BACKGROUND AND OBJECTIVES Disease-modifying treatments (DMTs) are a major unmet need in Parkinson disease (PD). To date, trials investigating DMT candidates in PD most often used a randomized controlled trial (RCT) design. Unfortunately, RCTs to date have not led to a breakthrough, in part because of the large sample sizes and length of follow-up required. In the interest of testing DMT candidates in a more efficient manner, it may be worthwhile to perform futility trials, which are smaller clinical trials that have originally been developed as phase 2 trials in oncology and more recently been used in progressive multiple sclerosis. In this investigation, we used original, patient-level data from DATATOP and PRECEPT, 2 large RCTs in early PD, to explore the feasibility of using the Simon 2-Stage futility trial design in early PD. METHODS This is a post hoc analysis of original, patient-level data from the DATATOP and PRECEPT RCTs in early PD. In our analyses, we use descriptive statistics, survival analysis, and binary logistic regression to explore thresholds of change in the Unified Parkinson Disease Rating Scale (UPDRS) motor score as the primary outcome measure, length of follow-up, inclusion and exclusion criteria, and projected sample sizes for Simon 2-Stage futility trials in early PD. We also performed bootstrapping experiments to illustrate the ability of trials using the Simon 2-Stage futility design to identify selegiline as nonfutile and tocopherol as futile. RESULTS PRECEPT included 806 participants (mean age 59.7 years, SD 10.3, 64.4% male), and DATATOP included 800 participants (mean age 61.1 years, SD 9.5, 64.4% male). Our analyses suggest that futility trials using the Simon 2-Stage methodology are feasible in PD. We propose a 5-point worsening on the UPDRS motor score as the primary outcome measure and a length of follow-up of 12 months. Trial simulations based on these data suggest the required sample size for such clinical trials to be lower than 200 participants. DISCUSSION Based on our analysis of DATATOP and PRECEPT, phase 2 clinical trials using the Simon 2-Stage methodology are feasible in PD and may offer an opportunity to expedite the discovery of promising treatments in early PD.

中文翻译：

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Simon 2 阶段无效试验在早期帕金森病中的可行性：PRECEPT 和 DATATOP 试验数据集的分析。


背景和目标 疾病修饰治疗 （DMT） 是帕金森病 （PD） 中未满足的主要需求。迄今为止，调查 PD 中 DMT 候选者的试验最常使用随机对照试验 （RCT） 设计。不幸的是，迄今为止的 RCT 尚未取得突破，部分原因是样本量大且需要的随访时间长。为了以更有效的方式测试 DMT 候选药物，进行无效试验可能是值得的，这些试验是较小的临床试验，最初是作为肿瘤学 2 期试验开发的，最近被用于进行性多发性硬化症。在这项调查中，我们使用了来自 DATATOP 和 PRECEPT 的原始患者水平数据，这两项大型 RCT 治疗早期 PD，以探索在早期 PD 中使用 Simon 2 期无效试验设计的可行性。方法 这是对来自 DATATOP 和 PRECEPT RCT 的原始患者水平数据进行早期 PD 的事后分析。在我们的分析中，我们使用描述性统计、生存分析和二元逻辑回归来探索统一帕金森病评定量表 （UPDRS） 运动评分的变化阈值作为主要结果指标、随访时间、纳入和排除标准，以及早期 PD 中 Simon 2 期徒劳试验的预计样本量。我们还进行了自举实验，以说明使用 Simon 2 阶段无效设计的试验的能力，以确定司来吉兰是无用的，而生育酚是无用的。结果 PRECEPT 包括 806 名参与者 （平均年龄 59.7 岁，SD 10.3,64.4% 为男性），DATATOP 包括 800 名参与者 （平均年龄 61.1 岁，SD 9.5,64.4% 为男性）。我们的分析表明，使用 Simon 2 阶段方法的无效试验在 PD 中是可行的。 我们建议将 UPDRS 运动评分恶化 5 分作为主要结果指标，随访时间为 12 个月。基于这些数据的试验模拟表明，此类临床试验所需的样本量应低于 200 名参与者。讨论 根据我们对 DATATOP 和 PRECEPT 的分析，使用 Simon 2 阶段方法的 2 期临床试验在 PD 中是可行的，并且可能为加快发现早期 PD 中有前途的治疗方法提供机会。