© 2016 American Medical Association. IMPORTANCE Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases activemetabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES Primary end pointwas 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. RESULTS Ninety patients with Huntington disease (mean age, 53.7 years;40women [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 improvedfrom13.2(95%CI,12.2-14.3)to11.3(95%CI,10.0-12.5);themeanbetween-groupdifference 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 deutetrabenazinegroupvs6(13%)in theplacebogroup(P = .002). In thedeutetrabenazinegroup, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95%CI, 44.3-50.8) to47.4(44.3-50.5),whereasin the placebogroup, scores decreasedfrom43.2 (95%CI,40.2-46.3) to 39.9(95%CI, 36.2-43.6), for a treatment benefit of4.3 (95%CI,0.4to8.3) (P = .03). Therewas no difference between groups (mean difference of 1.0unit; 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 deutetrabenazinegroupandby1.3units(95%CI,0.4-2.2) intheplacebogroup.Adverseeventrates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE 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.