Browsing by Author "Factor, Stewart A."

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    Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial
    (2016-07) Frank, Samuel; Testa, Claudia M.; Stamler, David; Kayson, Elise; Davis, Charles; Edmondson, Mary C.; Kinel, Shari; Leavitt, Blair; Oakes, David; O'Neill, Christine; Vaughan, Christina; Goldstein, Jody; Herzog, Margaret; Snively, Victoria; Whaley, Jacquelyn; Wong, Cynthia; Suter, Greg; Jankovic, Joseph; Jimenez-Shahed, Joohi; Hunter, Christine; Claassen, Daniel O.; Roman, Olivia C.; Sung, Victor; Smith, Jenna; Janicki, Sarah; Clouse, Ronda; Saint-Hilaire, Marie; Hohler, Anna; Turpin, Denyse; James, Raymond C.; Rodriguez, Ramon; Rizer, Kyle; Anderson, Karen E.; Heller, Hope; Carlson, Alexis; Criswell, Susan; Racette, Brad A.; Revilla, Fredy J.; Nucifora, Frederick, Jr.; Margolis, Russell L.; Ong, MaryJane; Mendis, Tilak; Mendis, Neila; Singer, Carlos; Quesada, Monica; Paulsen, Jane S.; Brashers-Krug, Thomas; Miller, Amanda; Kerr, Jane; Dubinsky, Richard M.; Gray, Carolyn; Factor, Stewart A.; Sperin, Elaine; Molho, Eric; Eglow, Mary; Evans, Sharon; Kumar, Rajeev; Reeves, Christina; Samii, Ali; Chouinard, Sylvain; Beland, Monica; Scott, Burton L.; Hickey, Patrick T.; Esmail, Sherali; Fung, Wai Lun Alan; Gibbons, Clare; Qi, Lina; Colcher, Amy; Hackmyer, Cory; McGarry, Andrew; Klos, Kevin; Gudesblatt, Mark; Fafard, Lori; Graffitti, Laura; Schneider, Daniel P.; Dhall, Rohit; Wojcieszek, Joanne M.; LaFaver, Kathrin; Duker, Andrew; Neefus, Erin; Wilson-Perez, Hilary; Shprecher, David; Wall, Paola; Blindauer, Karen A.; Wheeler, Lynn; Boyd, James T.; Houston, Emily; Farbman, Eric S.; Agarwal, Pinky; Eberly, Shirley W.; Watts, Arthur; Tariot, Pierre N.; Feigin, Andrew; Evans, Scott; Beck, Chris; Orme, Constance; Edicola, Jon; Christopher, Emily; Department of Neurology, IU School of Medicine
    Importance 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. 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 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. Results 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. 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.
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    A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease
    (2017-01) McGarry, Andrew; McDermott, Michael; Kieburtz, Karl; de Blieck, Elisabeth A.; Beal, Flint; Marder, Karen; Ross, Christopher; Shoulson, Ira; Gibert, Peter; Mallonee, William M.; Guttman, Mark; Wojcieszek, Joanne; Kumar, Rajeev; LeDoux, Mark S.; Jenkins, Mary; Rosas, H. Diana; Nance, Martha; Biglan, Kevin; Como, Peter; Dubinsky, Richard M.; Shannon, Kathleen M.; O'Suilleabhain, Padraig; Chou, Kelvin; Walker, Francis; Martin, Wayne; Wheelock, Vicki L.; McCusker, Elizabeth; Jankovic, Joseph; Singer, Carlos; Sanchez-Ramos, Juan; Scott, Burton; Suchowersky, Oksana; Factor, Stewart A.; Higgins, Donald S., Jr.; Molho, Eric; Revilla, Fredy; Caviness, John N.; Friedman, Joseph H.; Perlmutter, Joel S.; Feigin, Andrew; Anderson, Karen; Rodriguez, Ramon; McFarland, Nikolaus R.; Margolis, Russell L.; Farbman, Eric S.; Raymond, Lynn A.; Suski, Valerie; Kostyk, Sandra; Colcher, Amy; Seeberger, Lauren; Epping, Eric; Esmail, Sherali; Diaz, Nancy; Fung, Wai Lun Alan; Diamond, Alan; Frank, Samuel; Hanna, Philip; Hermanowicz, Neal; Dure, Leon S.; Cudkowicz, Merit; Department of Neurology, School of Medicine
    Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD.