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

      research-article
      , MD a , c , , , MD d , , , Prof, PhD e , , , Prof, MD f , , , Prof, MD g , , , Prof, MD h , , , Prof, MD i , , , Prof, MD j , , , Prof, MD k , , , Prof, MD l , , , Prof, MD m , , , Prof, MD n , , , Prof, PhD e , , Prof, PhD e , , MD d , , MS d , , MS d , , MD f , , MD f , , MD g , , MD g , , MD h , , MD h , , MD i , , MD j , , MD k , , MD l , , MD m , , MD n , , MS b , , MD a , , MD a , , PhD b , , MD o , , MD a , p , , MD a , , BD q , , BD q , , BD q , , PhD r , , PhD s , , Prof, PhD t , u , , Prof, MD v , , Prof, MD w , , Prof, MD a , c , x , y , * , , Prof, MD a , x , y , z , **
      Lancet (London, England)
      Elsevier Ltd.

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          Summary

          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.

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          Most cited references1

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          Group sequential clinical trials with triangular continuation regions.

          In this paper a new class of group sequential procedures for clinical trials is introduced, and the use of these procedures is illustrated by reference to a recently completed comparative study. In a group sequential trial the decision to stop or to continue is made at regular intervals throughout the trial, but not as frequently as after every patient response. This more practical formulation retains most of the advantages of sequential analysis, particularly the economy in sample size. Comparisons are made with group sequential designs derived from the repeated significance test.
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            Author and article information

            Contributors
            Journal
            Lancet
            Lancet
            Lancet (London, England)
            Elsevier Ltd.
            0140-6736
            1474-547X
            29 April 2020
            29 April 2020
            Affiliations
            [a ]Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China
            [b ]Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
            [c ]Department of Respiratory Medicine, Capital Medical University, Beijing, China
            [d ]Jin Yin-tan Hospital, Wuhan, Hubei, China
            [e ]Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
            [f ]Wuhan Lung Hospital, Wuhan, China
            [g ]Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
            [h ]Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
            [i ]Wuhan Third Hospital, Wuhan, China
            [j ]Renmin Hospital of Wuhan University, Wuhan, China
            [k ]Zhongnan Hospital of Wuhan University, Wuhan, China
            [l ]Wuhan Fourth Hospital, Wuhan, China
            [m ]The Central Hospital of Wuhan, Wuhan, China
            [n ]Wuhan First Hospital, Wuhan, China
            [o ]Tsinghua University School of Medicine, Beijing, China
            [p ]Beijing University of Chinese Medicine, Beijing, China
            [q ]Tigermed Consulting, Hangzhou, China
            [r ]Teddy Clinical Research Laboratory, Shanghai, China
            [s ]Hangzhou DI'AN Medical Laboratory, Hangzhou, China
            [t ]Lancaster University, Lancaster, UK
            [u ]University of Cambridge, Cambridge, UK
            [v ]University of Virginia School of Medicine, Charlottesville, VA, USA
            [w ]International Severe Acute Respiratory and Emerging Infection Consortium, University of Oxford, Oxford, UK
            [x ]Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
            [y ]Tsinghua University–Peking University Joint Center for Life Sciences, Beijiing, China
            [z ]Peking Union Medical College, Beijing, China
            Author notes
            [* ]Correspondence to: Prof Bin Cao, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing 100029, China caobin_ben@ 123456163.com
            [** ]Prof Chen Wang, Peking Union Medical College, Beijing 100730, China wangchen@ 123456pumc.edu.cn
            [†]

            Contributed equally

            Article
            S0140-6736(20)31022-9
            10.1016/S0140-6736(20)31022-9
            7190303
            32423584
            e4e1426b-55d3-49f2-a6e9-376d9e827020
            © 2020 Elsevier Ltd. All rights reserved.

            Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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