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

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

OBJECTIVES: We 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. METHODS: We 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. RESULTS: The intention-to-treat population included 583 participants (lopinavir/ritonavir, n=145; lopinavir/ritonavir-IFN-β-1a, n=145; hydroxychloroquine, n=145; control, n=148), among whom 418 (71.7%) were male, the median age was 63 years (IQR, 54-71) and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval [CI] 0.55-1.26, P=0.39); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, P=0.08); hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, P=0.75). 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. CONCLUSION: In 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.