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Statistical Considerations in the Design of Clinical Trials Targeting Prodromal Parkinson Disease.
Neurology ( IF 9.9 ) Pub Date : 2022-08-16 , DOI: 10.1212/wnl.0000000000200897
Eric A Macklin 1 , Christopher S Coffey 1 , Michael C Brumm 1 , John Peter Seibyl 1
Affiliation  

Clinical trials testing interventions for prodromal Parkinson disease (PD) hold particular promise for preserving neuronal function and thereby slowing or even forestalling progression to overt PD. Selection of the appropriate target population and outcome measures presents challenges unique to prodromal PD. We propose 3 clinical trial designs, spanning phase 2a, phase 2b, and phase 3 development, that might serve as templates for prodromal PD trials. The proposed phase 2a trial is of a 3-arm design of short duration and focuses on proof of concept with respect to target engagement and change in a motor outcome in a subset of prodromal participants who already manifest asymptomatic but measurable motor dysfunction as an exploratory aim. The proposed phase 2b trial suggests progression of dopamine transporter imaging specific binding ratio as a primary outcome evaluated annually over 2 years with phenoconversion to PD as a key secondary outcome. The proposed phase 3 trial is a large, simple design of a nutraceutical or behavioral intervention with remote administration and phenoconversion as the primary outcome. We then consider what additional data are needed in the short term to better design prodromal PD trials and examine what longer-term goals would accelerate discovery of safe and effective therapies for individuals at risk of PD. Clear and potentially context-specific definitions of phenoconversion and validation of intermediate endpoints are needed in the short term. The use of adaptive trial designs, master protocols, and research registries would help accelerate therapy development in the long term.

中文翻译:

针对前驱性帕金森病的临床试验设计中的统计考虑。

测试前驱帕金森病 (PD) 干预措施的临床试验特别有望保护神经元功能,从而减缓甚至阻止进展为明显的 PD。选择适当的目标人群和结果测量是前驱 PD 所特有的挑战。我们提出了 3 种临床试验设计,跨越 2a​​ 期、2b 期和 3 期开发,可作为前驱 PD 试验的模板。拟议的 2a 期试验是一个短期的 3 臂设计,并侧重于在已经表现出无症状但可测量的运动功能障碍的前驱参与者子集中的目标参与和运动结果变化方面的概念证明作为探索性目标. 拟议的 2b 期试验表明,多巴胺转运蛋白成像特异性结合率的进展作为主要结果,每年评估超过 2 年,将表型转化为 PD 作为关键的次要结果。拟议的 3 期试验是一个大型、简单的营养或行为干预设计,以远程管理和 phenoconversion 作为主要结果。然后,我们考虑短期内需要哪些额外数据来更好地设计前驱 PD 试验,并检查哪些长期目标将加速为有 PD 风险的个体发现安全有效的疗法。短期内需要对表型转化和中间终点验证进行明确且可能针对具体情况的定义。使用适应性试验设计、主方案、
更新日期:2022-08-16
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