Eleanor and Lou Gehrig MDA/ALS Research Center, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Carolinas Neuromuscular/ALS-MDA Center, Joint Commission Disease Specific-Care Certified ALS Center, Department of Neurology, Carolinas Medical Center, Carolinas Healthcare System Neurosciences Institute, University of North Carolina School of Medicine, Charlotte, NC, USA.
Lancet Neurol. 2014 Nov;13(11):1127-1138. doi: 10.1016/S1474-4422(14)70129-2.
Amyotrophic lateral sclerosis (ALS) is one of the most rapidly progressive neurodegenerative diseases of unknown cause. Riluzole is the only drug that slows disease progression. More than 50 randomised controlled trials (RCTs) of proposed disease-modifying drugs have failed to show positive results in the past half-century. In the past decade, at least 18 drugs have been tested in large phase 2 or 3 RCTs, including lithium, which was tested in several RCTs. Potential reasons for the negative results can be classified into three categories: first, issues regarding trial rationale and preclinical study results; second, pharmacological issues; and third, clinical trial design and methodology issues. Clinical trials for stem cell therapy and RCTs targeting pharmacological or non-pharmacological symptomatic treatment in ALS are examples of areas that need novel design strategies. Only through critical analyses of the failed trials can new and important suggestions be identified for the future success of clinical trials in ALS.
肌萎缩侧索硬化症（ALS）是一种病因不明的进行性最快的神经退行性疾病之一。利鲁唑是唯一能减缓疾病进展的药物。在过去的半个世纪里，超过 50 项针对潜在疾病修饰药物的随机对照试验（RCT）都未能显示出积极的结果。在过去的十年中，至少有 18 种药物在大型 2 期或 3 期 RCT 中进行了测试，包括锂，它已在几项 RCT 中进行了测试。阴性结果的潜在原因可以分为三类：第一，与试验原理和临床前研究结果有关的问题；第二，药理学问题；第三，临床试验设计和方法学问题。干细胞治疗的临床试验和针对 ALS 的药理学或非药理学对症治疗的 RCT 是需要新设计策略的领域的例子。只有通过对失败试验的批判性分析，才能为 ALS 临床试验的未来成功提出新的重要建议。
