A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)

Study Overview
=================
Brief Summary
-----------------
Standard placebo-controlled, double-blind study design (TEV-50717 [low dose and high dose] vs. placebo in a 1:1:1 ratio) was chosen to determine whether study drug treatment results in a statistically significant effect on the tics in participants with TS.

Official Title
-----------------
A Well-Controlled, Fixed-Dose Study of TEV-50717 (Deutetrabenazine) for the Treatment of Tics Associated With Tourette Syndrome

Conditions
-----------------
Tourette Syndrome

Intervention / Treatment
-----------------
* Drug: TEV-50717
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant weighs at least 44 pounds (20 kg) at baseline. Participant meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5™) diagnostic criteria for TS and, in the opinion of the investigator, participant, and parent/legal guardian, the participant's active tics are causing distress or impairment. Participant has a TTS of 20 or higher on the YGTSS at screening and baseline. Participant is able to swallow study medication whole. -Additional criteria apply, please contact the investigator for more information Exclusion Criteria: Participant has a neurologic disorder other than TS that could obscure the evaluation of tics. The participant 's predominant movement disorder is stereotypy (coordinated movements that repeat continually and identically) associated with autism spectrum disorder. Participant has clinically significant depression at screening or baseline. Participant has a history of suicidal intent or related behaviors within 2 years of screening Participant has a history of a previous actual, interrupted, or aborted suicide attempt. Participant has a first-degree relative who has completed suicide. Participant has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder. Participant has received Comprehensive Behavioral Intervention for Tics for TS or Cognitive Behavioral Therapy for obsessive-compulsive disorder (OCD) within 4 weeks of screening. Participant has received treatment with deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation within 4 weeks of the screening visit for reduction of tics. Participant has a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Participant has participated in an investigational drug or device study and received investigational medicinal product (IMP)/intervention within 30 days or 5 drug half-lives of baseline, whichever is longer. Participant is a pregnant or lactating female, or plans to be pregnant during the study. -Additional criteria apply, please contact the investigator for more information

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TEV-50717 High-Dose<br>TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 8 weeks | Drug: TEV-50717<br>* 6-, 9-, 12-, 15-, and 18 mg oral tablets<br>* Other names: AUSTEDO, Deutetrabenazine;Drug: Placebo<br>* Placebo matched to TEV-50717 tablets will be taken BID.<br>|
| Experimental: TEV-50717 Low-Dose<br>TEV-50717 tablets BID up to 36 mg/day orally for a total of 8 weeks | Drug: TEV-50717<br>* 6-, 9-, 12-, 15-, and 18 mg oral tablets<br>* Other names: AUSTEDO, Deutetrabenazine;Drug: Placebo<br>* Placebo matched to TEV-50717 tablets will be taken BID.<br>|
| Placebo Comparator: Placebo<br>Placebo matched to TEV-50717 for a total of 8 weeks | Drug: Placebo<br>* Placebo matched to TEV-50717 tablets will be taken BID.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the TTS of the YGTSS at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | 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. Least square (LS) mean and standard error (SE) was calculated using mixed-model repeated-measures (MMRM) with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. | Baseline, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. | Baseline, Week 8 | 
| Change From Baseline in the TTS of the YGTSS at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | 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. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. | Baseline, Week 8 | 
| Change From Baseline in the TS-CGI Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates. | Baseline, Week 8 | 
| Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | 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, Week 8 | 
| Change From Baseline in the TS-PGII Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | 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, Week 8 | 
| Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 8 Between High-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | 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. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates. | Baseline, Week 8 | 
| Change From Baseline in the C&A-GTS-QOL ADL Subscale Score at Week 8 Between Low-Dose TEV-50717-Treated Participants and Placebo-Treated Participants | 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. LS mean and SE was calculated using MMRM with treatment group, week (3 levels: Weeks 2, 4, and 8), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates. | Baseline, Week 8 | 
| Change From Baseline in the Children's Depression Inventory Second Edition (CDI-2; Parent Version and Self-reported Version) Total Score at Week 9 | 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. 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. | Baseline, Week 9 | 
| Number of Participants at Baseline and Week 9 With Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS) | 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. | Baseline, Week 9 |