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.

Abstract

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.

• Authors: Robert A Hauser, Nobutaka Hattori, Hubert Fernandez, Stuart H Isaacson, Hideki Mochizuki, Olivier Rascol, Fabrizio Stocchi, June Li, Akihisa Mori, Yu Nakajima, Robert Ristuccia, Peter LeWitt
• Journal: Journal of Parkinson's disease (J Parkinsons Dis) Vol. 11 Issue 4 Pg. 1663-1675 ( 2021) ISSN: 1877-718X [Electronic] Netherlands
• PMID: 34486986 (Publication Type: Journal Article, Meta-Analysis)

Chemical References

• Adenosine A2 Receptor Antagonists
• Antiparkinson Agents
• Purinergic P1 Receptor Antagonists
• Purines
• Receptor, Adenosine A2A
• istradefylline
• Levodopa

Topics

• Adenosine A2 Receptor Antagonists
• Antiparkinson Agents (adverse effects)
• Double-Blind Method
• Dyskinesias
• Humans
• Levodopa (adverse effects)
• Parkinson Disease (drug therapy)
• Purinergic P1 Receptor Antagonists
• Purines (pharmacology)
• Randomized Controlled Trials as Topic
• Receptor, Adenosine A2A
• Treatment Outcome