Elsevier

The Lancet Neurology

Volume 16, Issue 7, July 2017, Pages 505-512
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(17)30115-1Get rights and content

Summary

Background

In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria.

Methods

In this phase 3, randomised, double-blind, parallel-group study, patients aged 20–75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1–4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686.

Findings

Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was −5·01 (SE 0·64) in the edavarone group and −7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99–3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal.

Interpretation

Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.

Funding

Mitsubishi Tanabe Pharma Corporation.

Introduction

The cause of amyotrophic lateral sclerosis (ALS) remains unknown, except for familial forms of ALS including those caused by mutations in SOD11 or C9orf72.2, 3 However, oxidative stress caused by free radicals might be an essential factor in the progression of the disease, being involved not only in motor neuron degeneration, but also in glial and endothelial cell dysfunctions.4, 5 Oxidative stress biomarkers (3-nitrotyrosine, coenzyme Q10, 8-hydroxydeoxyguanosine, and 4-hydroxy-2,3-nonenal) are higher in people with ALS than in people without,6, 7, 8, 9, 10 and as ALS progresses, nutritional deficiency, cachexia, and psychological stress might also contribute to increased oxidative stress biomarkers.4 Edaravone (also known as MCI-186), a free-radical scavenger of peroxyl radicals and peroxynitrite, has been shown to inhibit motor neuron death in animal models by reducing oxidative stress.11, 12, 13 Therefore, edaravone might work in a similar way to ameliorate the disease progression of ALS. Edaravone has been given to 1·7 million patients with acute ischaemic stroke in Japan since 2001 for improvement of neurological symptoms, disruption of daily activities, and functional impairment associated with acute ischaemic stroke.14

Research in context

Evidence before this study

Edaravone was discovered and developed as a potential free radical scavenger to reduce oxidative stress. As edaravone showed a protective effect on endothelial and neuronal cells exposed to high oxidative stress in animal models, it was initially developed for treatment of acute ischaemic stroke, and was approved for this indication in Japan in 2001. Animal models suggested potential benefit of edaravone to treat amyotrophic lateral sclerosis (ALS), and an open-label, phase 2 study of edaravone in patients with ALS showed a decreased concentration of an oxidative stress biomarker (3-nitrotyrosine), and a numerical decrease in Revised ALS Functional Rating Scale (ALSFRS-R) scores for 6 months after initiation of edaravone treatment, although this effect was not tested for significance. The first phase 3 study did not show a significant difference in the ALSFRS-R score between patients receiving edaravone and placebo. However, post-hoc analyses of this study identified a subpopulation in which edaravone did show efficacy.

Added value of this study

The safety and efficacy of edaravone were examined in this placebo-controlled, double-blind phase 3 study for patients with ALS who met all of the following criteria identified in post-hoc analyses of the previous phase 3 trial: scores of at least 2 points on all 12 items of ALSFRS-R, forcedvital capacity of at least 80%, definite or probable ALS (El Escorial and revised Airlie House diagnostic criteria), and disease duration of 2 years or less. The primary endpoint, change in ALSFRS-R at 24 weeks, was significantly smaller in the patients receiving edaravone, by comparison with placebo. The results of the secondary endpoints Modified Norris Scale (total) and ALS Assessment Questionnaire (ALSAQ-40), also supported the primary result.

Implications of all the available evidence

In a small, well defined group of patients with early stage ALS, the progression of ALS symptoms was slowed by edaravone. However, the effect of edaravone administration on the long term survival rate, the efficacy of edaravone in a wider population of patients with ALS, and the efficacy in patients with advanced disease were not considered in this study.

In an open-label phase 2 study of edaravone in patients with ALS, the change in Revised ALS Functional Rating Scale (ALSFRS-R) score15, 16 was significantly less during the 6 month treatment period with 60 mg edaravone compared with the 6 months before the start of edaravone.17 The concentration of 3-nitrotyrosine was low in the CSF of almost all patients in the phase 2 study, suggesting that edaravone might protect neuronal cells from oxidative stress in this population.17 Based on these findings, the first placebo-controlled phase 3 study of edaravone was done over 24 weeks of treatment. However, there was no significant difference in the primary endpoint of ALSFRS-R score for patients receiving edaravone compared with placebo.18 With the aim of finding out whether there is a subgroup of patients with ALS in whom edaravone might be effective in slowing disease progression, we did a post-hoc analysis that suggested a potential benefit of edaravone in patients with scores of 2 or more on all items of ALSFRS-R, forced vital capacity (FVC) of at least 80% at baseline, definite or probable ALS (El Escorial and revised Airlie House criteria19), and disease duration of 2 years or less. Since post-hoc analyses of clinical studies have limitations in their interpretability, in this phase 3 study we assessed safety and efficacy of edaravone in a prospectively defined population of patients meeting all these criteria.

Section snippets

Study design and participants

We did a randomised, double-blind, parallel-group, placebo-controlled study in patients recruited from 31 hospitals in Japan. Eligible patients were aged 20–75 years with a diagnosis of ALS with independent living status (grade 1 or 2 in the Japan ALS Severity Classification18) confirmed by local clinicians at time of enrolment, and decrease in the ALSFRS-R score of 1–4 during a 12-week observation period. Based on the post-hoc analysis findings of the first phase 3 study, eligible patients

Results

Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, 137 of whom completed the observation period and were randomly assigned to receive edaravone (n=69) or placebo (n=68; figure 1). Two patients in the edaravone group and eight patients in the placebo group discontinued the study in accordance with discontinuation criteria before completion of cycle 6. One patient in the edaravone group and two patients in the placebo group did not reach the end of cycle 3, so 134 patients were

Discussion

In this phase 3 study, the difference in the ALSFRS-R score was significant after treatment with edaravone compared with placebo in a well defined population of patients with ALS. The results of post-hoc analyses using ANOVA with LOCF using all available data for each patient and MMRM to assess bias generated by the LOCF method, were consistent with the result of the primary outcome.

Mean ALSFRS-R score in patients receiving edaravone at the end of cycle 6 (37·5, SD 5·3) was similar to the mean

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