Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD.
OBJECTIVE
To evaluate the safety and efficacy of the adenosine A(2A) receptor antagonist istradefylline (KW-6002) 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.


CONCLUSIONS
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.
Hauser
Robert A
RA
Department of Neurology, University of South Florida, and Tampa General Healthcare, 33606, USA. rhauser@hsc.usf.edu
Hubble
Jean P
JP
Truong
Daniel D
DD
D058917:Adenosine A2 Receptor Antagonists; D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D065098:Catechol O-Methyltransferase Inhibitors; D002908:Chronic Disease; D018491:Dopamine Agonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage; D008297:Male; D009325:Nausea / Q000139:chemically induced; D010300:Parkinson Disease / Q000188:drug therapy*; D011687:Purines / Q000009:adverse effects / Q000627:therapeutic use*; D012449:Safety; D012642:Selegiline / Q000008:administration & dosage; D016896:Treatment Outcome
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D011687:Purines; C111599:istradefylline; D012642:Selegiline; D007980:Levodopa