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Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

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  • Source:
    Lancet (london, england) 2020 395 10236, 1569 (1569-1578) Published by: Lancet Publishing Group United Kingdom
  • Additional Information
    • Author(s):
      Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B, Wang C
    • Contact Information:
      Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, China
    • Language:
      English
    • Publication Type:
      Journal Article; Multicenter Study; Randomized Controlled Trial
    • Record Status:
      This record is this issue.
    • Abstract:
      Background: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. Methods: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. Findings: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87–1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. Interpretation: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Funding: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.
    • EMBASE keywords:
      acute kidney failure /side effect; adult; adult respiratory distress syndrome /side effect; aged; anemia /side effect; article; China; constipation /side effect; controlled study; *coronavirus disease 2019 /drug therapy; deep vein thrombosis /side effect; diarrhea /side effect; double blind procedure; *drug efficacy; *drug safety; drug withdrawal; female; gastrointestinal hemorrhage /side effect; glucose blood level; heart arrest /side effect; heart failure /side effect; hospital discharge; hospital mortality; human; hyperlipidemia /side effect; hypoalbuminemia /side effect; hypokalemia /side effect; intention to treat analysis; leukocyte count; lipid blood level; lung embolism /side effect; lung insufficiency /side effect; major clinical study; male; multicenter study; multiple organ failure /side effect; nausea /side effect; neutrophil; oxygen saturation; partial pressure; potassium blood level; priority journal; randomized controlled trial; rash /side effect; respiratory failure /side effect; secondary infection /side effect; septic shock /side effect; side effect /side effect; single drug dose; sodium blood level; thrombocytopenia /side effect; urea nitrogen blood level; vomiting /side effect
      Aged
      Female
      Humans
      Male
      Middle Aged
      Adenosine Monophosphate/adverse effects
      Adenosine Monophosphate/therapeutic use
      Alanine/adverse effects
      Alanine/therapeutic use
      Antiviral Agents/adverse effects
      Betacoronavirus
      China
      Double-Blind Method
      Infusions, Intravenous
      Negative Results
      Pandemics
      Adenosine Monophosphate/*analogs & derivatives
      Alanine/*analogs & derivatives
      Antiviral Agents/*therapeutic use
      Coronavirus Infections/*drug therapy
      Pneumonia, Viral/*drug therapy
    • Accession Number:
      2005835598
    • Source:
      This document should be cited as: Wang Y Zhang D Du G Du R Zhao J Jin Y Fu S Gao L Cheng Z Lu Q Hu Y Luo G Wang K Lu Y Li H Wang S Ruan S Yang C Mei C Ding D Wu F Tang X Ye X Ye Y Liu B Yang J Yin W Wang A Fan G Zhou F Liu Z Gu X Xu J Shang L Zhang Y Cao L Guo T Wan Y Qin H Jiang Y Jaki T Hayden FG Horby PW Cao B Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial 2020 (The Cochrane Controlled Trials Register (CCTR/CENTRAL). DOI: 10.1016/S0140-6736(20)31022-9. Oxford: Update Software. Updated quarterly.
    • Accession Number:
      CN-02123497
  • Citations
    • ABNT:
      WANG Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet (london, england), [s. l.], v. 395, n. 10236, p. 1569–1578, 2020. DOI 10.1016/S0140-6736(20)31022-9. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cgh&AN=CN-02123497. Acesso em: 19 set. 2020.
    • AMA:
      Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet (london, england). 2020;395(10236):1569-1578. doi:10.1016/S0140-6736(20)31022-9
    • APA:
      Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, … Wang C. (2020). Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet (London, England), 395(10236), 1569–1578. https://doi.org/10.1016/S0140-6736(20)31022-9
    • Chicago/Turabian: Author-Date:
      Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, et al. 2020. “Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial.” Lancet (London, England) 395 (10236): 1569–78. doi:10.1016/S0140-6736(20)31022-9.
    • Harvard:
      Wang Y et al. (2020) ‘Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial’, Lancet (london, england), 395(10236), pp. 1569–1578. doi: 10.1016/S0140-6736(20)31022-9.
    • Harvard: Australian:
      Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B & Wang C 2020, ‘Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial’, Lancet (london, england), vol. 395, no. 10236, pp. 1569–1578, viewed 19 September 2020, .
    • MLA:
      Wang Y, et al. “Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial.” Lancet (London, England), vol. 395, no. 10236, Jan. 2020, pp. 1569–1578. EBSCOhost, doi:10.1016/S0140-6736(20)31022-9.
    • Chicago/Turabian: Humanities:
      Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, et al. “Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial.” Lancet (London, England) 395, no. 10236 (January 1, 2020): 1569–78. doi:10.1016/S0140-6736(20)31022-9.
    • Vancouver/ICMJE:
      Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet (london, england) [Internet]. 2020 Jan 1 [cited 2020 Sep 19];395(10236):1569–78. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cgh&AN=CN-02123497