Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients

Abstract

nOur objective was to confirm the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients. We conducted a 36-week confirmatory study, consisting of 12-week pre-observation period followed by 24-week treatment period. Patients received placebo or edaravone i.v. infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6. The efficacy primary endpoint was changed in the revised ALS functional rating scale (ALSFRS-R) scores during the 24-week treatment. Patients were treated with placebo (n = 104) and edaravone (n = 102). Changes in ALSFRS-R during the 24-week treatment were −6.35 ± 0.84 in the placebo group (n = 99) and −5.70 ± 0.85 in the edaravone group (n = 100), with a difference of 0.65 ± 0.78 (p = 0.411). Adverse events amounted to 88.5% (92/104) in the placebo group and 89.2% (91/102) in the edaravone group. In conclusion, the reduction of ALSFRS-R was smaller in the edaravone group than in the placebo group, but efficacy of edaravone for treatment of ALS was not demonstrated. Levels and frequencies of reported adverse events were similar in the two groups.

Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection

“…A second phase II RCT (NCT00330681)141 revealed similar results (proportion serious adverse events between arms: 23.1% placebo; 17.6% edaravone). Efficacy was not demonstrated in this small study.…”

“…A phase III RCT was done in 206 patients (Clinicaltrials.gov ID: NCT01492686). Once-daily intravenous edaravone (60 mg) showed a trend toward decreased deterioration in the ALSFRS-R scores over 24-weeks141 . The occurrence of adverse events was similar between groups.…”

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

“…It is characterized by the selective and gradual degeneration of motor neurons in the brain and spinal cord, leading to death 2–3 years after disease onset. The only medications available for ALS are riluzole, increasing life expectancy by only about 3 months [9], and edaravone [10], which has recently been approved by the FDA [11]. The most common mutation identified in ALS is the dynamic (GGGGCC) n hexanucleotide repeat expansion in the C9orf72 core promotor lying upstream of the coding region, which has also been shown to cause frontotemporal dementia (FTD) [12, 13].…”

A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies

“…Taken in context, these studies show that edaravone protects astrocytes, oligodendrocytes, and endothelial cells from oxidative stress damage (10,11). Furthermore, clinical studies have suggested edaravone can slow the progression of disability in patients with ALS (12)(13)(14).…”

“…Studies MCI186-16 and MCI186-19 were conducted in patients with grade 1 or grade 2 ALS severity, whereas patients in MCI186-18 had grade 3 ALS severity. Safety results for the three studies have been previously published (13)(14)(15). All three studies were conducted in compliance with the Japanese Ministerial Ordinance on Good Clinical Practice and in accordance with the ethics principles of the Declaration of Helsinki, and all patients gave written informed consent.…”