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    Clinical Trial Results:
    An Open-Label Extension Study to Assess the Safety and Tolerability of Sep-363856 in Subjects with Schizophrenia.

    Summary
    EudraCT number
    		 2019-000696-16
    Trial protocol
    		 LV   BG   HR  
    Global end of trial date
    09 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Nov 2024
    First version publication date
    23 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SEP361-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04109950
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, 20850
    Public contact
    Clinical Transparency, Otsuka Pharmaceutical Development & Commercialization, Inc., 11 8446878522 , clinicaltransparency@otsuka-us.com
    Scientific contact
    Clinical Transparency, Otsuka Pharmaceutical Development & Commercialization, Inc., 11 8446878522 , clinicaltransparency@otsuka-us.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
    09 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to the long-term safety and tolerability of flexibly- dosed SEP-363856 (25, 50, 75, 100 mg/day) in adult subjects with schizophrenia who completed Study SEP361-301 or Study SEP361-302 by the incidence of overall adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation.
    Protection of trial subjects
    Written informed consent, assent, or both were obtained from a legally acceptable representative (e.g., guardian) or from the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2019
    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
    Serbia: 169
    Country: Number of subjects enrolled
    United States: 105
    Country: Number of subjects enrolled
    Ukraine: 86
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Latvia: 1
    Worldwide total number of subjects
    463
    EEA total number of subjects
    42
    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)
    11
    Adults (18-64 years)
    452
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at investigational sites in the United States (US), Russia, Ukraine, Bulgaria, Latvia, Croatia, Colombia and Serbia from 20 Nov 2019 to 09 Nov 2023. Sumitomo Pharma America Inc. was the former Sponsor and conducted this study.

    Pre-assignment
    Screening details
    		 A total of 452 adult & 11 adolescent subjects entered current study, after completing 6-week, double-blind treatment period in one of core studies SEP361-301 or SEP361-302. 445 adults and 11 adolescent subjects received flexible doses of SEP363856. Otsuka took over study after IND was transferred and is concluding activities with registry postings.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adults: Prior Placebo
    Arm description
    		 Subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-363856
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg.

    Arm title
    		 Adults: Prior SEP-363856 50 mg/day
    Arm description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-363856
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg.

    Arm title
    		 Adults: Prior SEP-363856 75 mg/day
    Arm description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-363856
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg.

    Arm title
    		 Adults: Prior SEP-363856 100 mg/day
    Arm description
    		 Subjects who received SEP-363856 100 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-363856
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg.

    Arm title
    		 Adolescent: Prior Placebo
    Arm description
    		 Adolescent subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. Adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-363856
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day. Beginning on Day 18, the dose was adjusted within the range of 25 to 100 mg/day, if deemed clinically necessary by Investigator.

    Arm title
    		 Adolescent: Prior SEP-363856 50 mg/day
    Arm description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-363856
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day. Beginning on Day 18, the dose was adjusted within the range of 25 to 100 mg/day, if deemed clinically necessary by Investigator

    Arm title
    		 Adolescents: Prior SEP-363856 75 mg/day
    Arm description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent participants received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SEP-363856
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day. Beginning on Day 18, the dose was adjusted within the range of 25 to 100 mg/day, if deemed clinically necessary by Investigator.

    Number of subjects in period 1
    		Adults: Prior Placebo Adults: Prior SEP-363856 50 mg/day Adults: Prior SEP-363856 75 mg/day Adults: Prior SEP-363856 100 mg/day Adolescent: Prior Placebo Adolescent: Prior SEP-363856 50 mg/day Adolescents: Prior SEP-363856 75 mg/day
    Started
    158
    68
    161
    65
    7
    2
    2
    Completed
    53
    28
    62
    25
    0
    1
    1
    Not completed
    105
    40
    99
    40
    7
    1
    1
         Noncompliance with Study Drug
    3
    1
    1
    1
    -
    -
    -
         Consent withdrawn by subject
    36
    22
    42
    15
    3
    -
    1
         Adverse Event
    15
    7
    15
    10
    1
    1
    -
         Death
    -
    -
    1
    -
    -
    -
    -
         Pregnancy
    1
    -
    -
    -
    -
    -
    -
         Geopolitical Conflict Related
    3
    1
    1
    -
    -
    -
    -
         Lost to follow-up
    10
    1
    5
    7
    1
    -
    -
         Reason not specified
    29
    4
    22
    6
    2
    -
    -
         COVID-19 Related
    2
    2
    2
    -
    -
    -
    -
         Protocol deviation
    3
    1
    5
    1
    -
    -
    -
         Lack of efficacy
    3
    1
    5
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adults: Prior Placebo
    Reporting group description
    		 Subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 50 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 75 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 100 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 100 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescent: Prior Placebo
    Reporting group description
    		 Adolescent subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. Adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescent: Prior SEP-363856 50 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescents: Prior SEP-363856 75 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent participants received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group values
    		 Adults: Prior Placebo Adults: Prior SEP-363856 50 mg/day Adults: Prior SEP-363856 75 mg/day Adults: Prior SEP-363856 100 mg/day Adolescent: Prior Placebo Adolescent: Prior SEP-363856 50 mg/day Adolescents: Prior SEP-363856 75 mg/day Total
    Number of subjects
    		 158 68 161 65 7 2 2 463
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.1 ( 10.66 ) 35.1 ( 8.25 ) 37.6 ( 9.69 ) 36.5 ( 9.59 ) 15.7 ( 1.38 ) 15.5 ( 0.71 ) 14.5 ( 2.12 ) -
    Gender categorical
    Units: Subjects
        Female
    		 73 18 72 24 3 0 1 191
        Male
    		 85 50 89 41 4 2 1 272
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 1 8 4 0 1 0 18
        Not Hispanic or Latino
    		 154 67 153 61 7 1 2 445
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 1 0 0 1
        Asian
    		 1 0 0 0 1 0 0 2
        Native Hawaiian or Other Pacific Islander
    		 2 0 2 2 0 0 0 6
        Black or African American
    		 30 8 27 10 2 0 0 77
        White
    		 125 60 131 52 3 2 2 375
        More than one race
    		 0 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 1 1 0 0 0 2

    End points

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    End points reporting groups
    Reporting group title
    Adults: Prior Placebo
    Reporting group description
    		 Subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 50 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 75 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 100 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 100 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescent: Prior Placebo
    Reporting group description
    		 Adolescent subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. Adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescent: Prior SEP-363856 50 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescents: Prior SEP-363856 75 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent participants received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Primary: Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs or SAEs Leading to Study Discontinuation

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    End point title
    		 Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs or SAEs Leading to Study Discontinuation [1] [2]
    End point description
    An AE is any untoward medical occurrence associated with the use of a drug in subjects, whether or not considered drug related. Untoward medical occurrences that occurred after signing informed consent form (ICF) of the current study SEP361-303 were considered AEs. A SAE is an AE that meets one or more criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect.
    End point type
    Primary
    End point timeframe
    From signing of the ICF in the current study up to 7 days after last dose of study drug in the current study (approximately 53 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As prespecified in the protocol only descriptive statistics were planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was assessed only in adult population.
    End point values
    		 Adults: Prior Placebo Adults: Prior SEP-363856 50 mg/day Adults: Prior SEP-363856 75 mg/day Adults: Prior SEP-363856 100 mg/day
    Number of subjects analysed
    156
    66
    159
    64
    Units: participants
        AEs
    89
    31
    92
    30
        SAEs
    12
    4
    12
    4
        AEs or SAEs leading to study discontinuation
    15
    7
    16
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of the ICF in the current study up to 7 days after last dose of study drug in the current study (approximately 53 weeks)
    Adverse event reporting additional description
    The safety population included all the subjects that were enrolled and received at least one dose of study drug during the 52-week OLE treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Adults: Prior Placebo
    Reporting group description
    		 Subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 50 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 75 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adults: Prior SEP-363856 100 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 100 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adult subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was increased up to 100 mg/day, in increments of 25 mg, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescent: Prior Placebo
    Reporting group description
    		 Adolescent subjects who received placebo in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. Adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescent: Prior SEP-363856 50 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 50 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent subjects received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Reporting group title
    Adolescents: Prior SEP-363856 75 mg/day
    Reporting group description
    		 Subjects who received SEP-363856 75 mg/day in the double-blind phase 3 studies SEP361-301 [NCT04072354] or SEP361-302 [NCT04092686], received flexible doses of SEP-363856 in the current study, following a dose-escalation schedule. In the current study, adolescent participants received SEP-363856 tablets, orally, once daily at a starting dose of 50 mg on Day 1 through Day 3, followed by dose-escalation to 75 mg/day from Day 4 through Day 7. From Day 8, the dose was adjusted in the range of 25 – 75 mg/day, if deemed clinically necessary by the investigator, up to 52 weeks.

    Serious adverse events
    		 Adults: Prior Placebo Adults: Prior SEP-363856 50 mg/day Adults: Prior SEP-363856 75 mg/day Adults: Prior SEP-363856 100 mg/day Adolescent: Prior Placebo Adolescent: Prior SEP-363856 50 mg/day Adolescents: Prior SEP-363856 75 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 156 (7.69%)
    4 / 66 (6.06%)
    12 / 159 (7.55%)
    4 / 64 (6.25%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    8 / 156 (5.13%)
    4 / 66 (6.06%)
    10 / 159 (6.29%)
    4 / 64 (6.25%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 4
    2 / 10
    1 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    1 / 159 (0.63%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal behavior
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    1 / 64 (1.56%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    1 / 159 (0.63%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Adults: Prior Placebo Adults: Prior SEP-363856 50 mg/day Adults: Prior SEP-363856 75 mg/day Adults: Prior SEP-363856 100 mg/day Adolescent: Prior Placebo Adolescent: Prior SEP-363856 50 mg/day Adolescents: Prior SEP-363856 75 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 156 (23.08%)
    18 / 66 (27.27%)
    39 / 159 (24.53%)
    8 / 64 (12.50%)
    4 / 7 (57.14%)
    2 / 2 (100.00%)
    2 / 2 (100.00%)
    Investigations
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tri-iodothyronine increased
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 156 (12.18%)
    12 / 66 (18.18%)
    22 / 159 (13.84%)
    4 / 64 (6.25%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    28
    16
    27
    4
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    3 / 7 (42.86%)
    0 / 2 (0.00%)
    2 / 2 (100.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    8 / 156 (5.13%)
    5 / 66 (7.58%)
    9 / 159 (5.66%)
    2 / 64 (3.13%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    10
    6
    11
    2
    0
    1
    0
    Initial insomnia
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    16 / 156 (10.26%)
    7 / 66 (10.61%)
    17 / 159 (10.69%)
    2 / 64 (3.13%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    20
    11
    23
    2
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 66 (0.00%)
    0 / 159 (0.00%)
    0 / 64 (0.00%)
    3 / 7 (42.86%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2019
    An adolescent cohort was added based on feedback from the food drug administration (FDA).
    16 Sep 2020
    • For the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S), the specificity of “total score” was removed from the objectives and left for discussion under the endpoints and analysis sections. • PANSS response was added as an effectiveness endpoint. • Inclusion/exclusion criteria were updated, including the following: − Clarified that that the Medical Monitor must approve retesting of clinical laboratory tests or ECGs for use in determining eligibility. − Language regarding drug test results was clarified to indicate that positive results may not necessarily result in exclusion if the Investigator determined that the positive test was as a result of prescription medicine(s).

    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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