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NEUROLOGY 2008;70:2233-2240
© 2008 American Academy of Neurology

A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease

M. Stacy, MD, D. Silver, MD, T. Mendis, MD, J. Sutton, MD, A. Mori, PhD, P. Chaikin, PharmD, MD and N. M. Sussman, MD

From the Division of Neurology (M.S.), Duke University Medical Center, Durham, NC; Coastal Neurological Medical Group, Inc. (D.S.), La Jolla, CA; Parkinson’s and Neurodegenerative Disorders Clinic (T.M.), Ottawa, Ontario, Canada; Pacific Neuroscience Medical Group, Inc. (J.S.), Oxnard, CA; and Kyowa Pharmaceutical, Inc. (A.M., P.C., N.M.S.), Princeton, NJ.

Address correspondence and reprint requests to Dr. Mark Stacy, Duke University Medical Center, Durham, NC 27705 mark.stacy{at}duke.edu

Background: The safety and efficacy of istradefylline, a selective adenosine A2A receptor antagonist, was evaluated in a 12-week, double-blind study in levodopa-treated Parkinson disease (PD) subjects with motor complications.

Methods: Levodopa-treated PD subjects (n = 395) received istradefylline 20 mg/day (n = 163), istradefylline 60 mg/day (n = 155), or placebo (n = 77) at 40 sites. The primary efficacy variable was the change in the percentage of time per day spent in the OFF state. Secondary measurements assessed change in ON time, Unified Parkinson’s Disease Rating Scale, and Clinical Global Impression. Safety monitoring included clinical laboratory, electrocardiograms, vital signs, physical/neurologic examinations, and adverse events (AEs).

Results: Changes from baseline to endpoint in the percentage OFF time in the active groups compared with placebo were –4.35% (95% CI –8.16 to –0.54; p = 0.026) for istradefylline 20 mg/day and –4.49% (95% CI –8.35 to –0.62; p = 0.024) for 60 mg/day; these changes were significant (analysis of covariance). For total hours, istradefylline demonstrated mean differences from placebo of –0.64 hours (95% CI –1.30 to 0.01) for 20 mg/day and –0.77 hours (95% CI –1.44 to –0.11) for 60 mg/day (p = 0.065; overall treatment effect). Clinical response occurred by the second week and was maintained throughout the study. Istradefylline was well tolerated. The common AEs were dyskinesia, nausea, dizziness, and hallucinations.

Conclusions: Istradefylline demonstrated a significant reduction in the percentage of awake time per day spent in the OFF state, which resulted in a clinically meaningful reduction in OFF time, without an increase in ON time with troublesome dyskinesia, and was well tolerated as adjunctive treatment to levodopa in Parkinson disease.

Abbreviations: AE = adverse event; ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression–Improvement; GABAergic = {gamma}-aminobutyric acid mediated; ITT = intent to treat; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NOS = not otherwise specified; PD = Parkinson disease; UPDRS = Unified Parkinson’s Disease Rating Scale.

Disclosure: The authors acknowledge the assistance of Kyowa Pharmaceutical, Inc. in developing the research protocol, providing the data set, and conducting the statistical analysis of this clinical trial. Rocco Ballerini, PhD (Kyowa Pharmaceutical, Inc., Princeton, NJ), was responsible for the statistical analysis. M.S. was the principal investigator for the 6002-US-006 study on behalf of Kyowa Pharmaceutical, Inc., and he served as a consultant to the sponsor. D.S. has received compensation from Kyowa Pharmaceutical, Inc., for this and other studies of istradefylline. Pacific Neuroscience Medical Group (PNMG) has received compensation from Kyowa Pharmaceutical, Inc., for this and other studies of istradefylline; J.S. is the majority shareholder of PNMG. A.M., P.C., and N.M.S. are employees of Kyowa Pharmaceutical, Inc.

Received August 17, 2007. Accepted in final form February 25, 2008.






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