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    Clinical Trial Results:
    A 52-week, Multicenter, Open-label Study to Evaluate the Effectiveness of an Intramuscular Depot Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Patients with Bipolar I Disorder

    Summary
    EudraCT number
    2012-004334-42
    Trial protocol
    HU  
    Global end of trial date
    18 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2017
    First version publication date
    18 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    31-08-252
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01710709
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, Maryland, United States, 20850
    Public contact
    Senior Director, Global Clinical Development, Joan Amatniek, MD, MS, 609 512-4464, joan.amatniek@otsuka-us.com
    Scientific contact
    Senior Director, Global Clinical Development, Joan Amatniek, MD, MS, 609 512-4464, joan.amatniek@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
    07 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial evaluated effectiveness via assessment of safety and tolerability (primary objective) and efficacy (secondary objective) of aripiprazole IM depot as measured by maintenance of stability in subjects with bipolar I disorder.
    Protection of trial subjects
    The study was conducted according to 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. Informed consent was obtained from all subjects in writing before any trial related procedures were performed. Prior to start, copies of the protocol, any amendments, and the informed consent form (ICF) were reviewed and approved by the governing institutional review broad (IRB) or independent ethics committee (IEC). Essential information was fully explained in layman's language to the subject by the investigator or a qualified designee. Note: All subjects were 18 years and older at time of informed consent.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Nov 2012
    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
    Taiwan: 1
    Country: Number of subjects enrolled
    United States: 322
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Japan: 75
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 6
    Country: Number of subjects enrolled
    Malaysia: 10
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Romania: 10
    Worldwide total number of subjects
    464
    EEA total number of subjects
    47
    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)
    458
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants who had completed trial 31-08-250 (rollover - 85 participants) and who had not participated (de novo - 379 participants) were enrolled in the IM Depot Maintenance Phase and received at least 1 dose of IMP .

    Pre-assignment
    Screening details
    For de novo participants, screening took place from Days -42 to -2

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

    Arms
    Arm title
    Phase C: Open-label IM Depot Maintenance Phase
    Arm description
    All De novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant. Administration of rescue therapy was recommended for participants who did not meet stability criteria during the IM Depot Maintenance Phase, unless in the investigator’s judgment withdrawal from the trial was considered more appropriate.
    Arm type
    Experimental

    Investigational medicinal product name
    aripiprazole
    Investigational medicinal product code
    OPC-14597
    Other name
    Abilify Maintena
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Prior to injection, vials of aripiprazole IM depot 400 mg were reconstituted with a designated quantity of sterile water for injection. Participants received the drug through intramuscular route. The dosage details are given below: Initially 400 mg, every 4 weeks for ≤ 52 weeks; flexible dosing with 300 mg and 400 mg was permitted as often as necessary during the treatment period. De novo participants also received oral aripiprazole during the first 2 weeks to maintain therapeutic levels

    Number of subjects in period 1
    Phase C: Open-label IM Depot Maintenance Phase
    Started
    464
    Completed
    291
    Not completed
    173
         Participant withdrawn by investigator
    2
         Lack of efficacy
    3
         Participant met withdrawal criteria
    33
         Protocol Violation
    5
         Consent withdrawn by subject
    53
         Adverse Event
    48
         Lost to follow-up
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase C: Open-label IM Depot Maintenance Phase
    Reporting group description
    All De novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant. Administration of rescue therapy was recommended for participants who did not meet stability criteria during the IM Depot Maintenance Phase, unless in the investigator’s judgment withdrawal from the trial was considered more appropriate.

    Reporting group values
    Phase C: Open-label IM Depot Maintenance Phase Total
    Number of subjects
    464 464
    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)
    458 458
        From 65-84 years
    6 6
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.1 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    268 268
        Male
    196 196

    End points

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    End points reporting groups
    Reporting group title
    Phase C: Open-label IM Depot Maintenance Phase
    Reporting group description
    All De novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant. Administration of rescue therapy was recommended for participants who did not meet stability criteria during the IM Depot Maintenance Phase, unless in the investigator’s judgment withdrawal from the trial was considered more appropriate.

    Primary: Number of participants with Adverse Events

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    End point title
    Number of participants with Adverse Events [1]
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a participant enrolled in the clinical trial and which does not necessarily have to have a causal relationship with the investigational medicinal product (IMP). Any adverse events (AEs) were recorded from the signing of informed consent onward. At each visit, the occurrences of AEs and the participant's recorded AE information were assessed. AEs were assessed as a criteria for safety and tolerability. Analysis Population Description: IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase. TEAEs = Treatment-emergent adverse events (used in the result table).
    End point type
    Primary
    End point timeframe
    At baseline, Phase C trial weeks 1 to 52/early termination (ET) and post-treatment follow-up
    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 specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    464
    Units: Participants
    number (not applicable)
        Participants with adverse events
    374
        Participants with TEAEs
    374
        Participants with serious TEAEs
    30
        Participants with non- serious TEAEs
    367
        Participants with severe TEAEs
    41
        Discontinuation of IMP due to AEs
    47
        Discontinuation fo IMP due to AEs/death
    48
        Deaths
    1
    No statistical analyses for this end point

    Primary: Injection Site Pain Measured by mean Visual Analog Scale (VAS) scores

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    End point title
    Injection Site Pain Measured by mean Visual Analog Scale (VAS) scores [2]
    End point description
    Injection-site pain was evaluated by mean visual analog scale (VAS) scores as reported by the participant after each injection at visits where an injection occurred. The degree of pain at the most recent injection site was measured by VAS. The rating scale ranged from 0 (no pain) to 100 (unbearably painful). Participants were followed for 1 hour post-injection and then VAS was completed. Injection evaluations were completed on the same day that the injection was administered Analysis Population Description All participants who received at least one dose of aripiprazole IM depot. It is equivalent to safety set (SAF). Number analyzed (n) = Total number of participants with at least one observation of the given parameter (used in result table)
    End point type
    Primary
    End point timeframe
    At baseline and Phase C trial weeks 4, 8, 12 to 48
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    464
    Units: Participants
    arithmetic mean (standard deviation)
        1ST Injection (n= 462)
    4.9 ± 10.7
        2ND Injection (n= 435)
    4.1 ± 8.4
        3RD Injection (n= 422)
    3.4 ± 7.5
        4TH Injection (n= 402)
    3.6 ± 8.6
        5TH Injection (n= 387)
    2.9 ± 7.9
        6TH Injection (n= 366)
    2.4 ± 5.8
        7TH Injection (n= 353)
    2.6 ± 7
        8TH Injection (n= 293)
    2.4 ± 4.9
        9TH Injection (n= 284)
    2.6 ± 6.6
        10TH Injection (n= 264)
    2.5 ± 7.5
        11TH Injection (n= 255)
    2.4 ± 6.3
        12TH Injection (n= 247)
    1.8 ± 4.3
        13TH Injection (n= 223)
    2.2 ± 5.5
        Last Injection (n= 463)
    2.4 ± 5.9
    No statistical analyses for this end point

    Primary: Number of participants with Clinically Significant Abnormal Laboratory Test results

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    End point title
    Number of participants with Clinically Significant Abnormal Laboratory Test results [3]
    End point description
    Standard safety variables to be analyzed were included clinical laboratory tests. Analysis Population Description All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.
    End point type
    Primary
    End point timeframe
    At baseline and Phase C trial week 52/ET
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    464
    Units: Number
    number (not applicable)
        Fasting cholesterol
    53
        Fasting glucose
    39
        Fasting low-density lipoprotein cholestrol
    32
        Fasting triglycerides
    124
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Abnormal Vital Signs

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    End point title
    Number of Participants With Clinically Significant Abnormal Vital Signs [4]
    End point description
    Vital sign measurements included body temperature, systolic and diastolic blood pressure, and heart rate. Analysis Population Description: IM Depot Maintenance Phase Safety Sample: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase.
    End point type
    Primary
    End point timeframe
    At baseline, Phase C trial weeks 1 to 52/early termination (ET) and post-treatment follow-up
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    464
    Units: Number
    number (not applicable)
        Weight gain of ≥ 7% (n= 454)
    93
        Weight loss of ≥ 7% (n= 454)
    66
        Blood pressure increased
    4
        Heart rate increased
    3
        Blood pressure decreased
    2
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECGs)

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    End point title
    Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECGs) [5]
    End point description
    Twelve-lead ECGs were recorded at specified visits. For each time point, three 12-lead ECG recordings were obtained approximately 5 minutes apart. Additional 12-lead ECGs were permitted to be obtained at the investigator's discretion and were always obtained in the event of an early termination. The ECGs were evaluated at the investigational site to determine the participant's eligibility and to monitor safety during the trial.
    End point type
    Primary
    End point timeframe
    At baseline and Phase C trial week 52/ET
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    412
    Units: Number
    number (not applicable)
        Symmetrical T-wave inversion
    9
        Supraventricular premature beat
    8
        Ventricular premature beat
    4
        Myocardial ischemia
    2
    No statistical analyses for this end point

    Primary: Extrapyramidal Symptoms (EPS) assessed by Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Scale (SAS), Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS Used only in Japan), and Barnes Akathisia Rating Scale (BARS)

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    End point title
    Extrapyramidal Symptoms (EPS) assessed by Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Scale (SAS), Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS Used only in Japan), and Barnes Akathisia Rating Scale (BARS) [6]
    End point description
    Extrapyramidal symptoms were evaluated by calculating mean change from baseline in the following: AIMS assessment consisted of 10 items describing symptoms of dyskinesia. Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness/severe distress). The SAS consisted of a list of 10 symptoms of parkinsonism. Each item was rated on a 5-point scale, with a score of 1 representing absence of symptoms, and a score of 5 representing a severe condition. The SAS Total Score is the sum of the scores for all 10 items. The DIEPSS was a rating scale for assessing extrapyramidal symptoms that consisted of 8 items for assessing individual symptoms and 1 item for assessing general severity—9 items in all. Each item was assessed on a scale of 0 (no symptoms, normal) to 4 (severe). The BARS consisted of 4 items related to akathisia.
    End point type
    Primary
    End point timeframe
    At baseline and Phase C trial weeks 4, 8, 12 to 52/ET
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    464
    Units: Number
    arithmetic mean (standard deviation)
        AIMS, Week 28 (n= 457)
    0.07 ± 1
        AIMS, Week 52 (n= 457)
    0.05 ± 0.97
        SAS, Week 28 (n= 377)
    0.21 ± 1.59
        SAS, Week 52 (n= 377)
    0.2 ± 1.58
        DIEPSS, Week 28 (n= 75)
    0.32 ± 1.29
        DIEPSS, Week 52 (n= 75)
    0.21 ± 1.11
        BARS, Week 28 (n= 457)
    0.05 ± 0.61
        BARS, Week 52 (n= 457)
    0.04 ± 0.6
    No statistical analyses for this end point

    Primary: Assessment of Risk of Suicidal Events and Classification by Completion of Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    Assessment of Risk of Suicidal Events and Classification by Completion of Columbia Suicide Severity Rating Scale (C-SSRS) [7]
    End point description
    Suicidality was monitored by using the C-SSRS at every visit. The C-SSRS scale consisted of a screening/baseline evaluation that assessed the participant's lifetime experience and experience over the last 90 days with suicide events and suicidal ideation and a postbaseline/ "Since Last Visit" evaluation that focused on suicidality since the last trial visit. Analysis Population Description: All participants who received at least 1 dose of aripiprazole IM depot. Total = Participants with multiple ratings within the same category were counted towards the total (used in result table).
    End point type
    Primary
    End point timeframe
    At baseline and Phase C trial weeks 1 to 52/ET
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    461
    Units: Participants
    number (not applicable)
        Total
    46
        Completed Suicide
    0
        Suicide Attempt
    3
        Preparatory action toward imminent suicide
    4
        Suicidal ideation
    46
        Non-suicidal self-injurious behaviour
    4
    No statistical analyses for this end point

    Primary: Injection Site Evaluations (Pain, Redness, Swelling, Induration) by Investigator Rating

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    End point title
    Injection Site Evaluations (Pain, Redness, Swelling, Induration) by Investigator Rating [8]
    End point description
    Participants were followed for 1 hour post-injection and the investigator (or qualified designee) re-assessed localized pain, redness, swelling, and induration at the injection site at 1 hour (± 15 minutes) post-injection with focus on the most recent injection site. Injection evaluations were completed on the same day that the injection was administered. Investigators rated localized pain, redness, swelling, and induration at the most recent injection site using a 4-point categorical scale ranging from absent to severe. The participant indicated the degree of pain at the most recent injection site using a VAS. Ratings ranged from 0 (no pain) to 100 (unbearably painful). Analysis Population Description: All participants who received at least 1 dose of aripiprazole IM depot in the IM Depot Maintenance Phase
    End point type
    Primary
    End point timeframe
    At baseline and Phase C trial weeks 4, 8, 12 to 48
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    464
    Units: Participants
    number (not applicable)
        Participant with any injection-site TEAE
    42
        Injection Site Bruising
    2
        Injection Site Erythema
    1
        Injection Site Induration
    1
        Injection Site Mass
    2
        Injection Site Pain
    34
        Injection Site Swelling
    4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Remained Stable at End of Treatment in Phase C

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    End point title
    Percentage of Participants Who Remained Stable at End of Treatment in Phase C
    End point description
    To evaluate the efficacy, as measured by the percentage of stable partcipants at baseline who remained stable at the end of treatment in the IM depot maintenance phase C, of aripiprazole IM depot administered every 4 weeks for up to 52 weeks to participants with bipolar I disorder. Analysis Population Description IM Depot Maintenance Phase Efficacy Sample: All participants who entered the IM Depot Maintenance Phase, received at least 1 dose of aripiprazole IM depot, and had at least 1 post-baseline efficacy evaluation in the IM Depot Maintenance Phase. Number analyzed (n) is the number of participants evaluated at the specified trial week.
    End point type
    Secondary
    End point timeframe
    At baseline, and phase C trial weeks 2, 4, 8, 12 to 52/ET
    End point values
    Phase C: Open-label IM Depot Maintenance Phase
    Number of subjects analysed
    464
    Units: Percentage of participants
    number (not applicable)
        Baseline (n= 463)
    100
        Week 2 (n= 430)
    96.98
        Week 4 (n= 432)
    97.22
        Week 8 (n= 413)
    95.64
        Week 12 (n= 406)
    96.31
        Week 16 (n= 396)
    96.46
        Week 20 (n= 381)
    95.54
        Week 24 (n= 361)
    96.4
        Week 28 (n= 346)
    95.09
        Week 32 (n= 287)
    97.91
        Week 36 (n= 271)
    95.94
        Week 40 (n= 255)
    98.04
        Week 44 (n= 249)
    97.59
        Week 48 (n= 243)
    97.53
        Week 52 (n=237)
    95.78
        Last Visit (n= 460)
    88.91
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any adverse events (AEs) were recorded from the signing of informed consent onward.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Phase C: Open-label IM Depot Maintenance Phase
    Reporting group description
    All De novo participants received open-label aripiprazole 400/300 mg IM depot and the participants who completed Trial 31-08-250 entered phase C on aripiprazole IM depot 400 mg, regardless of their last dose of IM depot. De novo participants also received daily supplemental oral aripiprazole (10 to 20 mg daily for non-Japanese sites; 6 to 18 mg for Japanese sites) for the first 2 weeks to maintain therapeutic plasma concentrations. For participants who completed Trial 31-08-250 (some of whom had received double-blind placebo), the use of supplemental oral aripiprazole for the first ≤ 2 weeks was at the investigator's discretion based on the clinical status of the participant. Administration of rescue therapy was recommended for participants who did not meet stability criteria during the IM Depot Maintenance Phase, unless in the investigator’s judgment withdrawal from the trial was considered more appropriate.

    Serious adverse events
    Phase C: Open-label IM Depot Maintenance Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 464 (6.47%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 464 (0.22%)
         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 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tardive dyskinesia
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Mania
         subjects affected / exposed
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Social avoidant behaviour
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hyperprolactinaemia
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Kidney infection
         subjects affected / exposed
    1 / 464 (0.22%)
         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
    Phase C: Open-label IM Depot Maintenance Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    367 / 464 (79.09%)
    Investigations
    Weight increased
         subjects affected / exposed
    62 / 464 (13.36%)
         occurrences all number
    66
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    68 / 464 (14.66%)
         occurrences all number
    79
    Headache
         subjects affected / exposed
    29 / 464 (6.25%)
         occurrences all number
    37
    Tremor
         subjects affected / exposed
    28 / 464 (6.03%)
         occurrences all number
    38
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    34 / 464 (7.33%)
         occurrences all number
    50
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    46 / 464 (9.91%)
         occurrences all number
    60
    Depression
         subjects affected / exposed
    26 / 464 (5.60%)
         occurrences all number
    35
    Insomnia
         subjects affected / exposed
    51 / 464 (10.99%)
         occurrences all number
    54
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    56 / 464 (12.07%)
         occurrences all number
    87
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 464 (5.17%)
         occurrences all number
    27

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2013
    Amendment 1- Clarifications and additions to trial procedures and inclusion/exclusion criteria intended to enhance subject safety and accuracy of data.
    04 Feb 2015
    Amendment 2- Due to a well-established safety profile in the completed aripiprazole IM depot trials, as well as sufficient collection of safety data within this trial, the duration of the IM Depot Maintenance Phase of the trial was reduced from 52 weeks to 28 weeks for rollover subjects (but not for de novo subjects or subjects at sites in Japan). The reduction of the IM Depot Maintenance Phase is described in detail in CSR Section 9.1.4 and in protocol Amendment 2 (Section 16.1.1, Appendix 23).

    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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