Time on Remdesivir Not Tied to Severe COVID-19 Recovery

There was no significant difference in clinical improvement when the COVID-19 antiviral agent remdesivir was administered for 5 days or 10 days in hospitalized patients with severe illness, researchers found.

After 14 days, unadjusted data showed more of the 5-day group experiencing clinical improvement of 2 points or more compared with those receiving remdesivir for 10 days (64% vs 54%, respectively, P not reported).

But after adjusting for differences in baseline clinical status, the difference between the two groups was non-significant, reported Diana Brainard, MD, of drugmaker Gilead Sciences, and colleagues writing in the New England Journal of Medicine. The baseline-adjusted difference between groups was 6.5 percentage points trending in favor of the shorter treatment (95% CI -2.8 to 15.7).

Gilead previously released top-line data from this trial in a press release on the same day as results of the ACTT-1 randomized trial of remdesivir were announced by the National Institute of Allergy and Infectious Diseases.

Brainard and colleagues noted that prior clinical trials used a 10-day course of treatment based on efficacy in animal models of MERS virus, and was supported by prior data from Ebola virus.

“Understanding the appropriate length for a course of treatment with remdesivir is a key question as we think about how best to care for our patients,” said Francisco Marty, MD, of Brigham and Women’s Hospital in Boston, in a statement. “For many patients, a shorter course of treatment may be just as effective, which could reduce hospital stays and potential adverse events, and extend the limited supply of remdesivir available during this first phase of the pandemic.”

An accompanying editorial by Raphael Dolin, MD, of Beth Israel Deaconess Hospital in Boston, and Martin Hirsch, MD, of Massachusetts General Hospital in Boston, discussed which patients should receive the shorter course of the drug, especially given its limited availability.

“Priority should be given to a 5-day remdesivir regimen at the early stages of severe disease (i.e., when they are receiving supplemental oxygen but have not been intubated) since the evidence of benefit is clearest in this population,” they wrote, adding that as supplies increase and more data accrue, understanding which populations may benefit most from remdesivir may evolve.

The randomized phase III trial recruited hospitalized patients with COVID-19 with oxygen saturation of 94% or less while breathing ambient air and radiologic evidence of pneumonia, but not requiring mechanical ventilation. Patients were enrolled from 55 hospitals in the U.S., Europe, and Asia from March 6 to March 26. All patients received 200 mg of intravenous remdesivir on day 1, followed by 100 mg for the next 4 or 9 days.

The protocol was amended on March 15 to reduce patient age eligibility from 18 to 12, and to eliminate the requirement of fever reaching at least 36.6ºC. The primary outcome was clinical status on day 14, as assessed by a 7-point ordinal scale.

Overall, 397 patients began treatment — 200 for 5 days and 197 for 10 days. However, Brainard and colleagues detailed significant differences in baseline disease status: “greater proportions of patients in the 10-day group were in the two highest disease severity groups,” and 13 required mechanical ventilation between screening and treatment — four in the 5-day group and nine in the 10-day group. In addition, more patients in the 10-day group required high-flow oxygen support.

Of 200 patients in the 5-day group, 172 completed treatment with a median duration of 5 days, and of 197 patients in the 10-day group, 86 completed treatment with a median duration of 9 days. By day 14, there were 16 deaths in the 5-day group and 21 in the 10-day group, while 120 patients and 103 patients had been discharged from each respective group.

Median duration of hospital stay was similar for both groups (7 vs 8 days, respectively). A higher proportion of patients were discharged in the 5-day compared with the 10-day group (60% vs 52%) and mortality was lower in the 5-day group (8% vs 11%, respectively).

Adverse event rates were similar in both groups (70% vs 74%). The most common events were nausea (9% vs 10%), acute respiratory failure (6% vs 11%), increased alanine aminotransferase (6% vs 8%), and constipation (7% in both groups).

“The interpretation of these results is limited by the lack of a randomized placebo controlled group and the open-label design,” the authors wrote, but noted that the supply of matched placebo had already been allocated to other randomized trials. One of those is also sponsored by Gilead and is evaluating remdesivir in patients with moderate COVID-19 illness, expected to be completed later this week.

While Brainard and colleagues also acknowledged only 44% of patients in the 10-day group completed the course of remdesivir, early stoppage was often because patients had recovered enough to be discharged.