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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Coffey reported receiving research support/honoraria from the American Academy of Child and Adolescent Psychiatry, the National Institute of Mental Health, Neurocrine Biosciences, the Psychiatry Academy, Teva/Nuvelution, and the Tourette Association of America–Centers for Disease Control and Prevention partnership; serving as co-coordinating investigator during the conduct of the study; receiving grants from Emalex Biosciences, the National Institute of Mental Health, and Florida Children's Medical Services; receiving honoraria for invited talks from HMS/Psychiatry Academy, Partners Health Care, and the Tourette Association of America–Centers for Disease Control and Prevention partnership; and serving on the advisory board for Skyland Trail outside the submitted work. Dr Jankovic reported receiving research/training funding from Allergan Inc, the Cure Huntington’s Disease Initiative Foundation, Civitas/Acorda Therapeutics, the Dystonia Coalition, the Dystonia Medical Research Foundation, F. Hoffmann-La Roche Ltd, Huntington Study Group, Medtronic Neuromodulation, Merz Pharmaceuticals, the Michael J. Fox Foundation for Parkinson Research, the National Institutes of Health, Neurocrine Biosciences, the Parkinson Foundation, Nuvelution, Parkinson Study Group, Pfizer Inc, Prothena Biosciences Inc, Psyadon Pharmaceuticals Inc, Revance Therapeutics Inc, Teva Pharmaceutical Industries Ltd, and US WorldMeds; and serving as a consultant/advisory board member for Teva Pharmaceuticals during the conduct of this study. Dr Claassen reported receiving research support from the Griffin Foundation, Huntington’s Disease Society of America, Michael J. Fox Foundation, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging; receiving grants from AbbVie, Acadia, Biogen, Bristol Myers Squibb, Cerecor, Eli Lilly, Genentech, Jazz Pharmaceuticals, Lundbeck, the National Institutes of Health, Neurocrine, Prolenia, Teva Neuroscience, Vaccinex, and Wave Life Sciences; receiving personal fees from Huntington Study Group; and serving as a consultant or on an advisory board for Acadia, Adamas, Alterity, Lundbeck, Neurocrine, Teva Neuroscience, and Wave Life Sciences. Dr Jimenez-Shahed reported receiving research support from Impax Pharmaceuticals, St. Jude Medical, Medtronic, Lilly, Teva Pharmaceuticals, Sunovion, and the Michael J. Fox Foundation for Parkinson Research; receiving consulting fees from Teva Pharmaceuticals, St. Jude Medical, Medtronic, Boston Scientific, Bracket, and Nuvelution; and receiving personal fees from Blue Rock Therapeutics, AbbVie, Spark Therapeutics, Revance, and Amneal outside the submitted work. Dr Gertz reported being the managing director at Blackstone Life Sciences; receiving consulting fees from Twin Bridges Life Sciences LLC; and receiving personal fees from Nuvelution Pharma, Janssen Research & Development, EMD Serono, and Abide Therapeutics outside the submitted work. Dr Garofalo reported receiving consulting fees from Nuvelution TS Pharma Inc, Pfizer Inc, Pharmaceutical Product Development, Celgene, Anokion, AveXis, Acadia, MMS Holdings, and Teva Pharmaceuticals. Dr Stamler reported being a former employee of Teva Pharmaceuticals, USA; receiving a salary and benefits from Auspex Pharmaceuticals; and having patents pending (US20160346270, US20160287574). Ms Wieman reported being a former employee of Teva Pharmaceuticals, USA. Dr Savola reported being a former employee of Teva Pharmaceuticals International, GmbH, Switzerland. Drs Gordon and Alexander reported being employees of Teva Pharmaceuticals, USA. Drs Barkay and Harary reported being employees of Teva Pharmaceuticals, Israel. No other disclosures were reported.

Figures

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.