The new england journal of medicine Original Article Remdesivir for the Treatment of Covid-19 — Preliminary Report J.H. Beigel, K.M. Tomashek, L.E. Dodd, A.K. Mehta, B.S. Zingman, A.C. Kalil, E. Hohmann, H.Y. Chu, A. Luetkemeyer, S. Kline, D. Lopez de Castilla, R.W. Finberg, K. Dierberg, V. Tapson, L. Hsieh, T.F. Patterson, R. Paredes, D.A. Sweeney, W.R. Short, G. Touloumi, D.C. Lye, N. Ohmagari, M. Oh, G.M. Ruiz-Palacios, T. Benfield, G. Fätkenheuer, M.G. Kortepeter, R.L. Atmar, C.B. Creech, J. Lundgren, A.G. Babiker, S. Pett, J.D. Neaton, T.H. Burgess, T. Bonnett, M. Green, M. Makowski, A. Osinusi, S. Nayak, and H.C. Lane, for the ACTT-1 Study Group Members*​​ ABSTRACT BACKGROUND Although several therapeutic agents have been evaluated for the treatment of coro- The authors’ full names, academic de- navirus disease 2019 (Covid-19), none have yet been shown to be efficacious. grees, and affiliations are listed in the Ap- pendix. Address reprint requests to Dr. METHODS Beigel at the National Institute of Allergy and Infectious Diseases, National Insti- We conducted a double-blind, randomized, placebo-controlled trial of intravenous tutes of Health, 5601 Fishers Ln., Rm. remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory 7E60, MSC 9826, Rockville, MD 20892- tract involvement. Patients were randomly assigned to receive either remdesivir 9826, or at jbeigel@ niaid . nih . gov. (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional *A complete list of members of the ACTT-1 Study Group is provided in the days) or placebo for up to 10 days. The primary outcome was the time to recovery, Supplementary Appendix, available at defined by either discharge from the hospital or hospitalization for infection- NEJM.org. control purposes only. This article was published on May 22, 2020, at NEJM.org. RESULTS A total of 1063 patients underwent randomization. The data and safety monitoring DOI: 10.1056/NEJMoa2007764 Copyright © 2020 Massachusetts Medical Society. 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. Pre- liminary 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 pla- cebo (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 un- derwent 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.) n engl j med nejm.org 1 The New England Journal of Medicine Downloaded from nejm.org on May 26, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. The new england journal of medicine novel coronavirus, severe acute non-European sites owing to a shortage of match- res piratory syndrome coronavirus 2 ing placebo; the infusions were masked with an A(SARS-CoV-2), was first identified in De- opaque bag and tubing covers to maintain blind- cember 2019 as the cause of a respiratory illness ing. All patients received supportive care accord- designated coronavirus disease 2019, or Covid-19.1 ing to the standard of care for the trial site hos- Several therapeutic agents have been evaluated for pital. If a hospital had a written policy or the treatment of Covid-19, but none have yet been guideline for use of other treatments for Covid-19, shown to be efficacious.2,3 Remdesivir (GS-5734), patients could receive those treatments. In the an inhibitor of the viral RNA-dependent, RNA absence of a written policy or guideline, other polymerase with inhibitory activity against SARS- experimental treatment or off-label use of mar- CoV and the Middle East respiratory syndrome keted medications intended as specific treat- (MERS-CoV),4-7 was identified early as a promis- ment for Covid-19 were prohibited from day 1 ing therapeutic candidate for Covid-19 because through day 29 (though such medications could of its ability to inhibit SARS-CoV-2 in vitro.8 In have been used before enrollment in this trial). addition, in nonhuman primate studies, remdes- The trial protocol was approved by the insti- ivir initiated 12 hours after inoculation with tutional review board at each site (or by a cen- MERS-CoV9,10 reduced lung virus levels and lung tralized institutional review board as applicable) damage. and was overseen by an independent data and To evaluate the clinical efficacy and safety of safety monitoring board. Informed consent was putative investigational therapeutic agents among obtained from each patient or from the patient’s hospitalized adults with laboratory-confirmed legally authorized representative if the patient Covid-19, we designed an adaptive platform to was unable to provide consent. Full details of the rapidly conduct a series of phase 3, randomized, trial design, conduct, oversight, and analyses can double-blind, placebo-controlled trials. Here, we be found in the protocol and statistical analysis describe the preliminary results of the first plan (available at NEJM.org). stage of the Adaptive Covid-19 Treatment Trial (ACTT-1), in which we evaluated treatment with Procedures remdesivir as compared with placebo. Patients were assessed daily during their hospi- talization, from day 1 through day 29. The pa- Methods tient’s clinical status on an eight-category ordinal scale (defined below) and the National Early Design Warning Score was recorded each day.11,12 All Enrollment for ACTT-1 began on February 21, serious adverse events and grade 3 or 4 adverse 2020, and ended on April 19, 2020. There were events that represented an increase in severity 60 trial sites and 13 subsites in the United States from day 1 and any grade 2 or higher suspected (45 sites), Denmark (8), the United Kingdom (5), drug-related hypersensitivity reactions were re- Greece (4), Germany (3), Korea (2), Mexico (2), corded. (See the full description of trial proce- Spain (2), Japan (1), and Singapore (1). Eligible dures in the Supplementary Appendix.) patients were randomly assigned in a 1:1 ratio to receive either remdesivir or placebo. Randomiza- Statistical Analysis tion was stratified by study site and disease se- The primary analysis was a stratified log-rank verity at enrollment (see the Supplementary Ap- test of the time to recovery with remdesivir as pendix, available with the full text of this article compared with placebo, with stratification by at NEJM.org, for details about stratification crite- disease severity. (See the Supplementary Appendix ria). Remdesivir was administered intravenously for more information about the planned statisti- as a 200-mg loading dose on day 1, followed by a cal analysis.) 100-mg maintenance dose administered daily on The primary outcome measure was the time days 2 through 10 or until hospital discharge or to recovery, defined as the first day, during the death. A matching placebo was administered 28 days after enrollment, on which a patient according to the same schedule and in the same satisfied categories 1, 2, or 3 on the eight-cate- volume as the active drug. A normal saline pla- gory ordinal scale. The categories are as follows: cebo was used at the European sites and at some 1, not hospitalized, no limitations of activities; n engl j med nejm.org 2 The New England Journal of Medicine Downloaded from nejm.org on May 26, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. Remdesivir for COVID-19 — Preliminary Report 2, not hospitalized, limitation of activities, home estimated number of recoveries needed for the oxygen requirement, or both; 3, hospitalized, not trial) and 81 deaths had been entered in the requiring supplemental oxygen and no longer re- database. At that time, the data and safety moni- quiring ongoing medical care (used if hospitaliza- toring board recommended that the preliminary tion was extended for infection-control reasons); primary analysis report and mortality data from 4, hospitalized, not requiring supplemental oxy- the closed safety report be provided to trial team gen but requiring ongoing medical care (Covid-19– members from the National Institute of Allergy related or other medical conditions); 5, hospital- and Infectious Diseases (NIAID). These results ized, requiring any supplemental oxygen; 6, were subsequently made public; the treating hospitalized, requiring noninvasive ventilation physician could request to be made aware of the or use of high-flow oxygen devices; 7, hospital- treatment assignment of patients who had not ized, receiving invasive mechanical ventilation or completed day 29 if clinically indicated (e.g., be- extracorporeal membrane oxygenation (ECMO); cause of worsening clinical status), and patients and 8, death. Other outcomes included mortality originally in the placebo group could be given at 14 and 28 days after enrollment and grade 3 remdesivir. This report summarizes the prelimi- and 4 adverse events and serious adverse events nary results from this ongoing trial.