From the Institute of Neurology (F.S.), IRCCS San Raffaele, Rome, Italy; Departments of Clinical Pharmacology and Neurosciences (O.R.), Clinical Investigation Center CIC1436, NS-Park Clinical Research Network, NeuroToul Centre of Excellence in Neurodegeneration, INSERM, Toulouse University Hospital and Toulouse University, France; Parkinson's Disease and Movement Disorders Center (R.A.H.), USF Health–Byrd Institute, Tampa, FL; and Merck & Co., Inc. (S.H., A.T., R.C., T.W.H., P.S., C.L., D.M., D.J.H.), Kenilworth, NJ.
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Objective:To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy.Methods:This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving L-dopa or dopamine agonists. Patients with a Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3).Results:The number of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 weeks. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a negative difference indicating improvement vs placebo) were preladenant 2 mg = 2.60 (0.86, 4.30), preladenant 5 mg = 1.30 (−0.41, 2.94), preladenant 10 mg = 0.40 (−1.29, 2.11), and rasagiline 1 mg = 0.30 (−1.35, 2.03). Post hoc analyses did not identify a single causal factor that could explain the finding of a failed trial. Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant 7%, rasagiline 3%, placebo 4%).Conclusions:No evidence supporting the efficacy of preladenant as monotherapy was observed in this phase 3 trial. The lack of efficacy of the active control rasagiline makes it difficult to interpret the results.Clinical trial registration:Clinicaltrials.gov: NCT01155479.Classification of evidence:This study provides Class I evidence that for patients with early PD, preladenant is not effective as monotherapy at the doses studied (2, 5, 10 mg).