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    Clinical Trial Results:
    A Double-blind, Placebo Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar Depression

    Summary
    EudraCT number
    2011-002334-39
    Trial protocol
    BG  
    Global end of trial date
    10 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Apr 2018
    First version publication date
    18 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RGH-MD-56
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01396447
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Forest Laboratories, LLC, an Allergan Affiliate
    Sponsor organisation address
    5 Giralda Farms, Madison, United States, NJ 07940
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@Allergan.com
    Scientific contact
    Therapeutic Area Head, Allergan plc, 001 862-261-7000, IR-CTRegistration@Allergan.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
    10 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy, safety, and tolerability of cariprazine relative to placebo in subjects with bipolar depression.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 65
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    Russian Federation: 93
    Country: Number of subjects enrolled
    Ukraine: 68
    Country: Number of subjects enrolled
    United States: 340
    Worldwide total number of subjects
    584
    EEA total number of subjects
    65
    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)
    581
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Adult subjects with a diagnosis of bipolar I disorder with a current major depressive episode were considered for participation in the study.

    Pre-assignment
    Screening details
    A total of 1013 subjects were screened for eligibility; 584 subjects were randomized to receive double-blind treatment; 578 subjects received at least 1 dose of double-blind treatment (Safety Population).

    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, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo orally once a day for 8 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo nontrade capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo orally once a day for 8 weeks.

    Arm title
    Cariprazine 0.75 mg
    Arm description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine nontrade capsules, 0.75 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.

    Arm title
    Cariprazine 1.5 mg
    Arm description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine nontrade capsules, 1.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.

    Arm title
    Cariprazine 3.0 mg
    Arm description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine nontrade capsules, 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.

    Number of subjects in period 1 [1]
    Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
    Started
    145
    141
    146
    146
    Completed
    105
    103
    117
    94
    Not completed
    40
    38
    29
    52
         Withdrawal of Consent
    11
    9
    4
    15
         Adverse event, non-fatal
    15
    12
    12
    17
         Lost to follow-up
    4
    8
    7
    9
         Other Miscellaneous Reasons
    -
    2
    1
    -
         Insufficient Therapeutic Response
    5
    5
    2
    4
         Protocol deviation
    5
    2
    3
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline Period is based on the Safety Population, that included all randomized participants who received at least 1 dose of investigational product. 6 participants did not receive study drug and are excluded.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo orally once a day for 8 weeks.

    Reporting group title
    Cariprazine 0.75 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.

    Reporting group title
    Cariprazine 1.5 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.

    Reporting group values
    Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg Total
    Number of subjects
    145 141 146 146 578
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    144 141 145 145 575
        From 65-84 years
    1 0 1 1 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    43.6 ( 12.0 ) 40.1 ( 11.2 ) 40.9 ( 11.4 ) 42.8 ( 10.8 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    89 91 92 88 360
        Male
    56 50 54 58 218
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    12 13 11 12 48
        Not Hispanic or Latino
    133 128 135 134 530
        Unknown or Not Reported
    0 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    2 1 1 3 7
        Asian
    1 1 2 0 4
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    30 26 30 26 112
        White
    110 111 109 113 443
        More than one race
    0 0 0 0 0
        Other
    2 2 4 4 12
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    79.98 ( 17.08 ) 80.81 ( 18.36 ) 81.43 ( 16.79 ) 81.45 ( 17.86 ) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.81 ( 5.27 ) 28.42 ( 5.71 ) 28.44 ( 5.39 ) 28.28 ( 5.64 ) -
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    91.40 ( 14.24 ) 93.32 ( 15.45 ) 93.38 ( 14.55 ) 93.24 ( 15.40 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo orally once a day for 8 weeks.

    Reporting group title
    Cariprazine 0.75 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.

    Reporting group title
    Cariprazine 1.5 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.

    Primary: Change From Baseline in the Montgomery-Åsberg Depression Rating Scale Total Score at Week 6

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    End point title
    Change From Baseline in the Montgomery-Åsberg Depression Rating Scale Total Score at Week 6
    End point description
    The Montgomery-Åsberg Depression Rating Scale is a 10-item, clinician-rated scale that evaluates the subject's depressive symptomatology during the past week. Subjects are rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each item is scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity. The scores on the 10 items are summed for a total score that can range from 0 to 60. A higher score indicates greater depression. A negative change score indicates improvement. Intent-to-treat population: All randomized subjects who took at least 1 dose of investigational product and had at least 1 post-baseline assessment of the Montgomery-Åsberg Depression Rating Scale.
    End point type
    Primary
    End point timeframe
    Baseline to Week 6
    End point values
    Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
    Number of subjects analysed
    141
    140
    145
    145
    Units: units on a scale
        least squares mean (standard error)
    -11.1 ( 0.9 )
    -13.0 ( 0.9 )
    -15.1 ( 0.8 )
    -13.7 ( 0.9 )
    Statistical analysis title
    Cariprazine 0.75 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 0.75 mg
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1292 [1]
    Method
    Repeated measures mixed-effects model
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    0.5
    Notes
    [1] - The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
    Statistical analysis title
    Cariprazine 1.5 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 1.5 mg
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [2]
    Method
    Repeated measures mixed-effects model
    Parameter type
    Mean difference (final values)
    Point estimate
    -4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.3
         upper limit
    -1.6
    Notes
    [2] - The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
    Statistical analysis title
    Cariprazine 3.0 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 3.0 mg
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0374 [3]
    Method
    Repeated measures mixed-effects model
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.9
         upper limit
    -0.1
    Notes
    [3] - The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.

    Secondary: Change From Baseline in the Clinical Global Impressions-Severity Total Score at Week 6

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    End point title
    Change From Baseline in the Clinical Global Impressions-Severity Total Score at Week 6
    End point description
    The Clinical Global Impressions-Severity scale is a clinician-rated scale that measures the overall severity of a subject's illness in comparison with the severity of illness in other subjects the physician has observed. The subject is rated on a scale from 1 to 7 with 1 indicating a "normal state" and 7 indicating "among the most extremely ill subjects." A higher score indicates greater illness. A negative change score indicates improvement. Intent-to-treat population: All randomized subjects who took at least 1 dose of investigational product and had at least 1 post-Baseline assessment of the Montgomery-Åsberg Depression Rating Scale.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
    Number of subjects analysed
    141
    140
    145
    145
    Units: units on a scale
        least squares mean (standard error)
    -1.0 ( 0.1 )
    -1.1 ( 0.1 )
    -1.4 ( 0.1 )
    -1.3 ( 0.1 )
    Statistical analysis title
    Cariprazine 0.75 mg vs Placebo
    Statistical analysis description
    The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
    Comparison groups
    Placebo v Cariprazine 0.75 mg
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3025
    Method
    Repeated measures mixed-effects model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.1
    Statistical analysis title
    Cariprazine 1.5 mg vs Placebo
    Statistical analysis description
    The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
    Comparison groups
    Placebo v Cariprazine 1.5 mg
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0044
    Method
    Repeated measures mixed-effects model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.2
    Statistical analysis title
    Cariprazine 3.0 mg vs Placebo
    Statistical analysis description
    The analysis included treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
    Comparison groups
    Placebo v Cariprazine 3.0 mg
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0489
    Method
    Repeated measures mixed-effects model
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    0

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected and recorded from the time the subject signs the informed consent form until 30 days after the last dose of treatment.
    Adverse event reporting additional description
    Safety population: All randomized subjects who took at least 1 dose of investigational product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo orally once a day for 8 weeks.

    Reporting group title
    Cariprazine 0.75 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2 and cariprazine 0.75 mg orally once a day starting on Day 3 for the remainder of the 8 week treatment period.

    Reporting group title
    Cariprazine 1.5 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, and cariprazine 1.5 mg orally once a day starting on Day 8 for the remainder of the 8 week treatment period.

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    Subjects received cariprazine 0.5 mg orally once on Days 1-2, cariprazine 0.75 mg orally once on Days 3-4, cariprazine 1.0 mg orally once on Days 5-7, cariprazine 1.5 mg orally on Days 8-14, and cariprazine 3.0 mg orally once a day starting on Day 15 for the remainder of the 8 week treatment period.

    Serious adverse events
    Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 145 (3.45%)
    1 / 141 (0.71%)
    2 / 146 (1.37%)
    2 / 146 (1.37%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 141 (0.00%)
    1 / 146 (0.68%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 141 (0.00%)
    0 / 146 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 141 (0.00%)
    1 / 146 (0.68%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Vertigo CNS origin
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 141 (0.00%)
    0 / 146 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
    0 / 146 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
    0 / 146 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 141 (0.71%)
    0 / 146 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 141 (0.00%)
    1 / 146 (0.68%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
    0 / 146 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
    0 / 146 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Cariprazine 0.75 mg Cariprazine 1.5 mg Cariprazine 3.0 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 145 (28.97%)
    43 / 141 (30.50%)
    51 / 146 (34.93%)
    56 / 146 (38.36%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    2 / 145 (1.38%)
    4 / 141 (2.84%)
    7 / 146 (4.79%)
    21 / 146 (14.38%)
         occurrences all number
    2
    4
    7
    24
    Headache
         subjects affected / exposed
    17 / 145 (11.72%)
    11 / 141 (7.80%)
    11 / 146 (7.53%)
    10 / 146 (6.85%)
         occurrences all number
    20
    12
    12
    10
    Somnolence
         subjects affected / exposed
    7 / 145 (4.83%)
    6 / 141 (4.26%)
    10 / 146 (6.85%)
    10 / 146 (6.85%)
         occurrences all number
    7
    6
    10
    11
    Gastrointestinal disorders
    Nausea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 145 (4.83%)
    12 / 141 (8.51%)
    12 / 146 (8.22%)
    12 / 146 (8.22%)
         occurrences all number
    10
    13
    15
    13
    Diarrhoea
         subjects affected / exposed
    10 / 145 (6.90%)
    2 / 141 (1.42%)
    9 / 146 (6.16%)
    3 / 146 (2.05%)
         occurrences all number
    11
    2
    9
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    12 / 145 (8.28%)
    16 / 141 (11.35%)
    10 / 146 (6.85%)
    17 / 146 (11.64%)
         occurrences all number
    13
    18
    11
    19
    Restlessness
         subjects affected / exposed
    5 / 145 (3.45%)
    4 / 141 (2.84%)
    4 / 146 (2.74%)
    9 / 146 (6.16%)
         occurrences all number
    5
    4
    5
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2011
    • Add the cariprazine 3 mg/day treatment group, which increased the number of treatment groups from 3 to 4 and increased the number of study centers • Increase the screening period from up to 7 days to up to 14 days and decrease the safety follow-up period from 2 weeks to 1 week • Allow hospitalization of study subjects per local clinical practice • Modify inclusion criteria #2, #3 (duration of current depressive episode), #4 (verification of previous manic or mixed episode), and #10 (body mass index [BMI]) • Modify exclusion criteria #7 (urine drug screen), #9 (prior treatment trials with antidepressants or mood stabilizers), #15 (prior treatment with clozapine), #16 (concomitant medications), #18 (vagus nerve stimulation and experimental treatments), and #30 (hepatitis C) • Revise the cariprazine starting dose from 0.25 mg/day to 0.50 mg/day and change investigational product form from tablets to capsules • Clarify the start of dosing on the evening of Visit 2 or the morning after Visit 2 • Clarify noncompliance due to missed doses • Remove Clinical Global Impressions–Improvement (CGI-I) assessment at all visits and Functioning Assessment Short Test (FAST) assessment at Visit 5 • Remove hepatitis C virus Recombinant ImmunoBlot Assay (HCV RIBA), propoxyphene, tricyclic antidepressants, folate and vitamin B testing and change hemoglobin A1c testing from reflex to required at Visits 1 and 7 • Revise the primary efficacy analysis section and sample size estimate to account for the additional treatment group and update endpoint to Week 6 and Week 8
    29 Sep 2011
    •Revise the efficacy analyses section to change the multiplicity strategy from a serial gatekeeping procedure to a matched parallel gatekeeping procedure • Update the power to reflect the new multiplicity strategy • Modify the study center pooling algorithm to require at least 2 intent-to-treat (ITT) subjects per treatment group at each study center • Specify the range of shift parameter values for the pattern-mixture model (PMM) sensitivity analysis • Modify inclusion criterion #4 to provide additional guidance on verifying previous manic episodes • Modify exclusion #9 to clarify and provide additional guidance on the definition of an adequate trial and exclusion #21b to clarify the contraceptive requirements • Update the concomitant medication section to clarify the use of allowed and disallowed medications • Clarify the order of assessing procedures at Visit 2 • Modify the collection of BP and pulse measurements.
    09 Nov 2012
    • Specify Week 6 as the primary endpoint for primary and secondary analysis, per FDA Feedback • Clarify inclusion criterion # 4; revise exclusion criterion #30 for consistency with other cariprazine studies • Update the sample size calculation section to reflect changes in the endpoint of primary and secondary parameters •Modify the analysis model for the imputed data with the PMM approach from mixed-effects model for repeated measures (MMRM) to analysis of covariance (ANCOVA).

    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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