Tornese Paolo, Lalli Stefania, Cocco Antoniangela, Albanese Alberto
Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Italy
J Neurol Neurosurg Psychiatry. 2022 May;93(5):521-529. doi: 10.1136/jnnp-2021-328470. Epub 2022 Feb 28.
We analysed clinical trials of pharmacological interventions on patients with amyotrophic lateral sclerosis (ALS), and compared study quality and design features. The systematic review included articles published in PubMed and trials registered in ClinicalTrials.gov. Included studies were randomised double-blind placebo-controlled clinical trials assessing a disease-modifying pharmacological intervention. Studies were excluded if primary end points were safety or dose finding. A total of 28 735 articles and 721 current trials were identified. 76 published articles and 23 ongoing trials met inclusion criteria; they referred to distinct populations comprising 22 817 participants with ALS. Most articles and all current trials had parallel group design; few articles had cross-over design. A run-in observation period was included in about 20% of published studies and ongoing trials. Primary end points included functional assessment, survival, muscle strength, respiratory function, biomarkers and composite measures. Most recent trials had only functional assessment and survival. Risk of bias was high in 23 articles, moderate in 35, low in 18. A disease modification effect was observed for 10 interventions in phase II studies, two of which were confirmed in phase III. Three confirmatory phase III studies are currently underway. The present review provides cues for the design of future trials. Functional decline and survival, as single or composite measures, stand as the reference end points. Post hoc analyses should not be performed, particularly in studies using composite end points. There is a general agreement on diagnostic criteria; but eligibility criteria must be improved. Run-in observations may be used for censoring patients but are discouraged for refining participants' eligibility. The ALS Functional Rating Scale-Revised needs improvement for use as an ordinal measure of functional decline.
我们分析了针对肌萎缩侧索硬化症（ALS）患者的药物干预临床试验，并比较了研究质量和设计特点。系统评价纳入了发表于PubMed的文章以及在ClinicalTrials.gov注册的试验。纳入的研究为评估疾病修饰性药物干预的随机双盲安慰剂对照临床试验。如果主要终点是安全性或剂量探索，则排除相关研究。共识别出28735篇文章和721项当前试验。76篇已发表文章和23项正在进行的试验符合纳入标准；它们涉及不同人群，包括22817名ALS参与者。大多数文章和所有当前试验采用平行组设计；少数文章采用交叉设计。约20%的已发表研究和正在进行的试验纳入了导入观察期。主要终点包括功能评估、生存、肌肉力量、呼吸功能、生物标志物和综合指标。最近的试验仅包括功能评估和生存。23篇文章存在高偏倚风险，35篇为中度，18篇为低度。在II期研究中，10种干预措施观察到疾病修饰效应，其中两种在III期得到证实。目前正在进行三项确证性III期研究。本综述为未来试验的设计提供了线索。功能衰退和生存作为单一或综合指标，应作为参考终点。不应进行事后分析，尤其是在使用综合终点的研究中。在诊断标准上已达成普遍共识；但纳入标准必须改进。导入观察可用于剔除患者，但不鼓励用于细化参与者的纳入标准。修订后的ALS功能评定量表在用作功能衰退的序贯测量方面需要改进。
