Spinal Cord Injury Center, 31031Balgrist University Hospital, Zurich, Switzerland.
ETH Zurich, Zurich, Switzerland.
Neurorehabil Neural Repair. 2022 Apr;36(4-5):274-285. doi: 10.1177/15459683221078302. Epub 2022 Feb 14.
New therapeutic approaches in neurological disorders are progressing into clinical development. Past failures in translational research have underlined the critical importance of selecting appropriate inclusion criteria and primary outcomes. Narrow inclusion criteria provide sensitivity, but increase trial duration and cost to the point of infeasibility, while broader requirements amplify confounding, increasing the risk of trial failure. This dilemma is perhaps most pronounced in spinal cord injury (SCI), but applies to all neurological disorders with low frequency and/or heterogeneous clinical manifestations.
Stratification of homogeneous patient cohorts to enable the design of clinical trials with broad inclusion criteria.
Prospectively-gathered data from patients with acute cervical SCI were analysed using an unbiased recursive partitioning conditional inference tree (URP-CTREE) approach. Performance in the 6-minute walk test at 6 months after injury was classified based on standardized neurological assessments within the first 15 days of injury. Functional and neurological outcomes were tracked throughout rehabilitation up to 6 months after injury.
URP-CTREE identified homogeneous outcome cohorts in a study group of 309 SCI patients. These cohorts were validated by an internal, yet independent, validation group of 172 patients. The study group cohorts identified demonstrated distinct recovery profiles throughout rehabilitation. The baseline characteristics of the analysed groups were compared to a reference group of 477 patients.
URP-CTREE enables inclusive trial design by revealing the distribution of outcome cohorts, discerning distinct recovery profiles and projecting potential patient enrolment by providing estimates of the relative frequencies of cohorts to improve the design of clinical trials in SCI and beyond.
在神经紊乱疾病的治疗方法中，新方法正在进入临床开发阶段。过去在转化研究中的失败强调了选择适当的纳入标准和主要结果的关键重要性。狭窄的纳入标准提高了试验的敏感性，但会增加试验的持续时间和成本，导致不可行性，而更广泛的要求会放大混杂因素，增加试验失败的风险。这种困境在脊髓损伤（SCI）中最为明显，但也适用于所有频率低和/或临床表现异质性的神经紊乱疾病。
对同质患者队列进行分层，以便能够设计具有广泛纳入标准的临床试验。
使用无偏递归分区条件推断树（URP-CTREE）方法分析急性颈段 SCI 患者的前瞻性收集数据。根据损伤后 15 天内的标准化神经评估，对损伤后 6 个月的 6 分钟步行测试的表现进行分类。在损伤后 6 个月的康复过程中，跟踪功能和神经学结果。
URP-CTREE 在 309 例 SCI 患者的研究组中确定了同质的结果队列。这些队列通过内部的、独立的 172 例患者验证组进行验证。研究组队列的分析结果表明，在康复过程中存在明显的恢复模式。分析组的基线特征与 477 例患者的参考组进行了比较。
URP-CTREE 通过揭示结果队列的分布、辨别不同的恢复模式以及通过提供队列的相对频率估计来预测潜在的患者入组，从而为改善 SCI 及其他神经紊乱疾病的临床试验设计提供了包容性的试验设计方法。
