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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of Lumateperone Monotherapy in the Treatment of Patients with Major Depressive Episodes Associated with Bipolar I or Bipolar II Disorder (Bipolar Depression) Conducted Globally

    Summary
    EudraCT number
    		 2017-002317-58
    Trial protocol
    		 BG   PL  
    Global end of trial date
    01 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2020
    First version publication date
    25 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ITI-007-404
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03249376
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Intra-Cellular Therapies, Inc.
    Sponsor organisation address
    430 East 29th Street, New York, NY, United States, 10016
    Public contact
    Program Manager, Intra-Cellular Therapies, Inc. (ITI), 1 646-440-9333,
    Scientific contact
    Program Manager, Intra-Cellular Therapies, Inc. (ITI), 1 646-440-9333,
    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 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of lumateperone administered orally once daily to that of placebo as measured by mean change from baseline to Day 43 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients with Bipolar Depression.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The study complied with the ICH Guidance on General Considerations for Clinical Trials and GCP, as well as CFR Part 312.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2017
    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
    Russian Federation: 66
    Country: Number of subjects enrolled
    Bulgaria: 92
    Country: Number of subjects enrolled
    Serbia: 19
    Country: Number of subjects enrolled
    Ukraine: 87
    Country: Number of subjects enrolled
    United States: 114
    Country: Number of subjects enrolled
    Colombia: 3
    Worldwide total number of subjects
    381
    EEA total number of subjects
    92
    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)
    358
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The Screening phase begins once the Informed Consent Form is signed. Patients are evaluated during the screening period lasting up to 2 weeks to ensure sufficient washout of restricted medications.

    Pre-assignment period milestones
    Number of subjects started
    		 546 [1]
    Number of subjects completed
    		 381

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen Failure: 165
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Pre-assignment period includes all pts that are screened. Worldwide number enrolled are those patients that have been randomized.
    Period 1
    Period 1 title
    Overall Trial (overall period)
    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
    		 Lumateperone 42mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lumateperone
    Investigational medicinal product code
    Other name
    ITI-007
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily oral administration

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily oral administration

    Number of subjects in period 1
    		Lumateperone 42mg Placebo
    Started
    191
    190
    Completed
    163
    159
    Not completed
    28
    31
         Consent withdrawn by subject
    7
    11
         Physician decision
    -
    2
         Adverse event, non-fatal
    11
    5
         Unavailable
    1
    1
         Lost to follow-up
    4
    5
         Lack of efficacy
    2
    4
         Protocol deviation
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lumateperone 42mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Lumateperone 42mg Placebo Total
    Number of subjects
    		 191 190 381
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 175 183 358
        From 65-84 years
    		 16 7 23
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.7 ± 14.1 44.1 ± 12.9 -
    Gender categorical
    Units: Subjects
        Female
    		 99 121 220
        Male
    		 92 69 161

    End points

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    End points reporting groups
    Reporting group title
    Lumateperone 42mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Modified intent-to treat
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Includes all randomized subjects who received at least one dose of study medication and who had a valid (pre-dose) baseline measurement and at least one valid post-baseline measurement of MADRS.

    Primary: Change from baseline to Day 43 in the total score on the Montgomery-Asberg Depression Rating Scale (MADRS)

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    End point title
    		 Change from baseline to Day 43 in the total score on the Montgomery-Asberg Depression Rating Scale (MADRS)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Day 43
    End point values
    		 Lumateperone 42mg Placebo
    Number of subjects analysed
    188
    188
    Units: Unit
        least squares mean (confidence interval 95%)
    -16.7 (-18.06 to -15.34)
    -12.1 (-13.45 to -10.79)
    Statistical analysis title
    		 Primary Efficacy Analysis
    Comparison groups
    Lumateperone 42mg v Placebo
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.34
         upper limit
    		 -2.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.89

    Secondary: Change from baseline to Day 43 in the total score on the Clinical Global Impression Scale, Bipolar Version-Severity (CGI-BP-S)

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    End point title
    		 Change from baseline to Day 43 in the total score on the Clinical Global Impression Scale, Bipolar Version-Severity (CGI-BP-S)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Day 43
    End point values
    		 Lumateperone 42mg Placebo
    Number of subjects analysed
    188
    188
    Units: Unit
        least squares mean (confidence interval 95%)
    -3.5 (-3.81 to -3.14)
    -2.5 (-2.86 to -2.21)
    Statistical analysis title
    		 Key Secondary Efficacy Analysis
    Comparison groups
    Lumateperone 42mg v Placebo
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.37
         upper limit
    		 -0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time the subject gives study-specific informed consent until the end of study procedures being completed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Lumateperone 42mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Lumateperone 42mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 189 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lumateperone 42mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 188 (54.79%)
    95 / 189 (50.26%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 188 (17.55%)
    19 / 189 (10.05%)
         occurrences all number
    33
    19
    Somnolence
         subjects affected / exposed
    16 / 188 (8.51%)
    2 / 189 (1.06%)
         occurrences all number
    16
    2
    Dizziness
         subjects affected / exposed
    9 / 188 (4.79%)
    10 / 189 (5.29%)
         occurrences all number
    9
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    12 / 188 (6.38%)
    4 / 189 (2.12%)
         occurrences all number
    12
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2018
    Increase sample size from 250 subjects to 350 subjects.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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