A 24-Week, Phase III, Double-Blind, Parallel-Group Study of Edaravone (MCI-186) for Treatment of Amyotrophic Lateral Sclerosis (ALS) (P3.189)

Objective:To investigate the efficacy and safety of edaravone versus placebo in a more narrowly defined population of patients (Edaravone MCI-186-J19/NCT01492686), intended to replicate the findings of a previous post hoc analysis. Background:The efficacy of edaravone was previously evaluated in a randomized placebo controlled phase III study (Abe K et al. Amyotroph Lateral Scler Frontotemporal Degener 2014; 15: 610-7). This study did not demonstrate efficacy versus placebo of edaravone as an investigative treatment for ALS, but hypothesis-driven post hoc analyses suggested an opportunity to demonstrate efficacy in a more narrowly defined patient population. Design/Methods: 137 patients were randomized 1:1 to receive edaravone or placebo following a 12-week pre-observation period. Selection criteria included: Definite or Probable ALS (El Escorial/revised Airlie House); Japan ALS severity classification grade<3; scoring≥2 points on each single ALSFRS-R item at screening; [percnt] forced vital capacity≥80[percnt]; and ALS duration≤2 years. Treatment consisted of 6 cycles of 60-mg edaravone/matching placebo treatment. Primary efficacy endpoint was change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at week 24. Secondary endpoints included change in ALS Assessment Questionnaire (ALSAQ40) scores. Safety endpoints included adverse events (AEs) and laboratory tests. Results:Mean change (±SE) in ALSFRS-R score was -7.50±0.66 (placebo) and -5.01±0.64 (edaravone): a between group difference of 2.49±0.76 (P=0.001). Between group difference for ALSAQ40 was -8.79±4.03 (P=0.031). Both groups showed similar AE incidence (84.1[percnt] edaravone, 83.8[percnt] placebo). Incidence of serious AEs was 15.9[percnt] (edaravone) and 23.5[percnt] (placebo). The most common AEs were contusion, and dysphagia (16[percnt] and 13[percnt] of patients, respectively). Incidence of adverse drug reactions (ADRs) was 2.9[percnt] (edaravone) and 7.4[percnt] (placebo). There were no serious ADRs and no AEs that lead to death. Conclusion:Edaravone treated ALS patients meeting the protocol inclusion criteria had less functional loss at 6 months, and had less quality of life deterioration compared to those receiving standard of care.