依达拉奉，一种腺苷 A2A 受体拮抗剂，作为帕金森病左旋多巴辅助治疗的疗效：8 项 2b/3 期试验的汇总分析。
Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson's Disease: A Pooled Analysis of 8 Phase 2b/3 Trials.
机构信息
Parkinson's Disease and Movement Disorders Center, Department of Neurology, University of South Florida, Tampa, FL, USA.
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
出版信息
J Parkinsons Dis. 2021;11(4):1663-1675. doi: 10.3233/JPD-212672.
BACKGROUND
Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson's disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor.
OBJECTIVE
This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline.
METHODS
Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline's FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor.
RESULTS
Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], -0.38 h [-0.61, -0.15]) and 40 mg/day (-0.45 h [-0.68, -0.22], p < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, -0.75 h [-1.10, -0.40]; 40 mg/day, -0.82 h [-1.17, -0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%).
CONCLUSION
In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.
背景
依曲替酯是一种选择性的腺苷 A2A 受体拮抗剂，用于治疗正在接受左旋多巴/脱羧酶抑制剂治疗的帕金森病（PD）患者出现开期。
目的
本汇总分析了八项随机、安慰剂对照、双盲 2b/3 期研究，评估了依曲替酯的疗效和安全性。
方法
在接受卡比多巴/苄丝肼左旋多巴治疗且出现运动波动的 PD 患者中评估了依曲替酯。进行了八项 12 或 16 周的试验（n=3245）；其中四项研究是依曲替酯获得 FDA 批准的基础。第 12 周时，患者完成的 24 小时 PD 日记中评估的开期时间变化是主要终点。所有研究均采用相同的方法设计，从而允许数据汇总。使用混合模型重复测量方法，包括研究作为因素，评估了每日一次口服依曲替酯（20 和 40mg/天）和安慰剂的汇总分析结果。
结果
在 2719 名患者（安慰剂，n=992；20mg/天，n=848；40mg/天，n=879）中，依曲替酯 20mg/天（LSMD 与安慰剂相比从基线下降[95%CI]，-0.38h[-0.61，-0.15]）和 40mg/天（-0.45h[-0.68，-0.22]）的剂量可减少第 12 周的开期时间，差异具有统计学意义（p<0.0001）；不伴有运动障碍的开期时间显著增加。四项研究的汇总结果也显示了相似的结果（开期时间，20mg/天，-0.75h[-1.10，-0.40]；40mg/天，-0.82h[-1.17，-0.47]）。依曲替酯通常具有良好的耐受性；所有研究中，依曲替酯治疗患者的平均研究完成率为 89.2%。最常见的不良事件是运动障碍（安慰剂，9.6%；20mg/天，16.1%；40mg/天，17.7%）。
结论
在本汇总分析中，与安慰剂相比，依曲替酯显著改善了开期时间和不伴有运动障碍的开期时间，且具有良好的耐受性。
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