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Remdesivir for the Treatment of COVID-19 — Preliminary Report

Our take —

Remdesivir (RDV) reduced time to symptom resolution and possibly reduced mortality. The finding of reduced duration of symptoms with RDV contrasts with a smaller trial of RDV which found no benefit (Wang et al. Lancet 2020). Differences between these trials include the smaller sample size and the use of other off-label agents in the Wang study. The preliminary results of this study support the use of RDV for COVID-19, and suggest that individuals requiring supplemental O2 (but not mechanical ventilation or ECMO) may yield the most benefit. Analysis of the final results of this study, when available, will be helpful. Further analysis of a larger sample size and additional studies are needed to test hypotheses on the ideal timing of RDV use in COVID-19 disease. These results formed the basis of the FDA emergency use authorization for RDV use.

Study design

Randomized Controlled Trial

Study population and setting

This was a randomized, double-blinded, placebo-controlled, multi-center clinical trial of a 10-day course of daily remdesivir (RDV) versus placebo among inpatients at 60 trial sites in North America, Europe, and Asia with a positive SARS-CoV-2 RT-PCR, and evidence of lower respiratory tract infection based on radiographic infiltrates, SpO2 ≤94% on room air, or requiring supplementation oxygen via nasal cannula, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). There was no limit to the duration of symptoms prior to enrollment. Inclusion required an alanine aminotransferase test and aspartate transaminase test <5x upper limit of normal, and an estimated glomerular filtration rate (eGFR)>30 mL/min/mm2 (liver function tests). The primary outcome was time to recovery during the 28 days after enrollment, with recovery defined as: 1) not hospitalized and no limitations of activities, 2) not hospitalized, limitation of activities, home oxygen requirement, or both, or 3) hospitalized but not requiring supplemental oxygen or inpatient medical care. A secondary outcome was mortality at 14 and 28 days after enrollment.

Summary of Main Findings

A total of 1063 patients were enrolled from 60 sites (79.8% from North America), 11.3% did not require supplemental O2, 88.7% had “severe” disease (required supplemental oxygen to maintain an oxygen saturation ≥94%), 25.6% were on mechanical ventilation or ECMO at the time of enrollment, the mean age was 58.9 years, and 64.3% were men. The median duration of symptoms prior to enrollment was 9 days (IQR 6 to 12). A total of 541 participants were assigned to RDV and 522 to placebo; 49 RDV and 53 placebo participants discontinued treatment before day 10 due to adverse events other than death or withdrawal of consent. At the time of analysis, 391 RDV and 340 placebo group participants had completed day 29 of follow-up, died, or recovered.

Participants in the RDV arm had a median of 11 days to recovery compared with 15 days in the placebo arm (rate ratio 1.32, 95% CI: 1.12 to 1.55, p<0.001). In subgroup analysis, the difference in recovery by 29 days was observed among the sub-group of participants receiving supplemental oxygen via nasal cannula but not those with either less or more severe disease: those not needing supplemental oxygen, receiving high-flow oxygen, noninvasive mechanical ventilation, mechanical ventilation, or ECHO; however, a test of interaction by baseline clinical status was not significant. In subgroup analysis among groups with either 10 or less days or more than 10 days of symptoms at the time of enrollment, there was no clear difference in the effect of RDV on time to clinical improvement (similar effect sizes and overlapping confidence intervals). The Kaplan-Meier estimates of mortality at 14 days were 7.1% and 11.9% for RDV and placebo, respectively (hazard ratio 0.7; 95% CI: 0.47 to 1.04).

The occurrence of serious adverse events was balanced between arms with 21.1% in the RDV arm and 27% in the placebo arm suffering a serious adverse event. Two events in each arm was adjudicated to be related to RDV or placebo. The frequency of serious adverse events was similar by arm except for respiratory failure and hypotension which occurred more frequently in the placebo arm. Non-serious adverse events were also similar by study arm including no difference in increase in transaminases or decrease in eGFR.

Study Strengths

This was a placebo-controlled RCT examining remdesivir efficacy and safety among people with SARS-CoV-2 infection. The study was powered for clinical efficacy and was completed with minimal drop-out and excellent ascertainment of study endpoints.

Limitations

The findings from this study should not be over-interpreted in terms of final outcomes. These results are preliminary, with follow-up incomplete at the time of analysis for some participants who had not had 28 days of observation from enrollment. In addition, the sample size for subgroups (oxygenation requirements and duration of symptoms at enrollment) are too small to draw strong conclusions regarding who may most benefit from RDV in terms of illness severity or duration of symptoms. Finally, RNA clearance is a commonly measured outcome in antiviral agent studies; it was missing from this report.

Value added

This well-conducted randomized controlled trial (RCT) demonstrated a clinical benefit of RDV use with the possibility of reduced mortality. It also suggests the safety of RDV, as there was no evidence of an increase in serious or non-serious adverse events among participants receiving the drug.