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NEUROSAE 2018 ANNUAL MEETING EDITION (VOLUME 10, ISSUE 3)
QUESTION 96 OF 100
A patient with a 4-year history of limb-onset amyotrophic lateral sclerosis (ALS) has a feeding tube in place, has been wheelchair bound for the past 2 years, and requires maximum assistance with transferring, dressing, and tube feeding. His most recent vital capacity is 45% of predicted, and noninvasive positive pressure ventilation is required up to 15 hours a day due to shortness of breath following assisted activities of daily living. He asks about the benefits associated with edaravone for ALS. Which of the following statements best addresses his question?
A. A recent phase III trial in Japan showed benefit in patients in earlier stages of ALS. The effect of the drug in other ALS populations is not known especially in patients in more advanced stages of disease **
B. Edaravone protects motor neurons from death and improves disability in ALS patients. Edaravone is expected to be of benefit as it may slow the progression of his disability.
C. There is no convincing evidence supporting its role in improving outcomes in patients with ALS. Given the patient’s signficant disability, he is likely to experience more side effects and no benefits.
D. Although edavarone is a free radical scavenger, the drug is unlikely to benefit the patient since high dose vitamin supplementation has not proven beneficial in most patients
E. Edaravone has shown great promise in other conditions such as stroke, and in patients with ALS. He is likely benefit, with an expectation of prolonged survival.
** = Your answer
Edaravone is a free radical scavenger designed to reduce oxidative stress. Authors of an open label study in Japan reported a protective effect on neuronal cells exposed to such stress in animal models, a decrease in an oxidative stress biomarker, and a decrease in ALSFRS-R compared with pretreatment scores. A 2014 phase II study of Japanese patients failed to show a beneficial change in ALSFRS at the end of study (24 weeks). Post hoc analysis, however, showed benefits in patients with early-stage disease, including forced vital capacity of at least 80%, ≤2 years’ duration of disease, and milder disability based on ALSFRS (i.e., subscores of 2 or more on all items). This led to another phase III study with inclusion criteria based on this subpopulation; results showed a 33% difference in ALSFRS at end of study in which patients treated with edaravone had less disability. This study eventually led to approval of the drug in the United States for patients with probable or definite ALS.
In light of this groundbreaking approval of only the second drug indicated for treatment of ALS, the applicability of study findings to patients in the United States and other countries has generated much discussion, especially given the diversity of the patient population, the predicted benefit in more advanced disease, and the fact the first phase III study post hoc analysis did not find an effect. In its current formulation, edaravone is administered IV for cycles of 2 weeks on and 2 weeks off and thus requires venous access for long-term administration.
For physicians treating patients with ALS, the appropriate response must reflect the current data and requires transparency regarding some of the potential limitations of the study, specifically its generalizability to ALS patients beyond the study population. Because the drug is approved for all patients regardless of disability or duration of disease, the decision to treat is based on a physician’s assessment of risks and benefits for a specific patient and the patient’s understanding of the study results, potential benefit, limitations, and potential side effects.
* Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017 Jul;16(7):505-512. doi: 10.1016/S1474-4422(17)30115-1. Epub 2017 May 15
* Abe K(1), Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, Hamada C, Kondo K, Yoneoka T, Akimoto M, Yoshino H; Edaravone ALS Study Group. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):610-7.