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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Study of TEV-50717 (Deutetrabenazine) for the Treatment of Tourette Syndrome in Children and Adolescents

    Summary
    EudraCT number
    		 2016-000622-19
    Trial protocol
    		 ES   DK  
    Global end of trial date
    12 Nov 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    TV50717-CNS-30046
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03452943
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 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 the efficacy 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 (eg, Code of Federal Regulations [CFR] 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
    05 Feb 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
    Canada: 21
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Serbia: 10
    Country: Number of subjects enrolled
    United States: 66
    Worldwide total number of subjects
    119
    EEA total number of subjects
    15
    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)
    62
    Adolescents (12-17 years)
    57
    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 119 participants were randomized in a 1:1 ratio to either TEV-50717 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
    Arm description
    		 TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEV-50717
    Investigational medicinal product code
    Other name
    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 specified in the arm.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to TEV-50717 BID for a total of 12 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 per schedule specified in the arm.

    Number of subjects in period 1
    		TEV-50717 Placebo
    Started
    59
    60
    Received at least 1 dose of study drug
    58
    59
    Modified ITT (mITT) Analysis Set
    58
    59
    Completed
    51
    56
    Not completed
    8
    4
         Consent withdrawn by subject
    5
    2
         Adverse event, non-fatal
    2
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEV-50717
    Reporting group description
    		 TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 12 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to TEV-50717 BID for a total of 12 weeks

    Reporting group values
    		 TEV-50717 Placebo Total
    Number of subjects
    		 59 60 119
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.5 ( 2.52 ) 11.5 ( 2.59 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 6 9 15
        Male
    		 53 51 104
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 8 13
        Not Hispanic or Latino
    		 51 50 101
        Unknown or Not Reported
    		 3 2 5
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 49 53 102
        Black
    		 3 3 6
        Asian
    		 1 1 2
        Native American
    		 1 0 1
        Multiple
    		 3 1 4
        Other
    		 2 2 4
    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)
    		 31.7 ( 5.81 ) 33.0 ( 5.96 ) -

    End points

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    End points reporting groups
    Reporting group title
    TEV-50717
    Reporting group description
    		 TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 12 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to TEV-50717 BID for a total of 12 weeks

    Primary: Change From Baseline in the TTS of the YGTSS at Week 12

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    End point title
    		 Change From Baseline in the TTS of the YGTSS at Week 12
    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 = none to 5 = severe). MTSS = sum of the 5 items for motor tic severity and VTSS is sum of the 5 items for vocal tic severity. TTS = 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 (5 levels: weeks 2, 4, 6, 9, and 12), and 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 12
    End point values
    		 TEV-50717 Placebo
    Number of subjects analysed
    58
    59
    Units: units on a scale
        least squares mean (standard error)
    -9.1 ( 1.28 )
    -8.4 ( 1.25 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    TEV-50717 v Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.692 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 2.8
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12

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    End point title
    		 Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12
    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 (5 levels: weeks 2, 4, 6, 9, and 12), 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 12
    End point values
    		 TEV-50717 Placebo
    Number of subjects analysed
    58
    59
    Units: units on a scale
        least squares mean (standard error)
    -0.7 ( 0.13 )
    -0.7 ( 0.12 )
    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 12

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    End point title
    		 Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 12
    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 12
    End point values
    		 TEV-50717 Placebo
    Number of subjects analysed
    58
    59
    Units: units on a scale
        arithmetic mean (standard error)
    -0.7 ( 0.18 )
    -0.4 ( 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 at Week 12

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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 12
    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 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 (5 levels: weeks 2,4,6,9, and 12), 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 12
    End point values
    		 TEV-50717 Placebo
    Number of subjects analysed
    58
    59
    Units: units on a scale
        least squares mean (standard error)
    -9.9 ( 2.37 )
    -8.8 ( 2.27 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events (AEs)

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    End point title
    		 Percentage of Participants With Adverse Events (AEs)
    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. 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. Safety analysis set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to follow-up (Week 14)
    End point values
    		 TEV-50717 Placebo
    Number of subjects analysed
    58
    59
    Units: percentage of participants
    number (not applicable)
        Any AEs
    65.5
    55.9
        Treatment-related AEs
    50.0
    20.3
        Serious AEs
    0
    0
        AEs leading to discontinuation
    1.7
    1.7
    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 14)
    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
    Reporting group description
    		 TEV-50717 tablets BID up to 48 mg/day orally for a total of 12 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to TEV-50717 BID for a total of 12 weeks

    Serious adverse events
    		 TEV-50717 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 59 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TEV-50717 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 58 (37.93%)
    23 / 59 (38.98%)
    Investigations
    Weight increased
         subjects affected / exposed
    7 / 58 (12.07%)
    1 / 59 (1.69%)
         occurrences all number
    7
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 58 (10.34%)
    6 / 59 (10.17%)
         occurrences all number
    6
    12
    Somnolence
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 59 (1.69%)
         occurrences all number
    8
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 58 (12.07%)
    3 / 59 (5.08%)
         occurrences all number
    8
    4
    Pyrexia
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 59 (1.69%)
         occurrences all number
    4
    1
    Nausea
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 59 (8.47%)
         occurrences all number
    5
    11
    Vomiting
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 59 (5.08%)
         occurrences all number
    3
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Depressed mood
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Enuresis
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 59 (0.00%)
         occurrences all number
    6
    0
    Suicidal ideation
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    0
    9
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2018
    The primary reason for this amendment was to include additional nonclinical data observed in rat toxicology studies; further clarify procedures to be carried out during the screening and enrollment periods (for example, informed consent/assent stipulations); update requirements on drug storage and security; update/clarify participant inclusion criteria, exclusion criteria, and withdrawal criteria; provide updates on allowed and prohibited medications; include additional guidance for evaluation and handling of suicidal ideation, suicidal behavior, and depression; and streamline birth control methods language for females of childbearing potential.
    25 Mar 2019
    The primary reason for this amendment was to update the anticipated participant enrollment numbers and related statistical considerations, update requirements on drug storage and security, update/clarify participant inclusion criteria and withdrawal criteria, update administrative details with regard to clinical study personnel contact information and vendor selection, and provide additional guidance on dose suspension.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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