Final Report of Remdesivir Trial Supports First FDA Approval of Treatment for COVID-19
The final report of remdesivir trial supports its approved treatment for COVID-19 after preliminary findings enabled emergency use authorization.
The final report of the phase 3 trial of remdesivir for COVID-19 confirms preliminary findings that supported the emergency use authorization, and provides the detail of potential benefit at different disease severity that informed the first FDA approval of treatment for COVID-19.
"Our overall findings were consistent with the findings of the preliminary report," John Beigel, MD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, and colleagues indicate in the study final report in the New England Journal of Medicine. "A 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19."
In an accompanying editorial, Raphael Dolin, MD, Department of Medicine, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston MA, and Martin Hirsch, MD, Massachusetts General Hospital, Partners AIDS Research Center, Boston welcomed the report, characterizing it as an important first step in the development and approval of effective treatments for COVID-19.
"The report from Beigel et al shows that remdesivir provides moderate clinical benefit in the treatment of patients with COVID-19," Dolin and Hirsch commented."These findings are a step forward on the road to developing effective therapy for SARS-CoV-2 infections and, as such, are an important advance."
The trial enrolled participants from February 21, 2020 through April 19, at 60 trial sites in 10 countries. A total of 1062 patients were randomized 1:1 to receive either placebo or a 10-day course of remdesivir, administered intravenously with 200mg loading dose on day 1, and100mg maintenance doses daily from day 2 to 10. The trial was conducted with "adaptive-design" to allow participants to receive other therapies indicated by protocols at their respective treatment centers.
The investigators described numerous challenges in conducting the large, multlnational trial early in a pandemic with a novel virus, including inadequate supplies of personal protective equipment and trial-related supplies, such as swabs.
"The trial was implemented during a time of restricted travel, and hospitals restricted the entrance of nonessential personnel," Beigel and colleagues recount. "Training site initiation visits, and monitoring visits often were performed remotely.Research staff were often assigned other clinical duties, and staff illnesses strained research resources."
The trial was also designed when little was known about the course of COVID-19, and so the primary outcome was changed early in the trial, from a comparison of outcomes on day 15 to a comparison of time to recovery up to day 29. The apparent shortening of time to recovery led to an early unblinding of the protocol so that patients on placebo could elect for active treatment.
The investigators report that time to recovery with active drug was a median 10 days, compared to 15 days with placebo. Patients on active drug also achieved greater clinical improvement, on ordinal scale score measure, at day 15; a shorter time to improvement, on one of two ordinal scale categories; and shorter length of initial hospital stay (median 12 days vs 17). All cause mortality was 11.4% with remdesivir and 15.2% with placebo.
The investigators found the active drug associated with lower incidence of new oxygen use, and a lower proportion of patients needing higher levels of respiratory support. For patients receiving oxygen or ECMO at study entry, the active drug was associated with fewer days of subsequent oxygen, and shorter subsequent duration of mechanical ventilation or ECMO.
Beigel and colleagues found that benefit was most apparent in patients who needed only low-flow oxygen at study entry. They acknowledge, however, that this may reflect the larger sample of patients at this level of severity; and also noted that the follow-up period with more severely ill patients may have been too short to adequately determine their benefit from the drug.
"Cumulatively, these findings suggest that treatment with remdesivir may not only reduce the disease burden but may also decrease the use of scarce health care resources during this pandemic," Beigel and colleagues indicate.