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    Clinical Trial Results:
    A 52-week, Multicenter, Open-label Study to Evaluate the Effectiveness of Aripiprazole Intramuscular Depot as Maintenance Treatment in Patients with Schizophrenia "ASPIRE OPEN-LABEL" (Aripiprazole Intramuscular Depot Progam in Schizophrenia)

    Summary
    EudraCT number
    2008-002699-83
    Trial protocol
    BE   FI   HU   AT   EE   DK   FR   GB   BG   SK  
    Global end of trial date
    07 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    29 May 2016
    First version publication date
    29 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1031-08-248
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00731549
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, MD 20850
    Public contact
    Timothy Peters-Strickland, Otsuka Pharmaceutical Development & Commercialization, Inc., 001 609 249-6559,
    Scientific contact
    Timothy Peters-Strickland, Otsuka Pharmaceutical Development & Commercialization, Inc., 001 609 249-6559,
    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
    07 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the safety and tolerability of aripiprazole intramuscular (IM) Depot administered every 4 weeks for 52 weeks to participants with schizophrenia. The secondary objective was to evaluate the efficacy.
    Protection of trial subjects
    In accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline, and the applicable local laws and regulatory requirements of the countries in which the trial was conducted, copies of the protocol, amendments, 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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Feb 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 125
    Country: Number of subjects enrolled
    Estonia: 27
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    United States: 354
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 49
    Country: Number of subjects enrolled
    Romania: 34
    Country: Number of subjects enrolled
    Slovakia: 20
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Argentina: 19
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Chile: 53
    Country: Number of subjects enrolled
    Croatia: 24
    Country: Number of subjects enrolled
    India: 50
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Mexico: 26
    Country: Number of subjects enrolled
    Malaysia: 24
    Country: Number of subjects enrolled
    Philippines: 18
    Country: Number of subjects enrolled
    Puerto Rico: 8
    Country: Number of subjects enrolled
    Russian Federation: 83
    Country: Number of subjects enrolled
    Serbia: 17
    Country: Number of subjects enrolled
    South Africa: 31
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Thailand: 10
    Worldwide total number of subjects
    1081
    EEA total number of subjects
    324
    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)
    1081
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This open label Phase 3 study enrolled participants from the maintenance phase of study 2008-002675-27 (31-07-246) and study 2008-002676-10 (31-07-247) and new participants. Participants received aripiprazole IM depot as maintenance treatment. 1081 participants were treated in the open-label maintenance phase.

    Pre-assignment
    Screening details
    Screening phase (applicable if enrolled late/new participants received antipsychotic treatment other than aripiprazole), conversion phase (Phase 1, to convert from other antipsychotics to aripiprazole), oral stabilization phase (Phase 2-aripiprazole 10-30 milligram [mg]), and open-label IM phase (Phase 3-aripiprazole 400 mg IM depot).

    Period 1
    Period 1 title
    Open-label maintenance phase (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Aripiprazole 400/300 mg IM depot
    Arm description
    Participants received open-label aripiprazole 400/300 mg IM depot into gluteal muscle every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole 300 mg and 400 mg was permitted in order to maximize retention of participants. Participants also received supplemental oral aripiprazole (10 mg to 20 mg daily) for the first two weeks to maintain therapeutic plasma concentrations.
    Arm type
    Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    OPC-14597, Lu AF41155
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received open-label aripiprazole 400/300 mg IM depot into gluteal muscle every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole 300 mg and 400 mg was permitted in order to maximize retention of participants. Participants also received supplemental oral aripiprazole (10 mg to 20 mg daily) for the first two weeks to maintain therapeutic plasma concentrations.

    Number of subjects in period 1
    Aripiprazole 400/300 mg IM depot
    Started
    1081
    Completed
    858
    Not completed
    223
         Protocol deviation
    1
         Physician decision
    16
         Met withdrawal criteria
    24
         Lack of efficacy without adverse event
    6
         Adverse event
    31
         Consent withdrawn by subject
    89
         Lack of efficacy with adverse event
    37
         Lost to follow-up
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label maintenance phase
    Reporting group description
    Participants received open-label aripiprazole 400/300 mg IM depot into gluteal muscle every 4 weeks for a maximum of 52 weeks. Flexible dosing with apipiprazole 300 mg and 400 mg was permitted in order to maximize retention of participants. Participants also received supplemental oral aripiprazole (10 mg to 20 mg daily) for the first two weeks to maintain therapeutic plasma concentrations.

    Reporting group values
    Open-label maintenance phase Total
    Number of subjects
    1081 1081
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    1081 1081
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.2 ± 10.6 -
    Gender categorical
    Units: Subjects
        Female
    439 439
        Male
    642 642

    End points

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    End points reporting groups
    Reporting group title
    Aripiprazole 400/300 mg IM depot
    Reporting group description
    Participants received open-label aripiprazole 400/300 mg IM depot into gluteal muscle every 4 weeks for a maximum of 52 weeks. Flexible dosing with aripiprazole 300 mg and 400 mg was permitted in order to maximize retention of participants. Participants also received supplemental oral aripiprazole (10 mg to 20 mg daily) for the first two weeks to maintain therapeutic plasma concentrations.

    Primary: Percentage of stable participants at Baseline who remained stable at endpoint (last visit).

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    End point title
    Percentage of stable participants at Baseline who remained stable at endpoint (last visit). [1]
    End point description
    "Stable" was defined as meeting all of the following criteria: Outpatient status; Positive and negative syndrome scale (PANSS) total score ≤ 80; Lack of specific psychotic symptoms on the PANSS as measured by a score of ≤ 4 on each of the following items (possible scores of 1 to 7 for each item): 1) conceptual disorganization 2) suspiciousness 3) hallucinatory behaviour 4) unusual thought content; Clinical Global Impression of Severity (CGI-S) ≤ 4 (moderately ill); and Clinical Global Impression for Severity of Suicidality (CGI-SS) ≤ 2 (mildly suicidal) on Part 1 and ≤ 5 (minimally worsened) on Part 2. The percentage of stable participants at baseline who remained stable at endpoint (last visit) is described here. All participants who entered the open-label phase and had at least one post-baseline efficacy evaluation were included. N defines number of stable participants at baseline who were evaluated at the specified trial week.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52/Last visit
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Percentage of participants
    number (not applicable)
        Baseline (N=1075)
    100
        Week 2 (N=1023)
    99.02
        Week 4 (N=1045)
    99.14
        Week 8 (N=1009)
    98.51
        Week 12 (N=988)
    97.47
        Week 16 (N=951)
    98.42
        Week 20 (N=919)
    98.15
        Week 24 (N=880)
    99.2
        Week 28 (N=854)
    98.95
        Week 32 (N=838)
    99.16
        Week 36 (N=814)
    99.26
        Week 40 (N=807)
    99.5
        Week 44 (N=784)
    99.11
        Week 48 (N=751)
    99.2
        Week 52 (N=671)
    98.96
        Last visit (N=1072)
    94.96
    No statistical analyses for this end point

    Secondary: Percentage of participants meeting exacerbation of psychotic symptoms/impending relapse criteria

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    End point title
    Percentage of participants meeting exacerbation of psychotic symptoms/impending relapse criteria
    End point description
    "Impending relapse criteria" defined as meeting; 1) Clinical Global Impression of Improvement (CGI-I) ≥ 5 (minimally worse), AND increase to score of >4 and absolute increase of ≥ 2 on individual PANSS items (conceptual disorganization, hallucinatory behaviour, suspiciousness, unusual thought content); or increase to score >4 and absolute increase of ≥ 4 on combined 4 PANSS items on any of these PANSS items (conceptual disorganization, hallucinatory behaviour, suspiciousness, unusual thought content) OR 2) Hospitalization due to worsening of psychotic symptoms, but excluding hospitalization for psychosocial reasons, OR 3) CGI-SS score of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2, OR 4) Violent behaviour resulting in clinically relevant self-injury, injury to another person, or property damage. All participants who entered open label phase and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Every week visit until Last visit.
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Percentage of participants
    number (not applicable)
        Week 2 (N=1028)
    0.49
        Week 4 (N=1049)
    0.48
        Week 8 (N=1011)
    0.79
        Week 12 (N=988)
    1.52
        Week 16 (N=948)
    0.84
        Week 20 (N=920)
    1.09
        Week 24 (N=883)
    0.45
        Week 28 (N=857)
    0.58
        Week 32 (N=838)
    0.36
        Week 36 (N=814)
    0.25
        Week 40 (N=808)
    0.25
        Week 44 (N=783)
    0.26
        Week 48 (N=750)
    0.27
        Week 52 (N=668)
    0.3
        Last visit (N=1079)
    4.17
        Overall (N=1079)
    8.25
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving remission.

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    End point title
    Percentage of participants achieving remission.
    End point description
    Remission is defined as a score of ≤ 3 on each of the following specific PANSS items, maintained for a period of six months: delusions, unusual thought content, hallucinatory behaviour, conceptual disorganization, mannerisms/posturing, blunted affect, social withdrawal, and lack of spontaneity. All participants who entered the open label maintenance phase and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Overall from every visit until Last visit
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: percentage of participants
        number (not applicable)
    51.7
    No statistical analyses for this end point

    Secondary: Percentage of participants stable at Baseline and remaining stable at Week 28.

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    End point title
    Percentage of participants stable at Baseline and remaining stable at Week 28.
    End point description
    "Stable" was defined as meeting all of the following criteria: Outpatient status; PANSS total score ≤ 80; Lack of specific psychotic symptoms on the PANSS as measured by a score of ≤ 4 on each of the following items (possible scores of 1 to 7 for each item): 1) conceptual disorganization 2) suspiciousness 3) hallucinatory behaviour 4) unusual thought content; Clinical Global Impression of Severity (CGI-S) ≤ 4 (moderately ill); and Clinical Global Impression for Severity of suicidality (CGI-SS) ≤ 2 (mildly suicidal) on Part 1 and ≤ 5 (minimally worsened) on Part 2. All participants who entered the open label maintenance phase and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Percentage of participants
    number (not applicable)
        Baseline (N=1075)
    100
        Week 28 (N=854)
    98.95
    No statistical analyses for this end point

    Secondary: Percentage of participants with time to first exacerbation of psychotic symptoms/impending relapse

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    End point title
    Percentage of participants with time to first exacerbation of psychotic symptoms/impending relapse
    End point description
    Participants who first time meet relapse criteria were considered as having an event at date of exacerbation of psychotic symptoms/impending relapse. Time to first event was calculated as the earliest date of meeting one of relapse criteria. Limited concurrent treatment with oral aripiprazole was permitted as rescue therapy. All participants who entered the open label maintenance phase and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1079
    Units: Percentage of participants
        number (not applicable)
    8.2
    No statistical analyses for this end point

    Secondary: Mean change from Baseline to endpoint (last visit) in Positive and Negative Syndrome Scale (PANSS) Total Score.

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    End point title
    Mean change from Baseline to endpoint (last visit) in Positive and Negative Syndrome Scale (PANSS) Total Score.
    End point description
    PANSS total score (range 30-210) is the sum of the rating scores for 7 positive scale items, 7 negative scale items and 16 general psychopathology scale items from the PANSS scale. PANSS positive subscale score (range 7-49) is the sum of the rating scores for the 7 positive scale items from the PANSS scale. PANSS negative subscale score (range 7-49) is the sum of the rating scores for the 7 negative scale items from the PANSS scale. The severity of each scale is rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. All participants who entered the open label maintenance phase and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 52 and last visit
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 12 (N=987)
    -1.69 ± 6.21
        Week 24 (N=882)
    -2.55 ± 7.08
        Week 52 (N=669)
    -3.55 ± 7.75
        Last visit (N=1078)
    -1.72 ± 10.21
    No statistical analyses for this end point

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

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    End point title
    Mean change from Baseline in Clinical Global Impression of Severity (CGI-S) Score.
    End point description
    To assess CGI-S, the rater or physician will answer the following question: “Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?” Response choices include: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. All participants who entered the open label maintenance phase 3 and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 52 and last visit
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 12 (N=987)
    -0.11 ± 0.52
        Week 24 (N=883)
    -0.17 ± 0.53
        Week 52 (N=668)
    -0.24 ± 0.56
        Last visit (N=1079)
    -0.14 ± 0.7
    No statistical analyses for this end point

    Secondary: Mean change from Baseline to endpoint in PANSS positive and negative subscales.

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    End point title
    Mean change from Baseline to endpoint in PANSS positive and negative subscales.
    End point description
    PANSS positive subscale score (range 7-49) is the sum of the rating scores for the 7 positive scale items from the PANSS scale. Positive subscale consists of 7 positive symptom constructs: delusions, conceptual disorganization, hallucinatory behaviour, excitement, grandiosity, suspiciousness/persecution, and hostility). PANSS negative subscale score (range 7-49) is the sum of the rating scores for the 7 negative scale items from the PANSS scale. Negative subscale consists of 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking). The severity of each scale is rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. All participants who entered the open label maintenance phase and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 52 and last visit.
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 12 positive subscale score (N=987)
    -0.42 ± 2.11
        Week 24 positive subscale score (N=882)
    -0.68 ± 2.26
        Week 52 positive subscale score (N=669)
    -1.04 ± 2.53
        Last visit positive subscale score (N=1078)
    -0.49 ± 3.38
        Week 12 negative subscale score (N=987)
    -0.4 ± 2.4
        Week 24 negative subscale score (N=882)
    -0.53 ± 2.52
        Week 52 negative subscale score (N=669)
    -0.8 ± 2.94
        Last visit negative subscale score (N=1078)
    -0.46 ± 3.19
    No statistical analyses for this end point

    Secondary: Mean Clinical Global Impression of Improvement (CGI-I) Score.

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    End point title
    Mean Clinical Global Impression of Improvement (CGI-I) Score.
    End point description
    To assess CGI-I the rater or physician will rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses will be compared to the participants condition at baseline. Response choices include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. All participants who entered the open label maintenance phase 3 and have at least one post-baseline efficacy evaluation are included.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 12, 24, 52 and last visit
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (N=1081)
    3.48 ± 0.82
        Week 2 (N=1026)
    3.52 ± 0.85
        Week 4 (N=1049)
    3.49 ± 0.86
        Week 12 (N=987)
    3.42 ± 0.92
        Week 24 (N=882)
    3.33 ± 0.98
        Week 52 (N=669)
    3.25 ± 0.99
        Last visit (N=1079)
    3.35 ± 1.1
    No statistical analyses for this end point

    Secondary: Percentage of participants who discontinued due to all causes.

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    End point title
    Percentage of participants who discontinued due to all causes.
    End point description
    Participants who discontinued due to any cause were noted. Limited concurrent treatment with oral aripiprazole was permitted as rescue therapy for participants not meeting stability criteria. Rescue therapy was initiated at 10 or 15 mg daily for participants receiving aripiprazole IM depot 300 mg and at 10 mg daily for participants receiving aripiprazole IM depot 400 mg. Dose of oral aripiprazole could be increased after one week to 15 mg for efficacy needs or decreased to 5 mg for tolerability at any point during oral rescue therapy. Rescue therapy was not to be given for more than 4 weeks between 3 consecutive IM depot injections. Rescue therapy could be discontinued when the participant achieved two consecutive weeks of stability, or oral rescue dose could be decreased for an additional week at investigator’s discretion, if the 4-week limit for the rescue therapy episode had not been reached. No more than 3 episodes of rescue therapy were permitted.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Aripiprazole 400/300 mg IM depot
    Number of subjects analysed
    1081
    Units: Percentage of participants
        number (not applicable)
    20.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of the open label maintenance phase until the end of treatment visit.
    Adverse event reporting additional description
    A treatment emergent adverse event was defined as an adverse event (AE) that began after the start of study medication (aripiprazole IM depot/oral tablets), or an AE that continued from Baseline and became serious, related to study treatment, or resulted in death, discontinuation, interruption or reduction of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Aripiprazole 400/300 mg IM depot
    Reporting group description
    Participants received open-label aripiprazole 400/300 milligrams (mg) IM depot into gluteal muscle every 4 weeks for a maximum of 52 weeks. Flexible dosing with apipiprazole 300 mg and 400 mg was permitted in order to maximize retention of participants. Participants also received supplemental oral aripiprazole (10 mg to 20 mg daily) for the first two weeks to maintain therapeutic plasma concentrations.

    Serious adverse events
    Aripiprazole 400/300 mg IM depot
    Total subjects affected by serious adverse events
         subjects affected / exposed
    95 / 1081 (8.79%)
         number of deaths (all causes)
    8
         number of deaths resulting from adverse events
    1
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypertension
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemangioma of liver
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal cancer metastatic
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Tongue neoplasm
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Facial pain
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Homicidal ideation
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    15 / 1081 (1.39%)
         occurrences causally related to treatment / all
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Schizophrenia
         subjects affected / exposed
    21 / 1081 (1.94%)
         occurrences causally related to treatment / all
    3 / 23
         deaths causally related to treatment / all
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    5 / 1081 (0.46%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 1081 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intentional overdose
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Tremor
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Open angle glaucoma
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomach mass
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 1081 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Genital candidiasis
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 1081 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syphilis
         subjects affected / exposed
    1 / 1081 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Aripiprazole 400/300 mg IM depot
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    254 / 1081 (23.50%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    82 / 1081 (7.59%)
         occurrences all number
    121
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    73 / 1081 (6.75%)
         occurrences all number
    98
    Insomnia
         subjects affected / exposed
    71 / 1081 (6.57%)
         occurrences all number
    92
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    76 / 1081 (7.03%)
         occurrences all number
    94

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2008
    Part 1: A number of additions to trial procedures intended to enhance participant safety and accuracy of data were made: Replaced Brief Assessment of Cognition in Schizophrenia with Trails A, Tower of London, and Letter-Number Span cognition assessments; revised post-treatment follow-up to include phone calls 20 and 26 weeks after the last visit; added assessment of haemoglobin A1c if fasting glucose was ≥125 milligrams/decilitre (mg/dL) and/or the urinalysis was positive for glucose; included varenicline as a prohibited concomitant medication; added assessment of electrocardiogram (ECG) at the end of the Conversion Phase for participants who terminated prematurely from the Conversion Phase; added individual durations of pregnancy monitoring based on formulation of aripiprazole; added details for the determination of starting dose in the Oral Stabilization Phase based on the participant’s prior history with the double-blind trials and oral aripiprazole; added descriptions for determination of body mass index and waist circumference; added requirement for withdrawal of participants who continued to meet exacerbation of psychotic symptoms/impending relapse criteria after receiving 3 episodes of oral aripiprazole tablet rescue therapy. Participants not meeting stability criteria, but not in impending relapse could continue in the trial at the investigator’s discretion; added requirement that participants meeting exacerbation of psychotic symptoms/impending relapse criteria must receive oral aripiprazole tablet rescue therapy.
    29 Jul 2008
    Part 2: Revised exclusion criterion related to abstinence/contraceptive use based on half-life of aripiprazole; clarified that participants who receiving aripiprazole in combination with any other antipsychotic(s) must enter the Conversion Phase in order to discontinue other antipsychotic(s). Only participants who received aripiprazole as monotherapy after the last visit of Trials 246/247 or at screening of Trial 31-08-248 (if applicable) could progress directly to the Oral Stabilization Phase; revised key secondary efficacy endpoints based on feedback from the Food and Drug Administration and adjusted statistical methods accordingly; clarified rules for rescue therapy; replaced Columbia Suicide Severity Rating Scale(C-SSRS) in protocol appendix; specified that a modified version of the CSSRS-European Version would be used for this trial to reduce redundant data capture and replace the sample form in the appendix with the modified form; removed table of trial day intervals for determination of visit dates; clarified that the last visit of the Open-label IM Depot Maintenance Phase was required to occur 379 days (1 year plus 2 weeks) after the first dose of open-label aripiprazole IM depot; clarified that Investigator Assessment and Patient Satisfaction with Medication Questionnaire -Modified should be completed only for participants who participated in the Conversion Phase of Trial 248 or de novo participants who had not been enrolled in Trials 246/247 so that treatment with aripiprazole IM depot could be compared with other antipsychotic(s) taken prior to entry into Trial 31-08-248; clarified that participants receiving more than one benzodiazepine at screening could qualify for the trial if they discontinued one of the benzodiazepines during the screening period; clarified that investigator- and subject-rated assessments of injection site were to be based on the site of the most recent injection; ECGs would be obtained “approximately” 5 minutes apart.
    18 Nov 2009
    Part 1: Updated general information on aripiprazole in introductory sections based on most recent Investigator Brochure and completed clinical study reports; revised trial design description to clarify antipsychotic medication requirements at screening (including definition of “lapse” in aripiprazole or antipsychotic medication at time of trial entry), as these requirements related to participant entry into the Conversion Phase vs directly into the Oral Stabilization Phase of the trial; clarified language regarding “non-generic oral aripiprazole monotherapy (trial drug).”; added a table delineating recommendation for switching from other generic oral aripiprazole to non-generic oral aripiprazole monotherapy; changed nomenclature of “additional” participants to “new” participants (participants who had not been enrolled in either Trial 31-07-246 or Trial 31-07-247 who enroll in Trial 31-08-248 as their first aripiprazole IM depot trial); Clarified Personal and Social Performance Scale as “other” assessments rather than “efficacy” assessments; added that a pharmacokinetic blood sample was to be collected in the event of a serious adverse event in the Open-label IM Depot Maintenance Phase (aripiprazole IM depot phase only); clarified that the aripiprazole IM depot injection site would be evaluated before and after each injection. Immediately prior to the first aripiprazole IM depot injection site, the anticipated injection site was to be evaluated; added assessment of C-SSRS at all postbaseline visits, rather than as determined by CGI-SS score, and renaming the “postbaseline C-SSRS” as “C-SSRS since last visit.”; refined exclusion criteria regarding screening ECG values for QTc interval; Clarified information that should be included in source documentation; clarified that prolactin levels would be assessed at Week 6/end of the Conversion Phase/ET; clarified that participants who discontinued any phase of the trial were not eligible to be rescreened to enter the trial
    18 Nov 2009
    Part 2: Included explanation that the Letter-Number Span assessment of cognition was not able to be completed in countries with Cyrillic and character-based languages; included a requirement for the physical examination to include the genitourinary body system with the option that the assessment could be performed within 1 year prior to the end of the screening period provided that documentation of the examination and records of results were provided to the trial investigator. A genitourinary examination was required annually (every 52 weeks) during the trial; clarified allowances/restrictions regarding concomitant medications (zolpidem extended-release, propranolol); added instruction to investigators regarding subject false-positive drug screen results during the trial; revised statistical analysis methods; replaced PANSS and C-SSRS in protocol appendix with most current versions; revised Resource Utilization Questionnaire; added Subject Experience with IM Depot Medication survey; clarified initiation of rescue therapy strategy; updated trial design to include the long-term extension trial; clarified the stability assessment to be done at Weeks 3, 6, and 10; increased the number of participants from 500 to 500-800. In addition, a number of administrative clarifications were made, including changes to text to enhance readability and correct typographical 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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