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

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Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
The Lancet ( IF 168.9 ) Pub Date : 2020-04-29 , DOI: 10.1016/s0140-6736(20)31022-9
Yeming Wang ₁ , Dingyu Zhang ₂ , Guanhua Du ₃ , Ronghui Du ₄ , Jianping Zhao ₅ , Yang Jin ₆ , Shouzhi Fu ₇ , Ling Gao ₈ , Zhenshun Cheng ₉ , Qiaofa Lu ₁₀ , Yi Hu ₁₁ , Guangwei Luo ₁₂ , Ke Wang ₃ , Yang Lu ₃ , Huadong Li ₂ , Shuzhen Wang ₂ , Shunan Ruan ₂ , Chengqing Yang ₄ , Chunlin Mei ₄ , Yi Wang ₅ , Dan Ding ₅ , Feng Wu ₆ , Xin Tang ₆ , Xianzhi Ye ₇ , Yingchun Ye ₈ , Bing Liu ₉ , Jie Yang ₁₀ , Wen Yin ₁₁ , Aili Wang ₁₂ , Guohui Fan ₁₃ , Fei Zhou ₁₄ , Zhibo Liu ₁₄ , Xiaoying Gu ₁₃ , Jiuyang Xu ₁₅ , Lianhan Shang ₁₆ , Yi Zhang ₁₄ , Lianjun Cao ₁₇ , Tingting Guo ₁₇ , Yan Wan ₁₇ , Hong Qin ₁₈ , Yushen Jiang ₁₉ , Thomas Jaki ₂₀ , Frederick G Hayden ₂₁ , Peter W Horby ₂₂ , Bin Cao ₂₃ , Chen Wang ₂₄

Affiliation

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, 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.
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.
Tsinghua University School of Medicine, Beijing, China.
Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, 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.
Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China; Department of Respiratory Medicine, Capital Medical University, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China; Tsinghua University-Peking University Joint Center for Life Sciences, Beijiing, China.
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 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.

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.

更新日期：2020-04-29

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