van Eijk Ruben P A, van Loon Floris T, van Unnik Jordi W J, Weemering Daphne N, Seitidis Georgios, Mavridis Dimitris, van den Berg Leonard H, Nikolakopoulos Stavros
Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Biostatistics and Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
J Neurol. 2024 Dec 12;272(1):40. doi: 10.1007/s00415-024-12813-3.
Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.
We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm. Subsequently, we meta-analyzed attrition rates across studies, evaluated the difference between study arms, and explored the impact of study-level characteristics. Finally, a meta-regression model predicting study discontinuation for future clinical trials was translated into a web application.
In total, 60 randomized placebo-controlled clinical trials were included in the meta-analysis, randomizing 14,493 patients with ALS. Attrition varied significantly between studies, ranging from 3.1% to 75.7% of all randomized patients, with a pooled effect of 32.0% (90% prediction interval 6.1% to 66.3%). Attrition was similar between the intervention and placebo arm (odds ratio 1.08, 95% CI 0.89 to 1.31, p = 0.43). The follow-up duration was identified as the sole study-level predictor (0.032, 95% CI 0.026 to 0.039, p < 0.001), resulting in predicted attrition of 19.3% for 6-month, 36.4% for 12-month, and 55.6% for 18-month clinical trials.
ALS clinical trials encounter high attrition, which increases with the follow-up duration. These findings underscore the need to refine our strategies to manage attrition, preserving the integrity and generalizability of ALS clinical trials.
不良事件和疾病进展导致的受试者流失会影响临床试验的完整性和普遍性。本研究旨在通过全面的系统评价和荟萃分析，为肌萎缩侧索硬化症（ALS）临床试验中的受试者流失提供基于证据的估计，并确定与研究相关的预测因素。
我们系统地回顾了文献，以确定所有在ALS中进行的随机、安慰剂对照临床试验，并确定每个随机分组的研究中退出研究的患者数量。随后，我们对各研究的受试者流失率进行了荟萃分析，评估了各研究组之间的差异，并探讨了研究层面特征的影响。最后，将预测未来临床试验中研究中断情况的荟萃回归模型转化为一个网络应用程序。
荟萃分析共纳入了60项随机安慰剂对照临床试验，将14493例ALS患者进行了随机分组。各研究之间的受试者流失情况差异显著，在所有随机分组的患者中，流失率从3.1%到75.7%不等，合并效应为32.0%（90%预测区间为6.1%至66.3%）。干预组和安慰剂组之间的受试者流失情况相似（优势比为1.08，95%置信区间为0.89至1.31，p = 0.43）。随访时间被确定为唯一的研究层面预测因素（0.032，95%置信区间为0.026至0.039，p < 0.001），这导致6个月的临床试验预测受试者流失率为19.3%，12个月的为36.4%，18个月的为55.6%。
ALS临床试验中受试者流失率较高，且随随访时间增加。这些发现强调了改进我们管理受试者流失策略的必要性，以维护ALS临床试验的完整性和普遍性。
