Objective: To determine the efficacy of istradefylline combined with levodopa in PD patients experiencing motor fluctuations in a pooled analysis of 4 pivotal, randomized, placebo-controlled studies.

Background: Istradefylline, a selective adenosine A_2A receptor antagonist that acts via the indirect basal ganglia outflow pathway, is indicated in the US as adjunctive treatment to levodopa/carbidopa in adults with PD experiencing OFF episodes. Four 12-week, double-blind, randomized, placebo-controlled, parallel-group, randomized clinical trials were the basis for istradefylline’s FDA approval.

Method: The four 12-week, randomized, placebo-controlled, double-blind phase 2b/3 clinical studies were conducted globally; change in OFF-time in daily patient-completed 24-hour ON/OFF diaries was the primary endpoint. All studies were designed to share common methods. Istradefylline was evaluated in PD patients receiving levodopa with carbidopa or benserazide and having motor fluctuations. Other baseline anti-PD medications could be continued unchanged. Pooled analysis results for once-daily oral istradefylline (20 and 40mg/day) and placebo were evaluated using a mixed-model repeated-measures approach (with study as a factor).

Results: The pooled analysis included 1143 treated patients (placebo, n=420; 20mg, n=347; 40mg, n=376). At week 12, OFF time (hours/day) with 20 and 40mg istradefylline was reduced (LS mean difference from placebo in change from baseline [95%CI], -0.75 [-1.10,-0.40] and ‑0.82 [-1.17,-0.47], respectively). ON time without troublesome dyskinesia (hours/day) increased from baseline with istradefylline compared with placebo (LS mean difference from placebo [95%CI], 20mg, 0.68 [0.31,1.06]; 40mg, 0.69 [0.32,1.07]). Istradefylline was well tolerated and the study completion rate across the 4 studies was 88%-90%. Dyskinesia was the most frequent adverse event (20mg, 15%; 40mg, 17%; placebo, 8%).

Conclusion: Istradefylline acts through an adenosine A_2A receptor-mediated, non-dopaminergic mechanism for PD patients experiencing levodopa-induced motor fluctuations. This pooled analysis of the 4 registrational studies that were the basis of istradefylline’s US approval shows that istradefylline 20 and 40mg/day significantly improved OFF time and ON time without troublesome dyskinesia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-pooled-analysis-of-four-pivotal-randomized-controlled-trials-of-istradefylline-an-adenosine-a2a-receptor-antagonist-efficacy-as-adjunct-to-levodopa-in-parkinsons-disease-pd/