Post-hoc analysis of randomised, placebo-controlled, double-blind study (MCI186-19) of edaravone (MCI-186) in amyotrophic lateral sclerosis

Abstract

Post-hoc analyses of the ALS Functional Rating Scale-Revised (ALSFRS-R) score data, the primary endpoint in the 24-week double-blind placebo-controlled study of edaravone (MCI186-19, NCT01492686), were performed to confirm statistical robustness of the result. The previously reported original analysis had used a last observation carried forward (LOCF) method and also excluded patients with fewer than three completed treatment cycles. The post-hoc sensitivity analyses used different statistical methods as follows: 1) including all patients regardless of treatment cycles received (ALL LOCF); 2) a mixed model for repeated measurements (MMRM) analysis; and 3) the Combined Assessment of Function and Survival (CAFS) endpoint. Findings were consistent with the original primary analysis in showing superiority of edaravone over placebo. We also investigated the distribution of change in ALSFRS-R total score across all patients in the study as well as which ALSFRS-R items and domains may have contributed to the overall efficacy findings. The distribution of changes in ALSFRS-R total score from baseline to the end of cycle 6 (ALL LOCF) shifted in favour of edaravone compared to placebo. Edaravone was descriptively favoured for each ALSFRS-R item and each of the four ALSFRS-R domains at the end of cycle 6 (ALL LOCF), suggesting a generalised effect of edaravone in slowing functional decline across all anatomical regions. The effect of edaravone appeared to be similar in patients with bulbar onset and limb onset. Together, these observations would be consistent with its putative neuroprotective effects against the development of oxidative damage unspecific to anatomical regions.

Keywords:

• Amyotrophic lateral sclerosis
• edaravone
• double-blind
• study MCI186-19
• post-hoc

Acknowledgements

We thank David Hartree under contract with Mitsubishi Tanabe Pharma America, Inc. for medical writing assistance during second and subsequent drafts of the manuscript. We thank David Schoenfeld of Massachusetts General Hospital for statistical advice on MMRM for sensitivity analysis and Benjamin Rix Brooks of Carolinas HealthCare System for advice for subdomain analysis.

Declaration of interest

Mr. Takahashi is an employee of Mitsubishi Tanabe Pharma Corporation (MTPC). Mr. Takei, Dr. Liu, Ms. Tsuda are employees of Mitsubishi Tanabe Pharma Development America (MTDA). Dr. Palumbo is an employee of MTPC and MTDA. The edaravone (MCI-186) clinical trials were funded by Mitsubishi Tanabe Pharma Corporation. The ALSFTD supplement, Edaravone (MCI-186) in amyotrophic lateral sclerosis (ALS), was funded by Mitsubishi Tanabe Pharma America, Inc. The authors alone are responsible for the content of this paper.