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Ethyl-EPA in Huntington disease

A double-blind, randomized, placebo-controlled trial

B. K. Puri, MA, PhD, MB, BChir, DipStat, MRCPsych, MMath, B. R. Leavitt, MD, M. R. Hayden, MD, PhD, C. A. Ross, MD, PhD, A. Rosenblatt, MD, J. T. Greenamyre, MD, PhD, S. Hersch, MD, PhD, K. S. Vaddadi, MBBS, MPhil, FRCPsych, FRANZCP, DPM, A. Sword, MSc, D. F. Horrobin, DPhil, MA, BM, BCh, M. Manku, PhD and H. Murck, MD

From the MRI Unit (Dr. Puri), Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, UK; Department of Medical Genetics (Drs. Leavitt and Hayden), Centre for Molecular Medicine and Therapeutics, University of British Columbia Hospital, Vancouver, BC, Canada; Baltimore Huntington's Disease Center, Departments of Psychiatry (Drs. Ross and Rosenblatt) and Neurology and Neuroscience (Dr. Ross), The Johns Hopkins University School of Medicine, Baltimore MD; Department of Neurology (Dr. Greenamyre), Emory University School of Medicine, Atlanta, GA; Massachusetts General Hospital (Dr. Hersch), Boston, MA; Department of Psychological Medicine (Dr. Vaddadi), Monash University, Monash Medical Centre, Clayton, Victoria, Australia; Centum Limited (A. Sword), Stirling, UK; Amarin Neuroscience Ltd. (Drs. Horrobin, Manku, and Murck), Stirling, UK.

Address correspondence and reprint requests to Dr. Harald Murck, Amarin Neuroscience Ltd., Kings Park House, Laurelhill Business Park, Stirling, FK7 9JQ UK; e-mail: hmurck{at}amarin-neuro.com

Background: Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate (ethyl-EPA) in Huntington disease (HD).

Methods: A total of 135 patients with HD were randomized to enter a multicenter, double-blind, placebo-controlled trial on the efficacy of 2 g/d ethyl-EPA vs placebo. The Unified Huntington's Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS-4). Analysis of covariance (ANCOVA) and a ² test on response, defined as absence of increase in the TMS-4, were performed.

Results: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent-to-treat (ITT) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4. In the PP cohort, ethyl-EPA proved better than placebo on the ² test on TMS-4 (p < 0.05), but missed significance on ANCOVA (p = 0.06). Secondary end points (ITT cohort) showed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms.

Conclusions: Ethyl-eicosapentaenoate (ethyl-EPA) (purity >95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted.

Amarin Neuroscience Ltd. (formerly known as Laxdale Ltd.) was responsible for organizing and funding this clinical trial, and provided the active and placebo capsules. Dr. Horrobin was and Drs. Murck and Manku are full-time employees of Amarin Neuroscience Ltd. Dr. Vaddadi is the inventor of patents that have been assigned to Amarin Neuroscience Ltd. and received an advance against royalties payable on commercialization of ethyl-EPA in Huntington disease. Amarin Neuroscience Ltd. funded Dr. Vaddadi's research through an unrestricted grant to his research account and paid funding to Dr. Vaddadi's institution for salary support for his research assistant. The institutions employing Drs. Puri, Leavitt, Hayden, Ross, Rosenblatt, Greenamyre, and Hersch received financial remuneration from Amarin Neuroscience Ltd. for their participation in the study. Dr. Ross's institution has received an unrestricted grant and corporate financial support for their Huntington's Disease Society of America Center of Excellence from Amarin Pharmaceuticals Inc. Dr. Puri received partial salary support from Amarin Neuroscience Ltd. Pharmapart UK Ltd. received financial remuneration from Amarin Neuroscience Ltd. for the work undertaken by Dr. Sword on this study.

Deceased.

Received September 14, 2003. Accepted in final form April 15, 2005.