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Adenosine A 2A receptor antagonist istradefylline (KW‐6002) reduces “off” time in Parkinson's disease: A double‐blind, randomized, multicenter clinical trial (6002‐US‐005)
Author(s) -
LeWitt Peter A.,
Guttman M.,
Tetrud James W.,
Tuite Paul J.,
Mori Akihisa,
Chaikin Philip,
Sussman Neil M.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21315
Subject(s) - medicine , placebo , randomization , randomized controlled trial , adverse effect , clinical endpoint , clinical global impression , confidence interval , clinical trial , anesthesia , alternative medicine , pathology
Objective Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A 2A receptor antagonist, istradefylline, shows promise for the treatment of PD. Methods Istradefylline (40mg/day) was studied in levodopa‐treated PD subjects experiencing prominent wearing‐off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double‐blind, 12‐week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake “off” time, recorded by subjects using a patient PD diary. Secondary end points evaluated “on” time (including “on time with dyskinesia”), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression–Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results After randomization, approximately 88% of subjects completed the double‐blind period. Compared with baseline, the decrease of daily awake “off” time for istradefylline was a mean (± standard deviation) of −10.8 ± 16.6% (95% confidence interval, −13.46 to −7.52) and for placebo, −4.0 ± 15.7% (95% confidence interval, −7.73–0.31; p = 0.007 using two‐way analysis of variance). This effect corresponded to changes from baseline in total daily awake “off” time of −1.8 ± 2.8 hours for istradefylline and −0.6 ± 2.7 hours for placebo ( p = 0.005). Treatment‐emergent adverse effects with istradefylline were generally mild. Interpretation Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in “off” time without increased troublesome dyskinesia. Ann Neurol 2008