Efficacy and Safety of Fixed-Dose Deutetrabenazine in Children and Adolescents for Tics Associated With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. Objective: To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. Interventions: Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires.
Results: The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate. Conclusions and Relevance: In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03571256.

Introduction

Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor tics and at least 1 phonic tic persisting for greater than 1 year.[1,2] Approximately 1 in 360 children in the US are currently diagnosed with Tourette syndrome.[1,3] Onset of the disease typically occurs from ages 4 to 8 years, and it is approximately 4 times more common in boys than in girls.[4,5] Tic severity and frequency usually peak in early adolescence (age 9-12 years)[6] during a crucial academic and social-emotional developmental phase. This worsening of tics in adolescence magnifies the social stigma associated with Tourette syndrome, disrupts performance of everyday activities, and can have a long-term effect on quality of life.[2,6,7] Additionally, comorbid psychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depression and anxiety, and learning disorders, are common in individuals with Tourette syndrome and contribute to distress, disability, and academic underachievement.[2,3,8,9,10]

The only medications approved by the US Food and Drug Administration for the treatment of tics in Tourette syndrome are the dopamine-receptor antagonists haloperidol, pimozide, and aripiprazole.[8] They are associated with significant safety concerns, especially in youth, including increased risk for metabolic complications, tardive dyskinesia, parkinsonism, and neuroleptic malignant syndrome.[8,11,12] Thus, there is a substantial unmet need for safe and effective pharmacological treatments for Tourette syndrome.

Deutetrabenazine, a vesicular monoamine transporter type 2 inhibitor, is approved by the US Food and Drug Administration for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults.[13] Results from an open-label, phase 1b study showed that adolescents with troublesome motor and phonic tics associated with Tourette syndrome who received deutetrabenazine and were titrated up to 36 mg per day experienced a mean reduction in Yale Global Tic Severity Scale–Total Tic Score (YGTSS-TTS) of 11.6 points after 8 weeks of treatment, representing a 37.6% reduction in tic severity from baseline.[14] Based on these positive preliminary results, clinical development of deutetrabenazine was continued in the Alternatives for Reducing Tics in Tourette Syndrome (ARTISTS) program, which included 2 randomized, placebo-controlled trials (ARTISTS 1 and ARTISTS 2) and a long-term open-label extension study (ARTISTS). Here we report results from the phase 3, placebo-controlled ARTISTS 2 study that evaluated the efficacy and safety of fixed doses of deutetrabenazine in reduction of motor and phonic tics associated with Tourette syndrome.

Methods

The ARTISTS 2 study was a phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome. The study was conducted at 52 sites in the US, Argentina, Australia, Colombia, Hungary, Italy, Mexico, Poland, Republic of Korea, and Ukraine from June 21, 2018, to December 9, 2019.

Before study initiation, the protocol (Supplement 1) was approved by appropriate national and local authorities and independent ethics committees or institutional review boards at each study site. The study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice Tripartite Guideline E6 and applicable national and local laws and regulations. All participants and their parents or legal guardians were fully informed about the aims, methods, and potential benefits and hazards of study-specific procedures. A parent or legal guardian for each child or adolescent participant provided written informed consent. Depending on age, participants also provided assent to participate. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.

Participants

Eligible participants were aged 6 to 16 years (inclusive), weighed 20 kg or more at baseline, met the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) diagnostic criteria for Tourette syndrome and, in the opinion of the investigator, participant, and caregiver, had active tics that were causing distress or impairment. Race and ethnicity information were collected using predefined options in the case report form. Race and ethnicity were self-reported by the patients (or their parents) and were required fields on the case report form.

Participants were required to have a YGTSS-TTS greater than or equal to 20 points at screening and baseline. Key exclusion criteria included stereotypy associated with autism spectrum disorder, clinically significant obsessive-compulsive disorder at baseline considered to be the primary cause of impairment, or clinically significant depression at baseline. Full study exclusion criteria are provided in the eAppendix in Supplement 3.

Study Design

The study consisted of a prescreening period of up to 3 months for participants requiring discontinuation of prohibited concomitant medications, a screening period of up to 31 days, an 8-week treatment period followed by a 1-week washout period, and a 1-week follow-up period (eFigure 1 in Supplement 3). Eligible participants were randomized (1:1:1) to receive high-dose deutetrabenazine (up to 48 mg/d), low-dose deutetrabenazine (up to 36 mg/d), or matching placebo. Participants were stratified by age at baseline (6-11 or 12-16 years).

A predefined dose for each participant was based on body weight range (≥40 kg, 30 to <40 kg, or 20 to <30 kg) and cytochrome P450 2D6 (CYP2D6) impairment status at baseline (eTable 1 in Supplement 3). Participants were classified as CYP2D6 impaired if they were receiving a strong CYP2D6 inhibitor at baseline or metabolized CYP2D6 poorly based on a blinded assessment of CYP2D6 genotype. The dose of study medication for each participant was titrated over 4 weeks to the target dose, balancing perceived efficacy and adverse events (AEs), followed by a 4-week maintenance period. Doses were selected based on population pharmacokinetic modeling of deutetrabenazine’s active metabolites. Based on robust pharmacokinetic sampling data from a previous pilot study,[14] a population pharmacokinetic model was created to simulate total metabolite exposure across a range of pediatric and adolescent body weights to guide dose selection.

Efficacy Assessments

The primary efficacy end point was the change in YGTSS-TTS from baseline to week 8 for high-dose deutetrabenazine compared with placebo. The YGTSS rating scale is a semistructured clinician- or investigator-administered rating instrument in which participants or caregivers evaluate the number, frequency, intensity, complexity, and interference of motor and phonic tics in the prior week on a 6-point scale from 0 (none) to 5 (severe).[15,16] The total Motor Tic Severity Score (MTSS; 0-25 points) is added to the total Vocal Tic Severity Score (VTSS; 0-25 points) to determine the TTS (0-50 points).

Key secondary efficacy end points included (1) change from baseline to week 8 in the Tourette Syndrome Clinical Global Impression[17] (TS-CGI; high-dose deutetrabenazine vs placebo), (2) YGTSS-TTS for low-dose deutetrabenazine vs placebo, (3) TS-CGI for low-dose deutetrabenazine vs placebo, (4) Tourette Syndrome Patient Global Impression of Impact (TS-PGII) for high-dose deutetrabenazine vs placebo, (5) TS-PGII for low-dose deutetrabenazine vs placebo, (6) Child and Adolescent Gilles de la Tourette Syndrome–Quality of Life (CA-GTS-QOL) Activities of Daily Living (ADL) subscale score[18] for high-dose deutetrabenazine vs placebo, and (7) CA-GTS-QOL ADL subscale score for low-dose deutetrabenazine vs placebo. The TS-CGI and TS-PGII are single-item questionnaires administered by clinicians and patients, respectively, to assess the effect of tics on QOL. The CA-GTS-QOL ADL subscale consists of 3 items to assess the effect of Tourette syndrome symptoms on ADL.

Exploratory analyses included assessment of the proportion of responders (participants with ≥25% reduction from baseline in the YGTSS-TTS), along with changes from baseline in the YGTSS-MTSS and YGTSS-VTSS.

Safety Assessments

The incidence of AEs was assessed from informed consent signing to the end of the follow-up period. Preferred AE terms and system organ classes were coded using terminology from MedDRA, version 22.1 (International Federation of Pharmaceutical Manufacturers and Associations). Treatment-emergent AEs (TEAEs) were defined as AEs that began or worsened after first administration of the study drug. All TEAEs were considered treatment-related if the investigator assessed the events as having a reasonable possibility of being caused by the study drug. Standardized MedDRA queries for TEAEs of depression and suicide or self-injury were summarized.

The Children’s Depression Inventory 2 parent and self-report versions were used to assess depressive symptoms and depression-related behaviors.[19] The children’s Columbia Suicide Severity Rating Scale was used to assess past and current suicidal ideation and behaviors to determine suicide risk.[20] Observed values and changes from baseline were assessed for vital signs, electrocardiogram parameters, and clinical laboratory parameters.

Statistical Analysis

It was estimated that approximately 50 participants per study group would provide at least 90% power to detect a beneficial effect of at least 6.5 points in the change from baseline to week 8 in YGTSS-TTS for high-dose deutetrabenazine compared with placebo, assuming an SD of 9.5 and a 2-sided type 1 error rate of 5%, after accounting for dropouts.

The intention-to-treat (ITT) population included all randomized participants. Efficacy analyses were performed for the modified ITT population, defined as all participants in the ITT population who received at least 1 dose of study drug and had a baseline and at least 1 postbaseline YGTSS assessment. The safety population included all randomized participants who received at least 1 dose of study drug.

The primary end-point analysis was a mixed model for repeated measures with the change in YGTSS-TTS as the dependent variable and treatment group, week, and treatment group by week interaction as fixed effects. Baseline YGTSS-TTS, region, and age group were included as covariates. The least-squares (LS) mean change from baseline to week 8 in YGTSS-TTS was compared between high-dose deutetrabenazine and placebo using a 2-sided test at the α = .05 level of significance.

Change from baseline to week 8 in TS-CGI, CA-GTS-QOL ADL subscale scores, YGTSS-MTSS, and YGTSS-VTSS were analyzed in the same manner as the primary analysis, except that the baseline value of the given end point was included as the covariate. Change from baseline to week 8 in TS-PGII score was analyzed using a Cochran-Mantel-Haenszel row mean score test with modified ridit scoring, controlling for age group. The YGTSS responder rates at weeks 2, 4, and 8 were compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline age group. Secondary and exploratory end-point comparisons were tested between both high- and low-dose deutetrabenazine and placebo. A hierarchical testing method was used to maintain the experiment-wise type I error rate of 5% for primary and key secondary analyses. If an end point was not statistically significant, confirmatory hypothesis testing was not carried out on the remaining hypotheses, and the remaining hypotheses were considered exploratory rather than confirmatory. All data were analyzed from February 4 to April 22, 2020, using SAS software, version 9.4 (SAS Institute). The statistical analysis plan for this study is available in Supplement 2.

Results

A total of 193 participants with Tourette syndrome were screened, and 158 participants were enrolled and randomized (52 to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group) (Figure 1). Of these, 145 participants (91.8%) completed the study (46 [31.7%] in the high-dose deutetrabenazine group, 51 [35.2%] in the low-dose deutetrabenazine group, and 48 [33.1%] in the placebo group). The modified ITT population included 153 participants who were evaluated for efficacy, and the safety population included 157 participants.

Figure 1.

Patient Disposition

ITT indicates intention-to-treat; mITT, modified intention-to-treat.

aAll 3 patients withdrew due to “withdrawal by subject.” One occurred during the escalation period, 1 occurred during the maintenance period, and 1 occurred during the follow-up period.

bOne patient withdrew due to “other” reason during the escalation period. One patient withdrew due to “withdrawal by subject” during the maintenance period.

cOne patient withdrew due to “other” reason before receiving study drug. One patient withdrew due to “withdrawal by subject” during the escalation period.

Demographic and baseline characteristics were similar across treatment groups (Table 1). Participants had a mean (SD) age of 11.7 (2.6) years and included 119 boys (75%) and 39 girls (25%). Seven participants (4%) were Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean (SD) time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean (SD) baseline YGTSS-TTS was 33.8 (6.6) points. Prior Tourette syndrome treatment was more common in the deutetrabenazine high-dose group (43 participants; 83%) and low-dose group (45 participants; 83%) than the placebo group (33 participants; 63%). Across groups, the most frequently reported comorbid disorders were psychiatric (ADHD, 41 participants [26%]; obsessive-compulsive disorder, 19 participants [12%]; anxiety, 21 participants [13%]; and depression, 7 participants [4%]), and the most frequently prescribed medications included antipsychotics and psychostimulants (ie, for ADHD, 37 participants [24%]).

Table 1.

Baseline Demographic and Clinical Characteristics (ITT Population)

Characteristic	No. (%)
	Deutetrabenazine		Placebo (n = 52)	Total (N = 158)
	High-dose (n = 52)	Low-dose (n = 54)
Age, mean (SD), y	11.7 (2.6)	11.7 (2.7)	11.8 (2.6)	11.7 (2.6)
Age group, y
6-11	21 (40)	22 (41)	21 (40)	64 (41)
12-16	31 (60)	32 (59)	31 (60)	94 (59)
Sex
Male	37 (71)	42 (78)	40 (77)	119 (75)
Female	15 (29)	12 (22)	12 (23)	39 (25)
Raceb
Asian	0	3 (6)	4 (8)	7 (4)
Black	0	1 (2)	0	1 (1)
Native American	1 (2)	1 (2)	2 (4)	4 (3)
White	48 (92)	48 (89)	39 (75)	135 (85)
Multiple	0	0	2 (4)	2 (1)
Otherc	3 (6)	1 (2)	5 (10)	9 (6)
Region
North America	13 (25)	13 (24)	14 (27)	40 (25)
Europe	32 (62)	32 (59)	23 (44)	87 (55)
Latin America	6 (12)	6 (11)	11 (21)	23 (15)
Asia Pacific	1 (2)	3 (6)	4 (8)	8 (5)
Ethnicity
Hispanic or Latino	8 (15)	9 (17)	15 (29)	32 (20)
Not Hispanic or Latino	43 (83)	45 (83)	37 (71)	125 (79)
Unknown	1 (2)	0	0	1 (0.6)
Weight, mean (SD), kg	47.9 (17.4)	53.9 (22.9)	49.7 (16.9)	50.6 (19.4)
Weight group
20 to <30 kg	6 (12)	6 (11)	5 (10)	17 (11)
30 to <40 kg	12 (23)	9 (17)	10 (19)	31 (20)
≥40 kg	34 (65)	39 (72)	37 (71)	110 (70)
BMI categoryd
Underweight	5 (10)	5 (9)	0	10 (6)
Normal	32 (62)	22 (41)	33 (63)	87 (55)
Overweight	6 (12)	6 (11)	6 (12)	18 (11)
Obesity	9 (17)	21 (39)	13 (25)	43 (27)
Time since TS diagnosis, mean (SD), y	3.2 (2.8)	3.7 (2.7)	3.2 (2.9)	3.3 (2.8)
YGTSS-TTS score, mean (SD)	33.9 (6.2)	32.9 (7.2)	34.7 (6.3)	33.8 (6.6)
CYP2D6 status
Not impaired	44 (85)	44 (81)	45 (87)	133 (84)
Impaired	8 (15)	10 (19)	7 (14)	25 (16)
Psychiatric disorders	30 (58)	25 (46)	23 (44)	78 (49)
ADHD	17 (33)	12 (22)	12 (23)	41 (26)
OCD	8 (15)	6 (11)	5 (10)	19 (12)
Anxiety	9 (17)	7 (13)	5 (10)	21 (13)
Depression	3 (6)	1 (2)	3 (6)	7 (4)
Concomitant medicationse
ADHDf	13 (25)	12 (22)	12 (24)	37 (24)
Antidepressants	2 (4)	1 (2)	2 (4)	5 (3)
Previous TS treatment	43 (83)	45 (83)	33 (63)	121 (77)

Abbreviations: ADHD, attention-deficit hyperactivity disorder; BMI, body mass index; CYP2D6, cytochrome P450 2D6; ITT, intention-to-treat; OCD, obsessive-compulsive disorder; TS, Tourette syndrome; YGTSS-TTS, Yale Global Tic Severity Scale–Total Tic Score.

Percentages may not total to 100% due to rounding.

Race and ethnicity information was collected using predefined options in the case report form.

All 9 patients who reported “other” specified their race as “mixed.”

Percentiles based on age- and sex-based standardized growth chart categories were defined as follows: underweight, <5 percentile; normal, ≥5 to <85 percentile; overweight, ≥85 to <95 percentile; and obesity, ≥95 percentile.

Percentages are calculated based on the number of patients in the safety population (high-dose deutetrabenazine, n = 52; low-dose deutetrabenazine, n = 54; placebo, n = 51; total, N = 157).

Includes stimulant and nonstimulant medications.

Treatment Exposure

Mean (SD) duration of exposure was 7.51 (1.79) weeks in the high-dose deutetrabenazine group, 7.87 (1.38) weeks in the low-dose deutetrabenazine group, and 7.81 (1.28) weeks in the placebo group. The majority (≥90%) of participants in each treatment group who reached their target dose maintained that dose through week 8. Overall adherence was high (154 of 157 participants [98.1%] maintained adherence between 80% and 105%).

Efficacy

Changes from baseline through week 8 in primary and key secondary outcomes are shown in Figure 2 and eTable 2 in Supplement 3. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (Figure 2A). The LS mean (SE) change from baseline to week 8 in YGTSS-TTS was –7.8 (1.24) points in the high-dose deutetrabenazine group compared with –7.0 (1.16) points in the placebo group (LS mean difference, –0.8 points; 95% CI, –3.9 to 2.3 points; P = .60; Cohen d, –0.11).

Figure 2.

Change From Baseline Through Week 8 in Primary and Key Secondary Efficacy End Points

A, The Yale Global Tic Severity Scale rating scale is a semistructured, clinician-administered rating instrument in which the number, frequency, intensity, complexity, and degree of interference are each evaluated on a scale from 0 (none) to 5 (severe) points for both motor and vocal tics. The total motor tic score (0-25 points) is added to the total phonic tic score (0-25 points) to determine the total tic score (0-50 points). The primary end point was least-squares mean change from baseline at week 8 in Yale Global Tic Severity Scale–Total Tic Score between the high-dose deutetrabenazine and placebo groups. B, The Tourette Syndrome Clinical Global Impression is the clinician-reported impact of tics on the patient’s quality of life and is assessed using a 7-point Likert scale from 1 (normal) to 7 (extreme). The key secondary end point was least-squares mean change from baseline at week 8 in Tourette Syndrome Clinical Global Impression score. C, The Tourette Syndrome Patient Global Impression of Impact is a single-item questionnaire that asks the patient, “How much do your current tics disrupt things in your life?” on a scale from 1 (not at all) to 5 (very much) points. The key secondary end point was mean change from baseline at week 8 in Tourette Syndrome Patient Global Impression of Impact score. D, The Child and Adolescent Gilles de la Tourette Syndrome–Quality of Life activities of daily living subscale is a 3-question assessment in which patients rate the extent to which their quality of life related to performance of daily activities is affected by their Tourette syndrome symptoms. Scores range from 0 to 100 points, with higher scores indicating worse quality of life related to activities of daily living. The key secondary end point was least-squares mean change from baseline at week 8 in Child and Adolescent Gilles de la Tourette Syndrome–Quality of Life activities of daily living score. LS indicates least-squares.

There were no nominally significant differences between groups in change from baseline to week 8 for the key secondary outcomes (Figure 2B-D). Results of the exploratory statistical analyses for these end points are provided in eTable 2 in Supplement 3. Favorable numeric differences in the changes in YGTSS-TTS, TS-CGI, TS-PGII, and CA-GTS-QOL ADL were observed for the deutetrabenazine high-dose group and the deutetrabenazine low-dose group compared with placebo at the end of the titration period (week 4) (Figure 2A).

In the high-dose deutetrabenazine group, the proportion of responders (defined as participants with ≥25% reduction from baseline in the YGTSS-TTS) increased from week 2 (6 of 49; 12%) through week 8 (24 of 48; 50%) and was numerically higher compared with placebo at week 4 (20 of 48; 42% vs 10 of 51; 20%) and week 8 (24 of 48; 50% vs 19 of 49; 39%). In the low-dose deutetrabenazine group, the proportion of responders was numerically higher compared with placebo at weeks 2 and 4. In the placebo group, the proportion of responders increased to its highest level at week 8 (19 of 49; 39%) (eFigure 2 in Supplement 3). Numeric improvements were observed during titration for deutetrabenazine vs placebo in changes from baseline in YGTSS-MTSS. Improvements from baseline in YGTSS-VTSS were observed for both deutetrabenazine and placebo (eFigure 3 in Supplement 3).

Safety

During the overall study period, TEAEs were reported for 34 participants (65%) in the high-dose deutetrabenazine group, 24 (44%) in the low-dose deutetrabenazine group, and 25 (49%) in the placebo group (Table 2). Across all treatment groups, most AEs were mild or moderate in severity. There were no deaths. Serious TEAEs were reported by only 1 participant (2%) in the high-dose deutetrabenazine group. This was a boy aged 7 years with ADHD who discontinued atomoxetine (without known medical justification) and developed worsening of ADHD and tic symptoms. The investigator assessed this AE as moderate in severity. The study drug was interrupted for 2 doses because of this AE, and the participant required a 3-day hospitalization period to restart atomoxetine. Because of this hospitalization, the event was classified as a serious AE but was not considered related to the study drug. The participant’s ADHD and tic symptoms improved, and the study drug was resumed after being withheld for 1 day.

Table 2.

Summary of Treatment-Emergent Adverse Events (TEAEs)

Patients	No. (%)
	Deutetrabenazine		Placebo (n = 51)
	High dose (n = 52)	Low dose (n = 54)
Any TEAE	34 (65)	24 (44)	25 (49)
Treatment-related TEAE	25 (48)	14 (26)	7 (14)
Serious TEAE	1 (2)	0	0
Serious treatment-related TEAE	0	0	0
TEAE leading to
Death	0	0	0
Study drug discontinuation	3 (6)	0	1 (2)
Dose interruption	2 (4)	1 (2)	1 (2)
Dose reduction	3 (6)	0	0
Most common (>4%) TEAEs in any treatment group
Somnolence	8 (15)	2 (4)	1 (2)
Headache	6 (12)	8 (15)	4 (8)
Nasopharyngitis	6 (12)	2 (4)	3 (6)
Fatigue	5 (10)	1 (2)	0
Increased appetite	4 (8)	1 (2)	0
Vomiting	3 (6)	1 (2)	4 (8)
Tic	3 (6)	0	1 (2)
Nausea	2 (4)	3 (6)	0
Pain in extremity	2 (4)	0	3 (6)

No safety signals beyond those described in the current deutetrabenazine labeling were observed. The most common TEAEs in the overall study population that were more common with deutetrabenazine compared with placebo were headache (6 of 52 participants [12%] vs 4 of 51 participants [8%]), somnolence (8 [15%] vs 1 [2%]), and nasopharyngitis (6 [12%] vs 3 [6%]) (Table 2). The TEAEs that were more common in the high- and low-dose deutetrabenazine groups than in the placebo group included headache (high-dose, 6 [12%] and low-dose, 8 of 54 [15%] vs placebo, 4 [8%]) somnolence (8 [15%] and 2 [4%] vs 1 [2%]), increased appetite (4 [8%] and 1 [2%] vs 0), fatigue (5 [10%] and 1 [2%] vs 0), and nausea (2 [4%] and 3 [6%] vs 0).

During the 4-week titration period, TEAEs were reported for 22 of 52 participants (42%) in the high-dose deutetrabenazine group, 17 of 54 (31%) in the low-dose deutetrabenazine group, and 14 of 51 (27%) in the placebo group. During the maintenance period, TEAEs occurred in 22 of 49 participants (45%) in the high-dose deutetrabenazine group, 12 of 52 (23%) in the low-dose deutetrabenazine group, and 17 of 49 (35%) in the placebo group. If a participant had the same event during multiple periods, they were counted in each period.

Rates of TEAEs within the depression and suicide/self-injury standardized MedDRA queries were low (Table 3). In total, 4 of 52 participants (8%) in the high-dose deutetrabenazine group and 1 of 54 participants (2%) in the low-dose deutetrabenazine group had TEAEs within the depression standardized MedDRA queries. One participant (2%) in the high-dose deutetrabenazine group and 1 participant (2%) in the placebo group had TEAEs within the suicide or self-injury standardized MedDRA queries. Results from the parent and self-report versions of the Children’s Depression Inventory 2 indicated no worsening of depression with deutetrabenazine or placebo during the study (eFigure 4 in Supplement 3). According to the children’s Columbia Suicide Severity Rating Scale, suicidal ideation was reported by 2 of 51 participants (4%) in the placebo group at baseline and week 2, 3 of 154 (2%; 1 in each group) at week 4, 1 of 49 (2%) in the placebo group at week 8, and 0 participants at week 9. No participants showed suicidal behavior at baseline or during the study.

Table 3.

TEAEs Within the Depression and Suicide/Self-injury SMQs

Patients	No. (%)
	Deutetrabenazine		Placebo (n = 51)
	High-dose (n = 52)	Low-dose (n = 54)
Patients with ≥1 depressiona SMQ TEAE	4 (8)	1 (2)	0
Psychiatric disorders	2 (4)	1 (2)	0
Depression	1 (2)	0	0
Mood swings	1 (2)	0	0
Depressed mood	0	1 (2)	0
Nervous system disorders	2 (4)	0	0
Disturbance in attention	1 (2)	0	0
Psychomotor hyperactivity	1 (2)	0	0
Patients with ≥1 suicide or self-injury SMQ TEAE	1 (2)b	0	1 (2)c
Psychiatric disorders	1 (2)	0	1 (2)
Suicidal ideation	1 (2)	0	1 (2)
Intentional self-injury	0	0	1 (2)

Abbreviations: SMQ, standard MedDRA query; TEAE, treatment-emergent adverse event.

Excludes suicide and self-injury.

This participant experienced mild suicidal ideation lasting 1 day, considered unrelated to study drug.

This participant experienced moderate suicidal ideation, mild self-injury, and moderate behavior disorder. The self-injury and suicidal ideation were considered possibly related to study drug.

There were no clinically meaningful differences in changes from baseline in serum chemistry, hematology, urinalysis, vital signs, electrocardiogram measures, or metabolic parameters (cholesterol and glucose). Mean (SD) body weight increased from baseline to week 8 by 1.99 (1.88) kg in the high-dose deutetrabenazine group, by 2.55 (3.03) kg in the low-dose deutetrabenazine group, and by 0.34 (1.77) kg in the placebo group. There were no notable shifts to higher or lower body mass index categories at week 8.

Discussion

In this randomized clinical trial, fixed-dose treatment with deutetrabenazine was not significantly different from placebo in reducing tics based on changes from baseline to week 8 in the YGTSS-TTS. As shown in Figure 2, the slopes of the lines from week 4 to week 8 indicating a change from baseline were steeper in the placebo group than in the high- or low-dose deutetrabenazine groups, indicating a substantial placebo effect during maintenance therapy. Conversely, outcomes favored deutetrabenazine over placebo from baseline to week 4. Such favorable outcomes early in the course of treatment are not unexpected when using the YGTSS, which assesses a patient’s tic symptoms during the past week.[16,21]

Deutetrabenazine was generally well tolerated in this 8-week, placebo-controlled study of children and adolescents with Tourette syndrome. The TEAEs that were more common with deutetrabenazine than placebo included headache, somnolence, nasopharyngitis, worsened tics, increased appetite, fatigue, and nausea; these were mild or moderate in severity. Importantly, results from the Children’s Depression Inventory 2, the Columbia Suicide Severity Rating Scale, and evaluation of specific AEs of interest showed that there were no safety signals for increased risk of depression or suicidality with deutetrabenazine. These results are consistent with low rates of neuropsychiatric AEs, including depression and suicidal ideation, reported in previous studies of deutetrabenazine.[22,23,24] This is particularly noteworthy because individuals with Tourette syndrome have increased risks for death by suicide, suicidal behavior, self-injurious behavior, and depression compared with control individuals.[25,26] Specifically, an estimated 32% of young people with a chronic tic disorder experience clinically significant suicidal ideation, which is often associated with feelings of frustration and hopelessness about their inability to control tics.[27,28]

There was no evidence of any new safety signals in pediatric participants with Tourette syndrome treated with deutetrabenazine compared with the known safety profile of this medication in adult patients with Huntington disease or tardive dyskinesia. These results suggest that deutetrabenazine has a favorable safety profile in children and adolescents with Tourette syndrome.

Limitations

This study had some limitations. The current results are consistent with the ARTISTS 1 phase 2 and 3 study of flexible doses of deutetrabenazine.[29] Both of these studies may have been too short to accurately assess long-term effects of deutetrabenazine for treatment of tics over time. Future examination of pharmacokinetic data collected during these studies may provide insights into whether responses to deutetrabenazine differ based on drug exposure. Furthermore, given that the majority of participants were non-Hispanic White children, another limitation is lack of generalizability to more diverse populations.

Conclusions

In conclusion, in this 8-week randomized clinical trial of the efficacy and safety of fixed doses of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met, despite a numeric improvement at the end of the titration period. Secondary efficacy end-point results were generally similar to the primary end point. Deutetrabenazine was generally well tolerated in this 8-week study, with no evidence of any new safety signals compared with the known safety profile of deutetrabenazine.