Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial

Abstract

Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring. Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948, EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-beta-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population. Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420). At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29). Interpretation: Remdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15. Funding: European Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER "European Regional Development Fund", Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.

Remdesivir: A Review in COVID-19

“…The randomized, open-label, multinational, phase III DisCoVeRy trial, a European substudy of WHO SOLIDARITY, enrolled adults (≥ 18 years of age) hospitalized with COVID-19 who were in need of oxygen or ventilator support [ 38 , 39 ]. All patients had confirmed SARS-CoV-2 infection and presented with at least one of the following: evidence of rales or crackles on clinical examination and oxygen saturation of ≤ 94% on room air; or requirement of supplemental oxygen, high-flow oxygen, NIV or mechanical ventilation.…”

“…At baseline, the median age of patients was 64 years, and the most common co-existing conditions were obesity (34%), chronic cardiac disease (28%) and diabetes (27%). The primary endpoint was clinical status at day 15, as measured on a 7-point ordinal scale from 1 (not hospitalized, no limitation on activities) to 7 (death) [ 38 , 39 ].…”

“…Remdesivir plus SOC had no clinical benefit in hospitalized patients with COVID-19 who required oxygen support [ 38 ]. There was no significant difference between remdesivir plus SOC and SOC alone in the distribution of the 7-point ordinal scale at day 15 (OR 1.02; 95% CI 0.62–1.70) or at day 29 (OR 1.11; 95% CI 0.87–1.43).…”

Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19

“…This finding was consistent across all prespecified subgroup analyses. 2

Figure Clinical status at day 15 of patients included in the intention-to-treat population As measured by the 7-point ordinal scale. Reported numbers refer to the proportion of patients with the corresponding level in each group.

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“…Full results regarding secondary outcomes are available elsewhere. 2 Two secondary endpoints were not previously reported: in-hospital mortality and mortality at 3 months after randomisation. Remdesivir did not have a significant effect on in-hospital mortality (33 of 420 participants in the remdesivir group vs 38 of 423 participants in the control group; adjusted OR 0·84 [95% CI 0·51–1·37]; p=0·48), nor on mortality at 3 months (43 of 420 vs 49 of 423; 0·87 [0·56–1·36]; p=0·55).…”