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    Clinical Trial Results:
    A 52-week, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of an Intramuscular Depot Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Patients with Bipolar I Disorder

    Summary
    EudraCT number
    2012-002870-30
    Trial protocol
    PL  
    Global end of trial date
    09 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    06 May 2017
    First version publication date
    06 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    31-08-250
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01567527
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND No.: 114,284
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, MD 20850
    Public contact
    Otsuka Pharmaceutical Development & Commercialization, Inc., Otsuka Transparency Department, DT-inquiry@otsuka.jp
    Scientific contact
    Otsuka Pharmaceutical Development & Commercialization, Inc., Otsuka Transparency Department, DT-inquiry@otsuka.jp
    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
    09 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a double-blind, placebo-controlled, randomized withdrawal trial to assess the time to recurrence of any mood episode in subjects with bipolar I disorder who had maintained stability on aripiprazole IM depot for at least 8 weeks.
    Protection of trial subjects
    In accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline1 and the applicable local laws and regulatory requirements of the countries in which the trial was conducted, copies of the protocol, amendments, and informed consent form (ICF) were reviewed and approved by the governing institutional review board (IRB) or independent ethics committee (IEC) for each investigational site or country, as appropriate, prior to trial start or prior to implementation of the amendment at that site or country.This trial was conducted in compliance with the protocol, ICH GCP and applicable local laws and regulatory requirements. Note: All subjects were 18 to 65 years of age, inclusive, at time of informed consent.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Aug 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Romania: 34
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 608
    Worldwide total number of subjects
    731
    EEA total number of subjects
    44
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    726
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This trial was conducted in 1175 participants (including screen failures) at 103 trial sites in the following 7 countries: Canada, Japan, Republic of Korea, Poland, Romania, Taiwan, and the United States (US).

    Pre-assignment
    Screening details
    The trial consisted of a screening phase and 4 phases. In phases A-C (Conversion, Oral Stabilization and Depot Stabilization Phases), there was a single treatment group. In phase D (Double-blind, placebo-controlled phase), there were 2 treatment groups. All Outcome Measures were assessed in the double-blind, placebo-controlled phase of the study.

    Period 1
    Period 1 title
    Oral Conversion Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    All patients
    Arm description
    During the Oral Conversion Phase, patients were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral aripiprazole (The goal was to achieve a monotherapy target starting dose of 15mg/day at week 4 and no later than week 6) of the Conversion Phase.

    Number of subjects in period 1
    All patients
    Started
    466
    Completed
    367
    Not completed
    99
         Protocol deviation
    3
         Met withdrawal criteria
    10
         Lack of efficacy
    2
         Withdrawn by the investigator
    3
         Adverse events
    33
         Consent withdrawn by subject
    32
         Lost to follow-up
    16
    Period 2
    Period 2 title
    Oral Aripiprazole Stabilization Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    All patients
    Arm description
    During the Oral Stabilization Phase, patients were stabilized on an oral dose of aripiprazole. 632 subjects entered the Oral Stabilization Phase (367 subjects entered from the Conversation Phase and 265 subjects entered the Oral Stabilization Phase directly)
    Arm type
    Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Open-label oral aripiprazole monotherapy (Oral aripiprazole dose ranging from 15 to 30 mg daily)

    Number of subjects in period 2
    All patients
    Started
    367
    Completed
    425
    Not completed
    207
         Met withdrawal criteria
    41
         Lack of efficacy
    12
         Withdrawn by the investigator
    2
         Adverse events
    63
         Consent withdrawn by subject
    45
         Lost to follow-up
    44
    Joined
    265
         Subjects entered Oral Stabilization Phase directly
    265
    Period 3
    Period 3 title
    IM Depot Stabilization Phase
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Investigator [1]

    Arms
    Arm title
    All patients
    Arm description
    During the Depot Stabilization Phase, patients were stabilized on aripiprazole IM depot. The subjects were assigned to aripiprazole IM depot in the IM Depot Stabilization Phase for a minimum of 12 weeks and a maximum of 28 weeks. To proceed to the Double-blind, Placebo-controlled Phase, subjects were required to meet all the protocol-defined stability criteria for a minimum of 8 consecutive weeks (4 consecutive biweekly visits).
    Arm type
    Experimental

    Investigational medicinal product name
    Intramuscular (IM) Depot Aripiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Single-blind fashion, aripiprazole IM depot 400 mg, irrespective of the final oral dose of aripiprazole in Phase B. A single decrease to 300 mg was permitted , as was a single return to 400 mg, if required, in addition oral aripiprazole during the first 2 weeks to maintain therapeutic levels

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: An unblinded site study drug manager prepared and administered the single-blind IM depot injections every 4 weeks throughout the IM Depot Stabilization Phase.
    Number of subjects in period 3
    All patients
    Started
    425
    Completed
    266
    Not completed
    159
         Protocol deviation
    5
         Met withdrawal criteria
    26
         Lack of efficacy
    7
         Withdrawn by the investigator
    6
         Adverse events
    37
         Consent withdrawn by subject
    56
         Sponsor discontinued study
    1
         Lost to follow-up
    21
    Period 4
    Period 4 title
    Double-blind Placebo-controlled Phase
    Is this the baseline period?
    Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Aripiprazole Depot
    Arm description
    Patients received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Intramuscular (IM) Depot Aripiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular (IM) Depot Aripiprazole Formulation 400 mg or 300 mg, once a month injection

    Arm title
    Placebo
    Arm description
    Patients received placebo intramuscularly up to 52 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IM Depot Placebo 400 mg or 300 mg, once a month injection.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: In this study, Period 4 (Double-blind Placebo controlled Phase) was chosen as the baseline period and Baseline measures are based on the participants from the Double-blind Placebo-controlled Phase.
    Number of subjects in period 4 [3]
    Aripiprazole Depot Placebo
    Started
    133
    133
    Completed
    64
    38
    Not completed
    69
    95
         Protocol deviation
    1
    1
         Recurrence of any mood episode with AE
    16
    33
         Met withdrawal criteria
    4
    7
         AE without recurrence of any mood episode
    7
    1
         Consent withdrawn by subject
    13
    10
         Sponsor discontinued study
    1
    3
         Recurrence of any mood episode without AE
    19
    35
         Lost to follow-up
    8
    5
    Notes
    [3] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Since the results presented are of Period 4, this was chosen as the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aripiprazole Depot
    Reporting group description
    Patients received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo intramuscularly up to 52 weeks.

    Reporting group values
    Aripiprazole Depot Placebo Total
    Number of subjects
    133 133 266
    Age categorical
    Baseline measures are based on the participants from the Double-blind Placebo-controlled Phase
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    133 132 265
        From 65-84 years
    0 1 1
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.6 ± 10.8 40.6 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    83 70 153
        Male
    50 63 113
    Age at first manic episode (years)
    Units: Years
        arithmetic mean (standard deviation)
    25.2 ± 10.3 24.8 ± 9.9 -
    Number of mood episodes past 12 months
    Units: Number
        arithmetic mean (standard deviation)
    2.2 ± 1.2 2.2 ± 1.1 -
    Duration of disease prior to enrollment (years)
    Units: Years
        arithmetic mean (standard deviation)
    12.1 ± 9.2 13.6 ± 9.8 -
    Number of prior hospitalizations for a mood episode
    Units: Number
        arithmetic mean (standard deviation)
    3.5 ± 3.9 3.5 ± 4.1 -
    YMRS Total Score
    Units: Number
        arithmetic mean (standard deviation)
    2.9 ± 3.5 2.6 ± 3 -
    MADRS Total Score
    Units: Number
        arithmetic mean (standard deviation)
    3 ± 3.4 2.4 ± 3.4 -
    CGI-BP Severity - Mania
    Units: Number
        arithmetic mean (standard deviation)
    1.5 ± 0.7 1.4 ± 0.6 -

    End points

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    End points reporting groups
    Reporting group title
    All patients
    Reporting group description
    During the Oral Conversion Phase, patients were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy.
    Reporting group title
    All patients
    Reporting group description
    During the Oral Stabilization Phase, patients were stabilized on an oral dose of aripiprazole. 632 subjects entered the Oral Stabilization Phase (367 subjects entered from the Conversation Phase and 265 subjects entered the Oral Stabilization Phase directly)
    Reporting group title
    All patients
    Reporting group description
    During the Depot Stabilization Phase, patients were stabilized on aripiprazole IM depot. The subjects were assigned to aripiprazole IM depot in the IM Depot Stabilization Phase for a minimum of 12 weeks and a maximum of 28 weeks. To proceed to the Double-blind, Placebo-controlled Phase, subjects were required to meet all the protocol-defined stability criteria for a minimum of 8 consecutive weeks (4 consecutive biweekly visits).
    Reporting group title
    Aripiprazole Depot
    Reporting group description
    Patients received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo intramuscularly up to 52 weeks.

    Primary: Time from randomization to recurrence of any mood episode during Double-Bind Placebo Controlled phase

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    End point title
    Time from randomization to recurrence of any mood episode during Double-Bind Placebo Controlled phase
    End point description
    This endpoint was defined as meeting any of the following criteria: 1) Hospitalization for any mood episode OR 2) Any of the following: a) YMRS total score ≥ 15 OR b) MADRS total score ≥ 15 OR c) CGI-BP-S score > 4 (overall score) OR 3) SAE of worsening disease (bipolar I disorder) OR 4) Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR 5) Clinical worsening with the need for addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, and/or increase greater than the allowed benzodiazepine doses for treatment of symptoms of an underlying mood disorder OR 6) Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of “yes” on question 4 or 5 on the C-SSRS
    End point type
    Primary
    End point timeframe
    Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52)
    End point values
    Aripiprazole Depot Placebo
    Number of subjects analysed
    132
    133
    Units: Recurrence Rate (%)
        number (not applicable)
    26.5
    51.1
    Statistical analysis title
    Statistical analysis for Aripiprazole IM
    Comparison groups
    Aripiprazole Depot v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.451
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.299
         upper limit
    0.678
    Statistical analysis title
    Statistical analysis for IM Depot Placebo
    Comparison groups
    Aripiprazole Depot v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    2.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.475
         upper limit
    3.34

    Secondary: Proportion of subjects meeting criteria for recurrence of any mood episode (manic, mixed, depressive)

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    End point title
    Proportion of subjects meeting criteria for recurrence of any mood episode (manic, mixed, depressive)
    End point description
    Recurrence of any mood episode (manic, mixed, depressive)
    End point type
    Secondary
    End point timeframe
    Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52)
    End point values
    Aripiprazole Depot Placebo
    Number of subjects analysed
    132
    133
    Units: Percentage
        number (not applicable)
    26.52
    51.13
    Statistical analysis title
    Statistical analysis for any mood episode
    Comparison groups
    Aripiprazole Depot v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Fisher exact
    Parameter type
    Mean difference (final values)
    Point estimate
    -24.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.72
         upper limit
    -12.51

    Secondary: Mean change from randomization to endpoint in the CGI-BP-S (mania) score

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    End point title
    Mean change from randomization to endpoint in the CGI-BP-S (mania) score
    End point description
    Change From Randomization to Endpoint in Clinical Global Impression - Bipolar Version-Severity Scores. The CGI-BP scale referred 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).
    End point type
    Secondary
    End point timeframe
    Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52)
    End point values
    Aripiprazole Depot Placebo
    Number of subjects analysed
    131
    133
    Units: Number
    least squares mean (standard error)
        Week 2 (N = 123, 126)
    -0.07 ± 0.039
    0.09 ± 0.059
        Week 4 (N = 124, 121)
    -0.01 ± 0.041
    0.1 ± 0.064
        Week 6 (N = 117, 106)
    -0.03 ± 0.049
    0.11 ± 0.069
        Week 8 (N = 104, 100)
    -0.01 ± 0.053
    0.19 ± 0.072
        Week 10 (N = 103, 96)
    0.02 ± 0.06
    0.11 ± 0.079
        Week 12 (N = 95, 87)
    0.03 ± 0.072
    0.13 ± 0.083
        Week 14 (N = 99, 84)
    -0.05 ± 0.063
    0.07 ± 0.079
        Week 16 (N = 90, 82)
    -0.1 ± 0.044
    0.09 ± 0.067
        Week 18 (N = 87, 79)
    -0.08 ± 0.05
    -0.01 ± 0.064
        Week 20 (N = 83, 74)
    -0.08 ± 0.05
    0.08 ± 0.069
        Week 22 (N = 85, 71)
    -0.12 ± 0.054
    0.21 ± 0.097
        Week 24 (N = 79, 67)
    -0.09 ± 0.049
    0.14 ± 0.079
        Week 26 (N = 77, 62)
    -0.11 ± 0.055
    0.19 ± 0.082
        Week 28 (N = 81, 58)
    -0.14 ± 0.05
    0.12 ± 0.077
        Week 32 (N = 77, 56)
    -0.13 ± 0.062
    0.09 ± 0.08
        Week 36 (N = 72, 52)
    -0.07 ± 0.06
    0.25 ± 0.103
        Week 40 (N = 70, 51)
    -0.06 ± 0.069
    0.24 ± 0.113
        Week 44 (N = 69, 46)
    -0.15 ± 0.058
    0.24 ± 0.107
        Week 48 (N = 68, 43)
    -0.11 ± 0.059
    0.11 ± 0.075
        Week 52 (N = 64, 39)
    -0.16 ± 0.058
    0.27 ± 0.126
    Statistical analysis title
    Statistical Ananlysis for week 52
    Statistical analysis description
    Mixed model with fixed effects of treatment, region, week and interaction of treatment by week as terms and baseline by week as covariate. Heterogeneous compound symmetry covariance structure for observations within a subject is used.
    Comparison groups
    Aripiprazole Depot v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    Method
    Mixed model repeated measure analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    -0.17

    Secondary: Time from randomization to recurrence defined by hospitalization for a mood episode

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    End point title
    Time from randomization to recurrence defined by hospitalization for a mood episode
    End point description
    Analysis of Time from Randomization to Recurrence Defined by Hospitalization for a Mood Episode (Double-blind, Placebo-controlled Phase Efficacy Sample)
    End point type
    Secondary
    End point timeframe
    Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52)
    End point values
    Aripiprazole Depot Placebo
    Number of subjects analysed
    132
    133
    Units: Recurrence rate (percentage)
        number (not applicable)
    2.3
    13.5
    Statistical analysis title
    Statistical Analysis for Aripiprazole IM Depot
    Comparison groups
    Aripiprazole Depot v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.137
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.465
    Statistical analysis title
    Statistical Ananlysis for Placebo
    Comparison groups
    Placebo v Aripiprazole Depot
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    7.313
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.151
         upper limit
    24.865

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any AEs were recorded from the signing of informed consent onward.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Oral Aripiprazole Stabilization Phase
    Reporting group description
    During the Oral Stabilization Phase, patients were stabilized on an oral dose of aripiprazole ranging from 15 mg to 30 mg daily.

    Reporting group title
    IM Depot Stabilization Phase
    Reporting group description
    During the Depot Stabilization Phase, patients were stabilized on aripiprazole depot.

    Reporting group title
    Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase
    Reporting group description
    Patients received aripiprazole 300 mg or 400 mg depot intramuscularly

    Reporting group title
    Placebo-Double-blind, Placebo-controlled Phase
    Reporting group description
    Patients received placebo intramuscularly for 52 weeks

    Serious adverse events
    Oral Aripiprazole Stabilization Phase IM Depot Stabilization Phase Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase Placebo-Double-blind, Placebo-controlled Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 614 (5.70%)
    36 / 425 (8.47%)
    10 / 132 (7.58%)
    25 / 133 (18.80%)
         number of deaths (all causes)
    1
    0
    1
    0
         number of deaths resulting from adverse events
    1
    0
    1
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 614 (0.16%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 614 (0.16%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 614 (0.16%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Affective disorder
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    2 / 614 (0.33%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    3 / 133 (2.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    1 / 614 (0.16%)
    4 / 425 (0.94%)
    2 / 132 (1.52%)
    3 / 133 (2.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 614 (0.16%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    17 / 614 (2.77%)
    7 / 425 (1.65%)
    2 / 132 (1.52%)
    10 / 133 (7.52%)
         occurrences causally related to treatment / all
    1 / 17
    0 / 7
    0 / 2
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    1 / 132 (0.76%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    1 / 614 (0.16%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    4 / 614 (0.65%)
    8 / 425 (1.88%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressive symptom
         subjects affected / exposed
    2 / 614 (0.33%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 614 (0.16%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    3 / 614 (0.49%)
    3 / 425 (0.71%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 614 (0.16%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 614 (0.16%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic adhesions
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 614 (0.00%)
    1 / 425 (0.24%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Oral Aripiprazole Stabilization Phase IM Depot Stabilization Phase Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase Placebo-Double-blind, Placebo-controlled Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    342 / 614 (55.70%)
    287 / 425 (67.53%)
    100 / 132 (75.76%)
    99 / 133 (74.44%)
    Investigations
    Weight increased
         subjects affected / exposed
    22 / 614 (3.58%)
    47 / 425 (11.06%)
    31 / 132 (23.48%)
    24 / 133 (18.05%)
         occurrences all number
    23
    47
    31
    25
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    94 / 614 (15.31%)
    74 / 425 (17.41%)
    27 / 132 (20.45%)
    17 / 133 (12.78%)
         occurrences all number
    99
    82
    32
    20
    Headache
         subjects affected / exposed
    0 / 614 (0.00%)
    0 / 425 (0.00%)
    4 / 132 (3.03%)
    9 / 133 (6.77%)
         occurrences all number
    0
    0
    4
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 614 (3.09%)
    22 / 425 (5.18%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences all number
    19
    25
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    24 / 614 (3.91%)
    30 / 425 (7.06%)
    9 / 132 (6.82%)
    6 / 133 (4.51%)
         occurrences all number
    24
    36
    9
    6
    Insomnia
         subjects affected / exposed
    34 / 614 (5.54%)
    41 / 425 (9.65%)
    10 / 132 (7.58%)
    10 / 133 (7.52%)
         occurrences all number
    35
    47
    11
    12
    Restlessness
         subjects affected / exposed
    32 / 614 (5.21%)
    24 / 425 (5.65%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences all number
    34
    25
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 614 (1.79%)
    22 / 425 (5.18%)
    10 / 132 (7.58%)
    13 / 133 (9.77%)
         occurrences all number
    11
    30
    13
    29

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2012
    Amendment Number 1: This amendment served to reflect a number of clarifications and additions to study procedures intended to enhance subject safety and accuracy of data. In addition, a number of administrative clarifications were made, including changes to text to enhance readability and correct typographical errors.
    29 Oct 2013
    Amendment Number 2: This second amendment reflected clarifications and additions to study procedures, statistical methods, and inclusion/exclusion criteria intended to enhance subject safety and accuracy of data. In addition, administrative clarifications were made, including changes to text to enhance readability and consistency and correct typographical errors.
    19 Jun 2014
    Amendment Number 3: This third amendment provided for continuation of the trial at Japanese sites if Trial 31-08-250 was terminated early for any reason other than safety in order to meet the randomization requirement specified by the Pharmaceutical and Medical Devices Agency.

    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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