Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai, 201203, China.
State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Orphanet J Rare Dis. 2024 Feb 2;19(1):40. doi: 10.1186/s13023-024-03057-5.
Amyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development.
We conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points.
In total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5 months for a disease duration of 9 months, whereas it was 20.0 months for a disease duration of 36 months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100 mg daily), there was an association with a median OS extension of approximately 0.4 months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5 months, and the time to reach a plateau was about 40 months.
The established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.
肌萎缩侧索硬化症（ALS）是一种不可逆的退行性疾病。目前，安慰剂对照随机试验是评估 ALS 治疗药物临床疗效的主要试验设计。本研究旨在建立模型来定量描述 ALS 的病程，探索影响因素，并为 ALS 药物开发提供必要的信息。
我们对评估 ALS 治疗药物的安慰剂对照试验进行了全面的 PubMed 和 Cochrane 图书馆中央登记处检索。从这些试验中，我们提取了安慰剂组参与者的临床和人口统计学特征以及结局数据，包括总生存（OS）和肌萎缩侧索硬化功能评定量表（ALSFRS-R）评分在不同时间点的情况。
共纳入 47 项涉及 6118 名参与者的研究。疾病持续时间和接受利鲁唑治疗的患者比例被确定为影响安慰剂组 OS 的重要因素。具体来说，疾病持续时间为 9 个月时，中位 OS 为 35.5 个月，而疾病持续时间为 36 个月时，中位 OS 为 20.0 个月。此外，接受利鲁唑治疗的患者比例每增加 10%（每天 100mg），中位 OS 延长约 0.4 个月。从基线水平开始，安慰剂组的 ALSFRS-R 评分降至其最大效应的 50%所需的估计时间约为 17.5 个月，达到平台期的时间约为 40 个月。
历史安慰剂组建立的疾病进程模型在 ALS 药物临床开发的决策过程中具有重要价值。它不仅可作为评估单臂试验中受试药物疗效的外部对照，还可作为在小样本临床试验中准确估计安慰剂组疾病进程后验分布的先验信息。
