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    Clinical Trial Results:
    A 12-week, Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Aripiprazole Intramuscular Depot (OPC-14597, Lu AF41155) in the Acute Treatment of Adults With Schizophrenia

    Summary
    EudraCT number
    2012-003805-86
    Trial protocol
    LV  
    Global end of trial date
    30 Aug 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    31-12-291
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01663532
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, Maryland 20850
    Public contact
    Timothy Peters-Strickland, Otsuka Pharmaceutical Development & Commercialization, Inc, +1 609 249-6559, Timothy.Peters-Strickland@otsuka-us.com
    Scientific contact
    Timothy Peters-Strickland, Otsuka Pharmaceutical Development & Commercialization, Inc, +1 609 249-6559, Timothy.Peters-Strickland@otsuka-us.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the overall efficacy of aripiprazole intramuscular (IM) depot as acute treatment in participants with schizophrenia. The secondary objective of this trial was to evaluate the safety and tolerability of aripiprazole IM depot as acute treatment in participants with schizophrenia.
    Protection of trial subjects
    This trial was conducted in compliance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines for conducting, recording, and reporting trials, as well as for archiving essential documents. Consistent with ethical principles for the protection of human research subjects, no trial procedures were performed on trial candidates until written consent had been obtained from them. The informed consent form (ICF), protocol, and amendments for this trial were submitted to and approved by the institutional review board (IRB) or independent ethics committee (IEC) for each respective trial site or country.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Oct 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    United States: 327
    Country: Number of subjects enrolled
    Latvia: 2
    Worldwide total number of subjects
    340
    EEA total number of subjects
    13
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    339
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    340 participants were enrolled from 41 trial sites (37 in the United States, 2 in Croatia and 2 in Latvia).

    Pre-assignment
    Screening details
    This trial included a 13-Day Screening phase (which includes washout from previous antipsychotics for 7 days and/or washout from other prohibited medications), a 12-Week acute treatment phase, and a 14 (±2) Day safety follow-up.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    In this trial, participants and all other investigational site personnel, Sponsor employees, and other trial personnel remained blinded to the identity of the treatment assignments until every participant had completed trial treatment and the database had been locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Aripiprazole IM Depot 400/300mg
    Arm description
    Participants randomized to aripiprazole IM depot received aripiprazole IM depot 400 milligram (mg) as the initial dose with a single decrease to aripiprazole IM depot 300 mg permitted for tolerability per the study physician. The study treatment was injected into gluteal muscle every 4 weeks (Baseline/Day, Week 4, Week 8) during the 12-Week Acute Treatment Phase (ie, 3 IM depot injections). For 14 days beginning with the first injection, participants received concomitant oral aripiprazole (10 to 20 mg/day based on the study physician's clinical judgment).
    Arm type
    Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    OPC-14597, Lu AF41155
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Aripiprazole IM depot 400 mg was administered as the initial dose with a single decrease to aripiprazole IM depot 300 mg permitted for tolerability per the study physician. The study treatment was injected into gluteal muscle every 4 weeks (Baseline/Day, Week 4, Week 8) during the 12-Week Acute Treatment Phase (ie, 3 IM depot injections). For 14 days beginning with the first injection, participants received concomitant oral aripiprazole (10 to 20 mg/day based on the study physician's clinical judgment).

    Arm title
    Placebo
    Arm description
    Participants randomized to Placebo group received matching placebo. For 14 days beginning with the first injection, participants received concomitant oral placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Matching placebo was injected into the gluteal muscle every 4 weeks (Baseline/Day, Week 4, Week 8) during the 12-Week Acute Treatment Phase (ie, 3 IM depot injections). For 14 days beginning with the first injection, participants received concomitant oral placebo.

    Number of subjects in period 1
    Aripiprazole IM Depot 400/300mg Placebo
    Started
    168
    172
    Completed
    94
    65
    Not completed
    74
    107
         Physician decision
    1
    1
         Met withdrawal criteria
    7
    6
         Adverse event
    7
    13
         Lack of efficacy
    15
    60
         Consent withdrawn by subject
    35
    17
         Lost to follow-up
    9
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aripiprazole IM Depot 400/300mg
    Reporting group description
    Participants randomized to aripiprazole IM depot received aripiprazole IM depot 400 milligram (mg) as the initial dose with a single decrease to aripiprazole IM depot 300 mg permitted for tolerability per the study physician. The study treatment was injected into gluteal muscle every 4 weeks (Baseline/Day, Week 4, Week 8) during the 12-Week Acute Treatment Phase (ie, 3 IM depot injections). For 14 days beginning with the first injection, participants received concomitant oral aripiprazole (10 to 20 mg/day based on the study physician's clinical judgment).

    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to Placebo group received matching placebo. For 14 days beginning with the first injection, participants received concomitant oral placebo.

    Reporting group values
    Aripiprazole IM Depot 400/300mg Placebo Total
    Number of subjects
    168 172 340
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.1 ± 11 42.7 ± 10.9 -
    Gender categorical
    Units: Subjects
        Female
    38 33 71
        Male
    130 139 269

    End points

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    End points reporting groups
    Reporting group title
    Aripiprazole IM Depot 400/300mg
    Reporting group description
    Participants randomized to aripiprazole IM depot received aripiprazole IM depot 400 milligram (mg) as the initial dose with a single decrease to aripiprazole IM depot 300 mg permitted for tolerability per the study physician. The study treatment was injected into gluteal muscle every 4 weeks (Baseline/Day, Week 4, Week 8) during the 12-Week Acute Treatment Phase (ie, 3 IM depot injections). For 14 days beginning with the first injection, participants received concomitant oral aripiprazole (10 to 20 mg/day based on the study physician's clinical judgment).

    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to Placebo group received matching placebo. For 14 days beginning with the first injection, participants received concomitant oral placebo.

    Primary: Change from Baseline to Week 10 in Positive and Negative Syndrome Scale (PANSS) Total Score.

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    End point title
    Change from Baseline to Week 10 in Positive and Negative Syndrome Scale (PANSS) Total Score.
    End point description
    The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 that indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. The PANSS total score was the sum of the rating scores for 7 positive subscale items, 7 negative subscale items, and 16 general psychopathology subscale items from the PANSS panel. PANSS Total Score ranged from 30 (best possible outcome) to 210 (worst possible outcome). The primary statistical comparison was performed using the Mixed Effect Model Repeated Measure (MMRM) approach.
    End point type
    Primary
    End point timeframe
    Baseline to Week 10
    End point values
    Aripiprazole IM Depot 400/300mg Placebo
    Number of subjects analysed
    162
    167
    Units: Units on a scale
    least squares mean (standard error)
        Week 1 (N=162, 167)
    -8.9 ± 0.9
    -5 ± 0.9
        Week 2 (N=144, 157)
    -15.2 ± 1.2
    -8.3 ± 1.2
        Week 4 (N= 134, 140)
    -19 ± 1.4
    -9.8 ± 1.3
        Week 6 (N= 126, 117)
    -21.5 ± 1.5
    -10.3 ± 1.5
        Week 8 (N= 108, 96)
    -23.7 ± 1.6
    -9.7 ± 1.6
        Week 10 (N= 99, 81)
    -26.8 ± 1.6
    -11.7 ± 1.6
        Week 12 (N=99, 68)
    -27.2 ± 1.7
    -12.6 ± 1.8
    Statistical analysis title
    Statistical analysis at Week 1
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. Data for only 162 and 167 participants from aripiprazole and placebo groups were available. MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0005 [2]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.1
         upper limit
    -1.7
    Notes
    [1] - Null hypothesis of change from Baseline in PANSS total score of aripiprazole IM depot 400/300mg group is same as that of placebo group was tested. The sample size estimated a 1:1 randomization ratio (aripiprazole IM depot 400/300mg: placebo) to achieve 90% power and to preserve a nominal alpha level of 0.05 given a treatment difference of -7.5 points in change from Baseline with standard deviation of 20 points between aripiprazole and placebo using a two-sided z-test.
    [2] - Kenward-Rodger degree of freedom was used to test treatment effects and p-value was not adjusted as this is a primary efficacy endpoint.
    Statistical analysis title
    Statistical analysis at Week 2
    Statistical analysis description
    Null hypothesis of change from Baseline in PANSS total score of aripiprazole IM depot 400/300mg group is same as that of placebo group was tested. The sample size estimated a 1:1 randomization ratio (aripiprazole IM depot 400/300mg: placebo) to achieve 90% power and to preserve a nominal alpha level of 0.05 given a treatment difference of -7.5 points in change from Baseline with standard deviation of 20 points between aripiprazole and placebo using a two-sided z-test.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001 [4]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10
         upper limit
    -4
    Notes
    [3] - Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. Data for only 162 and 167 participants from aripiprazole and placebo groups were available. MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    [4] - Kenward-Rodger degree of freedom was used to test the treatment effects and p-value was not adjusted as this is a primary efficacy endpoint.
    Statistical analysis title
    Statistical analysis at Week 4
    Statistical analysis description
    Null hypothesis of change from Baseline in PANSS total score of aripiprazole IM depot 400/300mg group is same as that of placebo group was tested. The sample size estimated a 1:1 randomization ratio (aripiprazole IM depot 400/300mg: placebo) to achieve 90% power and to preserve a nominal alpha level of 0.05 given a treatment difference of -7.5 points in change from Baseline with standard deviation of 20 points between aripiprazole and placebo using a two-sided z-test.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.0001 [6]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -9.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.8
         upper limit
    -5.6
    Notes
    [5] - Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. Data for only 162 and 167 participants from aripiprazole and placebo groups were available. MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    [6] - Kenward-Rodger degree of freedom was used to test the treatment effects and p-value was not adjusted as this is a primary efficacy endpoint.
    Statistical analysis title
    Statistical analysis at Week 6
    Statistical analysis description
    Null hypothesis of change from Baseline in PANSS total score of aripiprazole IM depot 400/300mg group is same as that of placebo group was tested. The sample size estimated a 1:1 randomization ratio (aripiprazole IM depot 400/300mg: placebo) to achieve 90% power and to preserve a nominal alpha level of 0.05 given a treatment difference of -7.5 points in change from Baseline with standard deviation of 20 points between aripiprazole and placebo using a two-sided z-test.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -11.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15
         upper limit
    -7.3
    Notes
    [7] - Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. Data for only 162 and 167 participants from aripiprazole and placebo groups were available. MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    [8] - Kenward-Rodger degree of freedom was used to test the treatment effects and p-value was not adjusted as this is a primary efficacy endpoint.
    Statistical analysis title
    Statistical analysis at Week 8
    Statistical analysis description
    Null hypothesis of change from Baseline in PANSS total score of aripiprazole IM depot 400/300mg group is same as that of placebo group was tested. The sample size estimated a 1:1 randomization ratio (aripiprazole IM depot 400/300mg: placebo) to achieve 90% power and to preserve a nominal alpha level of 0.05 given a treatment difference of -7.5 points in change from Baseline with standard deviation of 20 points between aripiprazole and placebo using a two-sided z-test.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    < 0.0001 [10]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.4
         upper limit
    -9.6
    Notes
    [9] - Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. Data for only 162 and 167 participants from aripiprazole and placebo groups were available. MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    [10] - Kenward-Rodger degree of freedom was used to test the treatment effects and p-value was not adjusted as this is a primary efficacy endpoint.
    Statistical analysis title
    Statistical analysis at Week 10
    Statistical analysis description
    Null hypothesis of change from Baseline in PANSS total score of aripiprazole IM depot 400/300mg group is same as that of placebo group was tested. The sample size estimated a 1:1 randomization ratio (aripiprazole IM depot 400/300mg: placebo) to achieve 90% power and to preserve a nominal alpha level of 0.05 given a treatment difference of -7.5 points in change from Baseline with standard deviation of 20 points between aripiprazole and placebo using a two-sided z-test.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.0001 [12]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -15.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.4
         upper limit
    -10.8
    Notes
    [11] - Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. Data for only 162 and 167 participants from aripiprazole and placebo groups were available. MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    [12] - Kenward-Rodger degree of freedom was used to test the treatment effects and p-value was not adjusted as this is a primary efficacy endpoint.
    Statistical analysis title
    Statistical analysis at Week 12
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. Data for only 162 and 167 participants from aripiprazole and placebo groups were available. MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -14.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.3
         upper limit
    -10

    Secondary: Change from Baseline to Week 10 in Clinical Global Impression-Severity Scale (CGI-S) Score

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    End point title
    Change from Baseline to Week 10 in Clinical Global Impression-Severity Scale (CGI-S) Score
    End point description
    The severity of illness for each participants were rated using the CGI-S scale. The study physician were to answer the following question: "Considering your total experience with this particular population, how mentally ill is the patient at this time?" Response choices included were: 0= not assessed; 1= normal; not at all ill; 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 Week 10
    End point values
    Aripiprazole IM Depot 400/300mg Placebo
    Number of subjects analysed
    162
    168
    Units: Units on a scale
    least squares mean (standard error)
        Week 1 (N= 162, 168)
    -0.4 ± 0.1
    -0.2 ± 0.1
        Week 2 (N= 144, 157)
    -0.8 ± 0.1
    -0.4 ± 0.1
        Week 4 (N= 134, 140)
    -1 ± 0.1
    -0.4 ± 0.1
        Week 6 (N= 126, 117)
    -1.2 ± 0.1
    -0.5 ± 0.1
        Week 8 (N= 108, 96)
    -1.3 ± 0.1
    -0.6 ± 0.1
        Week 10 (N= 99, 81)
    -1.4 ± 0.1
    -0.6 ± 0.1
        Week 12 (N=99, 68)
    -1.4 ± 0.1
    -0.6 ± 0.1
    Statistical analysis title
    Statistical analysis at Week 1
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. After the comparison for primary efficacy endpoint was statistically significant, the comparison of change from Baseline in CGI severity score was conducted at same alpha level 0.05.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    -0.1
    Notes
    [13] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 2
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. After the comparison for primary efficacy endpoint was statistically significant, the comparison of change from Baseline in CGI severity score was conducted at same alpha level 0.05.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.2
    Notes
    [14] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 4
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. After the comparison for primary efficacy endpoint was statistically significant, the comparison of change from Baseline in CGI severity score was conducted at same alpha level 0.05.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    -0.4
    Notes
    [15] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 6
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. After the comparison for primary efficacy endpoint was statistically significant, the comparison of change from Baseline in CGI severity score was conducted at same alpha level 0.05.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    -0.5
    Notes
    [16] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 8
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. After the comparison for primary efficacy endpoint was statistically significant, the comparison of change from Baseline in CGI severity score was conducted at same alpha level 0.05.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    -0.5
    Notes
    [17] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 10
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. After the comparison for primary efficacy endpoint was statistically significant, the comparison of change from Baseline in CGI severity score was conducted at same alpha level 0.05.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    -0.6
    Notes
    [18] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 12
    Statistical analysis description
    Efficacy sample was defined as the ITT population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. After the comparison for primary efficacy endpoint was statistically significant, the comparison of change from Baseline in CGI severity score was conducted at same alpha level 0.05.
    Comparison groups
    Placebo v Aripiprazole IM Depot 400/300mg
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    -0.5

    Secondary: Change from Baseline to Week 10 in PANSS Positive Subscale Score.

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    End point title
    Change from Baseline to Week 10 in PANSS Positive Subscale Score.
    End point description
    The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. In positive subscale, the 7 positive symptom constructs were: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. PANSS Positive Subscale Score ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 10
    End point values
    Aripiprazole IM Depot 400/300mg Placebo
    Number of subjects analysed
    162
    167
    Units: Units on a scale
    least squares mean (standard error)
        Week 1 (N= 162, 167)
    -3.5 ± 0.3
    -2.1 ± 0.3
        Week 2 (N= 144, 157)
    -5.7 ± 0.4
    -3.4 ± 0.4
        Week 4 (N= 134, 140)
    -7 ± 0.5
    -3.9 ± 0.4
        Week 6 (N= 126, 117)
    -8.2 ± 0.5
    -4.4 ± 0.5
        Week 8 (N= 108, 96)
    -8.9 ± 0.5
    -4.1 ± 0.5
        Week 10 (N= 99, 81)
    -10 ± 0.5
    -4.9 ± 0.5
        Week 12 (N=99, 68)
    -9.9 ± 0.6
    -4.8 ± 0.6
    Statistical analysis title
    Statistical analysis at Week 1
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [19]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    -0.6
    Notes
    [19] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 2
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    -1.3
    Notes
    [20] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 4
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [21]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    -2
    Notes
    [21] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 6
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.1
         upper limit
    -2.6
    Notes
    [22] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 8
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.2
         upper limit
    -3.4
    Notes
    [23] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 10
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [24]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.4
         upper limit
    -3.7
    Notes
    [24] - MMRM analysis with treatment, pooled centers, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 12
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.7
         upper limit
    -3.6

    Secondary: Change from Baseline to Week 10 in PANSS Negative Subscale Score.

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    End point title
    Change from Baseline to Week 10 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 indicated- absence of symptoms and a score of 7 indicated- 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 were: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation and stereotyped thinking. PANSS Negative Subscale Score ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 10
    End point values
    Aripiprazole IM Depot 400/300mg Placebo
    Number of subjects analysed
    162
    167
    Units: Units on a scale
    least squares mean (standard error)
        Week 1 (N= 162, 167)
    -1.6 ± 0.2
    -0.7 ± 0.2
        Week 2 (N= 144, 157)
    -2.4 ± 0.3
    -1.2 ± 0.3
        Week 4 (N= 134, 140)
    -3.1 ± 0.4
    1.3 ± 0.4
        Week 6 (N= 126, 117)
    -3.5 ± 0.4
    1.3 ± 0.4
        Week 8 (N= 108, 96)
    -4 ± 0.4
    -1.4 ± 0.4
        Week 10 (N= 99, 81)
    -4.5 ± 0.5
    -1.6 ± 0.5
        Week 12 (N=99, 68)
    -4.7 ± 0.4
    -2.2 ± 0.5
    Statistical analysis title
    Statistical analysis at Week 1
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023 [25]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.3
    Notes
    [25] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 2
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0032 [26]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    -0.4
    Notes
    [26] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 4
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    -0.8
    Statistical analysis title
    Statistical analysis at Week 6
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [27]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    -1.3
    Notes
    [27] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 8
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Placebo v Aripiprazole IM Depot 400/300mg
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    -1.4
    Notes
    [28] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 10
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [29]
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.1
         upper limit
    -1.6
    Notes
    [29] - MMRM analysis with treatment, pooled centres, Week and treatment-by-Week, and Baseline-by-Week interaction as an unstructured covariate was performed.
    Statistical analysis title
    Statistical analysis at Week 12
    Statistical analysis description
    Efficacy sample was defined as the intent to treat (ITT) population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    Treatment difference
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    -1.3

    Secondary: Change from Baseline to Week 10 in Personal and Social Performance Scale (PSP) Score.

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    End point title
    Change from Baseline to Week 10 in Personal and Social Performance Scale (PSP) Score.
    End point description
    The PSP was a validated clinician scale that measured personal and social functioning in 4 domains: socially useful activities eg, work and study), personal and social relationships, self-care, disturbing and aggressive behaviours. Impairement in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval and the study physician's judgement to determine the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented varying degrees of disability (31 to 70) and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 10
    End point values
    Aripiprazole IM Depot 400/300mg Placebo
    Number of subjects analysed
    139
    146
    Units: Units on a scale
        least squares mean (standard error)
    12.3 ± 1.2
    5.2 ± 1.2
    Statistical analysis title
    Statistial analysis at Week 10
    Statistical analysis description
    Efficacy sample included participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had one Post-Baseline efficacy assessment. Last Observation Carried Forward (LOCF) was used to impute the missing data with the recorded value obtained at the preceding visit.
    Comparison groups
    Placebo v Aripiprazole IM Depot 400/300mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [30]
    Method
    ANCOVA
    Parameter type
    Treatment difference
    Point estimate
    7.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.1
         upper limit
    10.1
    Notes
    [30] - Analysis of Covariance (ANVOVA) model with treatment and pooled centres as factors and Baseline value as covariate for the comparison at other visits.

    Secondary: Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 10

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    End point title
    Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 10
    End point description
    The efficacy of study treatment was rated for each subject using the CGI-I scale. The rater or investigator rated the participant’s total improvement whether or not it was due entirely to study treatment. All responses were compared with the participant’s condition at Baseline (ie, randomization). Response choices included: 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
    Week 10
    End point values
    Aripiprazole IM Depot 400/300mg Placebo
    Number of subjects analysed
    162
    168
    Units: Units on a scale
        least squares mean (standard error)
    2.7 ± 1.2
    3.7 ± 1.3
    Statistical analysis title
    Statistical analysis at Week 10
    Statistical analysis description
    Efficacy sample was defined as the ITT population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. LOCF was used to impute the missing data with the recorded value obtained at the preceding visit.
    Comparison groups
    Placebo v Aripiprazole IM Depot 400/300mg
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [31]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [31] - Cochran-Mantel-Haenszel (CMH) raw mean scores differ test (Van Elteren test) controlling for pooled centres.

    Secondary: Responder rate at Week 10 based on PANSS Total Score.

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    End point title
    Responder rate at Week 10 based on PANSS Total Score.
    End point description
    Responder rate was defined as ≥30% reduction from Baseline in PANSS Total Score. PANSS Total Score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    Aripiprazole IM Depot 400/300mg Placebo
    Number of subjects analysed
    162
    167
    Units: Participants
        number (not applicable)
    60
    24
    Statistical analysis title
    Statistical analysis at Week 10
    Statistical analysis description
    Efficacy sample was defined as the ITT population which included randomized participants who took at least one injection of double-blind (aripiprazole IM depot or placebo) and had at least one Post-Baseline efficacy assessment. LOCF was used to impute the missing data with the recorded value obtained at the preceding visit.
    Comparison groups
    Aripiprazole IM Depot 400/300mg v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    22.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.9
         upper limit
    32.4
    Notes
    [32] - CMH test controlling by region (pooled sites).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were monitored from signing of the ICF until Safety Follow-up visit 14 (± 2) days after the last treatment.
    Adverse event reporting additional description
    One participant was randomly assigned to aripiprazole IM depot 400 mg/ 300 mg, but was not treated and did not have any post-randomization assessments and was not included in safety or efficacy assessments.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Aripiprazole IM Depot 400/300mg
    Reporting group description
    Participants randomized to aripiprazole IM depot received aripiprazole IM depot 400 milligram (mg) as the initial dose with a single decrease to aripiprazole IM depot 300 mg permitted for tolerability per the study physician. The study treatment was injected into gluteal muscle every 4 weeks (Baseline/Day, Week 4, Week 8) during the 12-Week Acute Treatment Phase (ie, 3 IM depot injections). For 14 days beginning with the first injection, participants received concomitant oral aripiprazole (10 to 20 mg/day based on the study physician's clinical judgment).

    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to Placebo group received matching placebo. For 14 days beginning with the first injection, participants received concomitant oral placebo.

    Serious adverse events
    Aripiprazole IM Depot 400/300mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 167 (4.79%)
    6 / 172 (3.49%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 167 (1.20%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    3 / 167 (1.80%)
    3 / 172 (1.74%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Aripiprazole IM Depot 400/300mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    91 / 167 (54.49%)
    68 / 172 (39.53%)
    Investigations
    Weight increased
         subjects affected / exposed
    28 / 167 (16.77%)
    12 / 172 (6.98%)
         occurrences all number
    29
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 167 (5.99%)
    10 / 172 (5.81%)
         occurrences all number
    10
    13
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    19 / 167 (11.38%)
    6 / 172 (3.49%)
         occurrences all number
    20
    6
    Headache
         subjects affected / exposed
    24 / 167 (14.37%)
    28 / 172 (16.28%)
         occurrences all number
    39
    39
    Sedation
         subjects affected / exposed
    9 / 167 (5.39%)
    2 / 172 (1.16%)
         occurrences all number
    9
    2
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    9 / 167 (5.39%)
    1 / 172 (0.58%)
         occurrences all number
    13
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    9 / 167 (5.39%)
    11 / 172 (6.40%)
         occurrences all number
    26
    19
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    16 / 167 (9.58%)
    12 / 172 (6.98%)
         occurrences all number
    20
    19
    Dyspepsia
         subjects affected / exposed
    10 / 167 (5.99%)
    11 / 172 (6.40%)
         occurrences all number
    14
    14
    Toothache
         subjects affected / exposed
    9 / 167 (5.39%)
    8 / 172 (4.65%)
         occurrences all number
    9
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2012
    Added Eudra CT number. Removed all references to interim analysis. Updated Schedule of Assessments to reflect administration of oral investigational medicinal product (IMP)during Screening Phase if needed to establish tolerability to aripiprazole. Clarified that no Week 12 data could be collected more than 100 days after first dose of IM depot IMP in addition to clarifying maximum amount of time allowed between injections. Corrected minor formatting errors.

    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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