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

Abstract

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.

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.

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.