BackgroundProgressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease‐modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect.ObjectiveThe objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease‐modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS.MethodsTo simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial.ResultsThe sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival.ConclusionsUse of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

中文翻译：

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功能和生存率的联合评估，以证明治疗对进行性核上性麻痹的影响


背景进行性核上性麻痹 （PSP） 是一种罕见且致命的神经退行性疾病，目前尚无疾病缓解治疗方法。最近关于潜在疗法的试验持续时间为 12 个月，由于死亡导致的非随机缺失，这可能不够。更长的持续时间，结合 PSP 评定量表和生存率，可以减少 II 型错误的可能性。选择对疾病改变更敏感的疗效措施可能有助于确定治疗效果。目的本研究的目的是评估模拟 3 期 PSP 试验，评估疾病缓解干预对包括功能 （PSP 评定量表） 和生存率在内的新联合主要终点、功能和生存联合评估 （CAFS） 的影响，并确定 CAFS 的操作特征。方法为了模拟试验人群中的 PSP 进展，我们使用已发表的临床研究数据开发了 PSP 评定量表和生存率模型。这些模型用于定义 CAFS 的操作特征，用于 3 期试验。结果与安慰剂相比，确定的样本量 （N = 384;1：1 随机化） 将提供 >80% 的功效来检测对 CAFS 的显着治疗效果。CAFS 具有良好的操作特性和更高的功效，可以检测 PSP 评定量表上的中等治疗效果。我们提出了一种试验设计，允许在参与者完成 12 个月的治疗后，在预先计划的中期分析中检测潜在的治疗效果，并评估治疗 （≤24 个月） 对生存的影响。结论使用 CAFS 可以为未来疗法的临床益处提供全面而稳健的估计。© 2024 UCB。 由 Wiley Periodicals LLC 代表国际帕金森和运动障碍协会出版的《运动障碍》。