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A 5-day course of remdesivir (Veklury) is associated with statistically significant improvement among patients hospitalized with moderate COVID-19 in comparison with standard care, a company-sponsored randomized trial shows. However, experts said the clinical benefit of the drug for these patients is ambiguous, given the small difference between trial groups.
Christoph D. Spinner, MD, from the Technical University of Munich School of Medicine at University Hospital Rechts der Isar in Germany, led the open-label trial of 584 patients at 105 hospitals in the United States, Europe, and Asia. Findings were published online August 21 in JAMA.
Additionally, patients randomly assigned to the longer 10-day remdesivir course (median length of treatment was 7 days) had not improved significantly compared with those who received standard care 11 days after treatment started.
Results with remdesivir in this trial and in two previously reported randomized trials varied, "raising the question of whether the discrepancies are artifacts of study design choices, including patient populations, or whether the drug is less efficacious than hoped," write Erin K. McCreary, Pharm D, and Derek C. Angus, MD, MPH, with the University of Pittsburgh School of Medicine in Pennsylvania, in an accompanying editorial.
Company Seeking to Expand the EUA
The US Food and Drug Administration (FDA) granted an emergency use authorization (EUA) in May for remdesivir for adults and children hospitalized with severe COVID-19 after trial data showed that the drug helped shorten hospital recovery time.
On the basis of these latest results, the manufacturer is pushing for expansion of that approval beyond treatment of severely ill hospitalized patients, even though trial results have been mixed.
Diana Brainard, head of clinical research at Gilead, told Reuters that Gilead's full FDA application for the drug, submitted earlier this month, asks that the drug be approved for all hospitalized patients with COVID-19.
The problem with expanding the EUA, Angus told Medscape Medical News, is that "it can interrupt or thwart efforts to execute the needed RCTs [randomized controlled trials].
"We think there really needs to be further evaluation of remdesivir in large-scale RCTs adequately powered to understand in which patients, at which dose, given at which point in the course of illness leads to what concrete and tangible improvement in clinical outcomes," he said.
"At this point, remdesivir definitely holds promise, but given the cost to produce and distribute the drug, it seems crucial to know with more certainty how best to use it," he said.
According to Reuters, Gilead has priced remdesivir at $2340 for a 5-day treatment in the United States and some other developed countries.
Angus also notes that it's unclear whether the same patients would benefit from inexpensive and widely available corticosteroids or whether remdesivir can play a complementary role. Those questions have not yet been tested in remdesivir trials, he said.
And although the FDA would likely say that RCTs investigating such questions were still welcome even with an expanded EUA, "[i]t's a bit like getting the genie back in the bottle," Angus said.
Once a drug becomes available for prescribing, clinicians and patients are less willing to participate in a trial in which only some of the patients receive the therapy, he said.
"Second, the company itself may be unwilling to fund trials at this point, since if they have the EUA, why risk testing the drug?" Angus said.
"I appreciate the pressure the FDA is under," Angus said. "I also understand why Gilead would want an expanded EUA. But, I think we are in a quagmire of uncertainty, largely because we probably issued the EUA too soon in the first place, and we'll only compound the problem if we expand it. If everyone leaned in to getting the right trials done right now, we could get the answers we need quickly."
Primary Endpoint Was Status on Day 11
In the newly reported trial, the average age of the patients was 57 years, and 61% were men. All had moderate COVID-19, which was defined for this study as having pneumonia as evidenced on lung scans and oxygen saturation >94% on room air. More than half of patients (56%) had cardiovascular disease; 42% had hypertension; and 40% had diabetes. Nearly all patients (91%) completed the trial.
Remdesivir was administered intravenously at doses of 200 mg on day 1 followed by 100 mg/day for the remainder of the treatment course.
The primary endpoint was clinical status on day 11, as determined using a 7-point ordinal scale in which 1 indicates death and 7 indicates hospital discharge.
On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status than those who received standard care (odds ratio [OR], 1.65; 95% CI, 1.09 – 2.48; P = .02). Clinical status on day 11 did not differ significantly between the 10-day remdesivir group and the standard care group (P = .18 by Wilcoxon rank sum test).
By day 28, two patients (1%) in the 5-day remdesivir group had died, compared with three (2%) in the 10-day group and four (2%) in the standard care group.
There were no significant differences between the remdesivir group and the standard care group in any prespecified secondary endpoints.
The trial was sponsored by Gilead. Spinner has received personal fees from AbbVie and grants and personal fees from Janssen-Cilag, Merck Sharp & Dohme, and ViiV Healthcare/GlaxoSmithKline. Full disclosures of other authors, including from Gilead, are available with the original article. Angus has received personal fees from Bristol-Myers Squibb, Bayer AG, and Ferring Pharmaceuticals Inc and stock options from Alung Technologies Inc. He holds a pending patent to selepressin for the treatment of sepsis and a pending patent to proteomic biomarkers of sepsis in elderly patients. He is an associate editor for JAMA.
Marcia Frellick is a freelance journalist based in Chicago. She has previously written for the Chicago Tribune and Nurse.com and was an editor at the Chicago Sun-Times, the Cincinnati Enquirer, and the St. Cloud (Minnesota) Times. Follow her on Twitter at @mfrellick.
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Cite this: More Mixed Results for Remdesivir: Moderate COVID-19 Patients - Medscape - Aug 25, 2020.