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

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03567291
• Collaborator: Nuvelution TS Pharma, Inc. (Industry)
• Enrollment: 228
• Locations: 76
• Arms: 3
• Actual Duration (Months): 23.7
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Tourette Syndrome	Drug: TEV-50717; Drug: Placebo	Phase 3

Detailed Description

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]).

Study Design

• Study Type: Interventional
• Actual Enrollment: 228 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 25, 2018
• Actual Primary Completion Date: May 15, 2020
• Actual Study Completion Date: May 15, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TEV-50717- Part A 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; 6, 9, and 12 mg oral tablets; Other Names: deutetrabenazine, SD-809
Experimental: TEV-50717- Part B RW TEV-50717 is administered during Part B Randomized Drug Withdrawal (RW) 2-week period.	Drug: TEV-50717; 6, 9, and 12 mg oral tablets; Other Names: deutetrabenazine, SD-809
Placebo Comparator: Placebo- Part B RW Placebo is administered during Part B Randomized Drug Withdrawal (RW) 2-week period only.	Drug: Placebo; Placebo comparator

Outcome Measures

Primary Outcome Measures

1. Number of Participants Reporting Treatment Emergent Adverse Events (AEs) for Parts A & B Combined [Day 1 to Week 55]

   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.

2. Number of Participants Reporting Treatment Emergent Adverse Events (AEs) in Part B (Period II) [Weeks 28 to 30]

   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.

3. Change From Baseline in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score [Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55]

   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.

4. Change From Baseline in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score [Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55]

   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.

5. Change From Randomized Withdrawal Baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score at Week 30 [Week 28, 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.

6. 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 [Week 28, 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.

7. Number of Participants Reporting Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS) [Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55]

   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.

8. 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 [Week 28, 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.

Secondary Outcome Measures

1. Change From Baseline in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) [Baseline, Weeks 8, 15, 28, 41, 54, and 55]

   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.

2. Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score [Baseline, Weeks 8, 15, 28, 41, 54, and 55]

   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.

3. Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score [Baseline, Weeks 8, 15, 28, 41, 54, and 55]

   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.

4. 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 [Baseline, Weeks 6, 28, 34, 54]

   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.

5. Change From Randomized Withdrawal Baseline (Week 28) in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) to Week 30 [Week 28, 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 046-0104	Dothan	Alabama	United States	36303
2	Teva Investigational Site 046-0107	Rogers	Arkansas	United States	72758
3	Teva Investigational Site 046-0126	Anaheim	California	United States	92805
4	Teva Investigational Site 046-0101	Sacramento	California	United States	95815
5	Teva Investigational Site 046-0111	San Diego	California	United States	92108
6	Teva Investigational Site 060-0160	Gainesville	Florida	United States	32608
7	Teva Investigational Site 060-0166	Gulf Breeze	Florida	United States	32561-4458
8	Teva Investigational Site 060-0161	Miami	Florida	United States	33136-2107
9	Teva Investigational Site 046-0115	Orlando	Florida	United States	32803
10	Teva Investigational Site 060-0153	Orlando	Florida	United States	32819
11	Teva Investigational Site 046-0114	Saint Petersburg	Florida	United States	33701
12	Teva Investigational Site 046-0116	Atlanta	Georgia	United States	30331
13	Teva Investigational Site 060-0155	Chicago	Illinois	United States	60612
14	Teva Investigational Site 060-0164	Chicago	Illinois	United States	60634
15	Teva Investigational Site 046-0133	Naperville	Illinois	United States	60563
16	Teva Investigational Site 046-0128	Boston	Massachusetts	United States	02114
17	Teva Investigational Site 060-0170	Bridgeton	Missouri	United States	63044
18	Teva Investigational Site 046-0110	Saint Charles	Missouri	United States	63304
19	Teva Investigational Site 046-0134	Lincoln	Nebraska	United States	68526-9467
20	Teva Investigational Site 046-0109	Voorhees	New Jersey	United States	08043
21	Teva Investigational Site 046-0124	New York	New York	United States	10029
22	Teva Investigational Site 060-0154	New York	New York	United States	10036
23	Teva Investigational Site 046-0102	Rochester	New York	United States	14618
24	Teva Investigational Site 046-0106	Oklahoma City	Oklahoma	United States	73116
25	Teva Investigational Site 060-0169	Charleston	South Carolina	United States	29414-5834
26	Teva Investigational Site 060-0156	Nashville	Tennessee	United States	37232-2551
27	Teva Investigational Site 046-0113	Dallas	Texas	United States	75243
28	Teva Investigational Site 060-0163	Fort Worth	Texas	United States	76104
29	Teva Investigational Site 046-0108	Houston	Texas	United States	77030
30	Teva Investigational Site 046-0120	San Antonio	Texas	United States	78249
31	Teva Investigational Site 046-0105	Orem	Utah	United States	84058
32	Teva Investigational Site 046-0118	Petersburg	Virginia	United States	23805
33	Teva Investigational Site 060-0162	Everett	Washington	United States	98201-4077
34	Teva Investigational Site 060-1407	Buenos Aires		Argentina	C1023AAB
35	Teva Investigational Site 060-1402	Buenos Aires		Argentina	C1425AHQ
36	Teva Investigational Site 060-1403	La Plata		Argentina	1900
37	Teva Investigational Site 060-1404	Mendoza		Argentina	5500
38	Teva Investigational Site 060-1802	Liverpool		Australia	2170
39	Teva Investigational Site 046-0201	Ajax	Ontario	Canada	L1Z0M1
40	Teva Investigational Site 046-0202	Ottawa	Ontario	Canada	K2G 1W2
41	Teva Investigational Site 060-1503	Bello		Colombia	051050
42	Teva Investigational Site 060-1504	Pereira		Colombia	660003
43	Teva Investigational Site 046-0302	Herlev		Denmark	2730
44	Teva Investigational Site 046-0301	Odense		Denmark	5000
45	Teva Investigational Site 060-0901	Budapest		Hungary	1021
46	Teva Investigational Site 060-0902	Szeged		Hungary	6725
47	Teva Investigational Site 060-1005	Cagliari		Italy	09121
48	Teva Investigational Site 060-1001	Catania		Italy	95123
49	Teva Investigational Site 060-1003	Naples		Italy	80131
50	Teva Investigational Site 060-1901	Seoul		Korea, Republic of	110-744
51	Teva Investigational Site 060-1903	Seoul		Korea, Republic of	138-736
52	Teva Investigational Site 060-1902	Seoul		Korea, Republic of	6351
53	Teva Investigational Site 060-1601	Culiacan		Mexico	80020
54	Teva Investigational Site 060-1603	Leon		Mexico	37000
55	Teva Investigational Site 060-1602	Monterrey		Mexico	64460
56	Teva Investigational Site 060-1604	Monterrey		Mexico	64610
57	Teva Investigational Site 060-1104	Gdansk		Poland	80-542
58	Teva Investigational Site 060-1101	Katowice		Poland	40-123
59	Teva Investigational Site 060-1105	Krakow		Poland	31503
60	Teva Investigational Site 060-1102	Poznan		Poland	60-693
61	Teva Investigational Site 060-1103	Warsaw		Poland	02-793
62	Teva Investigational Site 046-0704	Tomsk		Russian Federation	634050
63	Teva Investigational Site 046-0703	Voronezh		Russian Federation	394024
64	Teva Investigational Site 046-1702	Belgrade		Serbia	11000
65	Teva Investigational Site 046-1703	Belgrade		Serbia	11000
66	Teva Investigational Site 046-1701	Novi Sad		Serbia	21000
67	Teva Investigational Site 046-0605	Madrid		Spain	28009
68	Teva Investigational Site 046-0602	Madrid		Spain	28922
69	Teva Investigational Site 046-0603	Malaga		Spain	29620
70	Teva Investigational Site 046-0601	Sevilla		Spain	41013
71	Teva Investigational Site 060-2003	Dnipropetrovsk		Ukraine	49101
72	Teva Investigational Site 060-2001	Kharkiv		Ukraine	61068
73	Teva Investigational Site 060-2002	Kharkiv		Ukraine	61153
74	Teva Investigational Site 060-2007	Kiev		Ukraine	4080
75	Teva Investigational Site 060-2005	Kyiv		Ukraine	4209
76	Teva Investigational Site 060-2006	Vinnytsia		Ukraine	21005

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.
• Nuvelution TS Pharma, Inc.

Investigators

• Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

• Study Protocol - May 22, 2019
• Statistical Analysis Plan - Oct 29, 2019

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT03567291
• Other Study ID Numbers: TV50717-CNS-30047; 2016-000630-22
• First Posted: Jun 25, 2018
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: adolescents; children
• Additional relevant MeSH terms: Tourette Syndrome; Syndrome

Study Results

Participant Flow

Recruitment Details

228 participants with Tourette Syndrome were enrolled after completing one of two eligible parent studies.

Pre-assignment Detail

Period I (Part A) included a 28-week open-label period with a 7-week titration period followed by a maintenance period. Period II (Part B) included a two-week randomized drug withdrawal period (Weeks 28-30) in which participants were administered their current TEV50717 dose or placebo. Participants were re-titrated to TEV-50717 from Weeks 31-34. In Period III (Part A resumed), participants continued their open-label maintenance dose of TEV50717.

Arm/Group Title	TEV-50717	Randomized TEV-50717	Randomized Placebo	TEV-50717 Re-titration and Maintenance
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.	Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.	Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.	Participants who were randomized to placebo during the withdrawal period were re-titrated to their TEV-50717 maintenance dose. Participants who were randomized to TEV-50717 continued their maintenance dose.
Period Title: Period I
STARTED	228	0	0	0
Safety Set	227	0	0	0
Intent to Treat Set	228	0	0	0
COMPLETED	137	0	0	0
NOT COMPLETED	91	0	0	0
Period Title: Period I
STARTED	0	91	46	0
COMPLETED	0	88	45	0
NOT COMPLETED	0	3	1	0
Period Title: Period I
STARTED	0	0	0	133
COMPLETED	0	0	0	48
NOT COMPLETED	0	0	0	85

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Overall Participants	228
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	12 (2.59)
Sex/Gender, Customized (Count of Participants)
Male	182 79.8%
Female	45 19.7%
Unknown	1 0.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	38 16.7%
Not Hispanic or Latino	186 81.6%
Unknown or Not Reported	4 1.8%
Race/Ethnicity, Customized (Number) [Number]
White	197 86.4%
Black	4 1.8%
Asian	7 3.1%
Native American	5 2.2%
Other	15 6.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting Treatment Emergent Adverse Events (AEs) for Parts A & B Combined
Description	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.
Time Frame	Day 1 to Week 55

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	227
At least one adverse event	161 70.6%
At least one serious adverse event	2 0.9%
At least one severe adverse event	6 2.6%
At least one AE related to investigational product	95 41.7%
At least one adverse event leading to withdrawal	14 6.1%

2. Primary Outcome

Title	Number of Participants Reporting Treatment Emergent Adverse Events (AEs) in Part B (Period II)
Description	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.
Time Frame	Weeks 28 to 30

Outcome Measure Data

Analysis Population Description

Population includes all participants who completed Period I, were randomized in Period II, and who were administered any study drug in the randomized withdrawal period, Part B (Period II).

Arm/Group Title	Randomized TEV-50717	Randomized Placebo
Arm/Group Description	Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.	Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.
Measure Participants	84	42
At least one adverse event	16 7%	6 NaN
At least one serious adverse event	0 0%	0 NaN
At least one severe adverse event	0 0%	0 NaN
At least one AE related to investigational product	6 2.6%	1 NaN
At least one adverse event leading to withdrawal	0 0%	0 NaN

3. Primary Outcome

Title	Change From Baseline in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score
Description	Parents were asked to rate their child's behaviors in past 2 weeks on a 4-point Likert scale from "not at all" to "much or most of the time." It contains 2 subscales (emotional problems and functional problem). Total score: sum of 2 subscales, ranging from 0 to 51, with higher score indicating more depression-related behaviors.
Time Frame	Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'number analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	227
CDI-2 Parent Version Week 2	-0.7 (4.26)
CDI-2 Parent Version Week 4	-1.5 (4.39)
CDI-2 Parent Version Week 8	-1.5 (5.0)
CDI-2 Parent Version Week 15	-1.2 (5.79)
CDI-2 Parent Version Week 28	-1.1 (5.52)
CDI-2 Parent Version Week 34	-1.0 (6.08)
CDI-2 Parent Version Week 41	-1.1 (5.92)
CDI-2 Parent Version Week 54	-0.3 (5.83)
CDI-2 Parent Version Week 55	-0.9 (4.34)

4. Primary Outcome

Title	Change From Baseline in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score
Description	CDI-2 self-report: 28-item questionnaire assessing depressive symptoms in children 7 to 17 years of age with basic reading and comprehension skills. Children were asked to choose 1 of 3 statements that most closely aligns with their feelings in past 2 weeks. It contains 6 subscales (emotional problem, negative mood/physical symptoms, negative self-esteem, functional problems, ineffectiveness, interpersonal problems). Total score: sum of all subscales scores, ranging from 0 to 56, with higher score indicating greater depression severity.CDI-2 parent: 17-item questionnaire administered to parents to assess depression-related behaviors observed in their children.
Time Frame	Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'number analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	227
CDI-2 Self-reported Version Week 2	-0.3 (3.41)
CDI-2 Self-reported Version Week 4	-0.5 (3.57)
CDI-2 Self-reported Version Week 8	-0.3 (4.35)
CDI-2 Self-reported Version Week 15	-0.3 (4.83)
CDI-2 Self-reported Version Week 28	0.0 (4.65)
CDI-2 Self-reported Version Week 34	-0.5 (4.61)
CDI-2 Self-reported Version Week 41	-0.7 (4.74)
CDI-2 Self-reported Version Week 54	-0.5 (4.01)
CDI-2 Self-reported Version Week 55	-0.3 (4.52)

5. Primary Outcome

Title	Change From Randomized Withdrawal Baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Parent Version) Total Score at Week 30
Description	Parents were asked to rate their child's behaviors in past 2 weeks on a 4-point Likert scale from "not at all" to "much or most of the time." It contains 2 subscales (emotional problems and functional problem). Total score: sum of 2 subscales, ranging from 0 to 51, with higher score indicating more depression-related behaviors.
Time Frame	Week 28, Week 30

Outcome Measure Data

Analysis Population Description

Population includes all participants who completed Period I, were randomized in Period II, and who were administered any study drug in the randomized withdrawal period, Part B (Period II). Here, 'number analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Randomized TEV-50717	Randomized Placebo
Arm/Group Description	Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.	Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.
Measure Participants	83	41
Mean (Standard Deviation) [Units On A Scale]	-0.2 (4.68)	0.6 (3.62)

6. Primary Outcome

Title	Change From Randomized Withdrawal Baseline (Week 28) in the Children's Depression Inventory Second Edition (CDI-2; Self-reported Version) Total Score at Week 30
Description	CDI-2 self-report: 28-item questionnaire assessing depressive symptoms in children 7 to 17 years of age with basic reading and comprehension skills. Children were asked to choose 1 of 3 statements that most closely aligns with their feelings in past 2 weeks. It contains 6 subscales (emotional problem, negative mood/physical symptoms, negative self-esteem, functional problems, ineffectiveness, interpersonal problems). Total score: sum of all subscales scores, ranging from 0 to 56, with higher score indicating greater depression severity.CDI-2 parent: 17-item questionnaire administered to parents to assess depression-related behaviors observed in their children.
Time Frame	Week 28, Week 30

Outcome Measure Data

Analysis Population Description

Population includes all participants who completed Period I, were randomized in Period II, and who were administered any study drug in the randomized withdrawal period, Part B (Period II). Here, 'number analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Randomized TEV-50717	Randomized Placebo
Arm/Group Description	Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.	Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.
Measure Participants	82	39
Mean (Standard Deviation) [Units On A Scale]	-0.4 (3.30)	-0.6 (3.08)

7. Primary Outcome

Title	Number of Participants Reporting Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS)
Description	C-SSRS included responses for Suicidal Ideation or Suicidal Behavior in following 10 categories: 1 = Wish to be dead; 2 = Non-specific active suicidal thoughts; 3 = Active suicidal ideation with any methods (not plan) without intent to act; 4 = Active suicidal ideation with some intent to act, without specific plan; 5 = Active suicidal ideation with specific plan and intent; 6 = Preparatory acts or behavior; 7 = Aborted attempt; 8 = Interrupted attempt; 9 = Non-fatal suicide attempt; and 10 = Completed suicide. Number of participants with any suicidal ideation or suicidal behavior are reported. Any Suicidal ideation or Suicidal Behavior events reported as TEAEs along with all other reported TEAEs are included in the AE module.
Time Frame	Baseline, Weeks 2, 4, 8, 15, 28, 34, 41, 54, 55

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'number analyzed' signifies participants evaluable at specified timepoints.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	227
Baseline	0 0%
Week 2	0 0%
Week 4	2 0.9%
Week 8	0 0%
Week 15	1 0.4%
Week 28	0 0%
Week 34	0 0%
Week 41	1 0.4%
Week 54	0 0%
Week 55	0 0%

8. Primary Outcome

Title	Number of Participants Reporting Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS) at Randomized Withdrawal Baseline Visit (Week 28) and Week 30
Description	C-SSRS included responses for Suicidal Ideation or Suicidal Behavior in following 10 categories: 1 = Wish to be dead; 2 = Non-specific active suicidal thoughts; 3 = Active suicidal ideation with any methods (not plan) without intent to act; 4 = Active suicidal ideation with some intent to act, without specific plan; 5 = Active suicidal ideation with specific plan and intent; 6 = Preparatory acts or behavior; 7 = Aborted attempt; 8 = Interrupted attempt; 9 = Non-fatal suicide attempt; and 10 = Completed suicide. Number of participants with any suicidal ideation or suicidal behavior are reported. Any Suicidal ideation or Suicidal Behavior events reported as TEAEs along with all other reported TEAEs are included in the AE module.
Time Frame	Week 28, Week 30

Outcome Measure Data

Analysis Population Description

Population includes all participants who completed Period I, were randomized in Period II, and who were administered any study drug in the randomized withdrawal period, Part B (Period II). Here, 'number analyzed' signifies participants evaluable at specified timepoints.

Arm/Group Title	Randomized TEV-50717	Randomized Placebo
Arm/Group Description	Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.	Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.
Measure Participants	84	42
Week 28	0 0%	0 NaN
Week 30	0 0%	0 NaN

9. Secondary Outcome

Title	Change From Baseline in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS)
Description	YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
Time Frame	Baseline, Weeks 8, 15, 28, 41, 54, and 55

Outcome Measure Data

Analysis Population Description

ITT analysis set includes all participants enrolled in part I. Here, 'number analyzed' signifies participants evaluable at specified time points.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	228
Week 8	-6.9 (0.58)
Week 15	-7.8 (0.58)
Week 28	-6.2 (0.83)
Week 41	-8.3 (0.97)
Week 54	-6.5 (1.47)
Week 55	-4.3 (1.6)

10. Secondary Outcome

Title	Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score
Description	The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
Time Frame	Baseline, Weeks 8, 15, 28, 41, 54, and 55

Outcome Measure Data

Analysis Population Description

Data were not collected during Part B (Period II). ITT analysis set includes all participants enrolled in part I. Here, 'number analyzed' signifies participants evaluable at specified time points.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	228
Week 8	-0.7 (0.06)
Week 15	-0.7 (0.06)
Week 28	-0.6 (0.08)
Week 41	-0.6 (0.1)
Week 54	-0.8 (0.16)
Week 55	-0.4 (0.15)

11. Secondary Outcome

Title	Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score
Description	The TS-PGII is a single-item questionnaire that asks the participant to assess the degree of impact due to current tics (How much do your current tics disrupt things in your life?). The TS-PGII uses a 5-point scale, ranging from not at all (1) to very much (5), to assess overall response to therapy. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
Time Frame	Baseline, Weeks 8, 15, 28, 41, 54, and 55

Outcome Measure Data

Analysis Population Description

Data were not collected during Part B (Period II). ITT analysis set includes all participants enrolled in part I. Here, 'number analyzed' signifies participants evaluable at specified time points.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	228
Week 8	-0.5 (0.07)
Week 15	-0.5 (0.08)
Week 28	-0.5 (0.09)
Week 41	-0.6 (0.12)
Week 54	-0.5 (0.16)
Week 55	-0.1 (0.14)

12. Secondary Outcome

Title	Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score
Description	C&A-GTS-QOL is a 27-item questionnaire that asks participant to assess the extent to which their quality of life is impacted by their symptoms. C&A-GTS-QOL contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and uses a 5-point Likert scale ranging from no problem to extreme problem. Following 3 questions from 27-item questionnaire were assessed in ADL C&A-GTS-QOL subscale: Question 2 (Had difficulty with school or sport activities?), 24 (Felt you needed more help or support from other people?), and 26 (Had difficulty going out with other people?). Total score of ADL subscale ranged from 0 (no problem) to 12 (extreme problem). Lower score indicated better quality of life. Baseline is defined as the last measurement on or prior to the first dose of the open-label study medication.
Time Frame	Baseline, Weeks 6, 28, 34, 54

Outcome Measure Data

Analysis Population Description

Data were not collected during Part B (Period II). ITT analysis set includes all participants enrolled in part I. Here, 'number analyzed' signifies participants evaluable at specified time points.

Arm/Group Title	TEV-50717
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
Measure Participants	228
Week 6	-4.9 (1.12)
Week 28	-4.4 (1.48)
Week 34	-5.9 (1.82)
Week 54	-2.7 (2.1)

13. Secondary Outcome

Title	Change From Randomized Withdrawal Baseline (Week 28) in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) to Week 30
Description	YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic tics. YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 to severe). MTSS is the sum of the 5 items for motor tic severity and VTSS is the sum of the 5 items for vocal tic severity. TTS is the sum of MTSS and VTSS, ranges from 0 (none/absent) to 50 (severe). Higher scores indicate greater severity/worse outcome. The model is an ANCOVA model that includes fixed effects for treatment group. The randomized withdrawal baseline TTS and age group at baseline (2 levels: 6-11 years, 12-18 years) are included as covariates.
Time Frame	Week 28, Week 30

Outcome Measure Data

Analysis Population Description

All participants that completed Part 1, were randomized to Part 2, received at least one dose of study drug in the randomized withdrawal period and have an YGTSS TTS at both week 28 visit (randomized withdrawal baseline) and week 30 visit, and have a ≥25% reduction in the TTS from baseline in the parent study to week 28.

Arm/Group Title	Randomized TEV-50717	Randomized Placebo
Arm/Group Description	Participants were randomized to their current dose of TEV-50717, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period.	Participants were randomized to placebo, which was administered during the Part B Randomized Drug Withdrawal (RW) 2-week period only.
Measure Participants	54	26
Least Squares Mean (Standard Error) [Units on a scale]	1.6 (0.86)	2.0 (1.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TEV-50717, Randomized Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -3.4 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Baseline to Week 55
Adverse Event Reporting Description	Adverse events were analyzed for participants in Parts A & B combined as one group per planned analysis. Safety analysis set included all participants who received at least 1 dose of study drug.
Arm/Group Title	Total
Arm/Group Description	All participants underwent TEV-50717 dose titration in this study. They received 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose were determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study.
All Cause Mortality
	Total
	Affected / at Risk (%)	# Events
Total	0/227 (0%)
Serious Adverse Events
	Total
	Affected / at Risk (%)	# Events
Total	2/227 (0.9%)
Gastrointestinal disorders
Abdominal pain upper	1/227 (0.4%)	1
Psychiatric disorders
Self-injurious ideation	1/227 (0.4%)	1
Other (Not Including Serious) Adverse Events
	Total
	Affected / at Risk (%)	# Events
Total	108/227 (47.6%)
Gastrointestinal disorders
Vomiting	15/227 (6.6%)	30
General disorders
Pyrexia	13/227 (5.7%)	13
Infections and infestations
Nasopharyngitis	23/227 (10.1%)	33
Investigations
Weight increased	22/227 (9.7%)	22
Nervous system disorders
Headache	30/227 (13.2%)	55
Somnolence	28/227 (12.3%)	33
Psychiatric disorders
Anxiety	17/227 (7.5%)	18
Tic	15/227 (6.6%)	29

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.