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JAMA. 2016 Jul 5;316(1):40-50. doi: 10.1001/jama.2016.8655.

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

Author information

1
Harvard Medical School, Boston, Massachusetts.
2
Virginia Commonwealth University, Richmond, Virginia.
3
Teva Pharmaceuticals Ltd, Frazer, Pennsylvania.
4
Center for Human Experimental Therapeutics, University of Rochester, Rochester, New York.
5
CSD Biostatistics, Tucson, Arizona.
6
Duke University, Durham, North Carolina.
7
Huntington Study Group, Rochester, New York.
8
Centre of Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
9
University of Rochester, Rochester, New York.
10
Wake Forest School of Medicine, Winston-Salem, North Carolina.
11
Medical University of South Carolina, Charleston, South Carolina.
12
Hereditary Neurological Disease Centre, Wichita, Kansas.
13
Baylor College of Medicine, Houston, Texas.
14
Vanderbilt University Medical Center, Nashville, Tennessee.
15
University of Alabama School of Medicine, Birmingham, Alabama.
16
Columbia University, New York, New York.
17
Boston University Medical Campus, Boston, Massachusetts.
18
University of Florida College of Medicine, Gainesville, Florida.
19
Georgetown University, Washington, DC.
20
Washington University School of Medicine, St Louis, Missouri.
21
Greenville Health System, Greenville, South Carolina22University of South Carolina Medical School, Greenville, South Carolina.
22
Johns Hopkins University School of Medicine, Baltimore, Maryland.
23
Ottowa Parkinson's and Neurodegenerative Disorders Clinic, Ottawa, Canada.
24
University of Miami Health, Miami, Florida.
25
University of Iowa Carver College of Medicine, Iowa City, Iowa.
26
University of Kansas Medical Center, Kansas City.
27
Emory University, Atlanta, Georgia.
28
Albany Medical College, Albany, New York.
29
Rocky Mountain Movement Disorders Center, Englewood, Colorado.
30
University of Washington, Seattle, Washington.
31
Centre hospitalier de l'Université de Montréal, Montreal, Québec, Canada.
32
Hôpital Notre-Dame, Montréal, Québec, Canada.
33
North York General Hospital, Toronto, Canada.
34
North York General Hospital, Toronto, Canada35University of Toronto, Toronto, Ontario, Canada36Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
35
North York General Hospital, Toronto, Canada35University of Toronto, Toronto, Ontario, Canada.
36
Cooper University Hospital, Camden, New Jersey.
37
The Movement Disorders Clinic Oklahoma, Tulsa.
38
South Shore Neurologic Associates, Islip, New York.
39
Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
40
Parkinson's Institute and Clinical Center, Sunnyvale, California.
41
Indiana University School of Medicine, Indianapolis.
42
University of Louisville, Louisville, Kentucky.
43
University of Cincinnati, Cincinnati, Ohio.
44
University of Utah Health Care, Salt Lake City, Utah46Banner Sun Health Research Institute, Sun City, Arizona.
45
Medical College of Wisconsin, Milwaukee, Wisconsin.
46
University of Vermont Medical Center, Burlington, Vermont.
47
University of Nevada School of Medicine, Reno, Nevada.
48
Evergreen Neuroscience Institute, Kirkland, Washington.
49
Banner Alzheimer's Institute, Phoenix, Arizona.
50
Feinstein Institute for Medical Research, Manhasset, New York.
51
Harvard University, Boston, Massachusetts.

Abstract

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.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT01795859.

PMID:
27380342
DOI:
10.1001/jama.2016.8655
[Indexed for MEDLINE]
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