Parkinson's Disease and Movement Disorders Center, University of South Florida, National Parkinson Foundation Center of Excellence, Tampa.
Institute of Neurology, L'Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Rome, Italy.
JAMA Neurol. 2015 Dec;72(12):1491-500. doi: 10.1001/jamaneurol.2015.2268.
Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials.
To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations.
DESIGN, SETTING, AND PARTICIPANTS: Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations.
In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio.
The primary outcome measure was change in off time from baseline to week 12.
In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo).
In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials.
clinicaltrials.gov Identifier: NCT01155466 and NCT01227265.
Preladenant 是一种腺苷 2A 受体拮抗剂，在帕金森病（PD）患者的安慰剂对照 2b 期试验中减少了“关闭”时间。我们试图在 3 期试验中证实其疗效。
评估 preladenant 作为左旋多巴治疗 PD 伴运动波动患者的辅助药物。
设计、地点和参与者：这是两项为期 12 周的 3 期、随机、安慰剂对照、双盲试验，于 2010 年 7 月 15 日至 2013 年 4 月 16 日进行。地点包括美国、欧盟、东欧、印度和南非的神经病学诊所、临床研究中心和医院。参与者包括正在服用左旋多巴且伴有运动波动的中重度 PD 患者。
在试验 1 中，共 778 名符合条件的患者随机分为添加 preladenant（2mg、5mg 或 10mg，每日 2 次）、安慰剂或甲磺酸雷沙吉兰（1mg/d）的组，比例为 1:1:1:1:1。在试验 2 中，共 476 名符合条件的患者随机分为添加 preladenant（2mg 或 5mg，每日 2 次）或安慰剂的组，比例为 1:1:1。
主要观察指标是从基线到第 12 周时的关闭时间变化。
在试验 1 中，与安慰剂相比，preladenant 和雷沙吉兰均未显示出能减少从基线到第 12 周的关闭时间。与安慰剂相比，preladenant 2mg 每日 2 次的差异为-0.10 小时（95%CI，-0.69 至 0.46 小时），preladenant 5mg 每日 2 次的差异为-0.20 小时（95%CI，-0.75 至 0.41 小时），preladenant 10mg 每日 2 次的差异为 0.00 小时（95%CI，-0.62 至 0.53 小时），雷沙吉兰甲磺酸 1mg/d 的差异为-0.30 小时（95%CI，-0.90 至 0.26 小时）。在试验 2 中，与安慰剂相比，添加 preladenant 并未显著减少从基线到第 12 周的关闭时间。与安慰剂相比，preladenant 2mg 每日 2 次的差异为-0.20 小时（95%CI，-0.72 至 0.35 小时），preladenant 5mg 每日 2 次的差异为-0.30 小时（95%CI，-0.86 至 0.21 小时）。preladenant 耐受良好，最常见的不良反应是便秘，与安慰剂相比，这两种试验中都有增加（preladenant 为 6%-8%，安慰剂为 1%-3%）。
在这两项 3 期试验中，与安慰剂相比，preladenant 并未显著减少关闭时间。而阳性对照物雷沙吉兰也未能显示出关闭时间的显著减少，这表明研究设计或实施过程中的问题可能影响了这些试验。
clinicaltrials.gov 标识符：NCT01155466 和 NCT01227265。
