY-AACENT was used to detect changes in cognitive function subsequent to pharmacological or similar treatments for neurological or psychiatric problems. It was specifically designed to be used in paediatric populations (ages 12 to 17), but could have been utilized with other age groups, as appropriate.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Participants
        Working memory
    237
        Attention/vigilance
    306
        Verbal learning/memory
    233
        Visual learning/memory
    138
        Reasoning and problem solving
    308
        Speed of processing
    276
        Social congnition
    307
    No statistical analyses for this end point

    Secondary: Baseline and Post-Baseline Tanner Staging

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    End point title
    Baseline and Post-Baseline Tanner Staging
    End point description
    Tanner staging was completed together with the physical examination by the same trial-affiliated clinician in the most inconspicuous manner for the participant as possible. Tanner staging assessment consisted of 2 domains (pubic hair and breast development) for girls and 3 domains (pubic hair, penis development, and testes development) for boys. A participant who reached Stage 5 (both in pubic hair and genitalia) did not need to continue with Tanner Staging assessment and the Tanner Staging scales of this participant were imputed as 5 for all of the following scheduled time points up to and including the completion visit/early termination (ET) visit. The clinician arrived at a single score summarizing the domains (not individual domain scores) when evaluating the participant. The total shift data for last visit is presented below.
    End point type
    Secondary
    End point timeframe
    Baseline to Last Visit
    End point values
    Tanner score at Baseline of 1 Tanner score at Baseline of 2 Tanner score at Baseline of 3 Tanner score of Baseline of 4 Tanner score of Baseline of 5
    Number of subjects analysed
    7
    24
    79
    196
    204
    Units: Participants
        Last Vist (Post-Baseline score of 1) (N= 1)
    1
    0
    0
    0
    0
        Last Vist (Post-Baseline score of 2) (N= 9)
    4
    5
    0
    0
    0
        Last Vist (Post-Baseline score of 3) (N= 39)
    2
    9
    28
    0
    0
        Last Vist (Post-Baseline score of 4) (N= 134)
    0
    7
    33
    94
    0
        Last Vist (Post-Baseline score of 5) (N= 327)
    0
    3
    18
    102
    204
    No statistical analyses for this end point

    Secondary: Mean change from Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score

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    End point title
    Mean change from Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score
    End point description
    Suicidality was defined as reporting at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any type of suicidal behaviors (actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior). Suicidal ideation was defined as reporting any type of suicidal ideation. The suicidal ideation intensity total score is the sum of intensity scores of 5 items (frequency, duration, controllability, deterrents, and reasons for ideation). The score of each intensity item ranges from 0 (none) to 5 (worst) which leads to the range of the total score from 0 to 25. A missing score of any item resulted in a missing total score. If no suicidal ideation was reported, a score of 0 was given to the intensity scale.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 487)
    -0.4 ± 2.1
        Week 2 (N= 483)
    -0.4 ± 2.2
        Week 3 (N= 477)
    -0.4 ± 2.2
        Week 4 (N= 491)
    -0.4 ± 2.2
        Week 6 (N= 488)
    -0.3 ± 2.1
        Week 8 (N= 484)
    -0.4 ± 2
        Month 3 (N= 478)
    -0.3 ± 2.2
        Month 4 (N= 472)
    -0.3 ± 2.1
        Month 6 (N= 458)
    -0.2 ± 2.5
        Month 9 (N= 407)
    -0.2 ± 1.8
        Month 12 (N= 302)
    -0.3 ± 2
        Month 15 (N= 261)
    -0.2 ± 1.9
        Month 18 (N= 247)
    -0.1 ± 2
        Month 21 (N= 212)
    -0.1 ± 1.8
        Month 24 (N= 180)
    0 ± 1.9
        Last Visit (N= 507)
    -0.1 ± 2.5
    No statistical analyses for this end point

    Secondary: Percentage of participants who discontinued due to all adverse events

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    End point title
    Percentage of participants who discontinued due to all adverse events
    End point description
    The time to discontinuations due to all causes other than sponsor terminating the trial was measured from the date of entering the open-label treatment phase to the date of ET for discontinued participants in the open-label treatment phase (ie, time to discontinuation = date of discontinuation [or date of completion for completed participants] − date of participant entering the open-label treatment phase + 1). If the participants completed the trial or were discontinued due to the sponsor terminating the trial, they were censored at the time of completion or trial termination, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Discontinuation rate
    number (not applicable)
        From study P3109266 (N= 148)
    3.4
        De Novo (N= 362)
    7.7
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Positive and Negative Symptoms Score (PANSS) total score

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    End point title
    Mean change from Baseline in Positive and Negative Symptoms Score (PANSS) total score
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 414)
    -9.98 ± 14.66
        Month 24 (N= 267)
    -12.52 ± 15.7
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS positive subscale score

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    End point title
    Mean change from Baseline in PANSS positive subscale score
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 414)
    -2.57 ± 4.96
        Month 24 (N= 267)
    -2.91 ± 5.13
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS negative subscale score

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    End point title
    Mean change from Baseline in PANSS negative subscale score
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 414)
    -2.79 ± 4.17
        Month 24 (N= 267)
    -3.48 ± 4.63
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Clinical Global Impression-Severity (CGI-S) Score

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    End point title
    Mean change from Baseline in Clinical Global Impression-Severity (CGI-S) Score
    End point description
    The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 414)
    -0.66 ± 0.96
        Month 24 (N= 267)
    -0.77 ± 1.04
    No statistical analyses for this end point

    Secondary: Mean in Clinical Global Impression-Improvement (CGI-I) score

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    End point title
    Mean in Clinical Global Impression-Improvement (CGI-I) score
    End point description
    The efficacy of trial medication were rated for each participant using the CGI-I scale. The study physician must rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at baseline. Response choices include: 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 Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    510
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 408)
    2.62 ± 1.16
        Month 24 (N= 263)
    2.38 ± 1.15
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Young Mania Rating Scale (YMRS) score

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    End point title
    Mean change from Baseline in Young Mania Rating Scale (YMRS) score
    End point description
    The YMRS consists of 11 items assessing the core symptoms of mania and was used to assess participants with bipolar I disorder, manic and mixed episodes with or without psychotic features: elevated mood, increased motor activity - energy, sexual interest, sleep, irritability, speech (rate and amount), language - thought disorder, content, disruptive - aggressive behavior, appearance, and insight. Each item had 5 or 9 grades of severity, with lower scores indicating milder symptoms. The number of raters within each trial center was to be kept to a minimum. The YMRS Total Score (range 0 to 44) is the sum of the rating scores for 11 items for assessing the core symptoms of mania. A missing value for any YMRS assessment item(s) could have resulted in a missing YMRS Total Score. A higher YMRS Total Score represents greater severity. In this study, 94 participants had bipolar disorder, this explains the N=94 in the table below and these were de novo participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    94
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 93)
    -9.71 ± 10.23
        Month 24 (N= 93)
    -10.02 ± 10.21
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Clinical Global Impression Scale - Bipolar (CGI-BP) version severity score

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    End point title
    Mean change from Baseline in Clinical Global Impression Scale - Bipolar (CGI-BP) version severity score
    End point description
    The CGI-BP scale refers to the global impression of the subject with respect to bipolar disorder. The scale rated the subject’s Severity of Illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and Change From Preceding Phase (CGI-BP-Improvement: mania, depression, and overall bipolar illness) based on a 7- or 8-point scale. Severity of Illness (CGI-BP-Severity) was rated at all visits. At each visit other than Day 0 (Baseline), the Change From Preceding Phase (CGI-BP-Improvement) was judged with respect to participant's condition at Baseline. The CGI-BP Severity Scores (range 1 to 7), as well as CGI-BP Improvement Scores (range 1 to 7) are single-item rating scores, with higher scores representing greater severity or less improvement. Data for 94 de novo participants were available with bipolar disorder.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    94
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 93)
    -1.26 ± 1.33
        Month 24 (N= 93)
    -1.3 ± 1.37
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Clinical Global Impression Scale - Bipolar version improvement score

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    End point title
    Mean change from Baseline in Clinical Global Impression Scale - Bipolar version improvement score
    End point description
    The CGI-BP scale refers to the global impression of the subject with respect to bipolar disorder. The scale rated the subject’s Severity of Illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and Change From Preceding Phase (CGI-BP-Improvement: mania, depression, and overall bipolar illness) based on a 7- or 8-point scale. Severity of Illness (CGI-BP-Severity) was rated at all visits. At each visit other than Day 0 (Baseline), the Change From Preceding Phase (CGI-BP-Improvement) was judged with respect to participant's condition at Baseline. The CGI-BP Severity Scores (range 1 to 7), as well as CGI-BP Improvement Scores (range 1 to 7) are single-item rating scores, with higher scores representing greater severity or less improvement. Only 40 participants had data at Baseline to explain the N=40 in the table below and these were de novo participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    94
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 93)
    2.27 ± 1.28
        Month 24 (N= 93)
    2.17 ± 1.27
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in General Behavior Inventory (GBI) Scale Total Score for Mania and Depression in both Parent/Guardian and Subject versions of the scale

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    End point title
    Mean change from Baseline in General Behavior Inventory (GBI) Scale Total Score for Mania and Depression in both Parent/Guardian and Subject versions of the scale
    End point description
    The GBI is a self-report inventory with 73 items focusing on mood-related behaviors, including depressive, hypomanic, and biphasic symptoms. For this trial, two 20-item subscales were utilized: one was completed by the parent/guardian or legal representative, as applicable for local laws, and the other was completed by the participant. Responses were given on a 4-point Likert scale, with 0 being never or hardly ever and 3 being very often or almost constantly. The GBI Total Score for mania (range 0 to 30) is the sum of scores for items 1 to 10 and the GBI Total Score for depression (range 0 to 30) is the sum of scores for items 11 to 20 in the GBI Parent/Guardian or Subject Version panel. Scores from the Parent/Guardian and participant Versions were summarized separately. A missing value for any GBI assessment items could have resulted in a missing GBI Total Score. High scores represent greater psychopathology. Data was only available for 80 de novo participants with bipolar disorder.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    80
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 78)
    -1.62 ± 7.2
        Month 24 (N= 78)
    -1.82 ± 7.37
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in the Attention Deficit Hyperactive Disorders Rating (ADHD-RS-IV) scale score

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    End point title
    Mean change from Baseline in the Attention Deficit Hyperactive Disorders Rating (ADHD-RS-IV) scale score
    End point description
    The ADHD-RS-IV is a reliable and easy-to-administer instrument both for diagnosing ADHD in children and adolescents and for assessing treatment response. Containing 18 items, the scale was linked directly to DSM-IV-TR diagnostic criteria for ADHD. There were 3 versions of the scale: a parent questionnaire on home behaviors (English), a parent questionnaire on home behaviors (Spanish), and a teacher questionnaire on classroom behaviors. For this trial, the parent questionnaire on home behaviors (English) was utilized. The ADHD-RS-IV Total Score (range 0 to 54) is the sum of rating scores for 18 items, with higher scores representing greater severity. A missing value for any ADHD-RS-IV assessment items could have resulted in a missing ADHD-RS-IV Total Score. Data were only available for 82 participants with bipolar disorder and these were de novo participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    82
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 81)
    -3.25 ± 10.43
        Month 24 (N= 81)
    -2.53 ± 10.73
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Children's Global Assessment Scale (CGAS) in Bipolar (de novo participants)

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    End point title
    Mean change from Baseline in Children's Global Assessment Scale (CGAS) in Bipolar (de novo participants)
    End point description
    The CGAS is a 100-point rating scale measuring psychological, social, and school functioning for children aged 6 to 17. It was adapted from the Adults Global Assessment Scale. The Global Assessment Scale was a rating scale for evaluating the overall functioning of a participant during a specified time period on a continuum from psychological or psychiatric sickness to health. The CGAS is a valid and reliable tool for rating a child's general level of functioning on a health-illness continuum. The CGAS was developed by Schaffer and colleagues to provide a global measure of severity of disturbance in children and adolescents. The CGAS Score (range 1 to 100) is a single-item score for rating a child’s general level of functioning on a health-illness continuum, with higher scores representing better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    Open-label Treatment Phase
    Number of subjects analysed
    94
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 12 (N= 93)
    14.17 ± 16.01
        Month 24 (N= 93)
    14 ± 16.23
    No statistical analyses for this end point

    Secondary: Incidence of suicidality, suicidal behaviour and suicidal ideation

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    End point title
    Incidence of suicidality, suicidal behaviour and suicidal ideation
    End point description
    Suicidality was defined as reporting at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any type of suicidal behaviors (actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior). Suicidal ideation was defined as reporting any type of suicidal ideation. The below reported N value is the number of participants with specified suicidal ideation/behavior at the given time point.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    All Participants
    Number of subjects analysed
    507
    Units: Participants
    number (not applicable)
        Complete suicidality
    0
        Suicidality
    32
        Suicidal behavior
    5
        Emergence of suicidal behavior
    3
        Suicidal ideation
    31
        Emergence of suicidal ideation
    19
        Emergence of serious suicial ideation
    2
        Worsening of suicidal ideation
    26
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the signing of the informed consent until the follow-up visit 30 (± 3) days after the end of trial.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Conversion Phase
    Reporting group description
    Participants who entered this phase were converted from his or her antipsychotic to the minimum target dose of 10 mg/day aripiprazole monotherapy and continue to increase the dose up to a maximum of 30 mg/day, or for tolerability reasons, to reduce the aripiprazole dose to no less than 5 mg/day.

    Reporting group title
    Open-label Treatment Phase
    Reporting group description
    Participants who entered this phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.

    Serious adverse events
    Conversion Phase Open-label Treatment Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 297 (0.67%)
    49 / 510 (9.61%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Blood creatine phosphokinase
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Gilbert’s syndrome
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 297 (0.00%)
    18 / 510 (3.53%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 297 (0.00%)
    8 / 510 (1.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 297 (0.00%)
    7 / 510 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 297 (0.00%)
    3 / 510 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 297 (0.00%)
    3 / 510 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 510 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 510 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood swings
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Self injurious behaviour
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth disorder
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 510 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Laryngitis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 510 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Conversion Phase Open-label Treatment Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 297 (13.47%)
    194 / 510 (38.04%)
    Investigations
    Weight increased
         subjects affected / exposed
    1 / 297 (0.34%)
    38 / 510 (7.45%)
         occurrences all number
    1
    50
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 297 (7.74%)
    67 / 510 (13.14%)
         occurrences all number
    32
    87
    Somnolence
         subjects affected / exposed
    20 / 297 (6.73%)
    33 / 510 (6.47%)
         occurrences all number
    22
    39
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 297 (2.02%)
    32 / 510 (6.27%)
         occurrences all number
    6
    53
    Schizophrenia
         subjects affected / exposed
    1 / 297 (0.34%)
    30 / 510 (5.88%)
         occurrences all number
    1
    36
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 297 (1.35%)
    30 / 510 (5.88%)
         occurrences all number
    4
    53
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 297 (1.68%)
    34 / 510 (6.67%)
         occurrences all number
    5
    43

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2010
    In protocol amendment 1, provided instructions for titrating de novo subjects who were treated with a marketed long-acting intramuscular depot antipsychotic for <1 cycle plus 14 days or <60 days prior to screening. Updated the number of participants expected to rollover from Trial 31-09-266 from 180 to 63. Added child and adolescent participants with bipolar I disorder, manic or mixed episode with or without psychotic features to the trial population. Added the restrictions on treatment with benzodiazepines or propranolol within 8 hours or treatment with anticholinergic agents within 12 hours prior to all trial assessments during any phase of the trial. Added sections on YMRS, CGI-BP, GBI, ADHD-RS-IV, and K-SADS-PL to instruct investigators on these assessments. Instructed investigators to identify and to report participants (within 24 hours) who met the criteria for potential drug induced liver damage (Hy’s Law). Provided additional instructions on how long birth control was to be used for female participants of childbearing potential and female partners of male participants and included birth control depot injections as an acceptable form of birth control. Provided time windows for prohibited concomitant antidepressants prior to entry into the conversion phase or the open-label treatment phase. Clarified that all participants require a K-SADS-PL assessment prior to entering the conversion phase or the open-label treatment phase of Trial 31-09-267.
    14 Dec 2010
    In protocol amendment 2, Changed the trial designation from Phase 4 to Phase 3. Added 3 safety rating scales to the protocol: the Clinician Pediatric Adverse Event Rating Scale (PAERS), Sexual Adverse Event Scale (SAES), and NY-AACENT scales. Excluded participants who used clozapine at any time. Excluded participants with a positive cannabis test at screening. Excluded participants who used an intramuscular depot long-acting antipsychotic within 6 months of beginning trial treatment. Excluded participants with evidence of subclinical hypothyroidism. Updated the number of participants required to be screened. Changed the wording for parent or guardian to parent/guardian or legal representative, as applicable for local laws.
    28 Mar 2011
    In protocol amendment 3, Changed the exclusionary QTc value from ≥ 420 to ≥450 msec. Clarified that a clinically significant fasting blood glucose level, requiring trial exclusion was ≥125 mg/dL. Added statement that participants who previously screen failed due to QTc ≥ 420 msec were allowed to be rescreened. Changed second hypothyroidism to hyperthyroidism in the inclusion criteria 12. Added procedure at ET or completion visits that participants were discontinued in the Interactive voice response system/Interactive web response system (IVRS/IWRS). Added documentation of birth control status at the follow-up visit. Changed Phase 3 to Phase 2 in the following sentence: “The incidence of the symptom items recorded in the three adverse event scales at each visit will be summarized for the Phase 2 Safety Sample by disease under study and by treatment group (aripiprazole and placebo) for the Phase 3 Safety Sample.” Removed the planned summary of Tanner Staging scores using their cross frequencies at baseline and postbaseline by treatment group. Added protocol dates to the footer and added the Investigational New Drug (IND) number to the title page and protocol synopsis. Removed all references to the SAES and PAERS from the protocol. Updated the ECG language. Clarified which medications are prohibited. Changed the number of trial sites from up to 75 to approximately 75 sites. Clarified the titration requirements for rollover subjects from Trial 31-09-266. Clarified the use of titration cards for participants on < 5 and 5 mg/day of branded aripiprazole. Clarified that oral aripiprazole was not to be dispensed at Week 6/end of the conversion phase. Clarified that a rollover participants CGI-I baseline score was based on the participants status at the last visit of Trial 31-09-266.
    21 Mar 2012
    In protocol amendment 4, Increased the sample size to meet the requirement set forth as a key binding element of the European Medicines Agency (EMA) P/99/2011 Aripiprazole Paediatric Investigational Plan to provide 2 years of safety data for at least 100 subjects, including Tanner Staging and cognitive AEs. Adjusted the assumptions for screening failure rate and the discontinuation rate in the conversion phase based on actual trial data. Updated the amendment with new safety information and aripiprazole Investigator Brochure, Version No. 15. Deleted the version of MedDRA that was to be used to code AEs.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Sep 2014
    The study was terminated by the Sponsor as the European Medicines Agency P/99/2011Aripiprazole PIP which directed the sponsor to provide 2 years of safety data for at least 100 participants. The objective was met in April 2014.
    -

    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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