The global suffering wrought by SARS-CoV-2 pandemic is undeniable. But so is the ferocity with which the world has pursued a cure. And while some potential remedies have held more promise than others, the enthusiasm supporting these novel treatments often outpaced their evidentiary support. In fact, none have demonstrated efficacy backed by high quality randomized control trial data. The latest of these agents is a viral RNA-dependent, RNA polymerase inhibitor, remdesivir. Until now the data supporting its use consisted of a small RCT published in the Lancet finding no meaningful benefits (1), a strange report documenting its compassionate use in 61 patients (2), and preliminary hearsay of a large ACTT-1 trial announced by Dr. Anthony Fauci during a White House press event. Three weeks after Dr. Fauci’s assertions of efficacy, we finally have access to the manuscript in some form, the Adaptive Covid-19 Treatment Trial (ACTT-1) was published as a preliminary report in the NEJM (3).
Beigel et al enrolled adult patients with a PCR confirmed SARS-CoV-2 infection with at least one of the following: radiographic infiltrates by imaging study, peripheral oxygen saturation (SpO2) ≤94% on room air, or patients requiring supplemental oxygen to maintain an adequate O2 saturation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Eligible patients were randomized to receive either 200-mg of IV remdesivir or placebo on day 1, followed by 100-mg daily for 10 days. Some sites were required to use normal saline due to a shortage of the matching placebo, but the authors attempted to maintain blinding by using opaque bags over the medication and IV tubing.
Beigel et al randomized 1063 patients, 541 in the remdesivir group and 522 in the placebo group. The authors report a statistically significant benefit in patients receiving remdesivir in their primary outcome, time to recovery, as defined by improvements on an 8-category ordinal scale attempting to quantify the severity of respiratory illness. Median time to recovery was 11 vs 15 days in the remdesivir and placebo group, respectively. In patients with the most severe disease, those requiring noninvasive or invasive mechanical ventilation, remdesiviir appeared to be less efficacious, though given the limitations of power in this subgroup it is hard to take much from this finding. Despite a numerically lower value, the authors did not find a statistically significant difference in mortality in patients who received remdesivir (7.6% and 13.4% at 15-days, hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04).
The ordinal scale used by these authors to demonstrate benefit is compelling, especially when one examines the bar plots in fig S1 in the supplementary appendix, but does a 15-day metric truly encapsulate the breadth and length of this disease’s clinical course? At 15-days, 49.5% of patients in the placebo group vs 59.2% of patients in the remdesivir group were discharged home. 17.5% vs 21% of the placebo and remdesivir groups required HFNC, NIV or mechanical ventilation respectively. Most notably 301 patients did not have complete 29-day data available at the time of collection for this preliminary report.
This is what is known as censoring. Censoring occurs when data regarding an event of interest is incomplete. In this case, what has occurred is known as “right censoring”, or when the study period ends without complete outcome data on all participants. This typically occurs in one of two ways, either: 1) the event has not yet occurred for all study participants by the end of the study period, or 2) a number of patients are lost to follow up and outcome data is unavailable (4). In this case, 132 patients in the remdesivir group and 169 in the placebo group had not recovered or completed the day 29 follow-up at the time of data collection. The fate of these patients is yet to be determined. It hangs in the balance and could ultimately contribute to further events, shifting the final effect size in favor of either remdesivir or placebo. Given the prolonged course typical in patients with COVID-19, one could easily imagine a situation in which 15-day outcomes were markedly improved, but by day 29 the effects were far less impressive.
Assuming the findings presented by Beigel et al remain consistent in their final report, remdesivir is not the magic bullet we hoped for. That being said these findings suggest a moderate degree of clinical utility and will likely lead to broad use of this therapeutic agent. It will be interesting to see where and when the final analysis of this data set is published, especially if the results are less favorable then this initial report. I anticipate remdesivir or any of its lauded predecessors will not be the saviors that will ultimately turn the tide of this pandemic. Rather our eventual triumph will be due to the implementation of vital public health measures and frontline clinicians caring for the patients at the bedside.
- Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; 395:1569-78
- Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19 N Engl J Med. 2020;
- Beigel, JH, Tomashek KM, Dodd, LE, et al Remdesivir For The Treatment Of Covid-19 — Preliminary Report. NEJM. 2020. (published online)
- Leung KM, Elashoff RM, Afifi AA. Censoring issues in survival analysis. Annu Rev Public Health. 1997;18:83–104.