Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson's disease.

BACKGROUND: Preladenant is a selective adenosine A2A receptor antagonist under investigation for Parkinson's disease treatment. METHODS: A phase 2 36-week open-label follow-up of a double-blind study using preladenant 5 mg twice a day as a levodopa adjunct in 140 subjects with fluctuating Parkinson's disease was conducted. The primary end point was adverse event (AE) assessment. Secondary (efficacy) analyses included hours/day spent in OFF and ON states and dyskinesia prevalence/severity. RESULTS: The 36-week open-label phase was completed by 106 of 140 subjects (76%). AE-related treatment discontinuations occurred in 19 subjects (14%). Treatment-emergent AEs, reported by ≥15% of subjects, were dyskinesia (33%) and constipation (19%). Preladenant 5 mg twice a day provided OFF time reductions (1.4-1.9 hours/day) and ON time increases (1.2-1.5 hours/day) throughout the 36-week treatment relative to the baseline of the double-blind study. CONCLUSIONS: Long-term preladenant treatment (5 mg twice a day) was generally well tolerated and provided sustained OFF time reductions and ON time increases.

Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial.

BACKGROUND: Preladenant is an adenosine 2A (A2(A)) receptor antagonist. In animal models of Parkinson's disease, preladenant monotherapy improves motor function without causing dyskinesia and, as an adjunct to levodopa, it improves motor function without worsening dyskinesia. We aimed to assess the efficacy and safety of preladenant in patients with Parkinson's disease and motor fluctuations who were receiving levodopa and other antiparkinsonian drugs. METHODS: In this phase 2, dose-finding trial, patients with Parkinson's disease who were receiving levodopa were enrolled and treated at 44 sites in 15 countries between December, 2006, and November, 2008. Assignment to treatment was done centrally with an interactive voice response system, according to a block randomisation schedule that was computer generated by the sponsor. Patients were assigned to receive 1, 2, 5, or 10 mg oral preladenant twice daily, or matching placebo for 12 weeks. Patients, study staff, investigators, and all sponsor personnel were masked to treatment assignment. The primary outcome was change in mean daily off time from baseline to week 12, as assessed by home diaries. Efficacy analysis included all patients who received at least one dose of study drug and had data for assessments after baseline. This trial is registered with ClinicalTrials.gov, number NCT00406029. FINDINGS: 253 patients were randomised to receive preladenant (1 mg [n=49], 2 mg [n=49], 5 mg [n=49], 10 mg [n=57]) or placebo (n=49), of whom 234 on preladenant (1 mg [n=47], 2 mg [n=48], 5 mg [n=45], 10 mg [n=49]) and placebo (n=45) were eligible for the efficacy analysis. Mean daily off time from baseline to week 12 was reduced versus placebo in patients on 5 mg preladenant (difference -1·0 h, 95% CI -2·1 to 0·0; p=0·0486) and 10 mg preladenant (-1·2 h, -2·2 to -0·2; p=0·019). Changes in mean daily off time versus placebo were not significant for 1 mg preladenant (0·2 h, -0·9 to 1·2; p=0·753) or 2 mg preladenant (-0·7 h, -1·7 to 0·3; p=0·162). The most common adverse events in the combined preladenant group versus placebo were worsening of Parkinson's disease (22 [11%] vs 4 [9%]), somnolence (20 [10%] vs 3 [6%]), dyskinesia (18 [9%] vs 6 [13%]), nausea (17 [9%] vs 5 [11%]), constipation (15 [8%] vs 1 [2%]), and insomnia (15 [8%] vs 4 [9%]). INTERPRETATION: 5 and 10 mg preladenant twice daily might be clinically useful to reduce off time in patients with Parkinson's disease and motor fluctuations. FUNDING: Schering-Plough, a subsidiary of Merck.