Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P=0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P=0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined
In this open-label, randomized, multicenter, phase 3 trial among patients with severe Covid-19 pneumonia due to infection with SARS-CoV-2, we did not find a significant difference in efficacy between 5-day and 10-day courses of remdesivir. After adjustment for baseline imbalances in disease severity, outcomes were similar as measured by a number of end points: clinical status at day 14, time to clinical improvement, recovery, and death from any cause. However, these results cannot be extrapolated to critically ill patients receiving mechanical ventilation, given that few of the patients in our trial were receiving mechanical ventilation before beginning treatment with remdesivir.
The apparent trend toward better outcomes in patients treated with remdesivir for 5 days than in those treated for 10 days may have several causes. The 10-day group included a significantly higher percentage of patients in the most severe disease categories — those requiring invasive mechanical ventilation and high-flow oxygen — and a higher proportion of men (68%, vs. 60%), who are known to have worse outcomes with Covid-19.7 Although eligibility criteria excluded patients receiving invasive mechanical ventilation, 13 patients who were enrolled in the trial were intubated before the start of treatment with remdesivir or were categorized as having protocol deviations at enrollment. Of these 13 patients, 9 were assigned to the 10-day group, whereas only 4 were assigned to the 5-day group. Although the results could suggest that longer treatment with remdesivir may be detrimental, we note that the trend toward improved outcomes in the 5-day group was already evident at day 5 of the trial — when both groups had received the same amount of treatment — which suggests that differences between the groups were not due to treatment duration but to observed imbalances in baseline characteristics between the two groups.
Because our trial lacked a placebo control, it is not a test of the efficacy of remdesivir. Results from two clinical trials of remdesivir in patients with severe Covid-19 have been reported. Wang and colleagues conducted a randomized, double-blind, placebo-controlled trial at 10 hospitals in Hubei, China. However, owing to a decline in the incidence of Covid-19 in China, enrollment was only about half of the planned number of patients, with the result that the trial was not powered to show a statistical difference between the remdesivir and placebo groups.22Preliminary results from an ongoing randomized clinical trial conducted by the National Institute of Allergy and Infectious Diseases showed that 10 days of treatment with remdesivir was statistically superior to placebo for the primary end point, time to recovery.Our trial suggests that if remdesivir truly is an active agent, supplies that are likely to be limited can be conserved with shorter durations of therapy.
Transient elevations in liver enzymes have been observed after treatment with remdesivir in phase 1 studies among healthy volunteers, and preclinical studies revealed renal toxicity at exposures higher than those in humans. In our trial, 2.5% and 3.6% of patients in the 5-day and 10-day groups, respectively, discontinued treatment owing to aminotransferase elevations. Covid-19 itself has been found to be associated with liver injury.Patients in the 10-day group had more elevations in creatinine of grade 3 or higher and more declines in creatinine clearance than those in the 5-day group. The higher frequency of grade 4 decreases in creatinine clearance observed in the 10-day group may have been driven by the more severe disease status in that group, given that Covid-19 is associated with renal injury. Further studies will be needed to delineate the contribution of drug toxicity or the effects of the virus to these findings. Close monitoring of hepatic and renal tests is appropriate among patients who are severely ill.
The interpretation of these results is limited by the lack of a randomized placebo control group and the open-label design. We designed this as an open-label trial for two reasons: the available supply of matched placebo vials had been allocated to other ongoing randomized, controlled clinical trials,and, more important, given the stretched health care resources during the pandemic, it seemed appropriate to allow for patients to be discharged from the hospital as soon as medically indicated, regardless of whether they had completed the full assigned course of treatment with remdesivir. As a result, only 44% of patients in the 10-day treatment group completed the full course of therapy. Patients who were not discharged were presumably those with more severe illness, which may account for the different rates of adverse events seen in the two groups. Another important limitation is that we do not have SARS-CoV-2 viral-load results during and after treatment, owing to the variability in local access to testing and practices across the global sites.
Our trial did not show a significant difference in efficacy between a 5-day course and a 10-day course of intravenous remdesivir treatment in patients with severe Covid-19 due to SARS-CoV-2 who did not require mechanical ventilation at baseline. Patients who progress to mechanical ventilation may benefit from 10 days of remdesivir treatment; further evaluation of this subgroup and of other high-risk groups, such as immunocompromised persons, is needed to determine the shortest effective duration of therapy.
Reference & Source information: https://www.nejm.org/
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