Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial
Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial
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DOI：
10.1016/s1474-4422(11)70012-6
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发表时间：
2011-03-01
期刊：
影响因子：
48
通讯作者：
Wolski, Kenneth
中科院分区：
文献类型：
--
作者：
Hauser, Robert A.;Cantillon, Marc;Wolski, Kenneth
Preladenant是腺苷2A（A（2A））受体拮抗剂。在帕金森氏病的动物模型中，前药单药治疗改善运动功能而不引起运动障碍，并且作为左旋多巴的辅助治疗，它改善运动功能而不使运动障碍恶化。我们的目的是评估preladenant在帕金森病和运动波动的患者谁正在接受左旋多巴和其他antiparkinsoniandrug.Methods的有效性和安全性，在这第2阶段，剂量探索试验，帕金森病患者谁正在接受左旋多巴入组和治疗，在44个网站在15个国家之间，2006年12月，2008年11月。根据申办方计算机生成的区组随机化时间表，使用交互式语音应答系统集中完成治疗分配。患者被分配接受1，2，5，或10毫克口服preladenant每日两次，或匹配的安慰剂12周。患者、研究工作人员、研究者和所有申办方工作人员均对治疗分配设盲。主要结局是通过家庭日记评估的从基线到第12周的平均每日休息时间的变化。疗效分析包括接受至少一剂研究药物并有基线后评估数据的所有患者。该试验在www.example.com注册ClinicalTrials.gov，编号NCT 00406029。结果253名患者随机接受preladenant治疗，（1 mg [n=49]、2 mg [n=49]、5 mg [n=49]、10 mg [n=57]）或安慰剂（n=49），其中234例接受前药治疗（1 mg [n=47]、2 mg [n=48]、5 mg [n=45]、10 mg [n=49]）和安慰剂（n=45）有资格进行疗效分析。与安慰剂组相比，5 mg preladenant组（差异1.0 h，95% CI -2.1至0.0; p=0.0486）和10 mg preladenant组（-1.2 h，-2.2至-0.2; p=0.019）患者从基线至第12周的平均每日休息时间缩短。对于1 mg preladenant（0.2 h，-0.9至1.2; p=0.753）或2 mg preladenant（-0.7 h，-1.7至0.3; p=0.162），与安慰剂相比，平均每日休息时间的变化不显著。与安慰剂组相比，联合前药组最常见的不良事件是帕金森病恶化（22 [11%] vs 4 [9%]），嗜睡（20例[10%] vs 3例[6%]），运动障碍（18 [9%] vs 6 [13%]），恶心（17 [9%] vs 5 [11%]），便秘（15 [8%] vs 1 [2%]），和失眠（15 [8%] vs 4 [9%]）解释5和10毫克preladenant每日两次可能是临床上有用的，以减少帕金森氏病和运动波动患者的休息时间。
Background Preladenant is an adenosine 2A (A(2A)) 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.