Research in context
Evidence before this study
Edaravone was discovered and developed as a potential free radical scavenger to reduce oxidative stress. As edaravone showed a protective effect on endothelial and neuronal cells exposed to high oxidative stress in animal models, it was initially developed for treatment of acute ischaemic stroke, and was approved for this indication in Japan in 2001. Animal models suggested potential benefit of edaravone to treat amyotrophic lateral sclerosis (ALS), and an open-label, phase 2 study of edaravone in patients with ALS showed a decreased concentration of an oxidative stress biomarker (3-nitrotyrosine), and a numerical decrease in Revised ALS Functional Rating Scale (ALSFRS-R) scores for 6 months after initiation of edaravone treatment, although this effect was not tested for significance. The first phase 3 study did not show a significant difference in the ALSFRS-R score between patients receiving edaravone and placebo. However, post-hoc analyses of this study identified a subpopulation in which edaravone did show efficacy.
Added value of this study
The safety and efficacy of edaravone were examined in this placebo-controlled, double-blind phase 3 study for patients with ALS who met all of the following criteria identified in post-hoc analyses of the previous phase 3 trial: scores of at least 2 points on all 12 items of ALSFRS-R, forcedvital capacity of at least 80%, definite or probable ALS (El Escorial and revised Airlie House diagnostic criteria), and disease duration of 2 years or less. The primary endpoint, change in ALSFRS-R at 24 weeks, was significantly smaller in the patients receiving edaravone, by comparison with placebo. The results of the secondary endpoints Modified Norris Scale (total) and ALS Assessment Questionnaire (ALSAQ-40), also supported the primary result.
Implications of all the available evidence
In a small, well defined group of patients with early stage ALS, the progression of ALS symptoms was slowed by edaravone. However, the effect of edaravone administration on the long term survival rate, the efficacy of edaravone in a wider population of patients with ALS, and the efficacy in patients with advanced disease were not considered in this study.