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Perampanel in Parkinson Disease Fluctuations: A Double-Blind Randomized Trial With Placebo and Entacapone

Rascol, Olivier MD, PhD*; Barone, Paolo MD†‡; Behari, Madhuri MD§; Emre, Murat MD; Giladi, Nir MD; Olanow, C. Warren MD, FRCPC#**; Ruzicka, Evzen MD††; Bibbiani, Francesco MD‡‡; Squillacote, David MD‡‡; Patten, Anna PhD‡‡; Tolosa, Eduardo MD§§∥∥

doi: 10.1097/WNF.0b013e318241520b
Original Articles

Objectives Perampanel is a selective and noncompetitive α-amino-3-hydroxy-5-methylisoxazole propionic acid–type glutamate receptor antagonist that improves motor symptoms in animal models of Parkinson disease (PD). The aim of this study was to assess the efficacy and tolerability of perampanel in L-dopa–treated patients with moderately severe PD and motor fluctuations using an active comparator study design.

Methods This was a prospective, randomized, double-blind, 3-arm, parallel-group, controlled study assessing the effects of perampanel (4 mg/d), placebo, or entacapone (200 mg with each dose of L-dopa) in 723 L-dopa–treated patients with PD with “OFF” problems. The primary outcome measure was the change from baseline in mean total daily OFF time based on diaries. Secondary end points included change from baseline in Unified Parkinson’s Disease Rating Scale part II while OFF, Unified Parkinson’s Disease Rating Scale part III while “ON,” and mean total daily ON time without dyskinesias or with nontroublesome dyskinesias.

Results In total, 480 patients (66.4%) completed the study, which was terminated early after negative results of 2 other large placebo-controlled studies became available. Perampanel was not superior to placebo on any efficacy end point, whereas entacapone was superior to placebo on the primary end point (P = 0.034) and most secondary outcomes. Perampanel was generally well tolerated.

Conclusions Perampanel (4 mg/d) was well tolerated but did not have a clinically significant effect in improving motor symptoms of L-dopa–treated patients with moderately advanced PD and motor fluctuations. These patients did respond to the active comparator, entacapone, confirming the validity of the findings despite the early termination of the study.

*Institut National de la Santé et de la Recherche Médicale Clinical Investigation Center, Toulouse University Hospital and University of Toulouse, France; †University of Naples-Istituto di Diagnosi e Cura Hermitage, Naples; ‡University of Salerno, Salerno, Italy; §All India Institute of Medical Sciences, New Delhi, India; ∥Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; ¶Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; #Mount Sinai School of Medicine, New York, NY; **Institute of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy; ††Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; ‡‡Neuroscience Product Creation Unit, Eisai, Woodcliff Lake, NJ; §§Neurology Service, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas; and ∥∥Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.

Conflicts of Interest and Source of Funding: This study was sponsored by Eisai Co, Ltd. Compensation from Eisai was paid to the members of the steering committee for their membership of the committee.

Prof Olivier Rascol has received honoraria for consultancies with Abbott, Addex Pharmaceuticals, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Impax Pharmaceuticals, Lundbeck, Merck Serono, The Movement Disorders Society, Novartis, Oxford BioMedica, Schering-Plough, Servier, Teva, UCB, and XenoPort, Inc. He has also received grants from Abbott, Boehringer Ingelheim, Lundbeck, Eisai, GlaxoSmithKline, Novartis, Teva, and UCB.

Prof Paolo Barone has received honoraria as a consultant and advisory board member for Novartis, Schwarz Pharma/UCB, Merck Serono, Eisai, Solvay, General Electric, and Lundbeck. He has also received research support from Boehringer Ingelheim, Novartis, Schwarz Pharma/UCB, Merck Serono, Solvay, and Lundbeck and is a salaried employee of the Department of Neurological Sciences, University of Napoli.

Prof Madhuri Behari has no disclosures to report.

Prof Murat Emre has been on the clinical advisory committee and received honoraria from Eisai. In addition, his department has received clinical study grants from Lilly, Novartis, and Lundbeck.

Prof Nir Giladi has received research grants from Teva/Lundbeck, Novartis, Intec Pharma, NeuroDerm, Michael J. Fox Foundation, National Institutes of Health, European Union, National Parkinson Foundation, and Israeli Science Foundation. He has also received consulting fees or other remuneration from UCB, Teva/Lundbeck, Biogen Idec, Intec Pharma, and NeuroDerm and has participated in speakers’ bureaus for UCB and Teva/Lundbeck.

Prof C. Warren Olanow has served as a consultant to Novartis/Orion, Teva/Lundbeck, Abbot, Ceregene, and Clintrex.

Prof Evzen Ruzicka has received honoraria or consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Medtronic, and Novartis.

Prof Eduardo Tolosa has received honoraria for consultancies and lectures from Boehringer Ingelheim, Novartis, UCB, Abbott, Merck Serono, and Teva/Lundbeck and has participated in advisory boards for Eisai. He has also received research grants from the Spanish Fondo de Invesigaciones Sanitarias and the European Union. Francesco Bibbiani, David Squillacote, and Anna Patten are salaried employees of Eisai.

None of the authors have any further competing interests.

Address correspondence and reprint requests to Olivier Rascol, MD, PhD, Department of Clinical Pharmacology, Faculty of Medicine, University of Toulouse, 37 Allées J Guesde, 31000, Toulouse, France; E-mail:

© 2012 Lippincott Williams & Wilkins, Inc.