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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of SEP-4199 for the Treatment of Major Depressive Episode Associated with Bipolar I Disorder (Bipolar I Depression)

    Summary
    EudraCT number
    		 2018-000103-16
    Trial protocol
    		 BG   SK   PL  
    Global end of trial date
    23 Apr 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Jun 2023
    First version publication date
    23 Apr 2021
    Other versions
    		 v1
    Version creation reason
    Summary report(s)

    Trial information

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    Trial identification
    Sponsor protocol code
    SEP380-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03543410
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Japan: jRCT2031220302
    Sponsors
    Sponsor organisation name
    Sunovion Pharmaceuticals Inc.
    Sponsor organisation address
    84 Waterford Drive, Marlboro, United States, 01752
    Public contact
    CNS Medical Director, Sunovion Pharmaceuticals Inc., 01 18665036351, ClinicalTrialDisclosure@sunovion.com
    Scientific contact
    CNS Medical Director, Sunovion Pharmaceuticals Inc., 01 18665036351, ClinicalTrialDisclosure@sunovion.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
    23 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of SEP-4199 200 mg/day and 400 mg/day compared with placebo for major depressive episode associated with bipolar I disorder (diagnosed by DSM-5 criteria) as measured by Montgomery-Asberg Depression Rating Scale (MADRS) total score
    Protection of trial subjects
    The study was conducted according to the protocol, ICH Good Clinical Practice (GCP), ICH guidelines, and the ethical principles that have their origin in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jun 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
    Bulgaria: 43
    Country: Number of subjects enrolled
    Japan: 49
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    Serbia: 63
    Country: Number of subjects enrolled
    Slovakia: 19
    Country: Number of subjects enrolled
    Ukraine: 67
    Country: Number of subjects enrolled
    United States: 43
    Worldwide total number of subjects
    341
    EEA total number of subjects
    73
    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)
    339
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total 344 subjects were randomized in this study. Three subjects, who were randomized but never received any dose of study medication, were not included in the reporting.

    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, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SEP-4199 200 mg
    Arm description
    		 SEP-4199 200 mg/day (supplied in two 100mg tablets)
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-4199
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg/day (supplied in two 100mg tablets)

    Arm title
    		 SEP-4199 400 mg
    Arm description
    		 SEP-4199 400 mg/day (supplied in two 200mg tablets)
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-4199
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg /day (supplied in two tablets)

    Arm title
    		 Placebo
    Arm description
    		 Placebo (supplied in two tablets/day)
    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
    supplied in two tablets

    Number of subjects in period 1
    		SEP-4199 200 mg SEP-4199 400 mg Placebo
    Started
    113
    114
    114
    Completed
    92
    101
    99
    Not completed
    21
    13
    15
         Consent withdrawn by subject
    5
    2
    8
         NON-COMPLIANCE WITH STUDY DRUG
    -
    -
    2
         Adverse event, non-fatal
    10
    8
    2
         Not Due to COVID-19
    2
    -
    1
         Lost to follow-up
    -
    1
    -
         Due to COVID-19
    4
    -
    2
         Lack of efficacy
    -
    1
    -
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SEP-4199 200 mg
    Reporting group description
    		 SEP-4199 200 mg/day (supplied in two 100mg tablets)

    Reporting group title
    SEP-4199 400 mg
    Reporting group description
    		 SEP-4199 400 mg/day (supplied in two 200mg tablets)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (supplied in two tablets/day)

    Reporting group values
    		 SEP-4199 200 mg SEP-4199 400 mg Placebo Total
    Number of subjects
    		 113 114 114 341
    Age Categorical
    Units: Participants
        <=18 years
    		 1 1 1 3
        Between 18 and 65 years
    		 112 111 113 336
        >=65 years
    		 0 2 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 42 ( 11.65 ) 44.4 ( 12.72 ) 43.3 ( 12.10 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 69 76 64 209
        Male
    		 44 38 50 132
    Age, Customized
    Units: Subjects
        18-64 years
    		 113 112 114 339
        >=65 years
    		 0 2 0 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 0 2
        Asian
    		 16 16 17 49
        Black or African American
    		 6 8 8 22
        More than one race
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 1 2 1 4
        Unknown or Not Reported
    		 0 0 0 0
        White
    		 89 87 88 264
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 3 2 8
        Not Hispanic or Latino
    		 110 109 112 331
        Unknown or Not Reported
    		 0 2 0 2
    Country Name
    Units: Subjects
        Bulgaria
    		 11 10 22 43
        Japan
    		 16 16 17 49
        Poland
    		 5 1 5 11
        Russia
    		 18 20 8 46
        Serbia
    		 19 26 18 63
        Slovakia
    		 8 5 6 19
        Ukraine
    		 22 20 25 67
        United States
    		 14 16 13 43
    Region of Enrollment
    Units: Subjects
        Europe
    		 83 82 84 249
        Japan
    		 16 16 17 49
        United States
    		 14 16 13 43
    Baseline BMI Category
    Units: Subjects
        < 18.5 kg/m2
    		 0 3 0 3
        18.5 - <25.0 kg/m2
    		 51 50 45 146
        25.0 - <30.0 kg/m2
    		 42 33 40 115
        >=30.0 kg/m2
    		 20 28 29 77
    Baseline Weight (kg)
    Units: kg
        arithmetic mean (standard deviation)
    		 75.3 ( 14.47 ) 74.8 ( 16.19 ) 77.5 ( 16.59 ) -
    Baseline CGI-BP-S Depression Score
    Measure Description: Clinical Global Impressions - Severity: Bipolar Version (CGI-BP-S) score (depression) is a single value, clinician-rated assessment of illness severity, and 7-point scale with range from 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill subjects. A higher score is associated with greater illness severity.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 4.8 ( 0.66 ) 4.8 ( 0.65 ) 4.9 ( 0.70 ) -
    Baseline MADRS Total Score
    Measure Description: MADRS is a clinician-rated assessment of the subject's level of depression. The measure contains 10 items that measure apparent and reported sadness, inner tension, reduced sleep and appetite, difficulty concentrating, lassitude, inability to feel, and pessimistic and suicidal thoughts, each ranging from 0 to 6. The MADRS total score ranges from 0 to 60, with higher scores indicating increased depressive symptoms
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 33.5 ( 5.77 ) 33.8 ( 5.63 ) 34.1 ( 5.35 ) -
    Baseline BMI (kg/m^2)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 26.2 ( 4.53 ) 26.6 ( 4.91 ) 27 ( 4.94 ) -

    End points

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    End points reporting groups
    Reporting group title
    SEP-4199 200 mg
    Reporting group description
    		 SEP-4199 200 mg/day (supplied in two 100mg tablets)

    Reporting group title
    SEP-4199 400 mg
    Reporting group description
    		 SEP-4199 400 mg/day (supplied in two 200mg tablets)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (supplied in two tablets/day)

    Primary: Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 6

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    End point title
    		 Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 6
    End point description
    MADRS is a clinician-rated assessment of the subject’s level of depression. The measure contains 10 items that measure apparent and reported sadness, inner tension, reduced sleep and appetite, difficulty concentrating, lassitude, inability to feel, and pessimistic and suicidal thoughts, each ranging from 0 to 6. The MADRS total score ranges from 0 to 60, with higher scores indicating increased depressive symptoms
    End point type
    Primary
    End point timeframe
    6 Weeks
    End point values
    		 SEP-4199 200 mg SEP-4199 400 mg Placebo
    Number of subjects analysed
    96 [1]
    97 [2]
    96 [3]
    Units: units on a scale
        least squares mean (standard error)
    -19.485 ( 1.226 )
    -19.324 ( 1.182 )
    -16.196 ( 1.231 )
    Notes
    [1] - The analysis population was the ITT population, excluding subjects from Japan Region
    [2] - The analysis population was the ITT population, excluding subjects from Japan Region
    [3] - The analysis population was the ITT population, excluding subjects from Japan Region
    Statistical analysis title
    		 SEP-4199 400mg and Placebo
    Comparison groups
    SEP-4199 400 mg v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.051 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.273
         upper limit
    		 0.017
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.597
    Notes
    [4] - nominal p-value
    Statistical analysis title
    		 SEP-4199 200mg and Placebo
    Comparison groups
    Placebo v SEP-4199 200 mg
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.044 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.489
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.625
    Notes
    [5] - nominal p-value

    Secondary: Change from baseline in global severity assessed by the Clinical Global Impressions – Severity: Bipolar Version (CGI-BP-S) score (depression) at Week 6

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    End point title
    		 Change from baseline in global severity assessed by the Clinical Global Impressions – Severity: Bipolar Version (CGI-BP-S) score (depression) at Week 6
    End point description
    Clinical Global Impressions – Severity: Bipolar Version (CGI-BP-S) score (depression) is a single value, clinician-rated assessment of illness severity, and 7-point scale with range from 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill subjects. A higher score is associated with greater illness severity.
    End point type
    Secondary
    End point timeframe
    6 Weeks
    End point values
    		 SEP-4199 200 mg SEP-4199 400 mg Placebo
    Number of subjects analysed
    96 [6]
    97 [7]
    96 [8]
    Units: units on a scale
        least squares mean (standard error)
    -2.020 ( 0.144 )
    -1.958 ( 0.138 )
    -1.739 ( 0.144 )
    Notes
    [6] - The analysis population was the ITT population, excluding subjects from Japan Region
    [7] - The analysis population was the ITT population, excluding subjects from Japan Region
    [8] - The analysis population was the ITT population, excluding subjects from Japan Region
    Statistical analysis title
    		 SEP-4199 400mg and Placebo
    Comparison groups
    SEP-4199 400 mg v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.243 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.219
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.588
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.187
    Notes
    [9] - nominal p-value
    Statistical analysis title
    		 SEP-4199 200mg and Placebo
    Comparison groups
    SEP-4199 200 mg v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.143 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.281
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.658
         upper limit
    		 0.095
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.191
    Notes
    [10] - nominal p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were untoward medical occurrences that occurred on or after the first dose of study medication. Up to 7 weeks
    Adverse event reporting additional description
    Adverse events were untoward medical occurrences that occurred on or after the first dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SEP-4199 200 mg
    Reporting group description
    		 SEP-4199 200 mg/day (supplied in two 100mg tablets)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (supplied in two tablets/day)

    Reporting group title
    SEP-4199 400 mg
    Reporting group description
    		 SEP-4199 400 mg/day (supplied in two 200mg tablets)

    Serious adverse events
    		 SEP-4199 200 mg Placebo SEP-4199 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 114 (0.88%)
    0 / 114 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 114 (0.88%)
    0 / 114 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 114 (0.00%)
    0 / 114 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SEP-4199 200 mg Placebo SEP-4199 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 113 (18.58%)
    29 / 114 (25.44%)
    23 / 114 (20.18%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 114 (0.00%)
    9 / 114 (7.89%)
         occurrences all number
    0
    0
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 113 (9.73%)
    13 / 114 (11.40%)
    3 / 114 (2.63%)
         occurrences all number
    12
    16
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 113 (4.42%)
    7 / 114 (6.14%)
    5 / 114 (4.39%)
         occurrences all number
    6
    9
    6
    Anxiety
         subjects affected / exposed
    1 / 113 (0.88%)
    7 / 114 (6.14%)
    2 / 114 (1.75%)
         occurrences all number
    2
    7
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 113 (3.54%)
    6 / 114 (5.26%)
    4 / 114 (3.51%)
         occurrences all number
    4
    6
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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