Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

ADER, F.; PEIFFER-SMADJA, N.; POISSY, J.; BOUSCAMBERT-DUCHAMP, M.; BELHADI, D.; DIALLO, A.; DELMAS, C.; SAILLARD, J.; DECHANET, A.; MERCIER, N.; DUPONT, A.; ALFAIATE, T.; LESCURE, F.-X.; RAFFI, F.; GOEHRINGER, F.; KIMMOUN, A.; JAUREGUIBERRY, S.; REIGNIER, J.; NSEIR, S.; DANION, F.; CLERE-JEHL, R.; BOUILLER, K.; NAVELLOU, J.-C.; TOLSMA, V.; CABIE, A.; DUBOST, C.; COURJON, J.; LEROY, S.; MOOTIEN, J.; GACI, R.; MOURVILLIER, B.; FAURE, E.; POURCHER, V.; GALLIEN, S.; LAUNAY, O.; LACOMBE, K.; LANOIX, J.-P.; MAKINSON, A.; MARTIN-BLONDEL, G.; BOUADMA, L.; BOTELHO-NEVERS, e.; GAGNEUX-BRUNON, A.; EPAULA,

Background: Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective: To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design: Open-label, randomized, adaptive, controlled trial. Setting: Multi-center trial with patients from France. Participants: 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention: Standard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-beta-1a (44 micrograms of subcutaneous IFN-beta-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). Measurements: 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 and safety analyses. Results: Adjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-beta-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. Limitations: Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion: No improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. Registration: NCT04315948. Funding: PHRC 2020, Dim OneHealth, REACTing