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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled Study of Cariprazine as an Adjunct to Antidepressants in the Treatment of Patients With Major Depressive Disorder Who Have Had an Inadequate Response to Antidepressants Alone

    Summary
    EudraCT number
    2018-003164-31
    Trial protocol
    CZ   SK   PL   FI  
    Global end of trial date
    06 Sep 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Sep 2022
    First version publication date
    11 Sep 2022
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    3111-302-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03739203
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Allergan Limited
    Sponsor organisation address
    Marlow International The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Global Medical Services, AbbVie, AbbVie Deutschland GmbH & Co. KG, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, AbbVie Deutschland GmbH & Co. KG, 001 8006339110, abbvieclinicaltrials@abbvie.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
    06 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the efficacy, safety and tolerability of cariprazine as an adjunctive treatment to antidepressant therapy (ADT) in patients with MDD who have had an inadequate response to antidepressants alone.
    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
    10 Nov 2018
    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
    United States: 382
    Country: Number of subjects enrolled
    Czechia: 63
    Country: Number of subjects enrolled
    Finland: 20
    Country: Number of subjects enrolled
    Poland: 125
    Country: Number of subjects enrolled
    Serbia: 88
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Slovakia: 65
    Worldwide total number of subjects
    752
    EEA total number of subjects
    273
    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)
    743
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Out of 752 enroled subjects,751 took ≥1 dose of double-blind investigational product and comprised the Safety Population.1 subject was randomised but did not receive treatment&was excluded from study analyses.At end of treatment in Double-blind Period,subjects continued on their background antidepressant therapy(ADT)&entered SafetyFollow-up Period.

    Period 1
    Period 1 title
    Double-blind Treatment Period (6 Weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + ADT
    Arm description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo supplied in capsules

    Investigational medicinal product name
    Antidepressant Therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ADT as prescribed by the physician per standard of care in clinical practice.

    Arm title
    Cariprazine 1.5 mg/day + ADT
    Arm description
    Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    VRAYLAR®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cariprazine supplied in capsules

    Investigational medicinal product name
    Antidepressant Therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ADT as prescribed by the physician per standard of care in clinical practice.

    Arm title
    Cariprazine 3 mg/day + ADT
    Arm description
    Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    VRAYLAR®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cariprazine supplied in capsules

    Investigational medicinal product name
    Antidepressant Therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ADT as prescribed by the physician per standard of care in clinical practice.

    Number of subjects in period 1 [1]
    Placebo + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT
    Started
    250
    250
    251
    Modified Intent-to Treat(mITT)Population
    249
    250
    251
    Completed
    235
    233
    226
    Not completed
    15
    17
    25
         Adverse Event
    6
    9
    13
         Non-compliance With Study Drug
    1
    3
    1
         Lost to follow-up
    1
    1
    2
         Reason not Specified
    1
    -
    1
         Withdrawal by subject
    4
    4
    6
         Protocol deviation
    1
    -
    1
         Lack of efficacy
    1
    -
    1
    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: One participant was randomised but did not receive treatment and was excluded from the study analyses.
    Period 2
    Period 2 title
    Safety Follow-Up Period (4 Weeks)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Open-label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + ADT
    Arm description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6. Participants continued on their background ADT without placebo during the Safety Follow-up Period. The investigator may have initiated alternative treatment as clinically necessary.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo supplied in capsules

    Investigational medicinal product name
    Antidepressant Therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ADT as prescribed by the physician per standard of care in clinical practice.

    Arm title
    Cariprazine 1.5 mg/day + ADT
    Arm description
    Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6. Participants continued on their background ADT without cariprazine during the Safety Follow-up Period. The investigator may have initiated alternative treatment as clinically necessary.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    VRAYLAR®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cariprazine supplied in capsules

    Investigational medicinal product name
    Antidepressant Therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ADT as prescribed by the physician per standard of care in clinical practice.

    Arm title
    Cariprazine 3 mg/day + ADT
    Arm description
    Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6. Participants continued on their background ADT without cariprazine during the Safety Follow-up Period. The investigator may have initiated alternative treatment as clinically necessary.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    VRAYLAR®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cariprazine supplied in capsules

    Investigational medicinal product name
    Antidepressant Therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ADT as prescribed by the physician per standard of care in clinical practice.

    Number of subjects in period 2
    Placebo + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT
    Started
    235
    233
    226
    Completed
    240
    240
    238
    Not completed
    2
    2
    4
         Death
    1
    -
    -
         Lost to follow-up
    -
    -
    2
         Reason not Specified
    -
    -
    2
         Withdrawal by subject
    1
    2
    -
    Joined
    7
    9
    16
         Discontinued DB Period,Followedup in Safety Period
    7
    9
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + ADT
    Reporting group description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

    Reporting group title
    Cariprazine 1.5 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

    Reporting group title
    Cariprazine 3 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6.

    Reporting group values
    Placebo + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT Total
    Number of subjects
    250 250 251 751
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.2 ± 12.12 45.0 ± 12.95 45.8 ± 12.45 -
    Gender categorical
    Units: Subjects
        Female
    191 185 197 573
        Male
    59 65 54 178
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    30 38 34 102
        Not Hispanic or Latino
    220 212 217 649
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 2 2
        Asian
    4 0 5 9
        Native Hawaiian or Other Pacific Islander
    0 1 0 1
        Black or African American
    29 32 22 83
        White
    217 216 221 654
        More than one race
    0 1 1 2
    Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
    The MADRS is a 10-item,clinician-rated scale that evaluates the participant’s depressive symptomatology during the past week.Participants are rated on items assessing feelings of sadness,lassitude,pessimism,inner tension,suicidality,reduced sleep or appetite,difficulty in concentration;lack of interest.Each item is scored on a 7-point scale with a score of 0=no symptoms and score of 6=maximum severity.The total score ranges from 0 to 60 with a higher score=more depression. mITT Population=all randomised participants who had ≥1 postbaseline assessment of the MADRS total score.
    Units: score on a scale
        arithmetic mean (standard deviation)
    ± 32.00 ± 4.246 32.25 ± 4.688 -
    Clinical Global Impression-Severity (CGI-S) Scale Score
    The CGI-S is a clinician-rated scale used to rate the severity of the participant’s current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1=normal, not at all ill and 7=among the most extremely ill participants. Higher score indicates worsening of mental illness. mITT Population included all randomised participants who had ≥1 postbaseline assessment of the MADRS total score.
    Units: score on a scale
        arithmetic mean (standard deviation)
    ± 4.61 ± 0.586 4.65 ± 0.654 -
    Subject analysis sets

    Subject analysis set title
    Placebo + ADT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

    Subject analysis sets values
    Placebo + ADT
    Number of subjects
    249
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
    Race
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
    Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
    The MADRS is a 10-item,clinician-rated scale that evaluates the participant’s depressive symptomatology during the past week.Participants are rated on items assessing feelings of sadness,lassitude,pessimism,inner tension,suicidality,reduced sleep or appetite,difficulty in concentration;lack of interest.Each item is scored on a 7-point scale with a score of 0=no symptoms and score of 6=maximum severity.The total score ranges from 0 to 60 with a higher score=more depression. mITT Population=all randomised participants who had ≥1 postbaseline assessment of the MADRS total score.
    Units: score on a scale
        arithmetic mean (standard deviation)
    32.99 ± 4.789
    Clinical Global Impression-Severity (CGI-S) Scale Score
    The CGI-S is a clinician-rated scale used to rate the severity of the participant’s current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1=normal, not at all ill and 7=among the most extremely ill participants. Higher score indicates worsening of mental illness. mITT Population included all randomised participants who had ≥1 postbaseline assessment of the MADRS total score.
    Units: score on a scale
        arithmetic mean (standard deviation)
    4.67 ± 0.599

    End points

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    End points reporting groups
    Reporting group title
    Placebo + ADT
    Reporting group description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

    Reporting group title
    Cariprazine 1.5 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

    Reporting group title
    Cariprazine 3 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6.
    Reporting group title
    Placebo + ADT
    Reporting group description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6. Participants continued on their background ADT without placebo during the Safety Follow-up Period. The investigator may have initiated alternative treatment as clinically necessary.

    Reporting group title
    Cariprazine 1.5 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6. Participants continued on their background ADT without cariprazine during the Safety Follow-up Period. The investigator may have initiated alternative treatment as clinically necessary.

    Reporting group title
    Cariprazine 3 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6. Participants continued on their background ADT without cariprazine during the Safety Follow-up Period. The investigator may have initiated alternative treatment as clinically necessary.

    Subject analysis set title
    Placebo + ADT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

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

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    End point title
    Change From Baseline to Week 6 in the MADRS (Montgomery-Åsberg Depression Rating Scale) Total Score
    End point description
    The 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 item 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. The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change from Baseline indicates improvement. Mixed-effects Model for Repeated Measures (MMRM) was used for analyses.mITT Population included all randomised participants who had ≥1 postbaseline assessment of the MADRS total score. Number of subjects analysed are the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Baseline and Week 6
    End point values
    Placebo + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT
    Number of subjects analysed
    236
    237
    231
    Units: score on a scale
        least squares mean (standard error)
    -13.4 ± 0.70
    -13.8 ± 0.69
    -14.8 ± 0.70
    Statistical analysis title
    Cariprazine 1.5 mg/day Versus Placebo
    Comparison groups
    Placebo + ADT v Cariprazine 1.5 mg/day + ADT
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6798 [1]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.88
    Notes
    [1] - MMRM=Fixed effects:treatment group,ADT failure category,visit,treatment group-by-visit interaction,countries;Covariates:Baseline value& Baseline by-visit interaction.Unstructured covariance matrix models covariance of within-participant scores.
    Statistical analysis title
    Cariprazine 3 mg/day Versus Placebo
    Comparison groups
    Placebo + ADT v Cariprazine 3 mg/day + ADT
    Number of subjects included in analysis
    467
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1245 [2]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.11
         upper limit
    0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.89
    Notes
    [2] - MMRM=Fixed effects:treatment group,ADT failure category,visit,treatment group-by-visit interaction,countries;Covariates:Baseline value& Baseline by-visit interaction.Unstructured covariance matrix models covariance of within-participant scores.

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

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    End point title
    Change From Baseline to Week 6 in the Clinical Global Impressions-Severity (CGI-S) Score
    End point description
    The CGI-S is a clinician-rated scale used to rate the severity of the participant’s current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1=normal, not at all ill and 7=among the most extremely ill participants. Higher scores indicate worsening of mental illness. A negative change from Baseline indicates improvement. MMRM was used for analyses. mITT Population included all randomised participants who had ≥1 postbaseline assessment of the MADRS total score. Number of subjects analysed are the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    Placebo + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT
    Number of subjects analysed
    236
    237
    231
    Units: score on a scale
        least squares mean (standard error)
    -1.4 ± 0.09
    -1.4 ± 0.09
    -1.6 ± 0.09
    Statistical analysis title
    Cariprazine 1.5 mg/day Versus Placebo
    Comparison groups
    Placebo + ADT v Cariprazine 1.5 mg/day + ADT
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5152 [3]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [3] - MMRM=Fixed effects:treatment group,ADT failure category,visit,treatment group-by-visit interaction,countries;Covariates:Baseline value& Baseline by-visit interaction.Unstructured covariance matrix models covariance of within-participant scores.
    Statistical analysis title
    Cariprazine 3 mg/day Versus Placebo
    Comparison groups
    Placebo + ADT v Cariprazine 3 mg/day + ADT
    Number of subjects included in analysis
    467
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0573 [4]
    Method
    MMRM
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [4] - MMRM=Fixed effects:treatment group,ADT failure category,visit,treatment group-by-visit interaction,countries;Covariates:Baseline value& Baseline by-visit interaction.Unstructured covariance matrix models covariance of within-participant scores.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug until 30 days after the last dose of study drug (up to 12 weeks)
    Adverse event reporting additional description
    Safety Population included all participants in the randomised population who took ≥1 dose of double-blind investigational product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo + ADT
    Reporting group description
    Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

    Reporting group title
    Cariprazine 1.5 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6.

    Reporting group title
    Cariprazine 3 mg/day + ADT
    Reporting group description
    Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6.

    Serious adverse events
    Placebo + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 250 (0.80%)
    3 / 250 (1.20%)
    1 / 251 (0.40%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    Injury, poisoning and procedural complications
    ANIMAL BITE
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 250 (0.40%)
    0 / 251 (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
    FALL
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 250 (0.40%)
    0 / 251 (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
    FIBULA FRACTURE
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 250 (0.40%)
    0 / 251 (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
    LIGAMENT SPRAIN
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 250 (0.40%)
    0 / 251 (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
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 250 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 250 (0.00%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 250 (0.00%)
    0 / 251 (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
    Psychiatric disorders
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 250 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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 + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 250 (21.60%)
    70 / 250 (28.00%)
    85 / 251 (33.86%)
    Nervous system disorders
    AKATHISIA
         subjects affected / exposed
    9 / 250 (3.60%)
    19 / 250 (7.60%)
    29 / 251 (11.55%)
         occurrences all number
    10
    19
    34
    SOMNOLENCE
         subjects affected / exposed
    11 / 250 (4.40%)
    12 / 250 (4.80%)
    17 / 251 (6.77%)
         occurrences all number
    11
    13
    17
    HEADACHE
         subjects affected / exposed
    27 / 250 (10.80%)
    24 / 250 (9.60%)
    27 / 251 (10.76%)
         occurrences all number
    33
    32
    40
    Gastrointestinal disorders
    NAUSEA
         subjects affected / exposed
    10 / 250 (4.00%)
    14 / 250 (5.60%)
    16 / 251 (6.37%)
         occurrences all number
    15
    16
    21
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    9 / 250 (3.60%)
    16 / 250 (6.40%)
    25 / 251 (9.96%)
         occurrences all number
    12
    18
    29

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2018
    The following changes were made in Amendment 1:Added the EudraCT number. Added text to extend the safety follow-up period from 1 to 4 weeks. Blood alcohol at Visit 1 as measured by Breathalyzer was added to expedite turnaround time for blood alcohol concentration results. Included a 12-month lookback to the Columbia–Suicide Severity Rating Scale (C-SSRS) completed at Visit 1 (Screening). Specified primary estimand and alternative covariance structures; added one more sensitivity analysis. The reporting period for pregnancies was changed from 3 months to 12 weeks.
    27 Jul 2020
    The following changes were made in Amendment 3: Revised text to clarify expectation around inadequate response to 1-3 ADTs in the current episode. Added text to extend the screening period up to an additional 7 days if needed with Sponsor approval. Extended the maximum duration of current major depressive episode at screening from “not exceeding 18 months” to “less than 24 months”. Added protocol modifications for Coronavirus disease 2019 (COVID-19).

    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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