Peer-reviewed findings were published late Friday from one of the key trials of remdesivir, perhaps the most promising antiviral agent for COVID-19, confirming and extending topline results announced a month ago via press release.
Hospitalized patients with COVID-19 who received remdesivir had a median recovery time of 11 days versus 15 days with placebo (rate ratio for recovery 1.32, 95% CI 1.12-1.55, P<0.001), reported John Beigel, MD, of the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues.
Mortality estimates by 14 days were lower for the remdesivir group compared to placebo, but non-significant (HR for death 0.70, 95% CI 0.47-1.04), the authors wrote in the New England Journal of Medicine.
Interestingly, when researchers examined outcomes on an 8-point ordinal scale, they found patients with a baseline ordinal score of 5 had a rate ratio for recovery of 1.47 (95% CI 1.17-1.84), while patients with a baseline score of 7 had a rate ratio for recovery of 0.95 (95% CI 0.64-1.42).
Some of these data were released by the NIAID on April 29, but without further details such as 95% confidence intervals. On May 1, the FDA agreed to let remdesivir be used clinically under an emergency use authorization. Since then, however, clinicians and other researchers have clamored for a fuller report, to help guide their clinical practice. For example, questions were raised as to whether particular subgroups got more benefit from the drug than others.
David Aronoff, MD, of Vanderbilt University Medical Center in Nashville, who was not involved in the research, noted the drug seemed more effective when given to patients who weren’t as severely ill, earlier in the course of disease. He added this wasn’t surprising, given remdesivir’s mechanism of action as an antiviral, which works by blocking the virus from replicating.
“The drug doesn’t affect the host, it only affects the virus. What seems to cause major problems late in the course of disease is the inflammatory response to the initial damage the virus causes,” he told MedPage Today.
Aronoff likened the virus to an arsonist setting fires, and antivirals like remdesivir as the police trying to catch the arsonist before they set more fires.
“But once the building is on fire, it doesn’t matter where the arsonist is,” he noted.
This is why combining a drug to address the viral response with a drug to address the host response may be critical to treating the virus. Aronoff cited the NIAID’s ACTT-2 trial in progress, which will examine combination therapy with remdesivir and anti-inflammatory drug, baricitinib, versus remdesivir alone.
In Aranoff’s analogy, the anti-inflammatory would be akin to the firefighters putting out the fires the arsonist set.
The Adaptive Covid-19 Treatment Trial (ACTT-1) was comprised of 60 trial sites, including 45 sites in the U.S., along with sites in Europe and Asia. Participants hospitalized with COVID-19 with evidence of lower respiratory involvement were randomized to either intravenous remdesivir or placebo for up to 10 days. Primary outcome was time to recovery, meaning either hospitalization for infection control purposes only or discharge from the hospital.
An independent data and safety monitoring board recommended unblinding the results based on preliminary data from 1,059 patients — 538 assigned to remdesivir and 521 to placebo. As of April 28, only 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29 (either recovered or died).
Patients were a mean age of 59, and almost two-thirds were men, 53% were white, 23% were Hispanic or Latino and 21% were black. About 80% were enrolled at sites in North America. Half of patients had two or more pre-existing conditions, including half with hypertension, 37% with obesity and 30% with diabetes mellitus.
Beigel and colleagues included 33-day Kaplan-Meier curves for recovery among subgroups categorized by oxygen need. The greatest separation between the remdesivir and placebo groups (i.e., the greatest drug benefit) was seen for patients receiving oxygen but not at high flow or with noninvasive mechanical ventilation. There was no advantage for remdesivir in recovery rates among patients on high-flow oxygen or those on mechanical ventilation or extracorporeal membrane oxidation.
Among patients not receiving oxygen, a trend toward benefit with remdesivir was evident, but it did not reach statistical significance, probably because more than 80% of the placebo group in this category recovered.
There was no subgroup in which placebo clearly outperformed remdesivir. Many groups (such as racial minorities) didn’t have enough patients to show meaningful differences.
Notably, however, patients with symptom duration greater than 10 days benefited from remdesivir just as much as those with shorter duration.
Serious adverse events occurred in 21% of patients in the remdesivir group and 27% of patients in the placebo group, and two in each group were judged to be related to the study drug. Anemia or decreased hemoglobin was the most common adverse event in the remdesivir group (7.9% vs 9.0% in the placebo group). Pyrexia and hyperglycemia also occurred more often in the remdesivir group.
Aronoff said more will be known once final results from the study are released in a few weeks, but they will likely confirm the current report.
When asked if it would be appropriate to use this medication outside of a clinical trial setting, he noted there are reasons to hesitate, namely remdesivir’s availability, the optimal duration of therapy, and that it can only be given intravenously.
“It’s hard to implement it really early when you’re at a nursing home or somebody’s house,” Aronoff said. “It’s not a panacea and it’s not a cure-all. It has some barriers to widespread implementation.”
Remdesivir’s manufacturer Gilead Sciences is conducting two trials of its own with remdesivir, one of which includes a placebo control. Results from that trial are expected soon.
The trial was sponsored and primarily funded by the National Institute of Allergy and Infectious Diseases, the NIH, and funded in part by the NIAID and the National Cancer Institute, NIH. The trial has also been funded in part by the governments of Japan, Mexico, Denmark, and Singapore. The trial site in South Korea received funding from the Seoul National University Hospital. Support for the London International Coordinating Centre was also provided by the United Kingdom Medical Research Council.
Beigel disclosed no conflicts of interest.
Other co-authors disclosed support from NIH/NIAID/DMID, University of Minnesota, Medical Research Council U.K., Novo Nordisk Foundation, Simonsen Foundation, GSK, Pfizer, Boehringer Ingelheim, Gliead, MSD, Lundbeck Foundation, Merck, Sanofi-Pasteur,Cepheid, Ellume, Genentech, Janssen, ViiV Healthcare, Integrum Scientific LLC, UCL, Bristol University, Gilead Sciences Europe, ECDC, EU Social funds and National resources.
One co-author is an employee of the U.S. government.