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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
    		 2016-000756-98
    Trial protocol
    		 SK   HR   BG  
    Global end of trial date
    18 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2019
    First version publication date
    08 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RGH-MD-53
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02670538
    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
    18 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy, safety, and tolerability of cariprazine 1.5 milligrams (mg)/day and 3 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
    31 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: 32
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Slovakia: 18
    Country: Number of subjects enrolled
    Croatia: 21
    Country: Number of subjects enrolled
    Serbia: 68
    Country: Number of subjects enrolled
    Ukraine: 37
    Country: Number of subjects enrolled
    United States: 313
    Worldwide total number of subjects
    493
    EEA total number of subjects
    75
    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)
    491
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total of 866 participants were screened, 493 were randomised to receive double-blind treatment (Randomised Population); 490 participants received at least 1 dose of double-blind treatment (Safety Population) and 478 participants had at least 1 postbaseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score assessment (ITT 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
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Following a 7 to 14 day screening/washout period, matching placebo capsule, one per day, orally for 6 weeks.
    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
    Matching placebo capsule, one per day, orally for 6 weeks.

    Arm title
    		 Cariprazine 1.5 mg
    Arm description
    		 Following a 7 to 14 day screening/washout period, cariprazine 1.5 mg capsule, one per day, orally for 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cariprazine 1.5 mg capsule, one per day, orally for 6 weeks.

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

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Cariprazine 1.5 milligrams (mg) capsule, one per day, orally for 2 weeks increased to cariprazine 3.0 mg capsule one per day orally beginning on Day 15 for 4 weeks.

    Number of subjects in period 1
    		Placebo Cariprazine 1.5 mg Cariprazine 3.0 mg
    Started
    167
    168
    158
    Safety Population : Received Study Drug
    165
    167
    158
    Intent-to-Treat Population
    163
    162
    153
    Completed
    135
    136
    128
    Not completed
    32
    32
    30
         Withdrawal of Consent
    8
    6
    5
         Noncompliance with Study Drug
    1
    3
    2
         Adverse event
    5
    5
    11
         Lost to follow-up
    8
    12
    7
         Other Miscellaneous Reasons
    -
    1
    2
         Lack of efficacy
    7
    1
    2
         Protocol deviation
    3
    4
    1

    Baseline characteristics

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

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

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    		 Following a 7 to 14 day screening/washout period, cariprazine 1.5 mg capsule, one per day, orally for 2 weeks increased to 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
    		 167 168 158 493
    Age categorical
    Units: Subjects
        18 - 64 years
    		 165 168 158 491
        65 - 84 years
    		 2 0 0 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.4 ± 11.6 42.2 ± 12.0 43.9 ± 11.8 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 99 107 103 309
        Male
    		 68 61 55 184
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 121 121 117 359
        Black or African American
    		 46 41 39 126
        Asian
    		 0 3 2 5
        Multiple Races
    		 0 3 0 3
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 18 22 15 55
        Not Hispanic or Latino
    		 149 146 143 438
    Montgomery-Åsberg Depression Rating Scale (MADRS)
    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). ITT population: n=163,162,153.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 31.4 ± 4.5 31.5 ± 4.3 31.5 ± 4.8 -

    End points

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

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

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

    Primary: Change from Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS)

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    End point title
    		 Change from Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS)
    End point description
    MADRS is a 10-item, clinician-rated scale that evaluates the participants 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. Mixed-effects Model for Repeated Measures (MMRM) with fixed factors (treatment group, pooled study center, and visit), baseline (a covariate), and interactions (treatment group by visit, baseline by visit). Intent-to-treat (ITT) population consisted of all participants in Safety Population who had at least 1 postbaseline assessment of MADRS total score.
    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
    163
    162
    153
    Units: score on a scale
        least squares mean (standard error)
    -12.4 ± 0.75
    -14.8 ± 0.76
    -14.1 ± 0.78
    Statistical analysis title
    		 Cariprazine 1.5 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 1.5 mg
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0417 [1]
    Method
    		 Contrast t-test
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 -0.4
    Notes
    [1] - Adjusted p-value: adjustment was performed using matched parallel gatekeeping procedure to control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6.
    Statistical analysis title
    		 Cariprazine 3.0 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 3.0 mg
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1051 [2]
    Method
    		 Contrast t-test
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 0.4
    Notes
    [2] - Adjusted p-value: adjustment was performed using matched parallel gatekeeping procedure to control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6.

    Secondary: Change from Baseline in Clinical Global Impressions–Severity (CGI-S) Score

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    End point title
    		 Change from Baseline in Clinical Global Impressions–Severity (CGI-S) Score
    End point description
    CGI-S is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of other patients 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 patients”. A negative change from Baseline indicates improvement. MMRM with fixed factors (treatment group, pooled study center, and visit), baseline (a covariate), and interactions (treatment group by visit, baseline by visit). ITT population consisted of all participants in Safety Population who had at least 1 postbaseline assessment of MADRS total score.
    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
    163
    162
    153
    Units: score on a scale
        least squares mean (standard error)
    -1.2 ± 0.09
    -1.5 ± 0.09
    -1.4 ± 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
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0417 [3]
    Method
    		 Contrast t-test
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.1
    Notes
    [3] - Adjusted p-value: adjustment was performed using matched parallel gatekeeping procedure to control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6.
    Statistical analysis title
    		 Cariprazine 3.0 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 3.0 mg
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.137 [4]
    Method
    		 Contrast t-test
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.1
    Notes
    [4] - Adjusted p-value: adjustment was performed using matched parallel gatekeeping procedure to control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug up to Day 50
    Adverse event reporting additional description
    Safety Population included all participants in the Randomized Population who took at least 1 dose of double-blind investigational drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 7 to 14 day screening/washout period, matching placebo capsule, one per day, orally for 6 weeks.

    Reporting group title
    Cariprazine 3.0 mg
    Reporting group description
    		 Following a 7 to 14 day screening/washout period, cariprazine 1.5 mg capsule, one per day, orally for 2 weeks increased to cariprazine 3.0 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 day screening/washout period, cariprazine 1.5 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
    5 / 165 (3.03%)
    1 / 158 (0.63%)
    1 / 167 (0.60%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 158 (0.00%)
    0 / 167 (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
         subjects affected / exposed [1]
    0 / 97 (0.00%)
    1 / 103 (0.97%)
    0 / 107 (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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 158 (0.00%)
    0 / 167 (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
    Bipolar disorder
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 158 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 158 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 158 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 158 (0.00%)
    0 / 167 (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
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants exposed for Abortion is based on the number of females in the Safety Population.
    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
    36 / 165 (21.82%)
    45 / 158 (28.48%)
    45 / 167 (26.95%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    3 / 165 (1.82%)
    15 / 158 (9.49%)
    9 / 167 (5.39%)
         occurrences all number
    3
    17
    9
    Headache
         subjects affected / exposed
    14 / 165 (8.48%)
    14 / 158 (8.86%)
    14 / 167 (8.38%)
         occurrences all number
    14
    15
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 165 (1.21%)
    5 / 158 (3.16%)
    9 / 167 (5.39%)
         occurrences all number
    2
    6
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 165 (3.03%)
    8 / 158 (5.06%)
    13 / 167 (7.78%)
         occurrences all number
    5
    10
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 165 (4.24%)
    11 / 158 (6.96%)
    8 / 167 (4.79%)
         occurrences all number
    10
    18
    13
    Restlessness
         subjects affected / exposed
    5 / 165 (3.03%)
    11 / 158 (6.96%)
    4 / 167 (2.40%)
         occurrences all number
    6
    12
    4
    Agitation
         subjects affected / exposed
    10 / 165 (6.06%)
    7 / 158 (4.43%)
    3 / 167 (1.80%)
         occurrences all number
    14
    10
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2016
    •Use of the clinician-rated 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
    Revised the wording of exclusion criterion #18 to correct an error (i.e., the omission of the word “no” in the sub-bullet pertaining to the 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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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