Stocchi Fabrizio, Rascol Olivier, Hauser Robert A, Huyck Susan, Tzontcheva Anjela, Capece Rachel, Ho Tony W, Sklar Peter, Lines Christopher, Michelson David, Hewitt David J
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.
Neurology. 2017 Jun 6;88(23):2198-2206. doi: 10.1212/WNL.0000000000004003. Epub 2017 May 10.
To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy.
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 (UPDRS).
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 UPDRS 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%).
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.
Clinicaltrials.gov: NCT01155479.
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).
评估腺苷2A受体拮抗剂普雷拉登特作为一种非多巴胺能药物单药治疗帕金森病（PD）的效果。
这是一项随机、为期26周、安慰剂对照和活性药物对照、平行组、多中心、双盲试验，纳入诊断为PD且病程<5年、尚未接受左旋多巴或多巴胺激动剂治疗的成年人。统一帕金森病评定量表（UPDRS）第3部分（运动功能）评分≥10且霍恩&亚尔分级≤3的患者按1:1:1:1:1随机分组，分别接受每日2次、每次2mg、5mg或10mg的普雷拉登特，每日1次、每次1mg的雷沙吉兰（活性对照药），或安慰剂治疗。主要终点是第26周时UPDRS第2部分（日常生活活动）和第3部分评分总和相对于基线的变化。
共治疗1007例患者。26周后，普雷拉登特和雷沙吉兰均不优于安慰剂。与安慰剂相比，UPDRS评分的差异（95%置信区间）为：2mg普雷拉登特=2.60（0.86，4.30），5mg普雷拉登特=1.30（-0.41，2.94），10mg普雷拉登特=0.40（-1.29，2.11），1mg雷沙吉兰=0.30（-1.35，2.03）。事后分析未发现单一因果因素可解释试验失败的结果。普雷拉登特总体耐受性良好，因不良事件停药的患者较少（普雷拉登特7%，雷沙吉兰3%，安慰剂4%）。
在这项3期试验中，未观察到支持普雷拉登特单药治疗有效性的证据。活性对照药雷沙吉兰缺乏疗效使得难以解释结果。
Clinicaltrials.gov：NCT01155479。
本研究提供I级证据，表明对于早期PD患者，在所研究剂量（2mg、5mg、10mg）下，普雷拉登特单药治疗无效。
