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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Risperidone Extended-Release Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in Adult and Adolescent Patients with Schizophrenia

    Summary
    EudraCT number
    2018-001619-65
    Trial protocol
    BG  
    Global end of trial date
    03 Dec 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV46000-CNS-30072
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03503318
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc.
    Sponsor organisation address
    145 Brandywine Parkway, West Chester, United States, 19380
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
    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
    16 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of TV-46000 during maintenance treatment in adult participants with schizophrenia.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Apr 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 63
    Country: Number of subjects enrolled
    United States: 481
    Worldwide total number of subjects
    544
    EEA total number of subjects
    63
    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)
    1
    Adults (18-64 years)
    530
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants were randomized to receive TV-46000 once monthly (q1m) subcutaneous (SC) injections, TV-46000 once every 2 months (q2m) SC injections, or placebo q1m SC injections in 1:1:1 ratio. Open-label oral risperidone (2 to 5 mg/day) was used to stabilize participants to the treatments (dose was based on clinical judgment) before randomization.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received an SC injection of placebo matched to TV-46000 at baseline and every 4 weeks (q4w) thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to TV-46000 was administered per dose and schedule specified in the arm description.

    Arm title
    TV-46000 q1m
    Arm description
    Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
    Arm type
    Experimental

    Investigational medicinal product name
    TV-46000
    Investigational medicinal product code
    Other name
    Risperidone
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TV-46000 was administered per dose and schedule specified in the arm description.

    Arm title
    TV-46000 q2m
    Arm description
    Participants received an SC injection of TV-46000 at baseline and every 8 weeks (q8w) thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to TV-46000 was administered per dose and schedule specified in the arm description.

    Investigational medicinal product name
    TV-46000
    Investigational medicinal product code
    Other name
    Risperidone
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TV-46000 was administered per dose and schedule specified in the arm description.

    Number of subjects in period 1
    Placebo TV-46000 q1m TV-46000 q2m
    Started
    181
    183
    180
    Received at least 1 dose of study drug
    179
    183
    180
    Completed
    142
    144
    140
    Not completed
    39
    39
    40
         Protocol deviation
    5
    -
    3
         Other than specified
    1
    3
    3
         Adverse event, serious fatal
    1
    -
    4
         Adverse event, non-fatal
    3
    4
    2
         Consent withdrawn by subject
    12
    17
    16
         Lost to follow-up
    17
    15
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received an SC injection of placebo matched to TV-46000 at baseline and every 4 weeks (q4w) thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Reporting group title
    TV-46000 q1m
    Reporting group description
    Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Reporting group title
    TV-46000 q2m
    Reporting group description
    Participants received an SC injection of TV-46000 at baseline and every 8 weeks (q8w) thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Reporting group values
    Placebo TV-46000 q1m TV-46000 q2m Total
    Number of subjects
    181 183 180 544
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    49.2 ± 11.43 50.6 ± 10.30 48.1 ± 11.09 -
    Sex: Female, Male
    Units: participants
        Female
    71 71 70 212
        Male
    110 112 110 332
    Race/Ethnicity, Customized
    Units: Subjects
        White
    68 72 66 206
        Black or African American
    104 108 110 322
        Asian
    4 1 2 7
        Native Hawaiian or Other Pacific Islander
    1 1 0 2
        Not Reported
    2 1 0 3
        Other
    2 0 2 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    42 39 36 117
        Not Hispanic or Latino
    139 144 144 427
        Unknown or Not Reported
    0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received an SC injection of placebo matched to TV-46000 at baseline and every 4 weeks (q4w) thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Reporting group title
    TV-46000 q1m
    Reporting group description
    Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Reporting group title
    TV-46000 q2m
    Reporting group description
    Participants received an SC injection of TV-46000 at baseline and every 8 weeks (q8w) thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Primary: Number of Participants With Impending Relapse (Intent-to-treat [ITT] Analysis Set)

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    End point title
    Number of Participants With Impending Relapse (Intent-to-treat [ITT] Analysis Set)
    End point description
    Relapse was defined as 1 or more of following items: • Clinical Global Impression–Improvement (CGI-I) of ≥5, and - an increase of any of 4 Positive and Negative Syndrome Scale (PANSS) items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score >4 with an absolute increase of ≥2 on specific item or ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • Clinical Global Impression-Severity of Suicidality (CGI-SS) of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Data is presented as distribution of relapsing participants (number of participants with impending relapse). ITT analysis set: adult participants randomized to double-blind maintenance treatment, regardless if they received treatment or not.
    End point type
    Primary
    End point timeframe
    From randomization up to 108 weeks
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    181
    183
    179
    Units: participants
    53
    13
    23
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using the stratified Cox proportional hazard model, with treatment (placebo, TV-46000 q1m and TV-46000 q2m or placebo and TV-46000 overall [including q1m and q2m]) as explanatory variable and sex-dose as a stratification factor, and the stratified log rank test p-value (sex-dose as a stratification factor) referred to (TV-46000/placebo) comparison.
    Comparison groups
    Placebo v TV-46000 q1m
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.109
         upper limit
    0.367
    Notes
    [1] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using the stratified Cox proportional hazard model, with treatment (placebo, TV-46000 q1m and TV-46000 q2m or placebo and TV-46000 overall [including q1m and q2m]) as explanatory variable and sex-dose as a stratification factor, and the stratified log rank test p-value (sex-dose as a stratification factor) referred to (TV-46000/placebo) comparison.
    Comparison groups
    Placebo v TV-46000 q2m
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.375
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.227
         upper limit
    0.618
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Number of Participants With Impending Relapse (Extended ITT [eITT] Analysis Set)

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    End point title
    Number of Participants With Impending Relapse (Extended ITT [eITT] Analysis Set)
    End point description
    Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score >4 with an absolute increase of ≥2 on specific item or ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Data is presented as distribution of relapsing participants (adults and adolescents) (number of participants with impending relapse). eITT analysis set included all participants (adults and adolescents) randomized to the double-blind maintenance stage treatment, regardless if they had received treatment or not.
    End point type
    Secondary
    End point timeframe
    From randomization up to 108 weeks
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    181
    183
    180
    Units: participants
    53
    13
    24
    No statistical analyses for this end point

    Secondary: Proportion of Participants With Impending Relapse

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    End point title
    Proportion of Participants With Impending Relapse
    End point description
    Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score >4 with an absolute increase of ≥2 on specific item or ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Impending relapse rate at Week 24 was estimated using the Kaplan-Meier product estimate. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    181
    183
    179
    Units: proportion of participants
        number (confidence interval 95%)
    0.28 (0.205 to 0.347)
    0.07 (0.03 to 0.109)
    0.11 (0.065 to 0.165)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Maintain Stability at the Endpoint

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    End point title
    Number of Participants Who Maintain Stability at the Endpoint
    End point description
    Stability is defined as meeting all of the following criteria for at least 4 consecutive weeks: outpatient status; PANSS total score ≤80; minimal presence of specific psychotic symptoms on the PANSS, as measured by a score of ≤4 on each of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; Clinical Global Impression of Severity (CGI-S) score ≤4 (moderately ill); and CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2. The last valid participant assessment was used as the endpoint. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.
    End point type
    Secondary
    End point timeframe
    At the endpoint (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    181
    183
    179
    Units: Participants
    110
    159
    143
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving Remission at the Endpoint

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    End point title
    Number of Participants Achieving Remission at the Endpoint
    End point description
    The remission was achieved for participants that did not relapse during the study and in addition, over a period of at least 6 months preceding the endpoint, maintained scores of = 3 on each of the 8 specific PANSS items: P1 (delusions), G9 (unusual thought content), P3 (hallucinatory behavior), P2 (conceptual disorganization), G5 (mannerisms/posturing), N1 (blunted affect), N4 (social withdrawal), and N6 (lack of spontaneity). The last valid participant assessment was used as the endpoint. The participant population was limited to treated by the study drug for at least 6 months. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.
    End point type
    Secondary
    End point timeframe
    At Endpoint (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    181
    183
    179
    Units: Participants
    30
    39
    42
    No statistical analyses for this end point

    Secondary: Observed Rate of Impending Relapse (Number of Participants With Impending Relapse) at the Endpoint

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    End point title
    Observed Rate of Impending Relapse (Number of Participants With Impending Relapse) at the Endpoint
    End point description
    Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score >4 with an absolute increase of ≥2 on specific item or ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Observed rate of impending relapse was calculated as the number of participants who relapsed by endpoint divided by the number of participants in each treatment group, using the last valid participant assessment as the endpoint. ITT analysis set: adult participants randomized to double-blind maintenance treatment, regardless if they received treatment or not.
    End point type
    Secondary
    End point timeframe
    At the Endpoint (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    181
    183
    179
    Units: Participants
    53
    13
    23
    No statistical analyses for this end point

    Secondary: Time to Impending Relapse (Number of Participants With Impending Relapse) in the Adolescent Participants

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    End point title
    Time to Impending Relapse (Number of Participants With Impending Relapse) in the Adolescent Participants
    End point description
    Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score >4 with an absolute increase of ≥2 on specific item or ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Data is presented as distribution of relapsing participants (adolescents) (number of participants with impending relapse). eITT analysis set: all participants (adults and adolescents) randomized to the double-blind maintenance stage treatment, regardless if they received treatment or not. Here, 'Overall number of participants analysed' = adolescent participants.
    End point type
    Secondary
    End point timeframe
    From randomization up to 108 weeks
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    0 [3]
    0 [4]
    1
    Units: participants
    1
    Notes
    [3] - There were no adolescent participants in this arm.
    [4] - There were no adolescent participants in this arm.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Drug Attitudes Inventory 10-item Version (DAI-10) Total Score at the Endpoint and End of Treatment

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    End point title
    Change From Baseline in Drug Attitudes Inventory 10-item Version (DAI-10) Total Score at the Endpoint and End of Treatment
    End point description
    DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a participant who was fully adherent to the prescribed medication answered as "True" and 4 items (2, 5, 6, and 8) that a participant who was fully adherent to the prescribed medication answered as "False." A correct answer was scored +1 and an incorrect answer was scored -1. The total score was the sum of pluses and minuses, which ranged from -10 to 10 in increments of 2. A positive total score indicated a positive subjective response (compliant) and a negative total score indicated a negative subjective response (non-compliance). Higher scores denoted better compliance. The last valid participant assessment was used as the endpoint. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they received treatment or not. Here, 'Overall number of participants analysed' = participants evaluable for this endpoint, 'n' = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, endpoint and end of treatment (up to Week 108)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    178
    182
    179
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=178,182,179)
    6.1 ± 3.23
    5.8 ± 3.63
    5.7 ± 3.13
        Change at the Endpoint (n=125,139,137)
    -0.8 ± 3.88
    0.1 ± 3.34
    -0.3 ± 3.65
        Change at the End of Treatment (n=55,84,79)
    -0.9 ± 3.42
    0.3 ± 2.84
    0.3 ± 3.51
    No statistical analyses for this end point

    Secondary: Change From Baseline in Schizophrenia Quality of Life Scale (SQLS) Total Score at the Endpoint and End of Treatment

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    End point title
    Change From Baseline in Schizophrenia Quality of Life Scale (SQLS) Total Score at the Endpoint and End of Treatment
    End point description
    The SQLS comprises 33 items categorized in 2 domains: psychosocial feelings (20 items) and cognition and vitality (13 items). The items were scored on a 5-point scale (1 - never, 2 - rarely, 3 - sometimes, 4 - often, 5 - always). Individual domain and total scores were standardized by scoring algorithm to a 0 (best health status) to 100 (worst health status) scale, with higher scores indicating comparatively lower quality of life. The last valid participant assessment was used as the endpoint. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not. Here, 'Overall number of participants analysed' signifies participants evaluable for this endpoint, 'n' signifies participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, endpoint and end of treatment (up to Week 108)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    178
    182
    179
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=178,182,179)
    34.0 ± 16.06
    33.1 ± 16.79
    34.2 ± 15.70
        Change at the Endpoint (n=158,172,163)
    0.9 ± 14.24
    -4.5 ± 14.31
    -4.1 ± 15.23
        Change at the End of Treatment (n=55,85,79)
    -2.3 ± 13.26
    -7.2 ± 13.79
    -7.3 ± 12.30
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring after the first dose of the study drug until 120 days after the last dose of study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.
    End point type
    Secondary
    End point timeframe
    From randomization up to 120 days after last dose of study drug (up to Week 125)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    179
    183
    180
    Units: participants
    92
    111
    121
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Abnormal Involuntary Movement Scale (AIMS) Score at the End of Treatment

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    End point title
    Change From Baseline in Total Abnormal Involuntary Movement Scale (AIMS) Score at the End of Treatment
    End point description
    The AIMS is a 14-item scale that includes assessments of orofacial movements, extremity and truncal dyskinesia, examiner’s judgment of global severity, subjective measures of awareness of movements and distress, and a yes/no assessment of problems concerning teeth and/or dentures. Total AIMS score is a sum of item 1 through 7. Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 0 (no dyskinesia) to 4 (severe dyskinesia) scale. Total AIMS score for Items 1-7 ranged from 0 to 28; with higher scores indicating greater severity of the condition. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, n' signifies participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    179
    183
    180
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=179,183,180)
    0.4 ± 1.30
    0.5 ± 1.83
    0.2 ± 0.79
        Change at the End of Treatment (n=55,93,81)
    0.0 ± 1.10
    0.1 ± 0.62
    0.1 ± 1.00
    No statistical analyses for this end point

    Secondary: Change From Baseline in Simpson-Angus Scale (SAS) Mean Score at the End of Treatment

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    End point title
    Change From Baseline in Simpson-Angus Scale (SAS) Mean Score at the End of Treatment
    End point description
    The SAS is a 10-item instrument for the assessment of neuroleptic-induced parkinsonism. The items on the scale include measurements of hypokinesia, rigidity, glabellar reflex, tremor, and salivation. Each item was rated on a 5-point scale (0 [None/Normal] to 4 [Extreme/Severe]). The mean score was calculated by adding the individual item scores and dividing by 10. The total mean score ranged from 0-40, with a higher score indicating greater severity of symptoms. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'n' signifies participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    179
    183
    180
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=179,183,180)
    0.07 ± 0.137
    0.09 ± 0.195
    0.06 ± 0.134
        Change at the End of Treatment (n=55,93,81)
    0.04 ± 0.134
    0.02 ± 0.211
    0.00 ± 0.102
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Barnes Akathisia Rating Scale (BARS) Score at the End of Treatment

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    End point title
    Change From Baseline in Total Barnes Akathisia Rating Scale (BARS) Score at the End of Treatment
    End point description
    The BARS is an instrument that assesses the severity of drug-induced akathisia. The BARS includes 3 items for rating objective restless movements, subjective restlessness, and any subjective distress associated with akathisia that were scored on a 4-point scale of 0 (normal/no distress) to 3 (constant restlessness/severe distress). Total score was the sum of scores of each item and ranged from 0-9, with higher scores indicating greater severity of akathisia. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'n' signifies participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    179
    183
    180
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=179,183,180)
    0.2 ± 0.63
    0.1 ± 0.39
    0.2 ± 0.57
        Change at the End of Treatment (n=55,93,81)
    -0.1 ± 0.56
    0.0 ± 0.51
    -0.1 ± 0.56
    No statistical analyses for this end point

    Secondary: Number of Participants Reporting Suicidal Behavior and Suicidal Ideation Using Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline and Post-Baseline

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    End point title
    Number of Participants Reporting Suicidal Behavior and Suicidal Ideation Using Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline and Post-Baseline
    End point description
    The C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline, post-baseline (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    179
    183
    180
    Units: participants
        Baseline: Suicidal behavior
    0
    0
    3
        Baseline: Suicidal ideation
    6
    5
    7
        Post-baseline: Suicidal behavior
    3
    1
    1
        Post-baseline: Suicidal ideation
    12
    7
    12
    No statistical analyses for this end point

    Secondary: Change From Baseline in Calgary Depression Scale for Schizophrenia (CDSS) Score at the End of Treatment

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    End point title
    Change From Baseline in Calgary Depression Scale for Schizophrenia (CDSS) Score at the End of Treatment
    End point description
    The CDSS is specifically designed to assess the level of depression separate from the positive, negative, and EPS in schizophrenia. This clinician-administered instrument consists of 9 items, each rated on a 4-point scale from 0 (absent) to 3 (severe) that were added together to form the total CDSS depression score of the participant. The total score ranged from 0-27, with higher scores indicating greater severity of the condition. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'n' signifies participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    179
    183
    180
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=179,183,180)
    1.6 ± 2.14
    1.3 ± 1.92
    1.5 ± 1.93
        Change at the End of Treatment (n=55,93,81)
    -0.4 ± 2.72
    -0.3 ± 1.39
    -0.8 ± 2.24
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression-Severity of Suicidality (CGI-SS) Score at the End of Treatment

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    End point title
    Change From Baseline in Clinical Global Impression-Severity of Suicidality (CGI-SS) Score at the End of Treatment
    End point description
    The CGI-SS scale provides an overall clinician-rated assessment of the risk of suicidality. The CGI-SS consists of a 5-point scale in Part 1 (the most severe level of suicidality experience) ranging from 1 (not at all suicidal) to 5 (attempted suicide) and a 7-point scale in Part 2 (change in participant suicidality) ranging from 1 (very much improved) to 7 (very much worse). Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'Overall number of participants analysed' signifies participants evaluable for this endpoint, 'n' signifies participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    179
    183
    179
    Units: units on a scale
    arithmetic mean (standard deviation)
        Part 1 at Baseline (n=179,183,179)
    1.0 ± 0.00
    1.0 ± 0.00
    1.0 ± 0.00
        Part 2 at the End of Treatment (n=55,93,81)
    4.0 ± 0.00
    4.0 ± 0.00
    4.0 ± 0.00
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone)

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    End point title
    Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone)
    End point description
    Pharmacokinetics (PK) analysis set included all randomized participants who received ≥1 dose of study treatment or placebo and who also had ≥1 plasma concentration measured. Here, 'Number analysed' signifies participants evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    1 hour prior to dosing at Baseline (Day 1) and at the end of treatment (EOT) visit (up to 108 weeks)
    End point values
    Placebo TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    178
    178
    177
    Units: ng/mL
    arithmetic mean (full range (min-max))
        Risperidone at Baseline (n=178,178,177)
    4.694 (0.050 to 58.376)
    6.452 (0.050 to 97.935)
    5.364 (0.05 to 125.524)
        Risperidone at EOT (n=52,87,79)
    1.323 (0.050 to 47.683)
    13.215 (0.050 to 136.184)
    8.838 (0.05 to 75.95)
        9-OH-Risperidone at Baseline (n=178,178,177)
    14.965 (0.150 to 84.471)
    18.473 (0.15 to 105.26)
    15.187 (0.15 to 107.316)
        9-OH-Risperidone at EOT (n=52,87,79)
    2.982 (0.150 to 40.730)
    26.202 (0.15 to 101.354)
    17.778 (0.15 to 88.333)
        Total Active Moiety at Baseline (n=178,178,177)
    19.060 (0.050 to 95.595)
    24.200 (0.050 to 134.202)
    19.945 (0.05 to 172.763)
        Total Active Moiety at EOT (n=52,87,79)
    4.078 (0.050 to 62.621)
    38.429 (0.050 to 159.498)
    25.947 (0.05 to 135.823)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization up to 120 days after last dose of study drug (up to Week 125)
    Adverse event reporting additional description
    Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Reporting group title
    TV-46000 q2m
    Reporting group description
    Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Reporting group title
    TV-46000 q1m
    Reporting group description
    Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.

    Serious adverse events
    Placebo TV-46000 q2m TV-46000 q1m
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 179 (7.82%)
    10 / 180 (5.56%)
    8 / 183 (4.37%)
         number of deaths (all causes)
    1
    4
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory tract procedural complication
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 180 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 180 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 180 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 180 (0.00%)
    0 / 183 (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
    Acute psychosis
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 180 (0.00%)
    0 / 183 (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
    Mental status changes
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 180 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 179 (1.12%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic symptom
         subjects affected / exposed
    2 / 179 (1.12%)
    0 / 180 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    4 / 179 (2.23%)
    2 / 180 (1.11%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 180 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 180 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 180 (0.00%)
    0 / 183 (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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 180 (0.00%)
    0 / 183 (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
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (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
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 180 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (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
    COVID-19
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 180 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (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
    Pelvic abscess
         subjects affected / exposed [1]
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 180 (0.00%)
    0 / 183 (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
    Sepsis
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 180 (0.56%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 180 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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: This is a gender-specific AE that affects only female participants
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo TV-46000 q2m TV-46000 q1m
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 179 (19.55%)
    48 / 180 (26.67%)
    49 / 183 (26.78%)
    Investigations
    Weight increased
         subjects affected / exposed
    6 / 179 (3.35%)
    13 / 180 (7.22%)
    10 / 183 (5.46%)
         occurrences all number
    6
    14
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 179 (5.59%)
    11 / 180 (6.11%)
    9 / 183 (4.92%)
         occurrences all number
    11
    11
    10
    General disorders and administration site conditions
    Injection site nodule
         subjects affected / exposed
    6 / 179 (3.35%)
    13 / 180 (7.22%)
    12 / 183 (6.56%)
         occurrences all number
    20
    23
    29
    Injection site pain
         subjects affected / exposed
    11 / 179 (6.15%)
    12 / 180 (6.67%)
    9 / 183 (4.92%)
         occurrences all number
    37
    14
    13
    Injection site pruritus
         subjects affected / exposed
    4 / 179 (2.23%)
    7 / 180 (3.89%)
    10 / 183 (5.46%)
         occurrences all number
    5
    10
    17
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 179 (5.59%)
    5 / 180 (2.78%)
    12 / 183 (6.56%)
         occurrences all number
    11
    6
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2018
    The following major procedural changes (not all-inclusive) were made to the protocol: • various revisions due to the introduced possibility of enrolling adolescent participants (including eligibility criteria, maximum dose to be administered, up to 3 additional PK samples to be collected from adolescents) • urine pregnancy test was added to the baseline visit clarification which scales were only performed in adult participants • definition of study completers added • clarification that collection of the unscheduled PK samples is only relevant for Stage 2 • clarification regarding blinding per updated sponsor template to enhance participant safety and ensure that the participant’s needs are first addressed • correction of blood volumes per updated laboratory manual • clarification regarding a positive urine drug screen result due to the high prevalence of recreational and medical use of various substances in this participant population.
    16 Oct 2019
    The following major procedural changes (not all-inclusive) were made to the protocol: • in addition to the originally planned, single interim analysis that was to be conducted when 125 relapse events were observed, an earlier interim analysis (when 90 relapse events were reached) was introduced • prolongation of study duration (although in case of a successful interim analysis, the study would be terminated earlier) • change of inclusion criterion to omit the body mass index (BMI) percentile limitation • updates to the planned number of enrolled participants per updated projections • clarification of procedures to be performed during unscheduled visits • updates to vendor information and personnel details following changes of responsibilities • clarification regarding highly effective birth control methods (that is, only highly effective birth control methods should have been used in this study).
    19 Apr 2020
    The following major procedural changes (not all-inclusive) were made to the protocol: • changes to various sections due to the planned earlier final analysis • change of responsibilities in the sponsor's medical expert • blood volumes updated to reflect longer treatment duration in Stage 2 of the study • COVID-19 pandemic-related operational updates and contingency measures were added to the study as a new appendix.

    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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