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Is Remdesivir a New COVID-19 Standard of Care? Clinicians Examine NEJM Data

MAY 24, 2020 | GRANT M. GALLAGHER
New data from a randomized clinical trial of remdesivir have come to light, published by investigators of the Adaptive COVID-19 Treatment Trial (ACTT-1) in the New England Journal of Medicine (NEJM).

The preliminary results were highly anticipated, particularly given Anthony Fauci, MD, director of the National Institutes of Allergy and Infectious Diseases (NIAID) made optimistic statements about the drug in late April. The investigators reported on a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with coronavirus disease 2019 (COVID-19) with evidence of lower respiratory tract involvement.  

The trial, supported by NIAID, began on February 21, 2020. The study team enrolled 1063 participants from across 10 countries. The volunteers were randomly assigned to receive standard care with a 10-day course of placebo or standard care with a 10-day course of remdesivir.

Among participants assigned to the treatment group, remdesivir was administered intravenously as a 200-mg loading dose on the first day of treatment, followed by a 100-mg maintenance dose administered each day on days 2 through 10. A total of 1059 of the participants were ultimately incorporated into the analysis.

Patients receiving remdesivir appeared to have a shorter time to recovery than those who received placebo. The median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo, a statistically significant difference.

“The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group,” study authors wrote.

It was also observed that on day 15, odds of improvement in the order scale appeared better in the remdesivir treatment arm than the placebo arm.

While such results are not statistically significant, there was additionally a 14-day mortality rate of 7.1% for the group receiving remdesivir, comparable with the 11.9% 14-day mortality rate for the placebo group.

“Ultimately, the findings support remdesivir as the standard therapy for patients hospitalized with COVID-19 and requiring supplemental oxygen therapy, according to the authors...On May 8, 2020, NIAID began a clinical trial (known as ACTT 2) evaluating remdesivir in combination with the anti-inflammatory drug baricitinib compared with remdesivir alone,” authors of an NIAID statement wrote.

As was the case when a dizzying array of more preliminary information about remdesivir was released on April 29, clinicians took to social media to make sense of the development.

Sam Aitken, PharmD, MPH, of MD Anderson Cancer Center, inquired what colleagues thought about the need for the report to incorporate a competing risk analysis in place of a Kaplan–Meier estimator. This speculation was rooted in concerns about previous analyses of the relationship between morality and time-to-recovery remdesivir data.

Andrew Althouse, PhD, assistant professor at the University of Pittsburgh’s Division of General Internal Medicine, tweeted back that “deaths were assigned a failure to recover and the “worst” time possible, so this does not result in a biased estimate of recovery.”

Jason Pogue, PharmD, BCPS, BCIDP, Clinical Pharmacist Specialist in Infectious Diseases at The University of Michigan Health System, repeated that results were preliminary, but called them compelling.
 

However, the timing of the release, whatever one’s interpretation, was also not lost on some clinicians.
 

Clancy previously spoke with Contagion® around the time of the initial April 29 trio of conflicting study results.

The most pessimistic of those trials, published in The Lancet, was worthy of cautious interpretation for a variety of reasons, investigators of the NEJM study argued.

“That trial failed to complete full enrollment (owing to the end of the outbreak), had lower power than the present trial (owing to the smaller sample size and a 2:1 randomization), and was unable to demonstrate any statistically significant clinical benefits of remdesivir,” study authors wrote.

In an interview at the time of pending US Food and Drug Administration decision, Contagion®  Editor-in-Chief Jason Gallagher, PharmD, FCCP, FIDSA, BCPS, a clinical professor at the Temple University College of Pharmacy, discussed the immediate impact of the remdesivir emergency use authorization subsequently made on May 1.

 

As Gallagher pointed out, the main driver of COVID-19 care thus far has been clinical trial enrollment. With remdesivir becoming largely available, he imagined study participation may decline.

“If you’re in a remdesivir clinical trial and you could be randomized to placebo, are you going to enroll now?” he said. “I don’t think so.”

Gallagher discussed the benefit of a having new data to assess in COVID-19 treatment, but noted the challenges which arise from the authorization any highly-publicized drug.

“Once the horse is out of the barn, we’re going to have to manage everything based upon what people are going to see as a new standard," he said.

Authors of the recent NEJM preliminary report indeed suggested that their results support the use of remdesivir for COVID-19 patients, with continued investigation of combination therapeutics.

“These preliminary findings support the use of remdesivir for patients who are hospitalized with COVID-19 and require supplemental oxygen therapy. However, given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient. Future strategies should evaluate antiviral agents in combination with other therapeutic approaches or combinations of antiviral agents to continue to improve patient outcomes in COVID-19,” study authors concluded.

Though Gallagher’s comments were made nearly a full month ago by now, they are salient in highlighting that even if remdesivir is truly a new “standard of care,” real world rollout through a strained health system has only just begun.
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