<b>Importance: </b>Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.<b>OBJECTIVE: </b>To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.<b>Design, Setting, and Participants: </b>Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.<b>INTERVENTIONS: </b>Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.<b>Main Outcomes and Measures: </b>Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.<b>RESULTS: </b>Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.<b>Conclusions and Relevance: </b>Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.<b>Trial Registration: </b>clinicaltrials.gov Identifier: NCT01795859.
Objective: The Swallowing Disturbance Questionnaire (SDQ) was administered to patients with Huntington disease (HD) as part of a randomized, controlled study of deutetrabenazine for the treatment of chorea of HD. Here we describe the impact of deutetrabenazine on swallowing. Background: Swallowing function is an important clinical problem in patients with HD, but dysphagia severity is not surveyed or quantified in the Unified Huntington Disease Rating Scale (UHDRS). The SDQ is a 15‐item survey developed and validated to assess swallowing dysfunction in Parkinson's disease (PD) and has been shown to reliably detect swallowing impairment arising from various etiologies other than PD. It is recommended in the Parkinsonism National Institute of Neurological Disorders and Stroke Common Data Elements. This is the first time the SDQ was used as a screening tool and swallowing assessment in HD. Methods: Participants with HD (N=90) were randomized 1:1 to receive deutetrabenazine or placebo in a 12‐week multicenter Phase III trial that included an eight‐week titration. A normal SDQ score (<11) was required at screening. SDQ and patient weight data were collected at baseline and Weeks 2, 4, 6, 9, and 12. Reports of dysphagia as an adverse event were monitored up to Week 12. Results: A number of screening failures were attributed to high SDQ scores at baseline (n=8). Deutetrabenazine improved SDQ score 1.2 (SE 0.4) versus worsening placebo 0.3 (SE 0.4) at Week 9 (P=.014), which was maintained up to Week 12 (P=.016). No deutetrabenazine‐treated patients and one patient given placebo reported dysphagia as an adverse event. There was a 2.1‐kg treatment effect for weight gain in deutetrabenazine‐treated patients at Week 12, Conclusions: Deutetrabenazine significantly improved swallowing function, as measured by SDQ, which may have contributed to the observed weight gain in deutetrabenazine‐treated patients with HD. However, since swallowing was in the normal range for all participants, given the improved swallowing function in deutetrabenazine‐treated patients, further study of chorea‐associated dysphagia is warranted. These results obtained using the SDQ in HD support future validation of this scale including HD specific "normal" cutoffs to assess swallowing function in this population.
Background: Deutetrabenazine (DTB) is a novel, highly selective vesicular monoamine transporter type 2 (VMAT2) inhibitor that contains deuterium, a naturally occurring, nontoxic form of hydrogen. Deuterium forms a stronger bond with carbon than does hydrogen, requiring more energy for cleavage. Deuterium attenuates metabolism and results in a unique pharmacokinetic profile that leads to more uniform systemic exposure without altering the target pharmacology of the original molecule. The resultant pharmacokinetic profile may enable less‐frequent, lower daily doses, achieving adequate systemic exposure with lower peak concentration. Collectively, deuterium technology has the potential to improve the risk‐benefit profile of medications. OBJECTIVE: To assess whether DTB provides a clinical benefit for patients with chorea associated with Huntington disease (HD) in the First‐HD study and tardive dyskinesia (TD) in the ARM‐TD study. METHODS: Patients with HD or TD were randomized 1:1 to DTB or placebo in the respective 12‐week, double‐blind trials, First‐HD (N=90) and ARM‐TD (N=117), which evaluated efficacy, safety, and tolerability. The primary efficacy endpoint of First‐HD was the change from baseline to maintenance in the UnifiedHuntington'sDiseaseRating Scale (UHDRS) total maximal chorea (TMC) score. The primary efficacy endpoint of ARM‐TD was the change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to Week 12. Adverse events (AEs) and specific safety scales were monitored throughout both studies. RESULTS: In First‐HD, DTB significantly decreased the UHDRS TMC score compared with placebo (‐4.4 vs‐1.9; P?0.0001). In ARM‐TD, DTB significantly reduced mean AIMS scores compared with placebo (‐3.0 vs‐1.6; P=0.0188). DTB was generally well tolerated in both studies. In First‐HD, AEs were mostly mild to moderate, and AE rates were similar for DTB and placebo; both groups also had the same low rates of dose reductions (6.7% each), suspensions (2.2% each), and withdrawals (2.2% each) due to AEs. Likewise, the incidence of AEs in ARM‐TD was also similar between DTB and placebo. These were also mostly mild to moderate in nature. For the DTB and placebo groups in ARM‐TD, respectively, there were low rates of dose reductions (10.3% vs 5.1%), suspensions (5.2% vs 8.5%), and study withdrawals (1.7% vs 3.4%) due to AEs. CONCLUSIONS: The favorable efficacy and safety profile of DTB observed in the HD and TD populations in First‐HD and ARM‐TD may be attributed to the unique pharmacokinetic profile of DTB achieved by deuterium substitution.
