LAUSR

Recently, ALSFTD published an editorial entitled “Is edaravone harmful? (A placebo is not a control)” (1). The editorial questioned whether the mode of administration of study drug in pivotal Study 19 affected the disease trajectory of amyotrophic lateral sclerosis (ALS) in both placebo and edaravone treated patients (2). Edaravone represents a significant advance in the treatment of ALS and has been determined by regulatory authorities in Japan, South Korea, the United States (US), and Canada to be well tolerated and effective at slowing disease progression (3). In our opinion, the conclusions described in the editorial were derived from a potential misconception regarding the mode of administration of edaravone, which we therefore wish to correct, in order that the role of edaravone in the management of ALS may be appropriately interpreted. The main argument made in the editorial is that there appears to be a sharp change in the rate of decline in the ALS Function Rating ScaleRevised (ALSFRS-R) score between the preobservation period (during which no study drug was administered) and the double-blind treatment period. This observation is based on the author’s own calculations of the change in the rate of ALSFRS-R decline before and after randomization. Importantly, Study 19 was designed to enroll patients who were mildly affected at the start of the trial but who would be expected to decline measurably in ALSFRS-R during the double-blind period of the trial (2). In this regard, it is not uncommon to observe a period of relatively slow rate of decline in ALSFRS-R score followed by a more rapid decline. A recent analysis of the change in ALSFRS-R score and its relationship to symptom onset found that ALSFRS-R may lack sensitivity in patients at the milder end of the disease spectrum, while more rapid decline was observed in the middle stages of ALS (4). In addition, approximately 20% of patients in a recent clinical study experienced a plateau in ALSFRS-R, followed by a rapid rate of decline (5). In the opinion article, as an explanation for the greater rate of decline after randomization, the author proposed that study drug administration (i.e., infusions) via semipermanent intravenous access may have had a negative effect on ALSFRS-R score. Importantly, the author assumed that at least a portion of the patients were administered the study drug either via a peripherally inserted central catheter (PICC) or a surgically inserted central venous catheter. However, none of the patients in Study 19 received the study drug through semipermanent central intravenous access (6,7). Thus, the potential risks associated with this method of study drug administration do not apply to Study 19. Since the introduction of edaravone in the US in August 2017, 80% of patients have received the medication via an implanted port or PICC line and pharmacovigilance data as of April 6, 2018, has indicated a safety profile consistent with that in the clinical trial program (8,9). The editorial also pointed out that there was an imbalance in Japan ALS Severity Scale (JALSS) classification between the study groups in Study 19. To be eligible for the study, all patients had to have either a grade 1 or grade 2 classification and at baseline, 68% of the edaravone group had a grade 2 classification versus 76% in the placebo group (2). Change in the JALSS grade during the clinical trial post-randomization was reviewed by the US Food and Drug Administration and found