Post-hoc analysis of open-label extension period of study MCI186-19 in amyotrophic lateral sclerosis

Abstract

Study MCI186-19 investigated the safety and efficacy of edaravone in the treatment of ALS. The 24-week, double-blind period was followed by a 24-week, open-label, active extension period. Patients originally receiving edaravone continued edaravone (E-E group, n = 65), and patients originally receiving placebo switched to edaravone (P-E group, n = 58). Because no statistical tests had been prospectively planned in the open-label period, we performed post-hoc analyses to assist in the interpretation of efficacy data. A mixed model for repeated measures (MMRM) and the Combined Assessment of Function and Survival (CAFS) were assessed. Additionally, slopes of time-dependent change between baseline in cycle 1 and the end of cycle 6 (24 weeks double-blind) and between the end of cycle 6 and end of cycle 12 (24 weeks open-label) were calculated using a random coefficient model including all available data during each period. At week 48, the MMRM analysis showed significantly less decline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score in the E-E group than in the P-E group (least-squares mean change from baseline ± standard error, 4.17 ± 1.40, p = 0.0037), meaning that the differences in the ALSFRS-R total score during the 24-week double-blind period were maintained in patients receiving edaravone for an additional 24 weeks. The CAFS endpoint (p = 0.0089) supported this finding. The slope analysis during the double-blind period showed a significant difference between the treatment groups, while there was no significant difference between the groups during the active extension period. These analyses suggest a potential benefit of early and continued edaravone treatment over delayed edaravone treatment.