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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter, Fixed-dose Clinical Trial Evaluating the Efficacy, Safety and Tolerability of Cariprazine in Patients with Bipolar I Depression

    Summary
    EudraCT number
    2016-000757-13
    Trial protocol
    EE   LT   PL   BG  
    Global end of trial date
    19 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Nov 2018
    First version publication date
    24 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RGH-MD-54
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02670551
    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
    19 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the efficacy, safety, and tolerability of cariprazine 1.5 milligram (mg)/day and 3.0 mg/day relative to placebo in participants with bipolar I depression.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Mar 2016
    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: 116
    Country: Number of subjects enrolled
    Estonia: 10
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Poland: 63
    Country: Number of subjects enrolled
    United States: 290
    Worldwide total number of subjects
    488
    EEA total number of subjects
    198
    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)
    485
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Total 782 participants were screened for eligibility; 488 participants randomised to receive double-blind treatment; 480 participants received at least 1 dose of double-blind treatment (Safety Population) and 474 participants had at least 1 postbaseline Montgomery-Åsberg Depression Rating Scale total score assessment (Intent-to-Treat 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
    Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 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
    Participants received placebo-matching cariprazine capsule, orally, once a day for 6 weeks.

    Arm title
    Cariprazine 1.5 mg
    Arm description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks.
    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
    Participants received cariprazine 1.5 mg capsule, orally, once a day for 6 weeks.

    Arm title
    Cariprazine 3.0 mg
    Arm description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 mg capsule, one per day, orally beginning on Day 15 for 4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine nontrade capsules, 3.0 mg
    Investigational medicinal product code
    RGH-188
    Other name
    VRAYLAR®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received cariprazine 3.0 mg capsule, orally, once a day beginning on Day 15 for 4 weeks.

    Number of subjects in period 1
    Placebo Cariprazine 1.5 mg Cariprazine 3.0 mg
    Started
    163
    160
    165
    Received Treatment (Safety Population)
    158
    157
    165
    Completed
    135
    134
    134
    Not completed
    28
    26
    31
         Protocol deviation
    1
    -
    -
         Noncompliance with study drug
    3
    3
    2
         Withdrawal of Consent
    6
    3
    8
         Lack of efficacy
    2
    -
    3
         Other Miscellaneous Reasons
    2
    3
    3
         Adverse event, non-fatal
    4
    7
    9
         Did Not Receive Treatment
    5
    3
    -
         Lost to follow-up
    5
    7
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 weeks.

    Reporting group title
    Cariprazine 1.5 mg
    Reporting group description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks.

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 mg capsule, one per day, orally beginning on Day 15 for 4 weeks.

    Reporting group values
    Placebo Cariprazine 1.5 mg Cariprazine 3.0 mg Total
    Number of subjects
    163 160 165 488
    Age categorical
    Units: Subjects
        18 - 64 years
    161 159 165 485
        65 - 84 years
    2 1 0 3
        >= 85 Years
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    43.9 (18 to 65) 42.6 (18 to 65) 41.9 (19 to 64) -
    Sex: Female, Male
    Units: Subjects
        Female
    94 101 94 289
        Male
    69 59 71 199
    Race/Ethnicity, Customized
    Units: Subjects
        White
    118 126 126 370
        Black or African American
    39 29 37 105
        Asian
    3 2 0 5
        American Indian or Alaska Native
    1 1 1 3
        Native Hawaiian or Other Pacific Islander
    2 0 0 2
        Multiple
    0 2 1 3
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    13 15 14 42
        Not Hispanic or Latino
    150 145 151 446
    Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Baseline
    The Montgomery-Åsberg Depression Rating Scale is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants were rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each of the 10 items was scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity for a total possible score of 0 (best) to 60 (worst).
    Units: score on a scale
        arithmetic mean (standard deviation)
    ± ± ± -
    Clinical Global Impressions-Severity (CGI-S) Score at Baseline
    The Clinical Global Impressions-Severity (CGI-S) is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of other participants the physician has observed. The participant was rated on a scale from 1 to 7, with 1 indicating a "normal state" and 7 indicating "among the most extremely ill participants."
    Units: score on a scale
        arithmetic mean (standard deviation)
    ± ± ± -
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 weeks.

    Subject analysis set title
    Cariprazine 1.5 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks.

    Subject analysis set title
    Cariprazine 3.0 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 milligram (mg) capsule, one per day, orally beginning on Day 15 for 4 weeks.

    Subject analysis sets values
    Placebo Cariprazine 1.5 mg Cariprazine 3.0 mg
    Number of subjects
    156
    154
    164
    Age categorical
    Units: Subjects
        18 - 64 years
        65 - 84 years
        >= 85 Years
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White
        Black or African American
        Asian
        American Indian or Alaska Native
        Native Hawaiian or Other Pacific Islander
        Multiple
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
    Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Baseline
    The Montgomery-Åsberg Depression Rating Scale is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants were rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each of the 10 items was scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity for a total possible score of 0 (best) to 60 (worst).
    Units: score on a scale
        arithmetic mean (standard deviation)
    30.3 ± 4.5
    30.6 ± 4.2
    31.1 ± 4.8
    Clinical Global Impressions-Severity (CGI-S) Score at Baseline
    The Clinical Global Impressions-Severity (CGI-S) is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of other participants the physician has observed. The participant was rated on a scale from 1 to 7, with 1 indicating a "normal state" and 7 indicating "among the most extremely ill participants."
    Units: score on a scale
        arithmetic mean (standard deviation)
    4.5 ± 0.5
    4.5 ± 0.5
    4.5 ± 0.5

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 weeks.

    Reporting group title
    Cariprazine 1.5 mg
    Reporting group description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks.

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 mg capsule, one per day, orally beginning on Day 15 for 4 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 weeks.

    Subject analysis set title
    Cariprazine 1.5 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks.

    Subject analysis set title
    Cariprazine 3.0 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 milligram (mg) capsule, one per day, orally beginning on Day 15 for 4 weeks.

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

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    End point title
    Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Week 6
    End point description
    The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants were rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each of the 10 items was scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity for a total possible score of 0 (best) to 60 (worst). A negative change from Baseline indicates improvement. The Intent-to-Treat (ITT) Population included all participants from the safety population who had at least 1 postbaseline assessment of the MADRS total score. Overall number of participants analysed is the number of participants with data available for analysis at the given time-point.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) to Week 6
    End point values
    Placebo Cariprazine 1.5 mg Cariprazine 3.0 mg
    Number of subjects analysed
    137
    135
    136
    Units: score on a scale
        least squares mean (standard error)
    -12.6 ± 0.76
    -15.1 ± 0.77
    -15.6 ± 0.76
    Statistical analysis title
    Cariprazine 1.5 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 1.5 mg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0331 [2]
    Method
    Mixed Model Repeated Measures (MMRM)
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.6
         upper limit
    -0.4
    Notes
    [1] - To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.
    [2] - MMRM analysis was used. Fixed factors: treatment group, pooled study centre, visit, treatment-group-by-visit interaction. Covariates: Baseline value, baseline value-by-visit interaction. P-value was adjusted by matched parallel gatekeeping procedure.
    Statistical analysis title
    Cariprazine 3.0 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 3.0 mg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0103 [4]
    Method
    Mixed Model Repeated Measures (MMRM)
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.1
         upper limit
    -0.9
    Notes
    [3] - To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.
    [4] - MMRM analysis was used. Fixed factors: treatment group, pooled study centre, visit, treatment-group-by-visit interaction. Covariates: Baseline value, baseline value-by-visit interaction. P-value was adjusted by matched parallel gatekeeping procedure.

    Secondary: Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 6

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    End point title
    Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 6
    End point description
    The Clinical Global Impressions-Severity is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of other participants the physician has observed. The participant was rated on a scale from 1 to 7, with 1 indicating a "normal state" and 7 indicating "among the most extremely ill participants." A negative change from Baseline indicates improvement. ITT Population included all participants from the safety population who had at least 1 postbaseline assessment of the MADRS total score. Overall number of participants analysed is the number of participants with data available for analysis at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 6
    End point values
    Placebo Cariprazine 1.5 mg Cariprazine 3.0 mg
    Number of subjects analysed
    137
    135
    136
    Units: score on a scale
        least squares mean (standard error)
    -1.3 ± 0.09
    -1.6 ± 0.10
    -1.6 ± 0.09
    Statistical analysis title
    Cariprazine 1.5 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 1.5 mg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0714 [6]
    Method
    Mixed Model Repeated Measures (MMRM)
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    0
    Notes
    [5] - To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.
    [6] - MMRM analysis was used. Fixed factors: treatment group, pooled study centre, visit, treatment-group-by-visit interaction. Covariates: Baseline value, baseline value-by-visit interaction. P-value was adjusted by matched parallel gatekeeping procedure.
    Statistical analysis title
    Cariprazine 3.0 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 3.0 mg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0662 [8]
    Method
    Mixed Model Repeated Measures (MMRM)
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    0
    Notes
    [7] - To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.
    [8] - MMRM analysis was used. Fixed factors: treatment group, pooled study centre, visit, treatment-group-by-visit interaction. Covariates: Baseline value, baseline value-by-visit interaction. P-value was adjusted by matched parallel gatekeeping procedure.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose to 30 days past last dose (Up to 80 Days)
    Adverse event reporting additional description
    Safety Population included all randomised participants who took at least 1 dose of double-blind investigational product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 weeks.

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 milligram (mg) capsule, one per day, orally beginning on Day 15 for 4 weeks.

    Reporting group title
    Cariprazine 1.5 mg
    Reporting group description
    Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks.

    Serious adverse events
    Placebo Cariprazine 3.0 mg Cariprazine 1.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 158 (1.27%)
    2 / 165 (1.21%)
    2 / 157 (1.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 165 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 165 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 165 (0.61%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 165 (0.61%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 165 (0.00%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chronic tonsillitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 165 (0.00%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Cariprazine 3.0 mg Cariprazine 1.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 158 (27.22%)
    62 / 165 (37.58%)
    48 / 157 (30.57%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 158 (8.23%)
    12 / 165 (7.27%)
    7 / 157 (4.46%)
         occurrences all number
    17
    15
    7
    Akathisia
         subjects affected / exposed
    5 / 158 (3.16%)
    9 / 165 (5.45%)
    10 / 157 (6.37%)
         occurrences all number
    5
    9
    12
    Dizziness
         subjects affected / exposed
    3 / 158 (1.90%)
    6 / 165 (3.64%)
    8 / 157 (5.10%)
         occurrences all number
    3
    7
    8
    Somnolence
         subjects affected / exposed
    3 / 158 (1.90%)
    6 / 165 (3.64%)
    8 / 157 (5.10%)
         occurrences all number
    3
    6
    8
    Sedation
         subjects affected / exposed
    2 / 158 (1.27%)
    5 / 165 (3.03%)
    8 / 157 (5.10%)
         occurrences all number
    2
    5
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 158 (6.96%)
    12 / 165 (7.27%)
    7 / 157 (4.46%)
         occurrences all number
    11
    12
    7
    Restlessness
         subjects affected / exposed
    6 / 158 (3.80%)
    12 / 165 (7.27%)
    2 / 157 (1.27%)
         occurrences all number
    6
    14
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 158 (0.63%)
    15 / 165 (9.09%)
    6 / 157 (3.82%)
         occurrences all number
    1
    16
    6
    Dry mouth
         subjects affected / exposed
    9 / 158 (5.70%)
    3 / 165 (1.82%)
    6 / 157 (3.82%)
         occurrences all number
    9
    3
    6

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2016
    The following changes were implemented with Amendment 1: • Used the clinician-rated Columbia–Suicide Severity Rating Scale (C-SSRS), rather than the patient-rated scale, in order to provide greater clinical oversight • Clarification of the following exclusion criteria: - 6: was modified to reflect the classification of substance-related disorders - 16: was modified to clarify the allowed duration and to ensure consistency of bipolar disorder diagnosis - 18: was revised to clarify and limit the doses and allowances for benzodiazepines • Deletion of exclusion criterion 19: because cariprazine had been approved for prescription use (in the United States), there was no clinical rationale for excluding participants with prior participation in a cariprazine study. • Addition of an exclusion criterion (23) addressing use of contraception for male participants; and amendment of exclusion 24 to clarify allowable contraception methods Clarification of Table 9.4.5-1 (blister card configuration and dosing regimen); • Clarification on the use of lorazepam (or equivalent benzodiazepine) as rescue medication for agitation, restlessness, and hostility, and removal of the restriction on injectable benzodiazepine agents for use as rescue medication for agitation, restlessness, and hostility.
    17 Feb 2016
    The following changes were implemented with Amendment 2: Revised the wording of exclusion criterion 18 to correct an error (ie, the omission of the word “no” in the sub-bullet pertaining to use of benzodiazepines, which caused this exception to exclusion criterion 18 to convey the reverse of what was intended).

    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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