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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
    		 2018-002782-19
    Trial protocol
    		 DE   HU   BG   GB  
    Global end of trial date
    30 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2022
    First version publication date
    15 Oct 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3111-301-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03738215
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND number: 104,466
    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
    30 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety, and tolerability of cariprazine 1.5 mg/day and 3 mg/day compared with placebo as an adjunctive treatment to antidepressant therapy (ADT) in patients with major depressive disorder (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
    09 Nov 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Bulgaria: 103
    Country: Number of subjects enrolled
    Estonia: 29
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Ukraine: 100
    Country: Number of subjects enrolled
    United States: 458
    Worldwide total number of subjects
    757
    EEA total number of subjects
    190
    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)
    757
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 759 participants were randomized to double-blind treatment, 757 participants received at least 1 dose of double-blind investigational product (safety population), and 751 treated participants had at least 1 postbaseline assessment of Montgomery-Åsberg Depression Rating Scale (MADRS) total score (modified intent-to-treat population)

    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, Carer

    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
    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 1.5mg, orally, once daily in addition to their ongoing ADT (Same antidepressant and dose of ADT they were on at 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
    		Placebo + ADT Cariprazine 1.5 mg/day + ADT Cariprazine 3 mg/day + ADT
    Started
    253
    252
    252
    Completed
    229
    231
    219
    Not completed
    24
    21
    33
         Consent withdrawn by subject
    13
    11
    9
         Adverse event, non-fatal
    6
    3
    18
         Non-Compliance with study drug
    -
    1
    1
         Lost to follow-up
    3
    3
    5
         Lack of efficacy
    2
    2
    -
         Protocol deviation
    -
    1
    -
    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
    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 1.5mg, orally, once daily in addition to their ongoing ADT (Same antidepressant and dose of ADT they were on at 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
    229
    231
    219
    Completed
    237
    234
    230
    Not completed
    3
    5
    8
         Consent withdrawn by subject
    1
    1
    3
         Adverse event, non-fatal
    -
    -
    1
         Lost to follow-up
    2
    2
    4
         Reason not Specified
    -
    2
    -
    Joined
    11
    8
    19
         Discontinued DB Period,Followedup in Safety Period
    11
    8
    19

    Baseline characteristics

    		 Close Top of page
    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 1.5mg, orally, once daily in addition to their ongoing ADT (Same antidepressant and dose of ADT they were on at 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
    		 253 252 252 757
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.4 ± 11.89 43.3 ± 13.59 44.8 ± 13.33 -
    Gender categorical
    Units: Subjects
        Female
    		 184 191 180 555
        Male
    		 69 61 72 202
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 25 24 19 68
        Not Hispanic or Latino
    		 228 228 233 689
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 0 2
        Asian
    		 5 4 7 16
        Native Hawaiian or Other Pacific Islander
    		 1 3 0 4
        Black or African American
    		 43 37 30 110
        White
    		 203 205 215 623
        More than one race
    		 0 2 0 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 randomized participants who had ≥1 postbaseline assessment of the MADRS total
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    		 31.90 ± 5.680 32.81 ± 32.00 32.72 ± 4.920 -
    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 randomized participants who had ≥1 postbaseline assessment of the MADRS total score.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    		 31.90 ± 5.680 32.81 ± 4.951 32.72 ± 4.920 -
    Subject analysis sets

    Subject analysis set title
    Modified Intent-to-Treat Population (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT population includes all randomized participants who had ≥1 postbaseline assessment of the MADRS total score.

    Subject analysis sets values
    		 Modified Intent-to-Treat Population (mITT)
    Number of subjects
    751
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.8 ± 13.03
    Gender categorical
    Units: Subjects
        Female
    551
        Male
    200
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    68
        Not Hispanic or Latino
    683
    Race
    Units: Subjects
        American Indian or Alaska Native
    2
        Asian
    16
        Native Hawaiian or Other Pacific Islander
    4
        Black or African American
    109
        White
    618
        More than one race
    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 randomized participants who had ≥1 postbaseline assessment of the MADRS total
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    32.48 ± 5.203
    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 randomized participants who had ≥1 postbaseline assessment of the MADRS total score.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    32.48 ± 5.203

    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 1.5mg, orally, once daily in addition to their ongoing ADT (Same antidepressant and dose of ADT they were on at 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 1.5mg, orally, once daily in addition to their ongoing ADT (Same antidepressant and dose of ADT they were on at 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
    Modified Intent-to-Treat Population (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT population includes all randomized participants who had ≥1 postbaseline assessment of the MADRS total score.

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

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    End point title
    		 Total Score Change From Baseline to Week 6 in the MADRS (Montgomery-Åsberg Depression Rating Scale)
    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 randomized participants who had ≥1 postbaseline assessment of the MADRS total score. Number of subjects analyzed 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
    231
    231
    223
    Units: Score on a scale
        least squares mean (standard error)
    -11.5 ± 0.70
    -14.1 ± 0.70
    -13.1 ± 0.70
    Statistical analysis title
    		 Placebo v/s Cariprazine 1.5 mg/day
    Comparison groups
    Placebo + ADT v Cariprazine 1.5 mg/day + ADT
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [1]
    Method
    		 MMRM
    Parameter type
    		 Lease Squares Mean Difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.17
         upper limit
    		 -0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.88
    Notes
    [1] - Adjusted P-Value (based on truncated Hochberg with parameter=0.9)
    Statistical analysis title
    		 Placebo v/s Cariprazine 3 mg/day
    Comparison groups
    Placebo + ADT v Cariprazine 3 mg/day + ADT
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0727 [2]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.16
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Notes
    [2] - Adjusted P-Value (based on truncated Hochberg with parameter=0.9)

    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 randomized participants who had ≥1 postbaseline assessment of the MADRS total score. Number of subjects analyzed 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
    231
    231
    223
    Units: Score on a scale
        least squares mean (standard error)
    -1.1 ± 0.09
    -1.4 ± 0.09
    -1.3 ± 0.09
    Statistical analysis title
    		 Placebo v/s Cariprazine 1.5 mg/day
    Comparison groups
    Cariprazine 1.5 mg/day + ADT v Placebo + ADT
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0727 [3]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [3] - Adjusted P-Value (based on Hochberg procedure)
    Statistical analysis title
    		 Placebo v/s Cariprazine 3 mg/day
    Comparison groups
    Placebo + ADT v Cariprazine 3 mg/day + ADT
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0944 [4]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [4] - Adjusted P-Value (based on Hochberg procedure)

    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 randomized 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 / 253 (0.79%)
    3 / 252 (1.19%)
    3 / 252 (1.19%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 252 (0.40%)
    0 / 252 (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 / 253 (0.00%)
    1 / 252 (0.40%)
    0 / 252 (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
    Tibia fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 252 (0.40%)
    0 / 252 (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
    Nervous system disorders
    Multiple sclerosis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 252 (0.00%)
    0 / 252 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 252 (0.40%)
    0 / 252 (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
    Social circumstances
    Social stay hospitalisation
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 252 (0.40%)
    0 / 252 (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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 252 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 253 (0.00%)
    0 / 252 (0.00%)
    1 / 252 (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
    Kidney infection
         subjects affected / exposed
    0 / 253 (0.00%)
    0 / 252 (0.00%)
    1 / 252 (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
    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
    39 / 253 (15.42%)
    68 / 252 (26.98%)
    62 / 252 (24.60%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    3 / 253 (1.19%)
    13 / 252 (5.16%)
    20 / 252 (7.94%)
         occurrences all number
    3
    14
    23
    Headache
         subjects affected / exposed
    16 / 253 (6.32%)
    24 / 252 (9.52%)
    11 / 252 (4.37%)
         occurrences all number
    19
    25
    23
    Somnolence
         subjects affected / exposed
    7 / 253 (2.77%)
    13 / 252 (5.16%)
    11 / 252 (4.37%)
         occurrences all number
    7
    13
    12
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 253 (2.37%)
    20 / 252 (7.94%)
    16 / 252 (6.35%)
         occurrences all number
    6
    21
    19
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 253 (4.35%)
    18 / 252 (7.14%)
    16 / 252 (6.35%)
         occurrences all number
    18
    18
    16

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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”.

    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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