van Eijk Ruben P A, Westeneng Henk-Jan, Nikolakopoulos Stavros, Verhagen Iris E, van Es Michael A, Eijkemans Marinus J C, van den Berg Leonard H
From the Department of Neurology (R.P.A.v.E., H.-J.W., I.E.V., M.A.v.E., L.H.v.d.B.), Brain Center Rudolf Magnus, and Biostatistics & Research Support (R.P.A.v.E., S.N., M.J.C.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands.
Neurology. 2019 Jan 28;92(5):e451-e460. doi: 10.1212/WNL.0000000000006855.
To assess the effect of eligibility criteria on exclusion rates, generalizability, and outcome heterogeneity in amyotrophic lateral sclerosis (ALS) clinical trials and to assess the value of a risk-based inclusion criterion.
A literature search was performed to summarize the eligibility criteria of clinical trials. The extracted criteria were applied to an incidence cohort of 2,904 consecutive patients with ALS to quantify their effects on generalizability and outcome heterogeneity. We evaluated the effect of a risk-based selection approach on trial design using a personalized survival prediction model.
We identified 38 trials. A large variability exists between trials in all patient characteristics for enrolled patients ( < 0.001), except for the proportion of men ( = 0.21). Exclusion rates varied widely (from 14% to 95%; mean 59.8%; 95% confidence interval 52.6%-66.7%). Stratification of the eligible populations into prognostic subgroups showed that eligibility criteria lead to exclusion of patients in all prognostic groups. Eligibility criteria neither reduce heterogeneity in survival time (from 22.0 to 20.5 months, = 0.09) nor affect between-patient variability in functional decline (from 0.62 to 0.65, = 0.25). In none of the 38 trials were the eligibility criteria found to be more efficient than the prediction model in optimizing sample size and eligibility rate.
The majority of patients with ALS are excluded from trial participation, which questions the generalizability of trial results. Eligibility criteria only minimally improve homogeneity in trial endpoints. An individualized risk-based criterion could be used to balance the gains in trial design and loss in generalizability.
评估纳入标准对肌萎缩侧索硬化症（ALS）临床试验中排除率、普遍性及结果异质性的影响，并评估基于风险的纳入标准的价值。
进行文献检索以总结临床试验的纳入标准。将提取的标准应用于2904例连续的ALS发病队列患者，以量化其对普遍性和结果异质性的影响。我们使用个性化生存预测模型评估基于风险的选择方法对试验设计的影响。
我们识别出38项试验。除男性比例外（P = 0.21），各试验中纳入患者的所有患者特征存在很大差异（P < 0.001）。排除率差异很大（从14%至95%；平均59.8%；95%置信区间52.6%-66.7%）。将符合条件的人群分层为预后亚组显示，纳入标准导致所有预后组的患者被排除。纳入标准既未降低生存时间的异质性（从22.0个月降至20.5个月，P = 0.09），也未影响患者功能衰退的个体间变异性（从0.62至0.65，P = 0.25）。在38项试验中，均未发现纳入标准在优化样本量和符合率方面比预测模型更有效。
大多数ALS患者被排除在试验参与之外，这对试验结果的普遍性提出了质疑。纳入标准仅能在极小程度上改善试验终点的同质性。基于个体风险的标准可用于平衡试验设计中的收益和普遍性方面的损失。
