Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD

Objective: To evaluate the safety and efficacy of the adenosine A(2A) receptor antagonist istradefylline (KW6002) in patients with levodopa-treated Parkinson's disease (PD) with both motor fluctuations and peak-dose dyskinesias. Methods: This was a 12-week, double-blind, randomized, placebo-controlled, exploratory study in which PD subjects with both motor fluctuations and peak-dose dyskinesias were randomized to treatment with placebo (n = 29), istradefylline up to 20 mg/day (n = 26), or istradefylline up to 40 mg/day (n = 28). There was no prespecified primary outcome measure, and 19 outcome variables were analyzed. Results: As assessed by home diaries, subjects assigned to istradefylline experienced a mean (+/-SE) reduction in the proportion of awake time spent in the "off" state of 7.1 +/- 2.0% compared with an increase of 2.2 +/- 2.7% in the placebo group (p = 0.008). There was a decrease in "off" time of 1.2 +/- 0.3 hours in the istradefylline group compared with an increase of 0.5 +/- 0.5 hour in the placebo group (p = 0.004). Dyskinesia severity was unchanged, but "on" time with dyskinesia increased in the istradefylline group compared with the placebo group ( percent, p = 0.002; hours, p = 0.001). No differences were observed in change in Unified Parkinson's Disease Rating Scale scores or Clinical Global Impression of Change. Twenty-four percent of placebo-assigned subjects and 20% of istradefylline-assigned subjects withdrew from the study. Both dose regimens of istradefylline were generally well tolerated, and nausea was the most common adverse event. Conclusion: Istradefylline was generally well tolerated and reduced "off" time as assessed by home diaries. Severity of dyskinesia was unchanged, but "on" time with dyskinesia increased.