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    Clinical Trial Results:
    A Well-Controlled, Fixed-Dose Study of TEV-50717 (Deutetrabenazine) for the Treatment of Tics Associated with Tourette Syndrome

    Summary
    EudraCT number
    		 2017-002976-24
    Trial protocol
    		 HU   SE   IT   PL   FR   NL   RO  
    Global end of trial date
    09 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jun 2020
    First version publication date
    05 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV50717-CNS-30060
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03571256
    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
    24 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2019
    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 efficacy of fixed doses of TEV-50717 to reduce motor and phonic tics associated with Tourette Syndrome (TS).
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Tripartite Guideline (E6) and any applicable national and local laws and regulations (for example, Code of Federal Regulations Title 21, Parts 11, 50, 54, 56, 312, and 314 and European Union Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical studies on medicinal products for human use).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 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
    Argentina: 7
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    Ukraine: 34
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    158
    EEA total number of subjects
    53
    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)
    69
    Adolescents (12-17 years)
    89
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 158 participants were randomized in a 1:1:1 ratio to TEV-50717 high-dose, TEV-50717 low-dose or placebo group.

    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
    		 TEV-50717 High-Dose
    Arm description
    		 TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEV-50717
    Investigational medicinal product code
    Other name
    AUSTEDO, Deutetrabenazine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6-, 9-, 12-, 15-, and 18 mg oral tablets per dose and schedule as specified in the arm.

    Arm title
    		 TEV-50717 Low-Dose
    Arm description
    		 TEV-50717 tablets BID up to 36 mg/day orally for a total of 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEV-50717
    Investigational medicinal product code
    Other name
    AUSTEDO, Deutetrabenazine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6-, 9-, 12-, 15-, and 18 mg oral tablets per dose and schedule as specified in the arm.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to TEV-50717 for a total of 8 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to TEV-50717 tablets were taken BID.

    Number of subjects in period 1
    		TEV-50717 High-Dose TEV-50717 Low-Dose Placebo
    Started
    52
    54
    52
    Received at least 1 dose of study drug
    52
    54
    51
    Modified ITT (mITT) Analysis Set
    49
    53
    51
    Completed
    46
    51
    48
    Not completed
    6
    3
    4
         Consent withdrawn by subject
    3
    1
    1
         Adverse event, non-fatal
    3
    -
    1
         Other than specified
    -
    1
    1
         Protocol deviation
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEV-50717 High-Dose
    Reporting group description
    		 TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 8 weeks

    Reporting group title
    TEV-50717 Low-Dose
    Reporting group description
    		 TEV-50717 tablets BID up to 36 mg/day orally for a total of 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to TEV-50717 for a total of 8 weeks

    Reporting group values
    		 TEV-50717 High-Dose TEV-50717 Low-Dose Placebo Total
    Number of subjects
    		 52 54 52 158
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.7 ± 2.63 11.7 ± 2.70 11.8 ± 2.62 -
    Sex: Female, Male
    Units: participants
        Female
    		 15 12 12 39
        Male
    		 37 42 40 119
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 8 9 15 32
        Not Hispanic or Latino
    		 43 45 37 125
        Unknown or Not Reported
    		 1 0 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 48 48 39 135
        Black
    		 0 1 0 1
        Asian
    		 0 3 4 7
        Native American
    		 1 1 2 4
        Multiple
    		 0 0 2 2
        Other
    		 3 1 5 9
    Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)
    YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 for severe). Motor tic severity score (MTSS) is the sum of 5 items for motor tic severity and vocal tic severity score (VTSS) is the sum of 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 33.9 ± 6.17 32.9 ± 7.20 34.7 ± 6.29 -

    End points

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    End points reporting groups
    Reporting group title
    TEV-50717 High-Dose
    Reporting group description
    		 TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 8 weeks

    Reporting group title
    TEV-50717 Low-Dose
    Reporting group description
    		 TEV-50717 tablets BID up to 36 mg/day orally for a total of 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to TEV-50717 for a total of 8 weeks

    Primary: Change From Baseline in the TTS of the YGTSS at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the TTS of the YGTSS at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [1]
    End point description
    YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. Least square (LS) mean and standard error (SE) was calculated using mixed-model repeated-measures (MMRM) with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    Notes
    [1] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 High-Dose Placebo
    Number of subjects analysed
    49
    51
    Units: units on a scale
        least squares mean (standard error)
    -7.8 ± 1.24
    -7.0 ± 1.16
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    TEV-50717 High-Dose v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 2.3
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [3]
    End point description
    The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant’s quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [3] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 High-Dose Placebo
    Number of subjects analysed
    49
    51
    Units: units on a scale
        least squares mean (standard error)
    -0.8 ± 0.14
    -0.6 ± 0.13
    No statistical analyses for this end point

    Secondary: Change From Baseline in the TTS of the YGTSS at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the TTS of the YGTSS at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [4]
    End point description
    YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [4] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 Low-Dose Placebo
    Number of subjects analysed
    53
    51
    Units: units on a scale
        least squares mean (standard error)
    -5.9 ± 1.18
    -7.0 ± 1.16
    No statistical analyses for this end point

    Secondary: Change From Baseline in the TS-CGI Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the TS-CGI Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [5]
    End point description
    The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant’s quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [5] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 Low-Dose Placebo
    Number of subjects analysed
    53
    51
    Units: units on a scale
        least squares mean (standard error)
    -0.6 ± 0.13
    -0.6 ± 0.13
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [6]
    End point description
    The TS-PGII is a single-item questionnaire that asks the participant to assess the degree of impact due to current tics (How much do your current tics disrupt things in your life?). The TS-PGII uses a 5-point scale, ranging from not at all (1) to very much (5), to assess overall response to therapy. mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [6] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 High-Dose Placebo
    Number of subjects analysed
    49
    51
    Units: units on a scale
        arithmetic mean (standard error)
    -0.8 ± 0.17
    -0.7 ± 0.16
    No statistical analyses for this end point

    Secondary: Change From Baseline in the TS-PGII Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the TS-PGII Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [7]
    End point description
    The TS-PGII is a single-item questionnaire that asks the participant to assess the degree of impact due to current tics (How much do your current tics disrupt things in your life?). The TS-PGII uses a 5-point scale, ranging from not at all (1) to very much (5), to assess overall response to therapy. mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [7] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 Low-Dose Placebo
    Number of subjects analysed
    53
    51
    Units: units on a scale
        arithmetic mean (standard error)
    -0.7 ± 0.15
    -0.7 ± 0.16
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [8]
    End point description
    C&A-GTS-QOL is a 27-item questionnaire that contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and uses a 5-point Likert scale ranging from no problem to extreme problem. Following 3 questions were assessed in ADL C&A-GTS-QOL subscale: Question 2 (Had difficulty with school or sport activities?), 24 (Felt you needed more help from other people?), and 26 (Had difficulty going out with other people?). Total score of ADL subscale ranged from 0 (no problem) to 12 (extreme problem). Lower score = better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates. mITT analysis set: all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [8] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 High-Dose Placebo
    Number of subjects analysed
    49
    51
    Units: units on a scale
        least squares mean (standard error)
    -10.3 ± 2.85
    -9.0 ± 2.66
    No statistical analyses for this end point

    Secondary: Change From Baseline in the C&A-GTS-QOL ADL Subscale Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants

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    End point title
    		 Change From Baseline in the C&A-GTS-QOL ADL Subscale Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants [9]
    End point description
    C&A-GTS-QOL is a 27-item questionnaire that contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and uses a 5-point Likert scale ranging from no problem to extreme problem. Following 3 questions were assessed in ADL C&A-GTS-QOL subscale: Question 2 (Had difficulty with school or sport activities?), 24 (Felt you needed more help from other people?), and 26 (Had difficulty going out with other people?). Total score of ADL subscale ranged from 0 (no problem) to 12 (extreme problem). Lower score = better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates. mITT analysis set: all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [9] - 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 end point is reporting statistics for specified arms only.
    End point values
    		 TEV-50717 Low-Dose Placebo
    Number of subjects analysed
    53
    51
    Units: units on a scale
        least squares mean (standard error)
    -10.0 ± 2.68
    -9.0 ± 2.66
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Children’s Depression Inventory Second Edition (CDI-2; Parent Version and Self-reported version) Total Score at Week 9

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    End point title
    		 Change From Baseline in the Children’s Depression Inventory Second Edition (CDI-2; Parent Version and Self-reported version) Total Score at Week 9
    End point description
    CDI-2 self-report:28-item questionnaire assessing depressive symptoms in children 7 to 17 years of age with basic reading and comprehension skills. Children were asked to choose 1 of 3 statements that most closely aligns with their feelings in past 2 weeks. It contains 6 subscales (emotional problem,negative mood/physical symptoms,negative self-esteem,functional problems,ineffectiveness,interpersonal problems). Total score = 0 to 56, higher score = greater depression severity.CDI-2 parent:17-item questionnaire administered to parents to assess depression-related behaviors observed in children. Parents were asked to rate their child’s behaviors on a 4-point Likert scale from “not at all” to “much or most of the time.” It contains 2 subscales (emotional and functional problem). Total score = 0 to 51, higher score = more depression-related behaviors. Safety analysis set: all participants who received at least 1 dose of study drug. 'n' = participants evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 9
    End point values
    		 TEV-50717 High-Dose TEV-50717 Low-Dose Placebo
    Number of subjects analysed
    52
    54
    51
    Units: units on a scale
    arithmetic mean (standard deviation)
        CDI-2 Parent Version (n=45,52,48)
    -1.2 ± 6.53
    -3.8 ± 6.34
    -0.8 ± 5.36
        CDI-2 Self-Reported Version (n=45,49,46)
    -2.0 ± 4.13
    -2.6 ± 4.90
    -0.4 ± 4.99
    No statistical analyses for this end point

    Secondary: Number of Participants at Baseline and Week 9 with Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Participants at Baseline and Week 9 with Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS)
    End point description
    C-SSRS included responses for Suicidal Ideation or Suicidal Behavior in following 10 categories: 1 = Wish to be dead; 2 = Non-specific active suicidal thoughts; 3 = Active suicidal ideation with any methods (not plan) without intent to act; 4 = Active suicidal ideation with some intent to act, without specific plan; 5 = Active suicidal ideation with specific plan and intent; 6 = Preparatory acts or behavior; 7 = Aborted attempt; 8 = Interrupted attempt; 9 = Non-fatal suicide attempt; and 10 = Completed suicide. Number of participants with any suicidal ideation or suicidal behavior are reported. Any Suicidal ideation or Suicidal Behavior events reported as TEAEs along with all other reported TEAEs are included in the AE module. Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'number analyzed' signifies participants evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 9
    End point values
    		 TEV-50717 High-Dose TEV-50717 Low-Dose Placebo
    Number of subjects analysed
    52
    54
    51
    Units: participants
        Baseline
    0
    0
    2
        Week 9
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) to follow-up (Week 10)
    Adverse event reporting additional description
    Safety analysis set included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    TEV-50717 High-Dose
    Reporting group description
    		 TEV-50717 tablets BID up to 48 mg/day orally for a total of 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to TEV-50717 for a total of 8 weeks

    Reporting group title
    TEV-50717 Low-Dose
    Reporting group description
    		 TEV-50717 tablets BID up to 36 mg/day orally for a total of 8 weeks

    Serious adverse events
    		 TEV-50717 High-Dose Placebo TEV-50717 Low-Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 51 (0.00%)
    0 / 54 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 51 (0.00%)
    0 / 54 (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
    Tic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 51 (0.00%)
    0 / 54 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TEV-50717 High-Dose Placebo TEV-50717 Low-Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 52 (36.54%)
    12 / 51 (23.53%)
    16 / 54 (29.63%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 52 (11.54%)
    4 / 51 (7.84%)
    8 / 54 (14.81%)
         occurrences all number
    8
    4
    13
    Somnolence
         subjects affected / exposed
    8 / 52 (15.38%)
    1 / 51 (1.96%)
    2 / 54 (3.70%)
         occurrences all number
    11
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 51 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    6
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 51 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    2
    0
    3
    Vomiting
         subjects affected / exposed
    3 / 52 (5.77%)
    4 / 51 (7.84%)
    1 / 54 (1.85%)
         occurrences all number
    3
    5
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 51 (5.88%)
    0 / 54 (0.00%)
         occurrences all number
    2
    4
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 52 (11.54%)
    3 / 51 (5.88%)
    2 / 54 (3.70%)
         occurrences all number
    6
    4
    2
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 51 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    4
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2019
    The following major procedural changes (not all-inclusive) were made to the protocol:  The study sample size was increased.  Updated corresponding statistical considerations  Included additional nonclinical data observed in rat toxicology studies  Further clarified procedures carried out during the screening and enrollment periods (for example, informed consent/assent stipulations)  Updated the requirements on drug storage, accountability, and security  Updated and clarified the participant inclusion criteria, exclusion criteria, and withdrawal criteria  Updated the exploratory endpoints  Provided updates on allowed and prohibited medications  Included additional guidance for evaluation and management of suicidal ideation, suicidal behavior, and depression
    05 May 2019
    The following major procedural change (not all-inclusive) was made to the protocol:  Reverted the study sample size back to the original sample size prior to Amendment 02. This change was justified upon further evaluation of the external data that was used to support the sample size considerations per Amendment 02 (that is, valbenazine Phase 2 study results, efficacy of TEV-50717 in the treatment of Huntington's disease (HD) and tardive dyskinesia (TD), and ABILIFY Phase 3 data), and the decision had been made not to increase the sample size in the ongoing TV50717-CNS-30060 Phase 3 fixed-dose study. There was substantially lower efficacy in the Abilify Phase 3 study (Study 2) in which a titration regimen was utilized, relative to the efficacy seen with Abilify in the fixed-dose Phase 3 study (Study 1; United States Prescribing Information), which supported the above rationale.

    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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