Hauser RA, Hattori N, Fernandez H, Isaacson SH, Mochizuki H, Rascol O, Stocchi F, Li J, Mori A, Nakajima Y, Ristuccia R, and LeWitt P. Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson's Disease: A Pooled Analysis of 8 Phase 2b/3 Trials. J Parkinsons Dis 2021.
J Parkinsons Dis
BACKGROUND: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson's disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor.
OBJECTIVE: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline.
METHODS: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline's FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor.
RESULTS: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], -0.38 h [-0.61, -0.15]) and 40 mg/day (-0.45 h [-0.68, -0.22], p < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, -0.75 h [-1.10, -0.40]; 40 mg/day, -0.82 h [-1.17, -0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%).
CONCLUSION: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.
ePub ahead of print