普雷拉登特单药治疗早期帕金森病患者的随机试验。

Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease.

作者信息

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

机构信息

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.

出版信息

Neurology. 2017 Jun 6;88(23):2198-2206. doi: 10.1212/WNL.0000000000004003. Epub 2017 May 10.

DOI:10.1212/WNL.0000000000004003

PMID:28490648

Abstract

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 (UPDRS).

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 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%).

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).

摘要

目的

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。

方法

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。

结果

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%）。