The FLARE Four
- Remdesivir, a nucleotide analog that inhibits the RNA polymerase of SARS-CoV-2, received FDA emergency use authorization on May 1, 2020 for treatment of COVID-19
- Preliminary results from the Adaptive COVID-19 Treatment Trial-1 (ACTT-1) were the basis for the authorization
- Among the 1,063 participants, those who received remdesivir had a shorter time to recovery than those who received placebo (11 vs. 15 days)
- In subgroup analyses, remdesivir was beneficial for patients with serious disease (requiring supplemental oxygen) but not critical disease; however, the trial may have been underpowered to detect benefit in sicker patients
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The FDA's emergency use authorization of remdesivir for COVID-19 was based on data from the Adaptive COVID-19 Treatment Trial-1 (ACTT-1), sponsored by the National Institutes of Health, which has now been published in the New England Journal of Medicine. Arthur Kim, MD, director of the Viral Hepatitis Clinic in the Infectious Diseases Division, Eric Meyerowitz, MD, infectious diseases fellow, Alyssa Letourneau, MD, medical director of the Antimicrobial Stewardship Program, and Rajesh Gandhi, MD, physician in the Infectious Diseases Division, all of Massachusetts General Hospital, explicate the trial in a fast literature update posted on May 26, 2020.
68 sites in North America, Europe and Asia enrolled 1,063 patients who were admitted for COVID-19 between February and April 2020. Patients were randomized 1:1 to receive up to 10 days of remdesivir or placebo. The primary endpoint was time to recovery, defined as discharge from the hospital or hospitalization for infection-control purposes only.
The median time to recovery was 11 days with remdesivir versus 15 days with placebo (rate ratio for recovery, 1.32; 95% CI, 1.12–1.55; P < .001). These data are preliminary because about 30% of the cohort had not yet recovered or completed the day 29 follow-up visit when this paper was submitted.
Remdesivir showed no significant mortality benefit. The trial was stopped early, and a higher-powered trial might show different results.
Efficacy by Illness Severity
197 patients received high-flow nasal cannula or non-invasive positive pressure ventilation, 421 received supplemental oxygen and 272 received mechanical ventilation or extracorporeal membrane oxygenation. In terms of earlier recovery, remdesivir showed significant benefit only in the group requiring supplemental oxygen.
Since ACTT-1 did not enroll equally across categories of disease severity, due to power limitations these preliminary data neither demonstrate nor disprove remdesivir efficacy for patients less sick or sicker than those on supplemental oxygen.
No serious adverse event occurred at a significantly different rate between the remdesivir and placebo groups. No information is reported about how often remdesivir was stopped or held for elevated liver enzymes or when patients experienced a renal injury.
Nevertheless, safety does not appear to be a major limiting factor beyond the cautions that patients were excluded from enrollment if they had alanine or aspartate transaminase >5x the upper limit of normal or estimated glomerular filtration rate <30.
The benefit for the latter population, especially those with acute kidney injury and no plan for renal replacement therapy, must be weighed against the toxicity of the cyclodextrin vehicle given with remdesivir.
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Learn more about research in the Division of Infectious Diseases