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    Clinical Trial Results:
    An Open-Label, Long-Term Safety Study of SD-809 (Deutetrabenazine) for the Treatment of Moderate to Severe Tardive Dyskinesia

    Summary
    EudraCT number
    		 2014-001891-73
    Trial protocol
    		 CZ   PL   SK   HU  
    Global end of trial date
    14 Dec 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Dec 2021
    First version publication date
    27 Mar 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SD-809-C-20
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02198794
    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)
    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
    04 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the long-term safety, tolerability, and efficacy of SD-809 in reducing the severity of abnormal involuntary movements of moderate to severe tardive dyskinesia. The purpose of part B is to establish the durability of effect of SD-809 following 1-week period of randomized withdrawal (SD-809 and placebo), followed by 12 weeks of maintenance with SD-809.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (for example, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; EU Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 2014
    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
    Czechia: 26
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Poland: 89
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    United States: 195
    Worldwide total number of subjects
    337
    EEA total number of subjects
    142
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    258
    From 65 to 84 years
    79
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 343 participants who completed previous SD-809 studies, including study SD-809-C-18 (NCT02195700) or SD-809-C-23 (NCT02291861) were enrolled and 337 participants were eligible for analysis. 6 participants were not evaluable and were excluded from the analysis due to site data integrity issues as reported to the US FDA.

    Pre-assignment
    Screening details
    		 Study included 3 parts: A, B, and C. Participants in Part A who were on a stable dose for ≥4 weeks after a 6-week titration, were invited to participate in Part B. Participants who are noted as “Completed” for Part A: completed the study in Part A plus continued in Part B. EU participants who completed Part B were invited to participate in Part C.

    Period 1
    Period 1 title
    Part A: Open-Label (158 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 SD-809
    Arm description
    		 Participants received SD-809 orally BID starting at 12 mg/day, which was titrated based on dyskinesia control and tolerability up to a maximum total dose of 48 mg/day. Participants who declined to participate in Part B, continued at their stable dose of SD-809 BID up to Week 158.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SD-809
    Investigational medicinal product code
    TEV-50717
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SD-809 was administered per dose and schedule specified in the arm.

    Number of subjects in period 1
    		SD-809
    Started
    337
    Received at least 1 dose of study drug
    337
    Intent-to-Treat (ITT) Population
    337
    Participants participated in Part A only
    195
    Completed
    32
    Not completed
    305
         Adverse event, serious fatal
    8
         Study terminated
    1
         Consent withdrawn by subject
    79
         Agreed to continue in Part B
    142
         Adverse event, non-fatal
    33
         Protocol deviation
    1
         Noncompliance with study drug
    3
         Other than specified
    5
         Lost to follow-up
    24
         Lack of efficacy
    9
    Period 2
    Period 2 title
    Part B: Randomized (13 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part B: Placebo
    Arm description
    		 Participants received placebo matched to SD-809 for 1 week in randomized withdrawal period and thereafter received SD-809 (stable dose) for 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 SD-809 was administered per schedule specified in the arm.

    Arm title
    		 Part B: SD-809
    Arm description
    		 Participants received SD-809 (stable dose) for 1 week in randomized withdrawal period and continued to receive the same dose of SD-809 for an additional 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SD-809
    Investigational medicinal product code
    TEV-50717
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SD-809 was administered per dose and schedule specified in the arm.

    Number of subjects in period 2
    		Part B: Placebo Part B: SD-809
    Started
    16
    16
    Completed
    66
    68
    Not completed
    5
    3
         Consent withdrawn by subject
    3
    1
         Lost to follow-up
    2
    2
    Joined
    55
    55
         142 participants from Part A were randomized
    55
    55
    Period 3
    Period 3 title
    Part C: Safety Assessment (52 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part C: SD-809
    Arm description
    		 EU participants who completed Part B and willing to continue in the study continued treatment with SD-809 for 52 weeks at the current dose administered during the 12-week open-label period of Part B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SD-809
    Investigational medicinal product code
    TEV-50717
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SD-809 was administered per dose and schedule specified in the arm.

    Number of subjects in period 3 [1]
    		Part C: SD-809
    Started
    80
    Completed
    73
    Not completed
    7
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    3
         Adverse event, non-fatal
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 134 participants who completed Part B, 80 participants from the EU enrolled in Part C.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SD-809
    Reporting group description
    		 Participants received SD-809 orally BID starting at 12 mg/day, which was titrated based on dyskinesia control and tolerability up to a maximum total dose of 48 mg/day. Participants who declined to participate in Part B, continued at their stable dose of SD-809 BID up to Week 158.

    Reporting group values
    		 SD-809 Total
    Number of subjects
    		 337 337
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.9 ± 10.65 -
    Sex: Female, Male
    Units: participants
        Female
    		 188 188
        Male
    		 149 149
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaskan Native
    		 1 1
        Asian
    		 2 2
        Black
    		 69 69
        White
    		 264 264
        Other
    		 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 28 28
        Not Hispanic or Latino
    		 300 300
        Unknown or Not Reported
    		 9 9
    Total Motor Abnormal Involuntary Movement Scale (AIMS) Score
    AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 10.7 ± 4.68 -
    AIMS Individual Items (8-10) Scores: Severity of abnormal movements (Item 8) Score
    AIMS is composed of 12 clinician-administered and -scored items. Item 8 (used as an overall severity index indicating severity of abnormal movements) was rated on a 5-point anchored scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 9 and 10 (provide additional information with regard to participant's incapacitation due to abnormal movements and participant's awareness of abnormal movements) were rated on a 5-point anchored scale ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Higher scores indicated more severe disease.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 2.6 ± 0.78 -
    AIMS Individual Items (8-10) Scores: Incapacitation due to abnormal movements (Item 9) Score
    AIMS is composed of 12 clinician-administered and -scored items. Item 8 (used as an overall severity index indicating severity of abnormal movements) was rated on a 5-point anchored scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 9 and 10 (provide additional information with regard to participant's incapacitation due to abnormal movements and participant's awareness of abnormal movements) were rated on a 5-point anchored scale ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Higher scores indicated more severe disease.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 2.0 ± 1.07 -
    AIMS Individual Items (8-10) Scores: Participant's awareness of abnormal movements (Item 10) Score
    AIMS is composed of 12 clinician-administered and -scored items. Item 8 (used as an overall severity index indicating severity of abnormal movements) was rated on a 5-point anchored scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 9 and 10 (provide additional information with regard to participant's incapacitation due to abnormal movements and participant's awareness of abnormal movements) were rated on a 5-point anchored scale ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Higher scores indicated more severe disease.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 2.2 ± 1.08 -
    Modified Craniocervical Dystonia Questionnaire 24 (CDQ-24) Score
    CDQ-24 is a disease-specific quality of life questionnaire developed for use in participants with craniocervical dystonia. CDQ-24 was modified such that the questions focus more directly on the impact of TD on quality of life. The following domains were evaluated in mCDQ-24: stigma, emotional well-being, pain, activities of daily living, and social/family life. Each of the 24 questions were rated by participants on a scale of 0 = never or no impairment to 4 = always or very severe impairment. Total score ranged from 0 – 96, with higher score indicative of severe impairment.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 29.2 ± 18.96 -

    End points

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    End points reporting groups
    Reporting group title
    SD-809
    Reporting group description
    		 Participants received SD-809 orally BID starting at 12 mg/day, which was titrated based on dyskinesia control and tolerability up to a maximum total dose of 48 mg/day. Participants who declined to participate in Part B, continued at their stable dose of SD-809 BID up to Week 158.
    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Participants received placebo matched to SD-809 for 1 week in randomized withdrawal period and thereafter received SD-809 (stable dose) for 12 weeks.

    Reporting group title
    Part B: SD-809
    Reporting group description
    		 Participants received SD-809 (stable dose) for 1 week in randomized withdrawal period and continued to receive the same dose of SD-809 for an additional 12 weeks.
    Reporting group title
    Part C: SD-809
    Reporting group description
    		 EU participants who completed Part B and willing to continue in the study continued treatment with SD-809 for 52 weeks at the current dose administered during the 12-week open-label period of Part B.

    Subject analysis set title
    Part B: Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received placebo matched to SD-809 for 1 week in randomized withdrawal period and thereafter received SD-809 (stable dose) for 12 weeks.

    Subject analysis set title
    Part B: SD-809
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received SD-809 (stable dose) for 1 week in randomized withdrawal period and continued to receive the same dose of SD-809 for an additional 12 weeks.

    Primary: Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal

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    End point title
    		 Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal [1]
    End point description
    AEs were analyzed as 1 group combined for parts A and B per planned analysis. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE=prevents normal daily activities. Drug-related TEAEs=TEAEs with possible, probable, or definite relationship to study drug. Serious AEs=death, life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, significant disability or incapacity, congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in the definition. TEAE=an AE that began after the first administration of study drug or existing AEs that worsened after first dose of study drug. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Safety population included all participants who received any study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to the end of follow-up (4 weeks after the last dose of study drug; mean exposure: up to approximately 866.1 days)
    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: Of the 134 participants who completed Part B, 80 participants from the EU enrolled in Part C.
    End point values
    		 SD-809 Part C: SD-809
    Number of subjects analysed
    337
    80
    Units: participants
        Any TEAEs
    269
    23
        Serious TEAEs
    68
    5
        Severe TEAEs
    57
    3
        Drug-Related TEAEs
    154
    3
        TEAEs Leading to Withdrawal From Study
    42
    3
    No statistical analyses for this end point

    Primary: Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating

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    End point title
    		 Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating
    End point description
    The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia. The randomized withdrawal modified intent-to-treat (mITT) population included all participants enrolled in Part B who received study drug during the randomized withdrawal period and had a total motor AIMS score as assessed by blinded central video rating at both the pre-withdrawal visit and the post-withdrawal visit.
    End point type
    Primary
    End point timeframe
    Day 1 of Part B, Day 7 of Part B
    End point values
    		 Part B: Placebo Part B: SD-809
    Number of subjects analysed
    63
    65
    Units: units on a scale
    arithmetic mean (standard error)
        Pre-withdrawal
    5.7 ± 0.55
    5.0 ± 0.49
        Change at Post-withdrawal
    0.6 ± 0.28
    0 ± 0.29
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The statistical model was an analysis of covariance (ANCOVA) with treatment group and dopamine receptor antagonist status at the pre-withdrawal visit as fixed effects and the pre-withdrawal visit value as a covariate.
    Comparison groups
    Part B: Placebo v Part B: SD-809
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.121 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.42
         upper limit
    		 0.17
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Part A: Change From Baseline in Total Motor AIMS Score at Week 145, as Assessed by the Site Rating

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    End point title
    		 Part A: Change From Baseline in Total Motor AIMS Score at Week 145, as Assessed by the Site Rating
    End point description
    The AIMS is an assessment tool used to detect and follow the severity of tardive dyskinesia (TD) over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 145
    End point values
    		 SD-809
    Number of subjects analysed
    160
    Units: units on a scale
        arithmetic mean (standard error)
    -6.6 ± 0.37
    No statistical analyses for this end point

    Secondary: Part A: Change From Baseline in Total Motor AIMS Score at Week 158, as Assessed by the Site Rating

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    End point title
    		 Part A: Change From Baseline in Total Motor AIMS Score at Week 158, as Assessed by the Site Rating
    End point description
    The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 158
    End point values
    		 SD-809
    Number of subjects analysed
    34
    Units: units on a scale
        arithmetic mean (standard error)
    -6.3 ± 0.85
    No statistical analyses for this end point

    Secondary: Part A: Percent Change From Baseline in Total Motor AIMS Score at Week 145, as Assessed by the Site Rating

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    End point title
    		 Part A: Percent Change From Baseline in Total Motor AIMS Score at Week 145, as Assessed by the Site Rating
    End point description
    The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 145
    End point values
    		 SD-809
    Number of subjects analysed
    159
    Units: percent change
        arithmetic mean (standard error)
    -57.0 ± 2.43
    No statistical analyses for this end point

    Secondary: Part A: Percent Change From Baseline in Total Motor AIMS Score at Week 158, as Assessed by the Site Rating

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    End point title
    		 Part A: Percent Change From Baseline in Total Motor AIMS Score at Week 158, as Assessed by the Site Rating
    End point description
    The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 158
    End point values
    		 SD-809
    Number of subjects analysed
    34
    Units: percent change
        arithmetic mean (standard error)
    -54.9 ± 6.76
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Participants who had a 50% or Greater Reduction From Baseline in Total Motor AIMS Score, as Assessed by the Site Rating

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    End point title
    		 Part A: Percentage of Participants who had a 50% or Greater Reduction From Baseline in Total Motor AIMS Score, as Assessed by the Site Rating
    End point description
    The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 145
    End point values
    		 SD-809
    Number of subjects analysed
    159
    Units: percentage of participants
    67
    No statistical analyses for this end point

    Secondary: Part A: Change From Baseline in AIMS Items 8, 9, and 10 Score at Week 145, as Assessed by the Site Rating

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    End point title
    		 Part A: Change From Baseline in AIMS Items 8, 9, and 10 Score at Week 145, as Assessed by the Site Rating
    End point description
    AIMS is composed of 12 clinician-administered and -scored items. Items 8 to 10 deal with global severity as judged by the examiner, and the participant’s awareness of the movements and distress associated with them. Item 8 (used as an overall severity index indicating severity of abnormal movements) was rated on a 5-point anchored scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 9 and 10 (provide additional information with regard to participant's incapacitation due to abnormal movements and participant's awareness of abnormal movements) were rated on a 5-point anchored scale ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Higher scores indicated more severe disease. ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 145
    End point values
    		 SD-809
    Number of subjects analysed
    160
    Units: units on a scale
    arithmetic mean (standard error)
        Severity of abnormal movements
    -1.3 ± 0.07
        Incapacitation due to abnormal movements
    -1.3 ± 0.08
        Participant's awareness of abnormal movements
    -1.3 ± 0.09
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Participants who had a 70% or Greater Reduction From Baseline in Total Motor AIMS Score, as Assessed by the Site Rating

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    End point title
    		 Part A: Percentage of Participants who had a 70% or Greater Reduction From Baseline in Total Motor AIMS Score, as Assessed by the Site Rating
    End point description
    The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 145
    End point values
    		 SD-809
    Number of subjects analysed
    159
    Units: percentage of participants
    42
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Participants who Were a Treatment Success, Based on the Clinical Global Impression of Change (CGIC)

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    End point title
    		 Part A: Percentage of Participants who Were a Treatment Success, Based on the Clinical Global Impression of Change (CGIC)
    End point description
    A treatment success was defined as much or very much improved on the CGIC from baseline of this study. The CGIC is a single-item questionnaire that asks the investigator to assess a participant’s TD symptoms at specific visits/weeks after initiating therapy. The CGIC uses a 7-point Likert scale, ranging from -3 to +3 (-3 = very much worse, -2 = much worse, -1 = minimally worse, 0 = not changed, 1 = minimally improved, 2 = much improved, 3 = very much improved), to assess overall response to therapy. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 145
    End point values
    		 SD-809
    Number of subjects analysed
    160
    Units: percentage of participants
    73
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Participants who Were a Treatment Success, Based on the Patient Global Impression of Change (PGIC)

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    End point title
    		 Part A: Percentage of Participants who Were a Treatment Success, Based on the Patient Global Impression of Change (PGIC)
    End point description
    A treatment success was defined as much or very much improved on the PGIC from baseline of this study. The PGIC is single-item questionnaire that asks the participant to assess their TD symptoms at specific visits/weeks after initiating therapy. The PGIC uses a 7-point Likert scale, ranging from -3 to +3 (-3 = very much worse, -2 = much worse, -1 = minimally worse, 0 = not changed, 1 = minimally improved, 2 = much improved, 3 = very much improved), to assess overall response to therapy. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 145
    End point values
    		 SD-809
    Number of subjects analysed
    161
    Units: percentage of participants
    63
    No statistical analyses for this end point

    Secondary: Part A: Change From Baseline in Modified CDQ-24 Score at Week 158

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    End point title
    		 Part A: Change From Baseline in Modified CDQ-24 Score at Week 158
    End point description
    The CDQ-24 is a disease-specific quality of life questionnaire developed for use in participants with craniocervical dystonia, including both cervical dystonia (CD) and blepharospasm (BPS). The CDQ-24 was modified such that the questions focus more directly on the impact of TD (as opposed to CD/BPS) on quality of life. The following domains were evaluated in the mCDQ-24: stigma, emotional well-being, pain, activities of daily living, and social/family life. Each of the 24 questions were rated by participants on a scale of 0 = never or no impairment to 4 = always or very severe impairment. Total score ranged from 0 – 96, with higher score indicative of severe impairment. The ITT population included all participants who were enrolled in the study, regardless of whether or not a participant received a dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 158
    End point values
    		 SD-809
    Number of subjects analysed
    39
    Units: units on a scale
        arithmetic mean (standard error)
    -6.3 ± 2.61
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to the end of follow-up (4 weeks after the last dose of study drug; mean exposure: up to approximately 866.1 days)
    Adverse event reporting additional description
    Adverse events were analyzed as one group combined for Parts A and B and as a separate group for Part C per planned analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Part A and Part B Participants
    Reporting group description
    		 Participants received SD-809 orally BID starting at 12 mg/day, which was titrated based on dyskinesia control and tolerability up to a maximum total dose of 48 mg/day. Participants who declined to participate in Part B, continued at their stable dose of SD-809 BID up to Week 158. Participants who agreed to participate in Part B, received SD-809 or placebo matched to SD-809 for 1 week in randomized withdrawal period and thereafter received SD-809 (stable dose) for 12 weeks.

    Reporting group title
    Part C: SD-809
    Reporting group description
    		 EU participants who completed Part B and willing to continue in the study continued treatment with SD-809 for 52 weeks at the current dose administered during the 12-week open-label period of Part B.

    Serious adverse events
    		 Part A and Part B Participants Part C: SD-809
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 337 (20.18%)
    5 / 80 (6.25%)
         number of deaths (all causes)
    8
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal squamous cell carcinoma
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 337 (1.19%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressive symptom
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Homicidal ideation
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    5 / 337 (1.48%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    3 / 337 (0.89%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 337 (0.59%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised non-convulsive epilepsy
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic duct stenosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cyst
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium avium complex infection
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 337 (1.19%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A and Part B Participants Part C: SD-809
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 337 (51.04%)
    5 / 80 (6.25%)
    Investigations
    Weight decreased
         subjects affected / exposed
    32 / 337 (9.50%)
    0 / 80 (0.00%)
         occurrences all number
    34
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    18 / 337 (5.34%)
    0 / 80 (0.00%)
         occurrences all number
    23
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 337 (6.82%)
    1 / 80 (1.25%)
         occurrences all number
    25
    1
    Nervous system disorders
    Dyskinesia
         subjects affected / exposed
    22 / 337 (6.53%)
    2 / 80 (2.50%)
         occurrences all number
    29
    2
    Headache
         subjects affected / exposed
    24 / 337 (7.12%)
    0 / 80 (0.00%)
         occurrences all number
    31
    0
    Somnolence
         subjects affected / exposed
    34 / 337 (10.09%)
    0 / 80 (0.00%)
         occurrences all number
    41
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    27 / 337 (8.01%)
    0 / 80 (0.00%)
         occurrences all number
    32
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    41 / 337 (12.17%)
    0 / 80 (0.00%)
         occurrences all number
    51
    0
    Depression
         subjects affected / exposed
    35 / 337 (10.39%)
    0 / 80 (0.00%)
         occurrences all number
    45
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    20 / 337 (5.93%)
    2 / 80 (2.50%)
         occurrences all number
    28
    2
    Urinary tract infection
         subjects affected / exposed
    31 / 337 (9.20%)
    0 / 80 (0.00%)
         occurrences all number
    56
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2015
    The following major procedural changes (not all-inclusive) were made to the protocol: - Participants who previously participated in another study of TEV-50717 for the treatment of moderate to severe TD, including Study C-23, were allowed to participate in Study C-20. - The long-term treatment period was extended from 1 year to 2 years, and clinic visits were added at Weeks 67, 80, 93, and 106/end of treatment (ET). The follow-up clinic visit was changed to Week 107, and telephone contact was changed to Week 110. - Hepatic or renal impairment at screening of the parent study was considered exclusionary.
    27 Sep 2016
    The following major procedural changes (not all-inclusive) were made to the protocol: - The long-term treatment period was extended from 2 years to 3 years, and clinic visits were added at Weeks 119, 132, 145, and 158/ET. The follow-up clinic visit was changed to Week 159, and telephone contact was changed to Week 162. - Treatment modification instructions regarding maximum dosage were expanded with greater detail for weight-based dosing and strong CYP2D6 inhibitor use, allowing doses up to 42 mg for participants ≥100 kg and doses up to 36 for participants <100 mg. - It was added that participants who have not achieved adequate control of dyskinesia during the study may have up to 2 blood samples collected for future pharmacokinetic assessment of α- and β- dihydrotetrabenazine (HTBZ).
    08 Feb 2017
    The following major procedural changes (not all-inclusive) were made to the protocol: - As hypokalemia and hypomagnesaemia may contribute to QT prolongation, criteria for suspending treatment were added in case a participant's potassium or magnesium levels fall below the lower limit of normal. - If the participant met either of the following criteria, study treatment was discontinued and an ET visit was conducted: a mean QTcF value >500 msec or a mean change in QTcF of >60 msec from baseline. - Given the potential for many antipsychotics to prolong the QT interval, additional electrocardiogram (ECG) monitoring was added if participants increased antipsychotic dose, switched to a new antipsychotic, or had a new antipsychotic treatment added to their regimen.
    23 Jan 2018
    The following major procedural changes (not all-inclusive) were made to the protocol: - The optional double-blind, placebo-controlled randomization withdrawal period (Part B) was added to the study with the objective to evaluate the persistence of the therapeutic effect of TEV-50717. The previous study design was labeled Part A for differentiation. - The time period was updated from 3 to 4 weeks after EOT/ET visit. - The requirement for participants to discuss reasons for study withdrawal with medical monitor or sponsor clinician was removed. - Dose reduction instructions to include CYP2D were added. - The AIMS video recording measure was removed.

    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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