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    Clinical Trial Results:
    An Open-Label, Long-Term Safety Study Including a Double-Blind, Placebo-Controlled, Randomized Withdrawal Period of TEV-50717 (Deutetrabenazine) for the Treatment of Tourette Syndrome in Children and Adolescents

    Summary
    EudraCT number
    		 2016-000630-22
    Trial protocol
    		 HU   SE   ES   DK   PL   FR   NL   IT   RO  
    Global end of trial date
    15 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2020
    First version publication date
    27 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV50717-CNS-30047
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 1-888-483-8279, USMedInfo@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 001 1-888-483-8279, USMedInfo@tevapharm.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
    19 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the safety and tolerability of long-term therapy with TEV-50717.
    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
    15 May 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    United States: 79
    Worldwide total number of subjects
    228
    EEA total number of subjects
    61
    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)
    95
    Adolescents (12-17 years)
    133
    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
    		 228 participants with Tourette Syndrome were enrolled after completing one of two eligible parent studies.

    Pre-assignment
    Screening details
    		 Period I included an open-label period with titration and maintenance. Period II included randomized drug withdrawal in which participants were administered their current TEV50717 dose or placebo. Participants were re-titrated to TEV-50717. In Period III, participants continued their open-label maintenance dose of TEV50717.

    Period 1
    Period 1 title
    Period I - Part A
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label

    Arms
    Arm title
    		 TEV-50717
    Arm description
    		 All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEV-50717 (Deuterabenazine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants underwent TEV-50717 dose titration in this study. Participants received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.

    Number of subjects in period 1
    		TEV-50717
    Started
    228
    Completed
    137
    Not completed
    91
         Consent withdrawn by subject
    23
         Adverse event, non-fatal
    14
         Terminated by sponsor
    44
         Lost to follow-up
    2
         Missing or unknown
    7
         Protocol deviation
    1
    Period 2
    Period 2 title
    Period II - Part B
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Double-blind

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Randomized TEV-50717
    Arm description
    		 Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEV-50717 (Deuterabenazine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received their current dose of TEV-50717.

    Arm title
    		 Randomized Placebo
    Arm description
    		 Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.
    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 was administered during Part B Randomized Drug Withdrawal (RW) 2-week period only.

    Number of subjects in period 2
    		Randomized TEV-50717 Randomized Placebo
    Started
    91
    46
    Completed
    88
    45
    Not completed
    3
    1
         Adverse event, non-fatal
    1
    -
         Missing or unknown
    2
    1
    Period 3
    Period 3 title
    Period III - Part A Resumed
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label

    Arms
    Arm title
    		 TEV-50717 Re-titration and Maintenance
    Arm description
    		 Participants who were randomized to placebo during the withdrawal period were re-titrated to their TEV-50717 maintenance dose. Participants who were randomized to TEV-50717 continued their maintenance dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEV-50717 (Deuterabenazine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received their current dose of TEV-50717 or were re-titrated to TEV-50717 if randomized to the placebo in the previous period.

    Number of subjects in period 3
    		TEV-50717 Re-titration and Maintenance
    Started
    133
    Completed
    48
    Not completed
    85
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    4
         Terminated by sponsor
    68
         Lost to follow-up
    1
         Missing or unknown
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEV-50717
    Reporting group description
    		 All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.

    Reporting group values
    		 TEV-50717 Total
    Number of subjects
    		 228 228
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 95 95
        Adolescents (12-17 years)
    		 133 133
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 12 ± 2.59 -
    Sex/Gender, Customized
    Units: Participants
        Female
    		 45 45
        Male
    		 182 182
        Unknown
    		 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 38 38
        Not Hispanic or Latino
    		 186 186
        Unknown or Not Reported
    		 4 4
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 197 197
        Black
    		 4 4
        Asian
    		 7 7
        Native American
    		 5 5
        Other
    		 15 15

    End points

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    End points reporting groups
    Reporting group title
    TEV-50717
    Reporting group description
    		 All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
    Reporting group title
    Randomized TEV-50717
    Reporting group description
    		 Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.

    Reporting group title
    Randomized Placebo
    Reporting group description
    		 Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.
    Reporting group title
    TEV-50717 Re-titration and Maintenance
    Reporting group description
    		 Participants who were randomized to placebo during the withdrawal period were re-titrated to their TEV-50717 maintenance dose. Participants who were randomized to TEV-50717 continued their maintenance dose.

    Primary: Number of participants reporting treatment emergent adverse events (AEs) for Parts A & B

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    End point title
    		 Number of participants reporting treatment emergent adverse events (AEs) for Parts A & B [1]
    End point description
    An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Incudes clinically significant changes such as changes in vital signs or lab values. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, 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 the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
    End point type
    Primary
    End point timeframe
    Day 1 to Week 55
    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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 TEV-50717
    Number of subjects analysed
    227
    Units: Participants
        At least one adverse event
    161
        At least one serious adverse event
    2
        At least one severe adverse event
    6
        At least one AE related to investigational product
    95
        At least one adverse event leading to withdrawal
    14
    No statistical analyses for this end point

    Primary: Number of participants reporting treatment emergent adverse events (AEs) in Part B (Period II)

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    End point title
    		 Number of participants reporting treatment emergent adverse events (AEs) in Part B (Period II) [2]
    End point description
    An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Incudes clinically significant changes such as changes in vital signs or lab values. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, 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 the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
    End point type
    Primary
    End point timeframe
    Weeks 28 to 30
    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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 Randomized TEV-50717 Randomized Placebo
    Number of subjects analysed
    84
    42
    Units: Participants
        At least one adverse event
    16
    6
        At least one serious adverse event
    0
    0
        At least one severe adverse event
    0
    0
        At least one AE related to investigational product
    6
    1
        At least one adverse event leading to withdrawal
    0
    0
    No statistical analyses for this end point

    Primary: Change From baseline in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score

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    End point title
    		 Change From baseline in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score [3]
    End point description
    Parents were asked to rate their child's behaviors in past 2 weeks on a 4-point Likert scale from "not at all" to "much or most of the time." It contains 2 subscales (emotional problems and functional problem). Total score: sum of 2 subscales, ranging from 0 to 51, with higher score indicating more depression-related behaviors.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55
    Notes
    [3] - 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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 TEV-50717
    Number of subjects analysed
    227
    Units: Units On A Scale
    arithmetic mean (standard deviation)
        CDI-2 Parent Version Week 2
    -0.7 ± 4.26
        CDI-2 Parent Version Week 4
    -1.5 ± 4.39
        CDI-2 Parent Version Week 8
    -1.5 ± 5.0
        CDI-2 Parent Version Week 15
    -1.2 ± 5.79
        CDI-2 Parent Version Week 28
    -1.1 ± 5.52
        CDI-2 Parent Version Week 34
    -1.0 ± 6.08
        CDI-2 Parent Version Week 41
    -1.1 ± 5.92
        CDI-2 Parent Version Week 54
    -0.3 ± 5.83
        CDI-2 Parent Version Week 55
    -0.9 ± 4.34
    No statistical analyses for this end point

    Primary: Change From baseline in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score

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    End point title
    		 Change From baseline in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score [4]
    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: sum of all subscales scores, ranging from 0 to 56, with higher score indicating greater depression severity.CDI-2 parent: 17-item questionnaire administered to parents to assess depression-related behaviors observed in their children.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55
    Notes
    [4] - 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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 TEV-50717
    Number of subjects analysed
    227
    Units: Units On A Scale
    arithmetic mean (standard deviation)
        CDI-2 Self-reported Version Week 2
    -0.3 ± 3.41
        CDI-2 Self-reported Version Week 4
    -0.5 ± 3.57
        CDI-2 Self-reported Version Week 8
    -0.3 ± 4.35
        CDI-2 Self-reported Version Week 15
    -0.3 ± 4.83
        CDI-2 Self-reported Version Week 28
    0.0 ± 4.65
        CDI-2 Self-reported Version Week 34
    -0.5 ± 4.61
        CDI-2 Self-reported Version Week 41
    -0.7 ± 4.74
        CDI-2 Self-reported Version Week 54
    -0.5 ± 4.01
        CDI-2 Self-reported Version Week 55
    -0.3 ± 4.52
    No statistical analyses for this end point

    Primary: Change From randomized withdrawal baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score at Week 30

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    End point title
    		 Change From randomized withdrawal baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score at Week 30 [5]
    End point description
    Parents were asked to rate their child's behaviors in past 2 weeks on a 4-point Likert scale from "not at all" to "much or most of the time." It contains 2 subscales (emotional problems and functional problem). Total score: sum of 2 subscales, ranging from 0 to 51, with higher score indicating more depression-related behaviors.
    End point type
    Primary
    End point timeframe
    Week 28, Week 30
    Notes
    [5] - 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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 Randomized TEV-50717 Randomized Placebo
    Number of subjects analysed
    83
    41
    Units: Units On A Scale
        arithmetic mean (standard deviation)
    -0.2 ± 4.68
    0.6 ± 3.62
    No statistical analyses for this end point

    Primary: Change From randomized withdrawal baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score at Week 30

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    End point title
    		 Change From randomized withdrawal baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score at Week 30 [6]
    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: sum of all subscales scores, ranging from 0 to 56, with higher score indicating greater depression severity.CDI-2 parent: 17-item questionnaire administered to parents to assess depression-related behaviors observed in their children.
    End point type
    Primary
    End point timeframe
    Week 28, Week 30
    Notes
    [6] - 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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 Randomized TEV-50717 Randomized Placebo
    Number of subjects analysed
    82
    39
    Units: Units On A Scale
        arithmetic mean (standard deviation)
    -0.4 ± 3.3
    -0.6 ± 3.08
    No statistical analyses for this end point

    Primary: Number of participants reporting 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 reporting any suicidal ideation or suicidal behavior according to the Columbia Suicide Severity Rating Scale (C-SSRS) [7]
    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.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55
    Notes
    [7] - 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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 TEV-50717
    Number of subjects analysed
    227
    Units: Participants
        Baseline
    0
        Week 2
    0
        Week 4
    2
        Week 8
    0
        Week 15
    1
        Week 28
    0
        Week 34
    0
        Week 41
    1
        Week 54
    0
        Week 55
    0
    No statistical analyses for this end point

    Primary: Number of participants reporting any suicidal ideation or suicidal behavior according to the Columbia Suicide Severity Rating Scale (C-SSRS) at randomized withdrawal baseline visit (Week 28) and Week 30

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    End point title
    		 Number of participants reporting any suicidal ideation or suicidal behavior according to the Columbia Suicide Severity Rating Scale (C-SSRS) at randomized withdrawal baseline visit (Week 28) and Week 30 [8]
    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.
    End point type
    Primary
    End point timeframe
    Week 28, Week 30
    Notes
    [8] - 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 assessment for this endpoint was descriptive and no statistical analyses were performed for this endpoint.
    End point values
    		 Randomized TEV-50717 Randomized Placebo
    Number of subjects analysed
    84
    42
    Units: Participants
        Week 28
    0
    0
        Week 30
    0
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)

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    End point title
    		 Change from baseline in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)
    End point description
    YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. 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. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 15, 28, 41, 54, and 55
    End point values
    		 TEV-50717
    Number of subjects analysed
    228
    Units: Units on a scale
    arithmetic mean (standard error)
        Week 8
    -6.9 ± 0.58
        Week 15
    -7.8 ± 0.58
        Week 28
    -6.2 ± 0.83
        Week 41
    -8.3 ± 0.97
        Week 54
    -6.5 ± 1.47
        Week 55
    -4.3 ± 1.6
    No statistical analyses for this end point

    Secondary: Change from baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score

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    End point title
    		 Change from baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score
    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. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 15, 28, 41, 54, and 55
    End point values
    		 TEV-50717
    Number of subjects analysed
    228
    Units: Units on a scale
    arithmetic mean (standard error)
        Week 8
    -0.7 ± 0.06
        Week 15
    -0.7 ± 0.06
        Week 28
    -0.6 ± 0.08
        Week 41
    -0.6 ± 0.1
        Week 54
    -0.8 ± 0.16
        Week 55
    -0.4 ± 0.15
    No statistical analyses for this end point

    Secondary: Change from baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score

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    End point title
    		 Change from baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score
    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. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 15, 28, 41, 54, and 55
    End point values
    		 TEV-50717
    Number of subjects analysed
    228
    Units: Units on a scale
    arithmetic mean (standard error)
        Week 8
    -0.5 ± 0.07
        Week 15
    -0.5 ± 0.08
        Week 28
    -0.5 ± 0.09
        Week 41
    -0.6 ± 0.12
        Week 54
    -0.5 ± 0.16
        Week 55
    -0.1 ± 0.14
    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

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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
    End point description
    C&A-GTS-QOL is a 27-item questionnaire that asks participant to assess the extent to which their quality of life is impacted by their symptoms. C&A-GTS-QOL 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 from 27-item questionnaire were assessed in ADL C&A-GTS-QOL subscale: Question 2 (Had difficulty with school or sport activities?), 24 (Felt you needed more help or support 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 indicated better quality of life. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 6, 28, 34, 54
    End point values
    		 TEV-50717
    Number of subjects analysed
    228
    Units: Units on a scale
    arithmetic mean (standard error)
        Week 6
    -4.9 ± 1.12
        Week 28
    -4.4 ± 1.48
        Week 34
    -5.9 ± 1.82
        Week 54
    -2.7 ± 2.1
    No statistical analyses for this end point

    Secondary: Change from randomized withdrawal baseline (Week 28) in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) to Week 30

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    End point title
    		 Change from randomized withdrawal baseline (Week 28) in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) to Week 30
    End point description
    YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. 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. The model is an ANCOVA model that includes fixed effects for treatment group. The randomized withdrawal baseline TTS and age group at baseline (2 levels: 6-11 years, 12-18 years) are included as covariates.
    End point type
    Secondary
    End point timeframe
    Week 28, Week 30
    End point values
    		 Randomized TEV-50717 Randomized Placebo
    Number of subjects analysed
    54
    26
    Units: Units on a scale
        least squares mean (standard error)
    1.6 ± 0.86
    2.0 ± 1.24
    Statistical analysis title
    		 Least Squares Mean
    Comparison groups
    Randomized TEV-50717 v Randomized Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 2.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Week 55
    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
    Total
    Reporting group description
    		 All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.

    Serious adverse events
    		 Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 227 (0.88%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Self-injurious ideation
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    108 / 227 (47.58%)
    Investigations
    Weight increased
         subjects affected / exposed
    22 / 227 (9.69%)
         occurrences all number
    22
    Nervous system disorders
    Headache
         subjects affected / exposed
    30 / 227 (13.22%)
         occurrences all number
    55
    Somnolence
         subjects affected / exposed
    28 / 227 (12.33%)
         occurrences all number
    33
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    13 / 227 (5.73%)
         occurrences all number
    13
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    15 / 227 (6.61%)
         occurrences all number
    30
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    17 / 227 (7.49%)
         occurrences all number
    18
    Tic
         subjects affected / exposed
    15 / 227 (6.61%)
         occurrences all number
    29
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    23 / 227 (10.13%)
         occurrences all number
    33

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2017
    To change study conduct including number of participants randomized and clinical study personnel.
    15 Nov 2017
    To incorporate randomized drug withdrawal period and update prohibited medications.
    01 Feb 2018
    To correct the re-titration regiment in Part II.
    22 May 2019
    To address regulatory requirements such as updated number of participants, an interim analysis, and clarify screening procedures.

    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
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