ARTISTS1: Alternatives for Reducing Tics in Tourette Syndrome (TS): A Study of TEV-50717 (Deutetrabenazine) for the Treatment of Tourette Syndrome in Children and Adolescents

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03452943
• Collaborator: Nuvelution TS Pharma, Inc. (Industry)
• Enrollment: 119
• Locations: 42
• Arms: 2
• Actual Duration (Months): 21.2
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a study to evaluate the efficacy and safety of deutetrabenazine (TEV-50717) tablets for the reduction of motor and phonic tics associated with TS in children and adolescents 6 through 16 years of age.

Condition or Disease	Intervention/Treatment	Phase
Tourette Syndrome	Drug: TEV-50717; Drug: Placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 119 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Study of TEV-50717 (Deutetrabenazine) for the Treatment of Tourette Syndrome in Children and Adolescents
• Actual Study Start Date: Feb 5, 2018
• Actual Primary Completion Date: Nov 12, 2019
• Actual Study Completion Date: Nov 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TEV-50717 TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 12 weeks	Drug: TEV-50717; 6, 9, 12, 15, and 18 mg oral tablets; Other Names: Deutetrabenazine ; Drug: Placebo; Placebo matched to TEV-50717 tablets will be taken BID for 12 weeks.
Placebo Comparator: Placebo Placebo matched to TEV-50717 BID for a total of 12 weeks	Drug: Placebo; Placebo matched to TEV-50717 tablets will be taken BID for 12 weeks.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the TTS of the YGTSS at Week 12 [Baseline, Week 12]

   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 (5 levels: weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates.

Secondary Outcome Measures

1. Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12 [Baseline, Week 12]

   The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates.

2. Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 12 [Baseline, Week 12]

   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.

3. Change From Baseline in the Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life (C&A-GTS-QOL) Activities of Daily Living (ADL) Subscale Score at Week 12 [Baseline, Week 12]

   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 (5 levels: weeks 2, 4, 6, 9, and 12), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates.

4. Percentage of Participants With Adverse Events [Baseline (Day 1) to follow-up (Week 14)]

   An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 16 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant is 6 to 16 years of age, inclusive.

• Participant weighs at least 44 pounds (20 kilograms [kg]).

• The participant's active tics are causing distress or impairment.

• Participant is able to swallow study medication whole.

• Participant 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:

• Participant has a neurologic disorder other than TS that could obscure the evaluation of tics.

• Participant has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic 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 received comprehensive behavioral intervention for tics (CBIT) for TS or cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) within 4 weeks of screening.

• Participant has an unstable or serious medical illness at screening or baseline.

• Participant is pregnant or breastfeeding.

• 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 046-0117	Sun City	Arizona	United States	85351
3	Teva Investigational Site 046-0107	Rogers	Arkansas	United States	72758
4	Teva Investigational Site 046-0126	Anaheim	California	United States	92805
5	Teva Investigational Site 046-0101	Sacramento	California	United States	95815
6	Teva Investigational Site 046-0111	San Diego	California	United States	92108
7	Teva Investigational Site 046-0130	Santa Ana	California	United States	92705
8	Teva Investigational Site 046-0132	Miami	Florida	United States	33155
9	Teva Investigational Site 046-0115	Orlando	Florida	United States	32803
10	Teva Investigational Site 046-0114	Saint Petersburg	Florida	United States	33701
11	Teva Investigational Site 046-0116	Atlanta	Georgia	United States	30331
12	Teva Investigational Site 046-0133	Naperville	Illinois	United States	60563
13	Teva Investigational Site 046-0128	Boston	Massachusetts	United States	02114
14	Teva Investigational Site 046-0110	Saint Charles	Missouri	United States	63304
15	Teva Investigational Site 046-0134	Lincoln	Nebraska	United States	68526-9467
16	Teva Investigational Site 046-0109	Voorhees	New Jersey	United States	08043
17	Teva Investigational Site 046-0124	New York	New York	United States	10029
18	Teva Investigational Site 046-0102	Rochester	New York	United States	14618
19	Teva Investigational Site 046-0112	Rochester	New York	United States	14642
20	Teva Investigational Site 046-0125	Raleigh	North Carolina	United States	27607
21	Teva Investigational Site 046-0106	Oklahoma City	Oklahoma	United States	73116
22	Teva Investigational Site 046-0113	Dallas	Texas	United States	75243
23	Teva Investigational Site 046-0108	Houston	Texas	United States	77030
24	Teva Investigational Site 046-0103	Houston	Texas	United States	77090
25	Teva Investigational Site 046-0120	San Antonio	Texas	United States	78249
26	Teva Investigational Site 046-0105	Orem	Utah	United States	84058
27	Teva Investigational Site 046-0118	Petersburg	Virginia	United States	23805
28	Teva Investigational Site 046-0201	Ajax	Ontario	Canada	L1Z0M1
29	Teva Investigational Site 046-0202	Ottawa	Ontario	Canada	K2G 1W2
30	Teva Investigational Site 046-0302	Herlev		Denmark	2730
31	Teva Investigational Site 046-0301	Odense		Denmark	5000
32	Teva Investigational Site 046-0702	Stavropol		Russian Federation	355038
33	Teva Investigational Site 046-0704	Tomsk		Russian Federation	634050
34	Teva Investigational Site 046-0703	Voronezh		Russian Federation	394024
35	Teva Investigational Site 046-1702	Belgrade		Serbia	11000
36	Teva Investigational Site 046-1703	Belgrade		Serbia	11000
37	Teva Investigational Site 046-1701	Novi Sad		Serbia	21000
38	Teva Investigational Site 046-0604	Barcelona		Spain	08041
39	Teva Investigational Site 046-0605	Madrid		Spain	28009
40	Teva Investigational Site 046-0602	Madrid		Spain	28922
41	Teva Investigational Site 046-0603	Malaga		Spain	29620
42	Teva Investigational Site 046-0601	Sevilla		Spain	41013

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 - Mar 25, 2019
• Statistical Analysis Plan - Dec 2, 2019

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT03452943
• Other Study ID Numbers: TV50717-CNS-30046; 2016-000622-19
• First Posted: Mar 2, 2018
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• 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.: Tourette Syndrome; adolescents; children
• Additional relevant MeSH terms: Tourette Syndrome; Syndrome

Study Results

Participant Flow

Pre-assignment Detail	A total of 119 participants were randomized in a 1:1 ratio to either TEV-50717 or placebo group.

Arm/Group Title	TEV-50717	Placebo
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 milligrams (mg)/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status at baseline. Maximum total daily dose for participants greater than or equal to (≥) 40 kilograms (kg) was 48 mg/day (24 mg twice daily [BID]), 30 to less than (<) 40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.	Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.
Period Title: Titration Period (7 Weeks)
STARTED	59	60
Safety Analysis Set	58	59
Modified ITT (mITT) Analysis Set	58	59
COMPLETED	54	56
NOT COMPLETED	5	4
Period Title: Titration Period (7 Weeks)
STARTED	54	56
COMPLETED	51	56
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	TEV-50717	Placebo	Total
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to <40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.	Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.	Total of all reporting groups
Overall Participants	59	60	119
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.5 (2.52)	11.5 (2.59)	11.5 (2.54)
Sex: Female, Male (Count of Participants)
Female	6 10.2%	9 15%	15 12.6%
Male	53 89.8%	51 85%	104 87.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 8.5%	8 13.3%	13 10.9%
Not Hispanic or Latino	51 86.4%	50 83.3%	101 84.9%
Unknown or Not Reported	3 5.1%	2 3.3%	5 4.2%
Race/Ethnicity, Customized (Count of Participants)
White	49 83.1%	53 88.3%	102 85.7%
Black	3 5.1%	3 5%	6 5%
Asian	1 1.7%	1 1.7%	2 1.7%
Native American	1 1.7%	0 0%	1 0.8%
Multiple	3 5.1%	1 1.7%	4 3.4%
Other	2 3.4%	2 3.3%	4 3.4%
Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	31.7 (5.81)	33.0 (5.96)	32.3 (5.89)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the TTS of the YGTSS at Week 12
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. Least square (LS) mean and standard error (SE) was calculated using mixed-model repeated-measures (MMRM) with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and 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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.

Arm/Group Title	TEV-50717	Placebo
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to <40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.	Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.
Measure Participants	58	59
Least Squares Mean (Standard Error) [units on a scale]	-9.1 (1.28)	-8.4 (1.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TEV-50717, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.692
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -4.1 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Tourette Syndrome-Clinical Global Impression (TS-CGI) Score at Week 12
Description	The TS-CGI scale is a 7-point Likert scale that allows the clinician to use all available information to assess the impact of tics on the participant's quality of life. The TS-CGI is rated as follows: 1 (normal or no tics at all), 2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme, incapacitating tics). Lower scores indicate better quality of life. LS mean and SE was calculated using MMRM with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) as covariates.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.

Arm/Group Title	TEV-50717	Placebo
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to <40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.	Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.
Measure Participants	58	59
Least Squares Mean (Standard Error) [units on a scale]	-0.7 (0.13)	-0.7 (0.12)

3. Secondary Outcome

Title	Change From Baseline in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) Score at Week 12
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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.

Arm/Group Title	TEV-50717	Placebo
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to <40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.	Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.
Measure Participants	58	59
Mean (Standard Error) [units on a scale]	-0.7 (0.18)	-0.4 (0.14)

4. 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 at Week 12
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. LS mean and SE was calculated using MMRM with treatment group, week (5 levels: weeks 2, 4, 6, 9, and 12), and treatment group by week interaction as fixed effects; and baseline TTS, region, and age group at baseline (2 levels: 6-11 years, 12-16 years) as covariates.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

mITT analysis set included all randomized participants who received at least 1 dose of study drug and had both a baseline and at least 1 post-baseline YGTSS assessment.

Arm/Group Title	TEV-50717	Placebo
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to <40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.	Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.
Measure Participants	58	59
Least Squares Mean (Standard Error) [units on a scale]	-9.9 (2.37)	-8.8 (2.27)

5. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline (Day 1) to follow-up (Week 14)

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	Placebo
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to <40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.	Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.
Measure Participants	58	59
Any AEs	65.5 111%	55.9 93.2%
Treatment-related AEs	50.0 84.7%	20.3 33.8%
Serious AEs	0 0%	0 0%
AEs leading to discontinuation	1.7 2.9%	1.7 2.8%

Adverse Events

Time Frame	Baseline (Day 1) to follow-up (Week 14)
Adverse Event Reporting Description	Safety analysis set included all participants who received at least 1 dose of study drug.
Arm/Group Title	TEV-50717		Placebo
Arm/Group Description	Participants received TEV-50717 as oral tablets at a starting dose of 6 mg/day, with the dose titrated weekly for 7 weeks to an optimal level. The target maximum daily dose was determined by body weight and CYP2D6 impairment status at baseline. Maximum total daily dose for participants ≥40 kg was 48 mg/day (24 mg BID), 30 to <40 kg was 42 mg/day (21 mg BID), and 20 to <30 kg was 30 mg/day (15 mg BID). For those considered CYP2D6 impaired, maximum daily dose for participants ≥40 kg was 36 mg/day, 30 to <40 kg was 24 mg/day, and 20 to <30 kg was 18 mg/day. Total daily doses of ≥12 mg/day was divided into a BID administration. Depending on the dose, TEV-50717 tablets and/or placebo tablets were taken to maintain the blind. Participants then received TEV-50717 at the optimal level as maintenance therapy daily for 5 weeks.		Participants received placebo matched to TEV-50717 BID for a total of 12 weeks.
All Cause Mortality
	TEV-50717		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		0/59 (0%)
Serious Adverse Events
	TEV-50717		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	TEV-50717		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/58 (37.9%)		23/59 (39%)
Gastrointestinal disorders
Abdominal pain	1/58 (1.7%)	2	3/59 (5.1%)	3
Diarrhoea	4/58 (6.9%)	4	1/59 (1.7%)	1
Nausea	4/58 (6.9%)	5	5/59 (8.5%)	11
Vomiting	3/58 (5.2%)	3	3/59 (5.1%)	3
General disorders
Fatigue	7/58 (12.1%)	8	3/59 (5.1%)	4
Pyrexia	3/58 (5.2%)	3	2/59 (3.4%)	2
Infections and infestations
Upper respiratory tract infection	0/58 (0%)	0	7/59 (11.9%)	9
Investigations
Weight increased	7/58 (12.1%)	7	1/59 (1.7%)	1
Metabolism and nutrition disorders
Increased appetite	3/58 (5.2%)	3	1/59 (1.7%)	1
Nervous system disorders
Headache	6/58 (10.3%)	6	6/59 (10.2%)	12
Somnolence	5/58 (8.6%)	8	1/59 (1.7%)	1
Psychiatric disorders
Anxiety	2/58 (3.4%)	2	3/59 (5.1%)	3
Depressed mood	2/58 (3.4%)	2	3/59 (5.1%)	3
Enuresis	4/58 (6.9%)	6	0/59 (0%)	0
Suicidal ideation	1/58 (1.7%)	1	3/59 (5.1%)	3

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.