Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents

Study Overview
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Brief Summary
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This is an otherwise open-label, single-arm study that includes a 2-week, double-blind, placebo controlled, randomized drug withdrawal period followed by a 3 week blinded maintenance or re-titration, and then a maintenance period. This study aims to evaluate the safety and efficacy of TEV-50717 tablets in patients with tics associated with TS who have previously completed participation in any of the parent studies.

Detailed Description
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This is an otherwise open-label, single-arm study (Part A) that includes a 2-week, double-blind, placebo controlled, randomized drug withdrawal period (Part B) followed by a 3 week blinded maintenance or re-titration (Part A resumed), and then a maintenance period. This study aims to evaluate the safety and efficacy of TEV-50717 tablets in patients with tics associated with TS who have previously completed participation in any of the parent studies (SD-809-C-17 [Phase 1b], TV50717-CNS 30046 [Phase 2/3], or TV50717-CNS 30060 [Phase 3]).

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

Conditions
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Tourette Syndrome

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is younger than 18 years of age on day 1 Patient weighs at least 44 pounds (20 kg) The patient's active tics are causing distress or impairment Patient is able to swallow study medication whole Patient is in good general health Women/girls of childbearing potential whose male partners are of childbearing potential must use contraception for the duration of the study -- Additional criteria apply, please contact the investigator for more information Exclusion Criteria: Patient is 18 years of age or older. Patient has a neurologic disorder other than TS that could obscure the evaluation of tics. The patient's predominant movement disorder is stereotypy (coordinated movements that repeat continually and identically) associated with autism spectrum disorder. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder. Patient has clinically significant depression at screening or day 1. Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose for at least 6 weeks before screening. Patient has a history of suicidal intent or related behaviors within 2 years of screening Patient has a history of a previous actual, interrupted, or aborted suicide attempt. Patient has a first-degree relative who has completed suicide. Patient has clinically significant obsessive-compulsive disorder (OCD) on day 1 that, in the opinion of the investigator, is the primary cause of impairment. Patient has received comprehensive behavioral intervention for tics for TS or cognitive behavioral therapy for OCD within 4 weeks of screening. Patient has received treatment with deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation for reduction of tics within 4 weeks of the screening visit. Patient has an unstable or serious medical illness at screening or day 1 Patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Patient has received a monoamine oxidase inhibitor within 14 days of the day 1 visit. Patient has participated in an investigational drug or device study (with the exception of Study SD-809-C-17, Study TV50717-CNS-30046, or Study TV50717-CNS-30060) and received IMP/intervention within 30 days or 5 drug half-lives of day 1, whichever is longer. The patient is a pregnant or lactating female, or plans to become pregnant during the study. Patient has a history of, or acknowledges, alcohol-related disorder in the previous 12 months -- Additional criteria apply, please contact the investigator for more information

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TEV-50717- Part A<br>All patients will undergo TEV-50717 dose titration in this study. Patients will receive 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose will be determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study. | Drug: TEV-50717<br>* 6, 9, and 12 mg oral tablets<br>* Other names: deutetrabenazine, SD-809;|
| Experimental: TEV-50717- Part B RW<br>TEV-50717 is administered during Part B Randomized Drug Withdrawal (RW) 2-week period. | Drug: TEV-50717<br>* 6, 9, and 12 mg oral tablets<br>* Other names: deutetrabenazine, SD-809;|
| Placebo Comparator: Placebo- Part B RW<br>Placebo is administered during Part B Randomized Drug Withdrawal (RW) 2-week period only. | Drug: Placebo<br>* Placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Treatment Emergent Adverse Events (AEs) for Parts A & B Combined | Adverse events were analyzed for all participants in Parts A & B combined as one group for this outcome measure. An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Incudes clinically significant changes such as changes in vital signs or lab values. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Day 1 to Week 55 | 
| Number of Participants Reporting Treatment Emergent Adverse Events (AEs) in Part B (Period II) | Adverse events were analyzed for Part B for this outcome measure. An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Incudes clinically significant changes such as changes in vital signs or lab values. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Weeks 28 to 30 | 
| Change From Baseline in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score | 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, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55 | 
| Change From Baseline in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score | 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. | Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55 | 
| Change From Randomized Withdrawal Baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score at Week 30 | 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. | Week 28, Week 30 | 
| Change From Randomized Withdrawal Baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score at Week 30 | 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. | Week 28, Week 30 | 
| Number of Participants Reporting 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, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55 | 
| Number of Participants Reporting Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS) at Randomized Withdrawal Baseline Visit (Week 28) and Week 30 | 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. | Week 28, Week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) | YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication. | Baseline, Weeks 8, 15, 28, 41, 54, and 55 | 
| Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score | The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication. | Baseline, Weeks 8, 15, 28, 41, 54, and 55 | 
| Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score | The TS-PGII is a single-item questionnaire that asks the participant to assess the degree of impact due to current tics (How much do your current tics disrupt things in your life?). The TS-PGII uses a 5-point scale, ranging from not at all (1) to very much (5), to assess overall response to therapy. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication. | Baseline, Weeks 8, 15, 28, 41, 54, and 55 | 
| 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 | C&A-GTS-QOL is a 27-item questionnaire that asks participant to assess the extent to which their quality of life is impacted by their symptoms. C&A-GTS-QOL contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and uses a 5-point Likert scale ranging from no problem to extreme problem. Following 3 questions from 27-item questionnaire were assessed in ADL C&A-GTS-QOL subscale: Question 2 (Had difficulty with school or sport activities?), 24 (Felt you needed more help or support from other people?), and 26 (Had difficulty going out with other people?). Total score of ADL subscale ranged from 0 (no problem) to 12 (extreme problem). Lower score indicated better quality of life. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication. | Baseline, Weeks 6, 28, 34, 54 | 
| Change From Randomized Withdrawal Baseline (Week 28) in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) to Week 30 | YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. The model is an ANCOVA model that includes fixed effects for treatment group. The randomized withdrawal baseline TTS and age group at baseline (2 levels: 6-11 years, 12-18 years) are included as covariates. | Week 28, Week 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adolescents, children