Safety and Efficacy of Flexible-Dose Deutetrabenazine in Children and Adolescents With Tourette Syndrome: A Randomized Clinical Trial

Abstract

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults.

Objective: To examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents.

Design, setting, and participants: This phase 2/3, randomized, double-masked, placebo-controlled, parallel-group, dose-titration study included children and adolescents (aged 6-16 years) with Tourette syndrome with active tics causing distress or impairment (ie, Yale Global Tic Severity Scale-Total Tic Score [YGTSS-TTS] ≥20). The trial was conducted over 12 weeks, with 1 week of follow-up from February 2018 to November 2019 at 36 centers in the United States, Canada, Denmark, Russia, Serbia, and Spain. Data analysis was conducted from January 31 to April 22, 2020.

Intervention: Patients were randomized (1:1) to receive deutetrabenazine or placebo, titrated during 7 weeks to an optimal level, followed by a 5-week maintenance period. The maximum total daily deutetrabenazine dose was 48 mg/d.

Main outcomes and measures: The primary efficacy end point was change from baseline to week 12 in YGTSS-TTS. Key secondary end points included changes in Tourette Syndrome-Clinical Global Impression, Tourette Syndrome-Patient Global Impression of Impact, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety was assessed based on treatment-emergent adverse events, vital signs, questionnaires, and laboratory parameters.

Results: A total of 119 participants were randomized to deutetrabenazine (59 participants; mean [SD] age, 11.5 [2.5] years; 53 [90%] boys; 49 [83%] White; 3 [5%] Black) and placebo (60 participants; mean [SD] age, 11.5 [2.6] years; 51 [85%] boys; 53 [88%] White; 3 [5%] Black). At week 12, the difference in YGTSS-TTS score was not significant between deutetrabenazine and placebo (least squares mean difference, -0.7; 95% CI, -4.1 to 2.8; P = .69; Cohen d, -0.07). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 38 patients (66%) and 33 patients (56%) receiving deutetrabenazine and placebo, respectively, and were generally mild or moderate.

Conclusions and relevance: In this study of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. These results may be informative for future studies of treatments for tics in Tourette syndrome.

Trial registration: ClinicalTrials.gov Identifier: NCT03452943.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jankovic reported receiving research and/or training funding from Allergan Inc., the CHDI Foundation, Civitas/Acorda Therapeutics, Dystonia Coalition, Dystonia Medical Research Foundation, F. Hoffmann-La Roche, Huntington Study Group, Medtronic Neuromodulation, Merz Pharmaceuticals, Michael J. Fox Foundation for Parkinson’s Research, National Institutes of Health, Neurocrine Biosciences, Parkinson’s Foundation, Nuvelution, Parkinson Study Group, Pfizer, Prothena Biosciences, Psyadon Pharmaceuticals, Revance Therapeutics, Teva Pharmaceuticals, and US WorldMeds and serving as a consultant and advisory board member for Teva Pharmaceuticals outside the submitted work. Dr Coffey reported receiving honoraria for invited talks from the American Academy of Child and Adolescent Psychiatry, Abide Therapeutics, Psychiatry Academy, Partners Health Care, Neurocrine Biosciences, and the Tourette Association of America–Centers for Disease Control and Prevention Partnership; grants from Emalex, the National Institute of Mental Health, and Florida Children’s Medical Services; and serving on the advisory board of Skyland Trai outside the submitted work. Dr Claassen reported receiving research support from the Griffin Foundation, Huntington’s Disease Society of America, Michael J. Fox Foundation, National Institute of Neurological Disorders and Stroke, and National Institute on Aging; personal fees from Teva Neuroscience during the conduct of the study; grants from AbbVie, Acadia, Biogen, Bristol Myers Squibb, Cerecor, Eli Lilly, Jazz Pharmaceuticals, Lundbeck, Neurocrine, Genentech, Prolenia, the National Institute of Health, the Department of Defense, Teva Neuroscience, and Wave Life Sciences; and personal fees from Alterity, Acadia, and Huntington Study Group outside the submitted work. Dr Jimenez-Shahed reported receiving consulting fees from Medtronic, St Jude Medical, Boston Scientific, Blue Rock Therapeutics, Bracket Global, Teva, Nuvelution, CNS Ratings, AbbVie, Spark Therapeutics, Revance, Amneal, and Impel. Dr Gertz reported receiving personal fees from Nuvelution Pharma during the conduct of the study; serving as managing director of Blackstone Life Sciences; and receiving consulting fees from Twin Bridges Life Sciences for Nuvelution Pharma, Janssen Research & Development, EMD Serono, and Abide Therapeutics outside the submitted work. Dr Garofalo reported receiving personal fees from Nuvelution, Pfizer, PPD, Celgene, Anokion, AveXis, Acadia, MMS Holdings, and Teva Pharmaceuticals outside the submitted work. Dr Stamler reported being a former employee of Teva Pharmaceuticals; receiving salary and benefits from Auspex Pharmaceuticals; and having patents pending for US20160346270 and US20160287574. Ms Wieman and Dr Savola reported being former employees of Teva Pharmaceuticals. Drs Gordon, Alexander, Barkay, and Harary reported being employed by Teva Pharmaceuticals.

Figures

Figure 1.. Study Flowchart

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

Figure 2.. Change From Baseline Through Week 12 in Primary and Key Secondary Efficacy End Points

Whiskers indicate SEs; CA-GTS-QOL ADL, Child and Adolescent Gilles de la Tourette Syndrome–Quality of Life Activities of Daily Living; LS, least squares; TS-CGI, Tourette Syndrome–Clinical Global Impression; TS-PGII, Tourette Syndrome–Patient Global Impression of Impact; and YGTSS-TTS, Yale Global Tic Severity Scale–Total Tic Score. aThe YGTSS rating scale is a semistructured clinician-administered rating instrument in which the number, frequency, intensity, complexity, and degree of interference of tics are each evaluated on a scale from 0 (none) to 5 (severe) for both motor and phonic tics. The total motor tic score (0-25) is added to the total phonic tic score (0-25) to determine the TTS (0-50). The primary end point was LS mean change from baseline in YGTSS-TTS score. bThe TS-CGI is the clinician-reported impact of tics on the patient’s quality of life and is assessed using a 7-point Likert scale in which 1 indicates normal and 7 indicates extreme. The key secondary end point was LS mean change from baseline in TS-CGI score. cThe TS-PGII 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). The key secondary end point was LS mean change from baseline in TS-PGII score. dThe CA-GTS-QOL ADL 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 impacted by their Tourette syndrome symptoms. Scores range from 0 to 100, with higher scores indicating worse quality of life related to ADL. The key secondary end point was LS mean change from baseline in CA-GTS-QOL ADL score.

Figure 3.. Parent and Self-report Results From the Children’s Depression Inventory 2 (CDI-2) During Study Period

Whiskers indicate SEs.