Comparative Safety of Istradefylline Among Parkinson’s Disease Adjunctive Therapies: A Systematic Review and Meta-analysis of Randomized Controlled Studies
Yasar Torres-Yaghi1, Joyce Qian2, Hannah Cummings2, Hiroo Shimoda3, Satoru Ito3, Sarah Batson4, Stephen Mitchell4, Fernando Pagan5
1Georgetown University Hospital Dep of Neurology, 2Kyowa Kirin, Inc., 3Kyowa Kirin Co., 4Mtech Access, 5Georgetown University Hospital Dept of Neurology
Objective:
To evaluate the safety of istradefylline vs. other PD adjuncts based on randomized controlled trials (RCTs) available at the time of US approval.
Background:
Istradefylline has demonstrated a significant reduction in “OFF” time when used as an adjunct to levodopa/carbidopa in patients with Parkinson’s Disease (PD).
Design/Methods:
A systematic review (SR) published in 2011 was updated with additional RCTs 1/1/2010-4/15/2019 of dopamine agonists (DAs), catechol-O-methyl transferase (COMT) inhibitors, monoamine oxidase type B (MAO-B) inhibitors, amantadine, and istradefylline as adjuncts to levodopa. Pair-wise meta-analysis and Bucher indirect comparisons were used to generate estimates of relative safety. Results are presented as OR [95% CI].
Results:
Among 64 RCTs eligible for inclusion across the original (n=44) and updated (n=20) SRs, 57 RCTs involving 11,517 patients were included for meta-analysis. Istradefylline data were extracted from clinical study reports. At 40 mg, istradefylline demonstrated significantly lower odds of dyskinesia and somnolence compared to DAs (1.30 [1.01, 1.69] and 2.50 [1.28, 5.00], respectively) and lower odds of hypotension compared to MAO-B inhibitors (8.33 [1.67, 50.00]). At 20 mg, the odds of dyskinesia were significantly lower for istradefylline vs. COMT inhibitors (1.52 [1.09, 2.13]), DAs (1.61 [1.16, 2.22]), and all interventions (1.45 [1.06, 2.00]). Relative to istradefylline, amantadine had significantly increased odds of hallucinations (40mg: 3.57 [1.30, 10.00]; 20mg: 4.76 [1.64, 14.29]) vs. istradefylline at 40 and 20mg, and insomnia and withdrawals due to treatment emergent adverse events (TEAEs) at 20mg (8.33 [1.06, 50.00] and 2.86 [1.18, 6.67], respectively). The odds of overall incidence of TEAEs including constipation, dyskinesia, hallucination, hypotension, insomnia, orthostatic hypotension, and somnolence were significantly lower for istradefylline compared with COMT inhibitors (40mg: 1.33 [1.03, 1.75]; 20mg: 1.32 [1.01, 1.72]) and amantadine (40mg: 3.45 [1.85, 6.25]; 20mg: 3.33 [1.82, 6.25]).
Conclusions:
Istradefylline is associated with a generally favorable safety profile relative to others adjunct medications in this study.