Remdesivir in Adults With Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial
Journal: 2020/May - The Lancet
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.
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Lancet 395(10236): 1569-1578

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

+37 authors

Supplementary Material

Supplementary appendix:

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
Department of Respiratory Medicine, Capital Medical University, Beijing, China
Jin Yin-tan Hospital, Wuhan, Hubei, China
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Wuhan Lung Hospital, Wuhan, China
Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
Wuhan Third Hospital, Wuhan, China
Renmin Hospital of Wuhan University, Wuhan, China
Zhongnan Hospital of Wuhan University, Wuhan, China
Wuhan Fourth Hospital, Wuhan, China
The Central Hospital of Wuhan, Wuhan, China
Wuhan First Hospital, Wuhan, China
Tsinghua University School of Medicine, Beijing, China
Beijing University of Chinese Medicine, Beijing, China
Tigermed Consulting, Hangzhou, China
Teddy Clinical Research Laboratory, Shanghai, China
Hangzhou DI'AN Medical Laboratory, Hangzhou, China
Lancaster University, Lancaster, UK
University of Cambridge, Cambridge, UK
University of Virginia School of Medicine, Charlottesville, VA, USA
International Severe Acute Respiratory and Emerging Infection Consortium, University of Oxford, Oxford, UK
Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
Tsinghua University–Peking University Joint Center for Life Sciences, Beijiing, China
Peking Union Medical College, Beijing, China
Bin Cao: moc.361@neb_niboac; Chen Wang: nc.ude.cmup@nehcgnaw
Correspondence to: Prof Bin Cao, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing 100029, China moc.361@neb_niboac
Prof Chen Wang, Peking Union Medical College, Beijing 100730, China nc.ude.cmup@nehcgnaw
Contributed equally
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.

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.

Data are median (IQR), n (%), n/N (%), or mean (SE).

Data are median (IQR) or n (%).

Data are median (IQR), n (%), or n/N (%). Clinical improvement (the event) was defined as a decline of two categories on the modified seven-category ordinal scale of clinical status, or hospital discharge. OR=odds ratio.

Data are n (%) and include all events reported after antiviral treatment. Some patients had more than one adverse event. 36 patients discontinued the drug, 22 because of adverse events and 14 patients for other reasons (eg, hospital discharge or early death). COVID-19=coronavirus disease 2019.

We thank Gilead Sciences for providing the study drugs and Huyen Cao and Anu Osinusi for advice regarding safe use of remdesivir. We thank Joe Yao and Ella Lin for statistical consultation. We also thank members of the international data safety monitoring board (Jieming Qu [chair], Weichung Joe Shih, Robert Fowler, Rory Collins, and Chen Yao), independent statisticians (Xiaoyan Yan and Bin Shan), academic secretaries (Lingling Gao and Junkai Lai), and eDMC system providers (Tai Xie, Rong Ran, Peng Zhang, and Emily Wang) for their services. Roche Diagnostics (Shanghai) provided instruments and SARS-CoV-2 assay detection; SMO assistance was provided by Shanghai MedKey Med-Tech Development, Clinplus, Hangzhou SIMO, and MEDPISON. This work was supported by the Chinese Academy of Medical Sciences Emergency Project of COVID-19 (2020HY320001); Major Projects of National Science and Technology on New Drug Creation and Development (2020ZX09201012); the National Key Research and Development Program of China (2018YFC1200102); and the Beijing Science and Technology Project (Z19110700660000). TJ is funded by a National Institutes of Health Research (NIHR) Senior Research Fellowship (2015-08-001). PH is funded by the Wellcome Trust and the UK Department for International Development [215091/Z/18/Z], the Bill & Melinda Gates Foundation [OPP1209135], and NIHR [200907].

Contributors

BC, CW, and YeW had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. CW and BC decided to publish the paper. BC, CW, YeW, PWH, TJ, and FGH provided input on the trial design. BC, CW, YeW, FGH, and PWH were responsible for acquisition, analysis, and interpretation of data. YeW, FGH, PWH, and GF drafted the manuscript. BC, CW, PWH, FGH, GF, TJ, and XG critically revised the manuscript. YeW contributed to statistical analysis. GF gave valuable suggestions for data analysis. All authors contributed to conducting the trial.

Declaration of interests

FGH has served as non-compensated consultant to Gilead Sciences on its respiratory antiviral programme, outside the submitted work. All other authors declare no competing interests.

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