Is edaravone harmful? (A placebo is not a control)

Abstract

Edaravone is delivered by long-term daily intravenous infusions, yet the risk of infusion was not considered in the design or analysis of studies examining the efficacy of edaravone in ALS. A reappraisal of the pivotal edaravone study (Study 19) on which claims of efficacy are based suggests that this risk cannot be dismissed, that the efficacy of edaravone may be over-estimated, and that some differences between edaravone and placebo may not implicate the ALS disease process. When trial conditions may be harmful to both arms of a placebo-controlled trial, not only is it necessary that treatment prove superior to placebo, but also that treatment is better than no intervention. In Study 19, edaravone performed better than placebo, but both placebo and edaravone likely did worse than no intervention, an interpretation more in keeping with previous trial experience of drugs with similar mechanisms of action, and with previous trial experience with edaravone. Edaravone, as presently delivered, may be both ineffective and harmful.

Keywords:

• Edaravone
• ALS
• clinical trial design

This article responds to:

Edaravone administration in pivotal clinical Study 19

Author response to a Letter to the Editor entitled: Edaravone administration in pivotal clinical study 19 (Authors: Genge, Angela; Brooks, Benjamin)

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Notes

1 Interrogating the Pro-Act database for a control group matched to the Study 19 placebo group is not straightforward. There are inclusion criteria in the edaravone trial that cannot be matched, either because they do not exist (Japan ALS severity classification) or because they are not included (age). Moreover, the constituent trials in Pro-Act are not identified, and the database includes patients in the ceftriaxone trial, which required central venous access. With these caveats, 9640 patients could be identified as being treated with either drug or placebo, and of these 2028 had ALSFRS-R values (and 2647 had ALSFRS). Of the 2028, 627 had an FVC of 80% or more at randomization, and of these 145 had known symptom onset of 2 years or less, and a score of 2 or more in each subscale of the ALSFRS. Of these, very few had ALSFRS-R scores measured at 84 days, and using linear interpolation over 100 days to estimate slope, only 49 had slopes corresponding to a drop of −1 to −4 units over 12 weeks. The change in ALSFRS-R for these patients over 36 weeks is shown in Figure 1, with the regression line weighted according to the numbers contributing to each data point. (The median of individual slopes over the same period is −0.02462, very close to the slope of the regression line).

2 Each infusion of edaravone also contains 20 mg L-cysteine, 40 mg sodium bisulfite, phosphoric acid, and sodium hydroxide, adjusted to a pH of 4 (11). The first two are anti-oxidants on their own, albeit at low dose. Sodium bisulfite infusion causes thrombosis when delivered into rabbit ear veins (30). Acid solutions of this pH are a risk factor for infusion thrombophlebitis (31).