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Remdesivir for the Treatment of COVID-19—Preliminary Report
TAKE-HOME MESSAGE
- Adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement were randomized to receive intravenous remdesivir or placebo for up to 10 days. Median recovery time was 11 days in the remdesivir group versus 15 days in the placebo group (P < .001). The estimated mortality rate at 14 days was 7.1% with remdesivir and 11.9% with placebo. The risk of serious adverse events was 21.1% in the remdesivir group and 27.0% in the placebo group.
- Remdesivir was associated with a shortened time to recovery compared with placebo in adults hospitalized with COVID-19 and with lower respiratory tract involvement.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.
METHODS
We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.
RESULTS
A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).
CONCLUSIONS
Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.).
Additional Info
Disclosure statements are available on the authors' profiles:
Remdesivir for the Treatment of Covid-19—Preliminary Report
N. Engl. J. Med 2020 May 22;[EPub Ahead of Print], JH Beigel, KM Tomashek, LE Dodd, AK Mehta, BS Zingman, AC Kalil, E Hohmann, HY Chu, A Luetkemeyer, S Kline, D Lopez de Castilla, RW Finberg, K Dierberg, V Tapson, L Hsieh, TF Patterson, R Paredes, DA Sweeney, WR Short, G Touloumi, DC Lye, N Ohmagari, MD Oh, GM Ruiz-Palacios, T Benfield, G Fätkenheuer, MG Kortepeter, RL Atmar, CB Creech, J Lundgren, AG Babiker, S Pett, JD Neaton, TH Burgess, T Bonnett, M Green, M Makowski, A Osinusi, S Nayak, HC LaneFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Effective therapeutics for COVID-19 are urgently needed. Remdesivir is an investigational inhibitor of the viral RNA-dependent, RNA polymerase of SARS-CoV-2. This randomized, double-blind trial was designed to compare remdesivir with placebo in hospitalized patients with COVID-19 and evidence of lower respiratory involvement. Using an ordinal scale of eight clinical categories that ranged from mild illness to death, those who received remdesivir had a median recovery time of 11 days (95% CI, 9–12), as compared with 15 days (95% CI, 13–19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12–1.55; P < .001). Although there was a numerical trend for lower mortality in the remdesivir arm, this was not statistically significant at the time of this interim analysis. The clinical benefit was most apparent in those with severe COVID-19 who were not on mechanical ventilation.
This is a preliminary report, as approximately 30% of the 1063 participants had not completed the study visit through day 29 at the time of this publication. This is the first randomized clinical trial to demonstrate a clinically significant benefit of any antiviral or host-modifying therapy in persons with COVID-19. This is one of several ongoing studies examining the potential benefit of remdesivir. The results of these additional studies and the final analysis of this trial are needed to determine the role of this medication in the treatment of COVID-19. The agent is not FDA-approved; but, given these data, has been made available by the FDA through an Emergency Use Authorization.
A Definitive Study of Remdesivir
Primum non nocere. “First, do no harm” is widely (and possibly erroneously) attributed to the Hippocratic Oath. Nevertheless, it sets a basic principle of medicine. Our interventions are meant to help and to comfort, and not—on balance—cause harm. With a new intervention, the highest levels of evidence for safety and effectiveness comes from randomized, placebo-controlled trials (RCT) designed to remove systematic biases while evaluating an intervention’s benefits and risks.
I recently provided comment to PracticeUpdate readers centered on the press release describing interim analysis of a RCT comparing outcomes of remdesivir (200 mg IV on day one, followed by 100 mg IV for the following 9 days) to placebo for patients with COVID-19.[1] The official results are now in, and show that this nucleotide analogue is superior to placebo in shortening time to recovery, without significant adverse events, for adults hospitalized with COVID-19.[2] The results are the same as previously posted: median time to recovery was shortened from 15 days to 11 days (rate ratio for recovery = 1.32 [95% CI: 1.12—1.55]) in those receiving remdesivir.
Some caveats emerge from the full paper that should be of interest for clinicians. First, the benefit was most apparent for hospitalized patients receiving supplemental oxygen, but not requiring non-invasive ventilation, high-flow oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Second, younger patients did better. Third, black patients—which comprise a disproportionally high percentage of hospitalized cases in the U.S.—were under-represented in the study population. Fourth, no safety issues emerged; adverse events were balanced between remdesivir and placebo. Finally, there is now high quality evidence that remdesivir is superior to placebo for shortening the time to recovery from COVID-19 in hospitalized patients. Remdesivir is a drug under investigation by the FDA and approved for Emergency Use Authorization. The manufacturer has made nearly one million doses available for the Federal Government to distribute based on hospital case load algorithms.
Conducting a multi-nation RCT of a relatively novel agent for a disease that lacks full characterization in the midst of a global pandemic is challenging. The study team is to be commended in doing so quickly, but without cutting corners. Clinicians—burdened by significantly ill patients—desire to have effective treatments as soon as possible. This impatience, however, can clash with the sifting and winnowing necessary for high level evidence. Our best choices, however, are those informed by careful assessments using approaches that are transparent and replicable.
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