The Lancet Neurology NOVEMBER 01, 2017

Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial

Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group

Bottom Line

This phase 3 randomized controlled trial demonstrated that intravenous edaravone slowed the decline of physical function in a highly specific subgroup of patients with early-stage amyotrophic lateral sclerosis.

Key Findings

1. The primary endpoint, change in ALS Functional Rating Scale-Revised (ALSFRS-R) scores over 24 weeks, favored the edaravone group.

2. Patients receiving edaravone experienced a significantly slower decline in function, with a least-square mean change of -5.01 (SE 0.64) compared to -7.50 (SE 0.66) in the placebo group.

3. The absolute difference in ALSFRS-R score decline between the active treatment and placebo arms was 2.49 points (95% CI, 0.99 to 3.98; P = 0.0013), representing a 33% reduction in the rate of decline.

4. The safety profile was comparable between the edaravone and placebo groups, with no significant differences in the incidence of serious adverse events or deaths.

Study Design

Design

RCT

Double-Blind

Sample

137

Patients

Duration

24 wk

Median

Setting

Multicenter, Japan

Population Patients aged 20-75 years with definite or probable ALS, disease duration ≤2 years, scores on all items of the ALSFRS-R ≥2, and forced vital capacity (FVC) ≥80%.

Intervention 60 mg intravenous edaravone infusion once daily for 14 days followed by a 14-day observation period (Cycle 1), then 60 mg daily for 10 of 14 days in subsequent 28-day cycles (Cycles 2-6).

Comparator Matching intravenous placebo infusions administered according to the same schedule.

Outcome Change in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to the end of the 24-week treatment period.

Study Limitations

• Efficacy was demonstrated only in a tightly defined, post-hoc identified subgroup of patients with early-stage disease, high functional scores, and preserved respiratory function.

• The findings may not be generalizable to the broader, more heterogeneous population of patients with ALS, especially those in later stages of the disease.

• The study was conducted in Japan, which may limit the direct extrapolation of results to diverse international patient populations.

• The 24-week treatment period is relatively short to fully assess the impact of a chronic, slowly progressive neurodegenerative disease.

Clinical Significance

This trial served as the pivotal study for the FDA approval of edaravone in 2017, providing a modest but statistically significant slowing of functional decline in a select population of ALS patients, thus offering a limited therapeutic option in a disease with few effective treatments.

Historical Context

Prior to this trial, several clinical trials for ALS failed to demonstrate efficacy. Earlier Japanese trials of edaravone showed a trend toward benefit, but it was not statistically significant. A post-hoc analysis identified a specific subgroup that appeared to respond; this trial (MCI-186-19) was designed specifically to confirm these findings in that restricted, 'well-defined' early-stage population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the proposed biochemical mechanism of action of edaravone in ALS, and why is this relevant to the 'oxidative stress' theory of neurodegeneration?

Key Response

Edaravone is a potent free radical scavenger and antioxidant. In ALS, the pathophysiology is thought to involve mitochondrial dysfunction and the accumulation of reactive oxygen species (ROS) that cause oxidative damage to motor neurons. By scavenging these radicals, edaravone aims to mitigate oxidative stress-induced cell death, providing a basic science link between its mechanism and the proposed disease pathway.

Resident

The MCI186-19 trial demonstrated efficacy only in a 'well-defined' subgroup of ALS patients. Based on the study's inclusion criteria, which clinical parameters must a resident verify before recommending edaravone to a patient?

Key Response

To match the trial population where benefit was observed, patients should have 'Definite' or 'Probable' ALS (El Escorial criteria), a disease duration of less than 2 years, preserved respiratory function (FVC ≥80%), and a score of at least 2 points on every individual item of the ALSFRS-R. This ensures the patient is in an early stage with relatively preserved function.

Fellow

Contrast the results of the MCI186-19 trial with the earlier MCI186-16 trial. How does the concept of 'clinical enrichment' in trial design explain the different outcomes observed between these two phase 3 studies?

Key Response

The initial trial (MCI186-16) failed to meet its primary endpoint in a broad ALS population. However, post-hoc analysis suggested a benefit in a subgroup with faster progression but high functional capacity. The MCI186-19 trial was designed to prospectively test only this enriched subgroup. This demonstrates that for some ALS therapies, a signal may only be detectable in a 'sweet spot' of disease kinetics where the patient is progressing fast enough to measure change, but has enough functional reserve to respond to treatment.

Attending

Considering the 24-week functional benefit seen in this trial versus the logistics of intravenous administration (10-14 days per month), how do you approach the 'utility' of this drug in practice, and what are the limitations of using ALSFRS-R as a primary endpoint for long-term prognosis?

Key Response

While the 2.49-point difference in ALSFRS-R is statistically significant, its clinical impact on long-term survival or quality of life is debated. Attending-level practice involves balancing the high treatment burden (frequent IV infusions) against modest functional preservation. Furthermore, ALSFRS-R decline does not always correlate linearly with survival, making it difficult to extrapolate this 6-month functional 'slowing' to a definitive life-extending benefit.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of the 'Revised ALS Functional Rating Scale (ALSFRS-R)' as a primary endpoint in this trial. What are the statistical risks of relying on a sum score of ordinal items, and how might a 'joint rank' or 'combined assessment of function and survival (CAFS)' approach alter the interpretation?

Key Response

The ALSFRS-R is a composite of ordinal items, and summing them assumes each point decrease across different domains (e.g., speech vs. walking) is equal, which is not clinically true. Furthermore, functional scales are confounded by mortality; if a patient dies, their score drops to zero, which can skew the mean. A CAFS approach, which ranks survival time and functional decline together, provides a more robust statistical analysis of disease-modifying therapies in fatal neurodegenerative conditions.

Journal Editor

As a reviewer, how would you address the threat to internal validity posed by the 24-week study duration and the high exclusion rate (only ~7-10% of the ALS population met inclusion criteria) regarding the trial's editorial significance?

Key Response

A tough reviewer would flag that while the trial shows efficacy in a 'pure' population, the results are highly restrictive. The short 24-week window may not capture late-emerging adverse events or the eventual 'catch-up' of the placebo group. The primary concern for an editor is whether the study proves edaravone is an effective drug for 'ALS' in general, or merely a niche intervention for a highly specific, early-stage phenotype, which limits the manuscript's broad clinical impact.

Guideline Committee

Should the evidence from the MCI186-19 trial lead to a Grade A recommendation for edaravone in all ALS patients, or should the recommendation be restricted? Reference the alignment of these findings with current AAN or EAN guidelines.

Key Response

Current guidelines (e.g., AAN 2017/2022 updates and EAN) generally give edaravone a Level B or 'conditional' recommendation. The committee must emphasize that the evidence is strongest only for patients meeting the 'MCI186-19 criteria' (early-stage, fast-progressing, preserved FVC). Recommending it for all patients (Level A) would be an over-generalization of the data, as the trial specifically failed to show benefit in the broader, unselected population in the preceding phase 3 study.

Clinical Landscape

Noteworthy Related Trials

1996

Riluzole Phase III Trial

n = 155 · NEJM

Tested

Riluzole 100mg daily

Population

Patients with definite or probable ALS

Comparator

Placebo

Endpoint

Tracheostomy-free survival

Key result: Riluzole extended survival by approximately 3 months compared to placebo.

2017

Edaravone MCI186-19 Phase III Trial

n = 137 · Lancet Neurol

Tested

Edaravone 60mg intravenous infusion

Population

ALS patients with early disease progression and high functional independence

Comparator

Placebo

Endpoint

Change in ALSFRS-R score

Key result: Patients treated with edaravone showed a significantly smaller decline in ALSFRS-R scores over 24 weeks.

2020

CENTAUR Trial

n = 137 · NEJM

Tested

AMX0035 (sodium phenylbutyrate-taurursodiol)

Population

Patients with ALS

Comparator

Placebo

Endpoint

Change in ALS Functional Rating Scale-Revised (ALSFRS-R) score

Key result: The treatment group showed a statistically significant slower rate of decline in ALSFRS-R scores over 24 weeks.

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