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Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

2021; Elsevier BV; Volume: 22; Issue: 2 Linguagem: Inglês

10.1016/s1473-3099(21)00485-0

1474-4457

Florence Ader, Maude Bouscambert‐Duchamp, Maya Hites, Nathan Peiffer‐Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Minh Patrick Lê, Gilles Peytavin, Thérèse Staub, Richard Greil, Jérémie Guedj, José Artur Paiva, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Alexander Egle, Richard Greil, Michael Joannidis, Bernd Lamprecht, Antoine Altdorfer, Leïla Belkhir, Vincent Fraipont, Maya Hites, Gil Verschelden, Jérôme Aboab, Florence Ader, Hafid Aït-Oufella, Claire Andréjak, Pascal Andreu, Laurent Argaud, Firouzé Bani‐Sadr, François Bénézit, Mathieu Blot, Élisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kévin Bouiller, Fanny Vardon‐Bounes, D. Boutoille, Alexandre Boyer, Cédric Bruel, André Cabie, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clère-Jehl, Johan Courjon, Flora Crockett, François Danion, Agathe Delbove, Jean Dellamonica, Félix Djossou, C Dubost, Alexandre Duvignaud, Olivier Épaulard, Loïc Epelboin, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Tristan Ferry, C. Ficko, Samy Figueiredo, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux‐Brunon, Sébastien Gallien, Denis Garot, Guillaume Géri, Sébastien Gibot, François Goehringer, Marie Gousseff, Didier Gruson, Yves Hansmann, O. Hinschberger, Stéphane Jauréguiberry, Vanessa Jean-Michel, Solen Kernéis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Jean‐Philippe Lanoix, Odile Launay, Bruno Laviolle, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefèvre, Sylvie Leroy, François‐Xavier Lescure, Henry Lessire, Benjamin Leveau, Paul Loubet, Alain Makinson, Denis Malvy, Charles‐Hugo Marquette, Guillaume Martin‐Blondel, M. Martinot, Julien Mayaux, Armand Mekontso Dessap, Ferhat Meziani, Jean‐Paul Mira, Jean‐Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, M. Murris‐Espin, Jean-Christophe Navellou, Saad Nseir, Walid Oulehri, Nathan Peiffer‐Smadja, Thomas Perpoint, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Julien Poissy, Valérie Pourcher, Jean‐Pierre Quenot, François Raffi, Jean Reignier, Matthieu Revest, Jean‐Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saïdani, N. Sayre, É. Senneville, Albert Sotto, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiéry, Jean‐François Timsit, V. Tolsma, Jean-Marie Turmel, Florent Valour, Florent Wallet, Guilhem Wattecamps, Yazdan Yazdanpanah, Yoann Zerbib, Marc J. Berna, Jean Reuter, Thérèse Staub, Sandra Bráz, Joao-Miguel Ferreira Ribeiro, José Artur Paiva, Roberto Roncon‐Albuquerque, Maude Bouscambert‐Duchamp, Alexandre Gaymard, Minh Patrick Lê, Bruno Lina, Gilles Peytavin, Sarah Tubiana, Sandrine Couffin‐Cadiergues, Hélène Esperou, Drifa Belhadi, Charles Burdet, Dominique Costagliola, Aline Dechanet, Christelle Delmas, Alpha Diallo, Claire Fougerou, Jérémie Guedj, France Mentré, Noémie Mercier, Marion Noret, Juliette Saillard, Priyanka Velou,

SARS-CoV-2 and COVID-19 Research

SummaryBackgroundThe antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support.MethodsDisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h 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. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948.FindingsBetween March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome).InterpretationNo clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support.FundingEuropean Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation.TranslationFor the French translation of the abstract see Supplementary Materials section.