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




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.


Discussion

Our trial found that intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of virus in patients with serious COVID-19 compared with placebo. Compared were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement. Ongoing controlled clinical trials are expected to confirm or refute our findings. In one murine model of SARS, remdesivir treatment starting at 2 days after infection, after virus replication and lung airway epithelial damage had already peaked, significantly reduced SARS-CoV-1 lung titres but did not decrease disease severity or mortality.13 A need for early treatment has been found in non-human primate models of SARS and MERS in which virus replication is very short-lived and lung pathology appears to develop more rapidly than in human infections.17,19 Such findings argue for testing of remdesivir earlier in COVID-19.Remdesivir did not result in significant reductions in SARS-CoV-2 RNA loads or detectability in upper respiratory tract or sputum specimens in this study despite showing strong antiviral effects in preclinical models of infection with coronaviruses. In African green monkey kidney Vero E6 cells, remdesivir inhibited SARS-CoV-2 with a 50% effective concentration (EC50) of 0·46 μg/mL and an EC90 of 1·06 μg/mL.6 In human nasal and bronchial airway epithelial cells, a fixed 20 μM (12·1 μg/mL) concentration reduced estimated intra-cellular viral titres over 7·0 log10 50% tissue culture infective dose per mLat 48 h.18 In human airway epithelial cells, the EC50 for remdesivir was 0·042 μg/mL for SARS-CoV and 0·045 μg/mL for MERS-CoV.13 In a murine model of MERS, subcutaneous remdesivir showed significant antiviral and clinical effects with a dose regimen that maintained plasma concentrations greater than 1 μM (0·60 μg/mL) throughout the dosing interval.13 In rhesus macaques, a 5 mg/kg dose, reported to be roughly equivalent to 100-mg daily dosing in humans, was effective for treatment of MERS-CoV infection and reduced pulmonary virus replication when started at 12 h after infection.18 Healthy adult volunteers receiving doses similar to our trial (200 mg on day 1, 100 mg on days 2–4) had mean peak plasma concentrations of 5·4 μg/mL (percentage coefficient of variation 20·3) on day 1 and 2·6 μg/mL (12·7) on day 5.24Doses of 150 mg/day for 14 days have been adequately tolerated in healthy adults, and a daily dose regimen of 150 mg for 3 days followed by 225 mg for 11 days appeared to be generally well tolerated in one patient with Ebola meningoencephalitis.25 However, the phar-macokinetics of remdesivir in severely ill patients, and particularly the concentrations of the active nucleotide metabolite (GS-441524) triphosphate in respiratory tract cells of treated patients, are unknown. Studies of higher-dose regimens for which there are safety data (eg, 150–200 mg daily doses) warrant consideration in severe COVID-19. Our study found that remdesivir was adequately tolerated and no new safety concerns were identified. The overall proportion of patients with serious adverse events tended to be lower in remdesivir recipients than placebo recipients. However, a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped by the investigators because of adverse events including gastro-intestinal symptoms (anorexia, nausea, and vomiting), aminotransferase or bilirubin increases, and worsened cardiopulmonary status.Limitations of our study include insufficient power to detect assumed differences in clinical outcomes, initiation of treatment quite late in COVID-19, and the absence of data on infectious virus recovery or on possible emer-gence of reduced susceptibility to remdesivir. Of note, in non-human primates, the inhibitory effects of remdesivir on infectious SARS-CoV-2 recovery in bronchoalveolar lavages were much greater than in controls, but viral RNA detection in upper and lower respiratory tract specimens were not consistently decreased versus controls.19 Coronaviruses partially resistant to inhibition by remdesivir (about six-times increased EC50) have been obtained after serial in vitro passage, but these viruses remain susceptible to higher remdesivir concentrations and show impaired fitness.26 The frequent use of corticosteroids in our patient group might have promoted viral replication, as observed in SARS27 and MERS,28although these studies only reported prolongation of the detection of viral RNA, not infectious virus. Furthermore, we have no answer to whether longer treatment course and higher dose of remdesivir would be beneficial in patients with severe COVID-19.In summary, we found that this dose regimen of intravenous remdesivir was adequately tolerated but did not provide significant clinical or antiviral effects in seriously ill patients with COVID-19. However, we could not exclude clinically meaningful differences and saw numerical reductions in some clinical parameters. Ongoing studies with larger sample sizes will continue to inform our understanding of the effect of remdesivir on COVID-19. Furthermore, strategies to enhance the antiviral potency of remdesivir (eg, higher-dose regimens, combination with other antivirals, or SARS-CoV-2 neu-tralising antibodies) and to mitigate immunopathological host responses contributing to COVID-19 severity (eg, inhibitors of IL-6, IL-1, or TNFα) require rigorous study in patients with severe COVID-19


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