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Hospitalized COVID-19 patients receiving a shorter course of remdesivir were significantly more likely to experience clinical improvement than patients receiving standard care, an open-label randomized trial found.

On day 11, patients with "moderate" COVID-19 infection randomized to a 5-day course of remdesivir had significantly higher odds of a change in clinical status versus patients receiving standard care (OR 1.65, 95% CI 1.09-2.48, P=0.02), reported Diana Brainard, MD, of Gilead Sciences in Foster City, California, and colleagues.

However, there was no significant change in clinical status versus standard of care with the 10-day course of remdesivir, the authors noted in .

Remdesivir's manufacturer, Gilead, had published these topline results via press release in June.

An by Erin McCreary, PharmD, and Derek Angus, MD, both of the University of Pittsburgh School of Medicine, took issue with the trial's primary outcome: clinical status on day 11, as defined by a 7-point ordinal scale ranging from death (category 1) to discharge (category 7).

While they noted that this newly created scale is common in COVID-19 randomized trials -- and endorsed by the World Health Organization -- it is "potentially problematic," because "each step on the scale is not necessarily of equivalent clinical significance."

"For example, moving from the clinical state of 'not requiring' to 'requiring' supplemental oxygen is less important than moving from 'requiring mechanical ventilation' to 'death,'" the editorialists wrote.

"The main consequence of variable clinical significance across the scale is one of meaning: it is difficult to translate a summary odds ratio into a clinically meaningful statement for patients, clinicians, and policy makers."

They added that if an agent improves scores at one end of the scale, but worsens scores elsewhere, "there is no clear way to quantify the net benefit," which may have occurred when examining the 10-day course of remdesivir versus standard of care.

For their study, Brainard and colleagues examined data from 584 patients randomized 1:1:1 to receive either a 5-day or 10-day course of remdesivir, or standard care. Median age was 57, and 39% were women. More than half (56%) had cardiovascular disease, 42% had hypertension, and 40% had diabetes. Overall, 533 patients completed the trial.

Examining safety, the authors noted that nausea (10% vs 3%, respectively), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more common among patients in the remdesivir groups than standard of care. By day 28, there were four deaths in the standard care group, three in the 10-day group, and two in the 5-day group.

Three Different Trials, Three Different Results?

McCreary and Angus noted the long and winding data road for remdesivir. First, one trial in China, which may have been underpowered, , but the adequately powered Adaptive COVID-19 Treatment Trial (ACTT-1), sponsored by the National Institutes of Health, found a significantly shorter recovery time for mostly severe COVID-19 patients with up to 10 days of remdesivir versus placebo, but no significant difference in mortality.

This new trial in moderate illness, however, found no benefit in a 10-day course of remdesivir versus standard of care. In other words, the trial was unable to duplicate the results of ACTT-1.

"Thus, there are now three [randomized controlled trials] of remdesivir in hospitalized patients with differing results, 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," the editorialists wrote.

They discussed these differences: ACTT-1 was larger and better powered to find smaller differences, but whereas the other two trials recruited patients who required supplemental oxygen or ventilatory support, Brainard and colleagues included patients who did not require supplementary oxygen.

In addition, patients more often received "putative antiviral therapy" such as hydroxychloroquine in the standard care treatment group. While the editorialists said these agents "have not been shown to improve disease course," they may have impacted other aspects of background care in the treatment groups.

Ultimately, they characterized the study as "important new data" among patients with moderate COVID-19 infection that "suggests moderate clinical benefit" for a 5-day course of remdesivir versus standard care.

But they proposed a whole host of unanswered questions about remdesivir in COVID-19, including optimal patient population, duration of therapy, effect on discrete clinical outcomes, and the relative effect of the drug when the patient receives dexamethasone or other corticosteroids.

Given remdesivir's cost to produce and distribute at a larger scale, McCreary and Angus wrote, "large-scale" clinical trials are needed, especially to determine if the drug offers "incremental benefit" over more inexpensive and widely available corticosteroids.

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