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

    Summary
    EudraCT number
    2019-000063-24
    Trial protocol
    FR   BG  
    Global end of trial date
    02 Dec 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jun 2022
    First version publication date
    15 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV46000-CNS-30078
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03893825
    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., MedInfo@tevaeu.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., MedInfo@tevaeu.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
    20 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the long-term safety and tolerability of TV-46000 administered in adult and adolescent participants with schizophrenia.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) 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
    17 Apr 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
    United States: 300
    Country: Number of subjects enrolled
    Bulgaria: 36
    Worldwide total number of subjects
    336
    EEA total number of subjects
    36
    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)
    3
    Adults (18-64 years)
    322
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants who did not experience relapse and completed Study TV46000-CNS-30072 (NCT03503318) (roll-over participants) and new participants entered this study. Open-label oral risperidone (at dose of 2 to 5 milligrams [mg]/day, based on clinical judgment) for 12 weeks was given to stabilize new participants to the treatment before randomization.

    Pre-assignment
    Screening details
    Participants who were treated with TV-46000 once monthly (q1m) or once every 2 months (q2m) during Study TV46000-CNS-30072, continued their assigned treatment. Participants who were treated with placebo during Study TV46000-CNS-30072 were randomized to receive TV-46000 q1m or q2m SC injections equivalent to oral dose on which they were stabilized.

    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
    TV-46000 q1m
    Arm description
    Participants received a subcutaneous (SC) injection of TV-46000 at baseline and every 4 weeks (q4w) thereafter for up to 56 weeks. 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.
    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 for up to 56 weeks. 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.
    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 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
    TV-46000 q1m TV-46000 q2m
    Started
    174
    162
    Received at least 1 dose of study drug
    172
    162
    Completed
    135
    122
    Not completed
    39
    40
         Other than specified
    7
    6
         Adverse event, serious fatal
    2
    1
         Adverse event, non-fatal
    -
    2
         Consent withdrawn by subject
    19
    21
         Protocol deviation
    1
    -
         Lost to follow-up
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TV-46000 q1m
    Reporting group description
    Participants received a subcutaneous (SC) injection of TV-46000 at baseline and every 4 weeks (q4w) thereafter for up to 56 weeks. 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.

    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 for up to 56 weeks. 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.

    Reporting group values
    TV-46000 q1m TV-46000 q2m Total
    Number of subjects
    174 162 336
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.3 ± 10.28 49.8 ± 11.51 -
    Sex: Female, Male
    Units: participants
        Female
    61 59 120
        Male
    113 103 216
    Race/Ethnicity, Customized
    Units: Subjects
        White
    80 67 147
        Black or African American
    91 90 181
        Asian
    1 2 3
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Not reported
    1 1 2
        Other
    1 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    56 51 107
        Not Hispanic or Latino
    118 110 228
        Unknown or Not Reported
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    TV-46000 q1m
    Reporting group description
    Participants received a subcutaneous (SC) injection of TV-46000 at baseline and every 4 weeks (q4w) thereafter for up to 56 weeks. 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.

    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 for up to 56 weeks. 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.

    Primary: Number of Participants With Adverse Events (AEs)

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    End point title
    Number of Participants With Adverse Events (AEs) [1]
    End point description
    An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs 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. The safety analysis set included all participants who received at least 1 dose of TV46000 in TV-46000-CNS-30072 study or in TV46000-CNS-30078 study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 64
    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: The analysis is descriptive in nature.
    End point values
    TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    172
    162
    Units: participants
        AEs
    64
    74
    No statistical analyses for this end point

    Primary: Number of Participants With Serious Adverse Events

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    End point title
    Number of Participants With Serious Adverse Events [2]
    End point description
    An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs 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. The safety analysis set included all participants who received at least 1 dose of TV46000 in TV-46000-CNS-30072 study or in TV46000-CNS-30078 study.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 64
    Notes
    [2] - 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: The analysis is descriptive in nature.
    End point values
    TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    172
    162
    Units: Participants
    8
    11
    No statistical analyses for this end point

    Other pre-specified: Number of Participants who Were Withdrawn From the Treatment

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    End point title
    Number of Participants who Were Withdrawn From the Treatment
    End point description
    The number of participants who were withdrawn from the treatment due to any reason has been reported. The safety analysis set included all participants who received at least 1 dose of TV46000 in TV-46000-CNS-30072 study or in TV46000-CNS-30078 study.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 64
    End point values
    TV-46000 q1m TV-46000 q2m
    Number of subjects analysed
    172
    162
    Units: Participants
        Death
    2
    1
        Adverse event
    2
    5
        Withdrawal by participant
    21
    25
        Non-compliance with study drug
    1
    0
        Protocol deviation
    2
    1
        Pregnancy
    0
    0
        Lost-to-follow up
    5
    7
        Lack of efficacy
    1
    0
        Relapse
    3
    3
        Other
    11
    11
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 64
    Adverse event reporting additional description
    The safety analysis set included all participants who received at least 1 dose of TV46000 in TV-46000-CNS-30072 study or in TV46000-CNS-30078 study. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    TV-46000 q1m
    Reporting group description
    Participants received an SC injection of TV-46000 at baseline and q4w thereafter for up to 56 weeks. 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.

    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 for up to 56 weeks. 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.

    Serious adverse events
    TV-46000 q1m TV-46000 q2m
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 172 (4.65%)
    11 / 162 (6.79%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 162 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Self-injurious ideation
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    TV-46000 q1m TV-46000 q2m
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 172 (5.81%)
    12 / 162 (7.41%)
    General disorders and administration site conditions
    Injection site nodule
         subjects affected / exposed
    3 / 172 (1.74%)
    9 / 162 (5.56%)
         occurrences all number
    6
    13
    Injection site pain
         subjects affected / exposed
    9 / 172 (5.23%)
    7 / 162 (4.32%)
         occurrences all number
    24
    23

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2020
    The following major procedural changes (not all-inclusive) were made to the protocol: - COVID-19 pandemic-related operational updates were added to the study as a new appendix. - To avoid duplication and reduce participant burden, many of the baseline procedures and assessments outlined in this protocol related to the roll-over participants, were performed in the end of treatment visit of study 30072, and the results were transferred to this study's clinical database. - The volume of collected blood samples was corrected accordingly. - The biomarker sample collection became optional. - Gender was removed as a stratification factor for randomization of new participants and roll-over participants previously assigned to placebo. - Various clarifications were made, for example, blinding of personnel to the study treatment assignments in studies TV46000-CNS-30072 and TV46000-CNS-30078 (especially with regard to those also involved in the conduct of study TV46000-CNS-30072). - Since pin-pointing the onset of schizophrenia in adolescents is difficult, the time since the diagnosis of schizophrenia in the inclusion criterion for adolescents (aged 13-17) was reduced to 6 months to better align with the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, and the requirement for relapse in the last 24 months was removed due to the short time since diagnosis.

    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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