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Randomized Controlled Trial
. 2020 May 16;395(10236):1569-1578.
doi: 10.1016/S0140-6736(20)31022-9. Epub 2020 Apr 29.

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

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
Affiliations
Randomized Controlled Trial

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

Yeming Wang et al. Lancet. .

Erratum in

  • Department of Error.
    [No authors listed] [No authors listed] Lancet. 2020 May 30;395(10238):1694. doi: 10.1016/S0140-6736(20)31204-6. Lancet. 2020. PMID: 32473675 Free PMC article. No abstract available.

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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Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Time to clinical improvement in the intention-to-treat population Adjusted hazard ratio for randomisation stratification was 1·25 (95% CI 0·88–1·78). *Including deaths before day 28 as right censored at day 28, the number of patients without clinical improvement was still included in the number at risk.
Figure 3
Figure 3
Viral load by quantitative PCR on the upper respiratory tract specimens (A) and lower respiratory tract specimens (B) Data are mean (SE). Results less than the lower limit of quantification of the PCR assay and greater than the limit of qualitative detection are imputed with half of actual value; results of patients with viral-negative RNA are imputed with 0 log10 copies per mL.
See this image and copyright information in PMC

Comment in

  • Remdesivir for COVID-19: challenges of underpowered studies.
    Norrie JD. Norrie JD. Lancet. 2020 May 16;395(10236):1525-1527. doi: 10.1016/S0140-6736(20)31023-0. Epub 2020 Apr 29. Lancet. 2020. PMID: 32423580 Free PMC article. No abstract available.
  • COVID-19 Therapeutics: Making Sense of It All.
    Bakare LS, Allen JM. Bakare LS, et al. AACN Adv Crit Care. 2020 Sep 15;31(3):239-249. doi: 10.4037/aacnacc2020792. AACN Adv Crit Care. 2020. PMID: 32668460 No abstract available.
  • Remdesivir and COVID-19: What are the implications for Africa?
    Green RJ, Mustafa F, Sewlall N, Richards GA. Green RJ, et al. S Afr Med J. 2020 May 7;110(6):12942. S Afr Med J. 2020. PMID: 32880546 No abstract available.
  • Remdesivir and COVID-19.
    Glaus MJ, Von Ruden S. Glaus MJ, et al. Lancet. 2020 Oct 3;396(10256):952. doi: 10.1016/S0140-6736(20)32021-3. Lancet. 2020. PMID: 33010831 Free PMC article. No abstract available.
  • Remdesivir and COVID-19.
    Edwards JK, Cole SR, Adimora AA. Edwards JK, et al. Lancet. 2020 Oct 3;396(10256):953. doi: 10.1016/S0140-6736(20)32020-1. Lancet. 2020. PMID: 33010832 Free PMC article. No abstract available.
  • Remdesivir and COVID-19.
    Wang LY, Cui JJ, Ouyang QY, Zhan Y, Guo CX, Yin JY. Wang LY, et al. Lancet. 2020 Oct 3;396(10256):953-954. doi: 10.1016/S0140-6736(20)32019-5. Lancet. 2020. PMID: 33010833 Free PMC article. No abstract available.
  • The place for remdesivir in COVID-19 treatment.
    Young B, Tan TT, Leo YS. Young B, et al. Lancet Infect Dis. 2021 Jan;21(1):20-21. doi: 10.1016/S1473-3099(20)30911-7. Epub 2020 Nov 26. Lancet Infect Dis. 2021. PMID: 33248473 Free PMC article. No abstract available.

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