An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19 – Final results from the DisCoVeRy trial
Authors: Ader Florence , Peiffer-Smadja Nathan , Poissy Julien , Bouscambert-Duchamp Maude , Belhadi Drifa , Diallo Alpha , Delmas Christelle , Saillard Juliette , Dechanet Aline , Mercier Noémie , Dupont Axelle , Alfaiate Toni , Lescure François-Xavier , Raffi François , Goehringer François , Kimmoun Antoine , Jaureguiberry Stéphane , Reignier Jean , Nseir Saad , Danion François , Clere-Jehl Raphael , Bouiller Kévin , Navellou Jean-Christophe , Tolsma Violaine , Cabie André , Dubost Clément , Courjon Johan , Leroy Sylvie , Mootien Joy , Gaci Rostane , Mourvillier Bruno , Faure Emmanuel , Pourcher Valérie , Gallien Sébastien , Launay Odile , Lacombe Karine , Lanoix Jean-Philippe , Makinson Alain , Martin-Blondel Guillaume , Bouadma Lila , Botelho-Nevers Elisabeth , Gagneux-Brunon Amandine , Epaulard Olivier , Piroth Lionel , Wallet Florent , Richard Jean-Christophe , Reuter Jean , Staub Thérèse , Lina Bruno , Noret Marion , Andrejak Claire , Lê Minh Patrick , Peytavin Gilles , Hites Maya , Costagliola Dominique , Yazdanpanah Yazdan , Burdet Charles , Mentre France 
Published: February 2022

AbstractObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring.MethodsWe conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely.ResultsThe intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.