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

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. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. 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][1], 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 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. 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. ### Competing Interest Statement F.R. reports personal fees from Gilead Sciences, personal fees from MSD, personal fees from Pfizer, personal fees from TheraTechnologies, personal fees from ViiV Healthcare, outside the submitted work. F.G. reports grants from BioMerieux, personal fees and non-financial support from Gilead, non-financial support from Corevio, outside the submitted work. G.P. reports grants and personal fees from Gilead Sciences, grants and personal fees from Merck, grants and personal fees from ViiV Healthcare, grants and personal fees from TheraTechnologies, outside the submitted work. K.L. reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Y.Y. has nothing to disclose. He has been a board member receiving consultancy fees from ABBVIE, BMS, Gilead, MSD, J#x0026;J, Pfizer, and ViiV Healthcare, however all these activities have been stopped in the 03 past years. F.L. reports personal fees from Gilead, personal fees and non-financial support from MSD, non-financial support from Astellas, non-financial support from Eulmedica, outside the submitted work. A.K. reports personal fees from Baxter, personal fees from Aspen, personal fees from Aguettant, outside the submitted work. S.N. reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomerieux, personal fees from BioRad, outside the submitted work. F.D. reports personal fees from Gilead, outside the submitted work. J.N. reports non-financial support from MSD France, non-financial support from GILEAD Sciences, personal fees from PASCALEO, outside the submitted work. J.M. reports non-financial support from GILEAD, outside the submitted work. A.M. reports personal fees from MSD, personal fees from GILEAD, personal fees from JANSSEN, personal fees from Viiv Healthcare, outside the submitted work. M.H. reports grants from Fonds Erasme- COVID-Universite Libre de Bruxelles, grants from Belgian health Care Knowledge Center, during the conduct of the study; personal fees from Gilead advisory board on education on invasive fungal infections, personal fees from Pfizer: moderator for session on Isavuconazole, outside the submitted work. D.C. reports personal fees from Gilead, grants and personal fees from Janssen, outside the submitted work. C.B. reports personal fees from Da Volterra, personal fees from Mylan Pharmaceuticals, outside the submitted work. F.M. reports grants from Sanofi, grants and personal fees from Da Volterra, outside the submitted work. All other authors have nothing to disclose. ### Clinical Trial NCT04315948 ### Funding Statement The study was funded by Programme Hospitalier de Recherche Clinique (PHRC-20-0351) (Ministry of Health), from the DIM One Health Ile-de-France (R20117HD), and from REACTing, a French multi-disciplinary collaborative network working on emerging infectious diseases. Sanofi provided hydroxychloroquine, AbbVie provided lopinavir/ritonavir and Merck provided IFN-beta-1a, all free of charge. The funding sources had no role in the analysis of the data nor in the decision of publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The CPP Ile-de-France-IIIEthics Committee (#20.03.06.51744) waived ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04315948&atom=%2Fmedrxiv%2Fearly%2F2022%2F02%2F21%2F2022.02.16.22271064.atom