The Edaravone (MCI-186) ALS 19 Study Group reported on the safety and efficacy of edaravone in a phase 3 study of patients with earlystage amyotrophic lateral sclerosis. The primary endpoint was change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores from baseline to 24 weeks after randomisation. Before randomisation, patients entered a 12-week observation period, and those patients with a decrease in ALSFRS-R score of 1–4 points were randomly assigned to receive edaravone or placebo. T h e i m p l e m e n t a t i o n a n d methodology of the trial, as described in this Article, raise several questions. What was the rationale for selecting patients with a decrease in ALSFRS-R score of 1–4 points? In the legend of figure 2, the authors state that ”one patient’s evaluation at the end of cycle 2 was excluded from analysis as the clinician assessing ALSFRS-R score did not have adequate training”. It is difficult to judge what effect such data censoring might have had on the final outcome (ie, whether this data point corresponds to an outlier). This statement implies that a patient could be assessed by different clinicians throughout the study, thereby introducing inter-rater variability further to the inherent intra-rater variability. It is unclear whether censoring followed consistent rules, which criteria were used to determine whether the clinician was adequately trained, and if the training was certified. Providing information about the protocol of the trial might help to answer these questions. Another point that is worthy of discussion is the difference in the rate of decline in ALSFRS-R scores of the placebo group between the lead-in and treatment phases. During the lead-in period, most participants in the placebo group had a disease progression of 1–2 points decrease in ALSFRS-R scores; however, during the treatment phase, patients in the placebo group had a mean change of 7·5 points. This rapid acceleration of disease progression seems surprising, even though the treatment period was 24 weeks and the observational period included only 12 weeks, because of the average decline in terms of points per month.

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肥胖与神经系统：更多问题

依达拉奉 (MCI-186) ALS 19 研究组报告了依达拉奉在早期肌萎缩侧索硬化患者的 3 期研究中的安全性和有效性。主要终点是修订版肌萎缩侧索硬化功能评定量表 (ALSFRS-R) 评分从基线到随机化后 24 周的变化。随机化前，患者进入 12 周观察期，ALSFRS-R 评分下降 1-4 分的患者被随机分配接受依达拉奉或安慰剂治疗。如本文所述，试验的实施和方法提出了几个问题。选择 ALSFRS-R 评分降低 1-4 分的患者的基本原理是什么？在图2的图例中，作者指出，“由于评估 ALSFRS-R 评分的临床医生没有接受足够的培训，因此将第 2 周期结束时的一名患者的评估排除在分析之外”。很难判断这种数据审查可能对最终结果产生什么影响（即，该数据点是否对应于异常值）。该声明意味着患者可以在整个研究过程中由不同的临床医生进行评估，从而进一步引入评分者间的变异性，以进一步了解固有的评分者内变异性。目前尚不清楚审查是否遵循一致的规则，使用哪些标准来确定临床医生是否接受过充分培训，以及培训是否经过认证。提供有关试验方案的信息可能有助于回答这些问题。另一个值得讨论的点是安慰剂组在导入期和治疗期之间 ALSFRS-R 评分下降率的差异。在导入期间，安慰剂组的大多数参与者的 ALSFRS-R 评分的疾病进展降低了 1-2 分；然而，在治疗阶段，安慰剂组患者的平均变化为 7·5 分。这种疾病进展的快速加速似乎令人惊讶，即使治疗期为 24 周，观察期仅包括 12 周，因为每个月的得分平均下降。然而，在治疗阶段，安慰剂组患者的平均变化为 7·5 分。这种疾病进展的快速加速似乎令人惊讶，即使治疗期为 24 周，观察期仅包括 12 周，因为每个月的得分平均下降。然而，在治疗阶段，安慰剂组患者的平均变化为 7·5 分。这种疾病进展的快速加速似乎令人惊讶，即使治疗期为 24 周，观察期仅包括 12 周，因为每个月的得分平均下降。