Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005).
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.


CONCLUSIONS
Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia.
LeWitt
Peter A
PA
Department of Neurology, Henry Ford Hospital, Southfield, MI 48034, USA. palewitt@ameritech.net
Guttman
M
M
Tetrud
James W
JW
Tuite
Paul J
PJ
Mori
Akihisa
A
Chaikin
Philip
P
Sussman
Neil M
NM
D058917:Adenosine A2 Receptor Antagonists; D000368:Aged; D000978:Antiparkinson Agents / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D011687:Purines / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A / Q000502:physiology
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline