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