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 & 78 others 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. Racett, Fredy J. Revilla, Frederick Nucifora, Russell L. Margolis, Mary Jane 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 Wojcieszek, Kathrin La Faver, 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

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)40-50
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume316
Issue number1
DOIs
StatePublished - Jul 5 2016

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Chorea
Huntington Disease
Randomized Controlled Trials
Placebos
Therapeutics
Safety
Psychomotor Agitation
Cytochrome P-450 CYP2D6
deutetrabenazine
Deuterium
Anxiety
Pharmacology
Depression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of deutetrabenazine on chorea among patients with huntington disease : A randomized clinical trial. / 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; Racett, Brad A.; Revilla, Fredy J.; Nucifora, Frederick; Margolis, Russell L.; Ong, Mary Jane; 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; La Faver, 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.

In: JAMA - Journal of the American Medical Association, Vol. 316, No. 1, 05.07.2016, p. 40-50.

Research output: Contribution to journalArticle

Frank, S, Testa, CM, Stamler, D, Kayson, E, Davis, C, Edmondson, MC, Kinel, S, Leavitt, B, Oakes, D, O'Neill, C, Vaughan, C, Goldstein, J, Herzog, M, Snively, V, Whaley, J, Wong, C, Suter, G, Jankovic, J, Jimenez-Shahed, J, Hunter, C, Claassen, DO, Roman, OC, Sung, V, Smith, J, Janicki, S, Clouse, R, Saint-Hilaire, M, Hohler, A, Turpin, D, James, RC, Rodriguez, R, Rizer, K, Anderson, KE, Heller, H, Carlson, A, Criswell, S, Racett, BA, Revilla, FJ, Nucifora, F, Margolis, RL, Ong, MJ, Mendis, T, Mendis, N, Singer, C, Quesada, M, Paulsen, JS, Brashers-Krug, T, Miller, A, Kerr, J, Dubinsky, RM, Gray, C, Factor, SA, Sperin, E, Molho, E, Eglow, M, Evans, S, Kumar, R, Reeves, C, Samii, A, Chouinard, S, Beland, M, Scott, BL, Hickey, PT, Esmail, S, Fung, WLA, Gibbons, C, Qi, L, Colcher, A, Hackmyer, C, McGarry, A, Klos, K, Gudesblatt, M, Fafard, L, Graffitti, L, Schneider, DP, Dhall, R, Wojcieszek, J, La Faver, K, Duker, A, Neefus, E, Wilson-Perez, H, Shprecher, D, Wall, P, Blindauer, KA, Wheeler, L, Boyd, JT, Houston, E, Farbman, ES, Agarwal, P, Eberly, SW, Watts, A, Tariot, PN, Feigin, A, Evans, S, Beck, C, Orme, C, Edicola, J & Christopher, E 2016, 'Effect of deutetrabenazine on chorea among patients with huntington disease: A randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 316, no. 1, pp. 40-50. https://doi.org/10.1001/jama.2016.8655
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 ; Racett, Brad A. ; Revilla, Fredy J. ; Nucifora, Frederick ; Margolis, Russell L. ; Ong, Mary Jane ; 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 ; La Faver, 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. / Effect of deutetrabenazine on chorea among patients with huntington disease : A randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2016 ; Vol. 316, No. 1. pp. 40-50.
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abstract = "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.",
author = "Samuel Frank and Testa, {Claudia M.} and David Stamler and Elise Kayson and Charles Davis and Edmondson, {Mary C.} and Shari Kinel and Blair Leavitt and David Oakes and Christine O'Neill and Christina Vaughan and Jody Goldstein and Margaret Herzog and Victoria Snively and Jacquelyn Whaley and Cynthia Wong and Greg Suter and Joseph Jankovic and Joohi Jimenez-Shahed and Christine Hunter and Claassen, {Daniel O.} and Roman, {Olivia C.} and Victor Sung and Jenna Smith and Sarah Janicki and Ronda Clouse and Marie Saint-Hilaire and Anna Hohler and Denyse Turpin and James, {Raymond C.} and Ramon Rodriguez and Kyle Rizer and Anderson, {Karen E.} and Hope Heller and Alexis Carlson and Susan Criswell and Racett, {Brad A.} and Revilla, {Fredy J.} and Frederick Nucifora and Margolis, {Russell L.} and Ong, {Mary Jane} and Tilak Mendis and Neila Mendis and Carlos Singer and Monica Quesada and Paulsen, {Jane S.} and Thomas Brashers-Krug and Amanda Miller and Jane Kerr and Dubinsky, {Richard M.} and Carolyn Gray and Factor, {Stewart A.} and Elaine Sperin and Eric Molho and Mary Eglow and Sharon Evans and Rajeev Kumar and Christina Reeves and Ali Samii and Sylvain Chouinard and Monica Beland and Scott, {Burton L.} and Hickey, {Patrick T.} and Sherali Esmail and Fung, {Wai Lun Alan} and Clare Gibbons and Lina Qi and Amy Colcher and Cory Hackmyer and Andrew McGarry and Kevin Klos and Mark Gudesblatt and Lori Fafard and Laura Graffitti and Schneider, {Daniel P.} and Rohit Dhall and Joanne Wojcieszek and {La Faver}, Kathrin and Andrew Duker and Erin Neefus and Hilary Wilson-Perez and David Shprecher and Paola Wall and Blindauer, {Karen A.} and Lynn Wheeler and Boyd, {James T.} and Emily Houston and Farbman, {Eric S.} and Pinky Agarwal and Eberly, {Shirley W.} and Arthur Watts and Tariot, {Pierre N.} and Andrew Feigin and Scott Evans and Chris Beck and Constance Orme and Jon Edicola and Emily Christopher",
year = "2016",
month = "7",
day = "5",
doi = "10.1001/jama.2016.8655",
language = "English (US)",
volume = "316",
pages = "40--50",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "1",

}

TY - JOUR

T1 - Effect of deutetrabenazine on chorea among patients with huntington disease

T2 - A randomized clinical trial

AU - Frank, Samuel

AU - Testa, Claudia M.

AU - Stamler, David

AU - Kayson, Elise

AU - Davis, Charles

AU - Edmondson, Mary C.

AU - Kinel, Shari

AU - Leavitt, Blair

AU - Oakes, David

AU - O'Neill, Christine

AU - Vaughan, Christina

AU - Goldstein, Jody

AU - Herzog, Margaret

AU - Snively, Victoria

AU - Whaley, Jacquelyn

AU - Wong, Cynthia

AU - Suter, Greg

AU - Jankovic, Joseph

AU - Jimenez-Shahed, Joohi

AU - Hunter, Christine

AU - Claassen, Daniel O.

AU - Roman, Olivia C.

AU - Sung, Victor

AU - Smith, Jenna

AU - Janicki, Sarah

AU - Clouse, Ronda

AU - Saint-Hilaire, Marie

AU - Hohler, Anna

AU - Turpin, Denyse

AU - James, Raymond C.

AU - Rodriguez, Ramon

AU - Rizer, Kyle

AU - Anderson, Karen E.

AU - Heller, Hope

AU - Carlson, Alexis

AU - Criswell, Susan

AU - Racett, Brad A.

AU - Revilla, Fredy J.

AU - Nucifora, Frederick

AU - Margolis, Russell L.

AU - Ong, Mary Jane

AU - Mendis, Tilak

AU - Mendis, Neila

AU - Singer, Carlos

AU - Quesada, Monica

AU - Paulsen, Jane S.

AU - Brashers-Krug, Thomas

AU - Miller, Amanda

AU - Kerr, Jane

AU - Dubinsky, Richard M.

AU - Gray, Carolyn

AU - Factor, Stewart A.

AU - Sperin, Elaine

AU - Molho, Eric

AU - Eglow, Mary

AU - Evans, Sharon

AU - Kumar, Rajeev

AU - Reeves, Christina

AU - Samii, Ali

AU - Chouinard, Sylvain

AU - Beland, Monica

AU - Scott, Burton L.

AU - Hickey, Patrick T.

AU - Esmail, Sherali

AU - Fung, Wai Lun Alan

AU - Gibbons, Clare

AU - Qi, Lina

AU - Colcher, Amy

AU - Hackmyer, Cory

AU - McGarry, Andrew

AU - Klos, Kevin

AU - Gudesblatt, Mark

AU - Fafard, Lori

AU - Graffitti, Laura

AU - Schneider, Daniel P.

AU - Dhall, Rohit

AU - Wojcieszek, Joanne

AU - La Faver, Kathrin

AU - Duker, Andrew

AU - Neefus, Erin

AU - Wilson-Perez, Hilary

AU - Shprecher, David

AU - Wall, Paola

AU - Blindauer, Karen A.

AU - Wheeler, Lynn

AU - Boyd, James T.

AU - Houston, Emily

AU - Farbman, Eric S.

AU - Agarwal, Pinky

AU - Eberly, Shirley W.

AU - Watts, Arthur

AU - Tariot, Pierre N.

AU - Feigin, Andrew

AU - Evans, Scott

AU - Beck, Chris

AU - Orme, Constance

AU - Edicola, Jon

AU - Christopher, Emily

PY - 2016/7/5

Y1 - 2016/7/5

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84977592334&partnerID=8YFLogxK

U2 - 10.1001/jama.2016.8655

DO - 10.1001/jama.2016.8655

M3 - Article

VL - 316

SP - 40

EP - 50

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 1

ER -