Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial

Samuel Frank, Claudia M. Testa, David Stamler, Elise Kayson, Charles Davis, Mary C. Edmondson, Shari Kinel, Blair Leavitt, David Oakes, Christine O’Neill, Christina Vaughan, Jody Goldstein, Margaret Herzog, Victoria Snively, Jacquelyn Whaley, Cynthia Wong, Greg Suter, Joseph Jankovic, Joohi Jimenez-Shahed, Christine Hunter, Daniel O. Claassen, Olivia C. Roman, Victor Sung, Jenna Smith, Sarah Janicki, Ronda Clouse, Marie Saint-Hilaire, Anna Hohler, Denyse Turpin, Raymond C. James, Ramon Rodriguez, Kyle Rizer, Karen E. Anderson, Hope Heller, Alexis Carlson, Susan Criswell, Brad A Racette, Fredy J. Revilla, Frederick Nucifora, Russell L. Margolis, MaryJane Ong, Tilak Mendis, Neila Mendis, Carlos Singer, Monica Quesada, Jane S. Paulsen, Thomas Brashers-Krug, Amanda Miller, Jane Kerr, Richard M. Dubinsky, Carolyn Gray, Stewart A. Factor, Elaine Sperin, Eric Molho, Mary Eglow, Sharon Evans, Rajeev Kumar, Christina Reeves, Ali Samii, Sylvain Chouinard, Monica Beland, Burton L. Scott, Patrick T. Hickey, Sherali Esmail, Wai Lun Alan Fung, Clare Gibbons, Lina Qi, Amy Colcher, Cory Hackmyer, Andrew McGarry, Kevin Klos, Mark Gudesblatt, Lori Fafard, Laura Graffitti, Daniel P. Schneider, Rohit Dhall, Joanne M. Wojcieszek, Kathrin LaFaver, Andrew Duker, Erin Neefus, Hilary Wilson-Perez, David Shprecher, Paola Wall, Karen A. Blindauer, Lynn Wheeler, James T. Boyd, Emily Houston, Eric S. Farbman, Pinky Agarwal, Shirley W. Eberly, Arthur Watts, Pierre N. Tariot, Andrew Feigin, Scott Evans, Chris Beck, Constance Orme, Jon Edicola, Emily Christopher

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. To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. 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. Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. 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. 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. 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. clinicaltrials.gov Identifier: NCT01795859.