Trial of Treatments for COVID-19 in Hospitalized Adults

Summary

DisCoVeRy is a randomized controlled trial among adults (≥18-year-old) hospitalized for COVID-19. This study is an adaptive, randomized, open or blinded, depending on the drug to be evaluated, clinical trial to evaluate the safety and efficacy of possible therapeutic agents in hospitalized adult patients diagnosed with COVID-19. The study is a multi-centre/country trial that will be conducted in various sites in Europe with Inserm as sponsor. The study will compare different investigational therapeutic agents to a control group managed with the SoC including corticosteroids and anticoagulants. There will be interim monitoring to allow early stopping for safety and to introduce new therapies as they become available. If one therapy proves to be superior to others in the trial, this treatment may become part of the SoC for comparison(s) with new experimental treatment(s). In previous versions of the DisCoVeRy protocol, remdesivir, lopinavir/ritonavir with or without interferon ß-1a and hydroxychloroquine were evaluated as potential treatments for COVID-19. These treatments have been discontinued based on analyses review by both DSMC/DSMB, the Solidarity Executive Group and the DisCoVeRy steering committee. This version of the protocol, therefore, describes a randomized blinded placebo-controlled trial among adults (≥18-year-old) hospitalized for COVID-19 that randomly allocates them (1:1 ratio) between 2 arms: SoC + placebo versus SoC + AZD7442. Randomization will be stratified by region (according to the administrative definition in each country), antigenic status (positive or negative) obtained from the result of a rapid antigen test on nasopharyngeal swab performed at enrolment and vaccination initiation (yes or no). The primary analyses will be conducted on patients with antigen-positive results. A positive antigenic test is evidence of high viral shedding consistent with a recently started or uncontrolled infection. Overall, the number of antigen-negative patients will be at most 30% of all included subjects. The number of patients with vaccination (partly or fully) will be limited to 20% of all participants, split evenly between antigen positive and antigen negative patients (i.e. vaccinated patients can make up at most 20% of antigene positive patients and 20% of antigene negative patients). Sensitivity analyses will be performed in all patients, stratified by antigenic status and vaccination initiation. A global independent data and safety monitoring board (DSMB) monitors interim data to make recommendations about early study closure or changes to conduct, including adding or removing treatment arms. However, the current version of the protocol does not allow for efficacy or futility analysis, and the ability to add trial arms will be limited by the study being blinded and placebo-controlled during the investigation of AZD7442.

Timeline

Start

2020-03-22

Primary completion

2022-07-09

Completion

2023-09-25

Publications

• Background Ader F; Discovery French Trial Management Team. Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults. BMJ Open. 2020 Sep 21;10(9):e041437. doi: 10.1136/bmjopen-2020-041437.
• Background EU-Response investigators group; Diallo A, Troseid M, Simensen VC, Boston A, Demotes J, Olsen IC, Chung F, Paiva JA, Hites M, Ader F, Arribas JR, Baratt-Due A, Melien O, Tacconelli E, Staub T, Greil R, Tsiodras S, Briel M, Esperou H, Mentre F, Eustace J, Saillard J, Delmas C, LeMestre S, Dumousseaux M, Costagliola D, Rottingen JA, Yazdanpanah Y. Accelerating clinical trial implementation in the context of the COVID-19 pandemic: challenges, lessons learned and recommendations from DisCoVeRy and the EU-SolidAct EU response group. Clin Microbiol Infect. 2022 Jan;28(1):1-5. doi: 10.1016/j.cmi.2021.10.011. Epub 2021 Nov 8. No abstract available.
• Background Troseid M, Hentzien M, Ader F, Cardoso SW, Arribas JR, Molina JM, Mueller N, Hites M, Bonnet F, Manuel O, Costagliola D, Grinsztejn B, Olsen IC, Yazdapanah Y, Calmy A; EU RESPONSE; COMBINE. Immunocompromised patients have been neglected in COVID-19 trials: a call for action. Clin Microbiol Infect. 2022 Sep;28(9):1182-1183. doi: 10.1016/j.cmi.2022.05.005. Epub 2022 May 25. No abstract available.
• Background Terzic V, Levoyer L, Figarella M, Bigagli E, Mercier N, De Gastines L, Gibowski S, Troseid M, Demotes J, Olsen IC, Hites M, Ader F, Lopez JRA, Mentre F, Esperou H, Costagliola D, Rottingen JA, Poissy J, Roze JC, Warris A, O'Leary J, Fernandes RM, Assoumou L, Hankard R, Turner MA, Yazdanpanah Y, Diallo A; EU-Response safety group; c4c safety group. Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia. Br J Clin Pharmacol. 2023 Apr;89(4):1318-1328. doi: 10.1111/bcp.15669. Epub 2023 Feb 8.
• Background Amstutz A, Speich B, Mentre F, Rueegg CS, Belhadi D, Assoumou L, Burdet C, Murthy S, Dodd LE, Wang Y, Tikkinen KAO, Ader F, Hites M, Bouscambert M, Trabaud MA, Fralick M, Lee TC, Pinto R, Barratt-Due A, Lund-Johansen F, Muller F, Nevalainen OPO, Cao B, Bonnett T, Griessbach A, Taji Heravi A, Schonenberger C, Janiaud P, Werlen L, Aghlmandi S, Schandelmaier S, Yazdanpanah Y, Costagliola D, Olsen IC, Briel M. Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials. Lancet Respir Med. 2023 May;11(5):453-464. doi: 10.1016/S2213-2600(22)00528-8. Epub 2023 Feb 21.
• Background Le MP, Peiffer-Smadja N, Guedj J, Neant N, Mentre F, Ader F, Yazdanpanah Y, Peytavin G. Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial. J Antimicrob Chemother. 2020 Sep 1;75(9):2376-2380. doi: 10.1093/jac/dkaa191.
• Background Le MP, Peiffer-Smadja N, Guedj J, Neant N, Mentre F, Ader F, Yazdanpanah Y, Peytavin G; C-20-15 DisCoVeRy French Steering Committee. Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial-authors' response. J Antimicrob Chemother. 2021 Jan 1;76(1):277-279. doi: 10.1093/jac/dkaa415. No abstract available.
• Background Mercier N, Belhadi D, DeChanet A, Delmas C, Saillard J, Dumousseaux M, Le Mestre S, Fougerou-Leurent C, Ferrane A, Burdet C, Esperou H, Ader F, Hites M, Peiffer-Smadja N, Poissy J, Andrejak C, Paiva JA, Tacconelli E, Staub T, Greil R, Costagliola D, Mentre F, Yazdanpanah Y, Diallo A; DisCoVeRy Safety Working group. Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial. Pharmacol Res Perspect. 2023 Jun;11(3):e01072. doi: 10.1002/prp2.1072.
• Background Fougerou-Leurent C, Delmas C, Saillard J, Dumousseaux M, Ferrane A, Mercier N, Terzic V, Le Mestre S, Dechanet A, Belhadi D, Metois A, Burdet C, Mentre F, Noret M, Diallo A, Petrov-Sanchez V, Couffin-Cadiergues S, Hites M, Ader F, Esperou H. Ensuring quality control in a COVID-19 clinical trial during the pandemic: The experience of the Inserm C20-15 DisCoVeRy study. Contemp Clin Trials. 2023 Aug;131:107267. doi: 10.1016/j.cct.2023.107267. Epub 2023 Jun 9.
• Background Beaulieu M, Gaymard A, Massonnaud C, Peiffer-Smadja N, Bouscambert-Duchamp M, Carcelain G, Lingas G, Mentre F, Ader F, Hites M, Poignard P, Guedj J. Antiviral effect of Evusheld in COVID-19 hospitalized patients infected with pre-Omicron or Omicron variants: a modelling analysis of the randomized DisCoVeRy trial. J Antimicrob Chemother. 2024 Nov 4;79(11):2887-2895. doi: 10.1093/jac/dkae301.
• Background Siempos II, Kalil AC, Belhadi D, Veiga VC, Cavalcanti AB, Branch-Elliman W, Papoutsi E, Gkirgkiris K, Xixi NA, Kotanidou A, Hermine O, Porcher R, Mariette X; CORIMUNO-19 Collaborative Group; DisCoVeRy Study Group; ACTT-2 Study Group; ACTT-3 Study Group. Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials. EClinicalMedicine. 2024 Feb 9;69:102472. doi: 10.1016/j.eclinm.2024.102472. eCollection 2024 Mar.
• Background Smadja DM, Massonnaud CR, Philippe A, Rosa M, Luneau S, Rauch A, Peiffer-Smadja N, Gagneux-Brunon A, Poissy J, Gruest M, Ung A, Pourcher V, Raffi F, Piroth L, Bouiller K, Esperou H, Delmas C, Belhadi D, Diallo A, Saillard J, Dechanet A, Mercier N, Dupont A, Lescure FX, Goehringer F, Jaureguiberry S, Danion F, Tolsma V, Cabie A, Courjon J, Leroy S, Mootien J, Mourvillier B, Gallien S, Lanoix JP, Botelho-Nevers E, Wallet F, Richard JC, Reuter J, Gaymard A, Greil R, Martin-Blondel G, Andrejak C, Yazdanpanah Y, Burdet C, Diehl JL, Hites M, Ader F, Susen S, Mentre F, Dupont A; Discovery Study Group. sST2 is a key outcome biomarker in COVID-19: insights from discovery randomized trial. Sci Rep. 2025 Apr 24;15(1):14348. doi: 10.1038/s41598-025-95122-7.
• Background Massonnaud CR, Hites M, Peiffer-Smadja N, Rancic J, Yazdanpanah Y, Luneau S, Dupont A, Delmas C, Diehl JL, Philippe A, Susen S, Mentre F, Ader F, Smadja DM; DisCoVeRy Study group. Hydroxychloroquine does not affect endotheliopathy or coagulopathy biomarkers in COVID-19: longitudinal results from the DisCoVeRy randomized trial. Angiogenesis. 2025 Dec 7;29(1):8. doi: 10.1007/s10456-025-10023-7.
• Background Gendron N, Rial C, Massonnaud CR, Nguyen A, Philippe A, Rus K, Nunes H, Sanchez O, Diehl JL, Peiffer-Smadja N, Hites M, Rancic J, Yazdanpanah Y; DisCoVeRy Study Group; Mentre F, Ader F, Israel-Biet D, Espitia O, Smadja DM. Plasma CXCL13 and fibrosis biomarkers in COVID-19 compared with idiopathic pulmonary fibrosis. Sci Rep. 2026 Jun 25. doi: 10.1038/s41598-026-55451-7. Online ahead of print.
• Results Marchal A, Kerdiles T, Perrin A, Gervais A, Bastard P, Bizien L, Lingas G, Massonnaud CR, Bouscambert-Duchamp M, Gaymard A, Peiffer-Smadja N, Mentre F, Guedj J, Abel L, Casanova JL, Puel A, Hites M, Ader F, Bertrand J, Cobat A; DisCoVeRy Study Group. High Nasopharyngeal SARS-CoV-2 Load and Delayed Clearance in Hospitalized Patients With Blood Autoantibodies Neutralizing Type I Interferons. J Infect Dis. 2026 Apr 29:jiag172. doi: 10.1093/infdis/jiag172. Online ahead of print.
• Results WHO Solidarity Trial Consortium; Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernandez Garcia C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, Garcia PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portoles A, Rasmin MR, Raza A, Rees H, Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen KAO, Trelle S, Zaid H, Rottingen JA, Swaminathan S. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2.
• Results 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 FX, Raffi F, Goehringer F, Kimmoun A, Jaureguiberry S, Reignier J, Nseir S, Danion F, Clere-Jehl R, Bouiller K, Navellou JC, 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 JP, Makinson A, Martin-Blondel G, Bouadma L, Botelho-Nevers E, Gagneux-Brunon A, Epaulard O, Piroth L, Wallet F, Richard JC, Reuter J, Staub T, Lina B, Noret M, Andrejak C, Le MP, Peytavin G, Hites M, Costagliola D, Yazdanpanah Y, Burdet C, Mentre F; DisCoVeRy study group. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin Microbiol Infect. 2021 Dec;27(12):1826-1837. doi: 10.1016/j.cmi.2021.05.020. Epub 2021 May 26.
• Results Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Poissy J, Belhadi D, Diallo A, Le MP, Peytavin G, Staub T, Greil R, Guedj J, Paiva JA, Costagliola D, Yazdanpanah Y, Burdet C, Mentre F; DisCoVeRy Study Group. 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. Lancet Infect Dis. 2022 Feb;22(2):209-221. doi: 10.1016/S1473-3099(21)00485-0. Epub 2021 Sep 14.
• Results Lingas G, Neant N, Gaymard A, Belhadi D, Peytavin G, Hites M, Staub T, Greil R, Paiva JA, Poissy J, Peiffer-Smadja N, Costagliola D, Yazdanpanah Y, Wallet F, Gagneux-Brunon A, Mentre F, Ader F, Burdet C, Guedj J, Bouscambert-Duchamp M. Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial. J Antimicrob Chemother. 2022 Apr 27;77(5):1404-1412. doi: 10.1093/jac/dkac048.
• Results Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Mentre F, Burdet C; DisCoVeRy Study Group. Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19. Lancet Infect Dis. 2022 Jun;22(6):764-765. doi: 10.1016/S1473-3099(22)00295-X. No abstract available.
• Results Ader F; DisCoVeRy Study Group. An open-label randomized, controlled trial of the effect of lopinavir and ritonavir, lopinavir and ritonavir plus interferon-beta-1a, and hydroxychloroquine in hospitalized patients with COVID-19: final results. Clin Microbiol Infect. 2022 Sep;28(9):1293-1296. doi: 10.1016/j.cmi.2022.04.016. Epub 2022 May 7. No abstract available.
• Results Neant N, Lingas G, Gaymard A, Belhadi D, Hites M, Staub T, Greil R, Paiva JA, Poissy J, Peiffer-Smadja N, Costagliola D, Yazdanpanah Y, Bouscambert-Duchamp M, Gagneux-Brunon A, Ader F, Mentre F, Wallet F, Burdet C, Guedj J; DisCoVeRy study group. Association between SARS-CoV-2 viral kinetics and clinical score evolution in hospitalized patients. CPT Pharmacometrics Syst Pharmacol. 2023 Dec;12(12):2027-2037. doi: 10.1002/psp4.13051. Epub 2023 Oct 11.
• Results WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. 2022 May 21;399(10339):1941-1953. doi: 10.1016/S0140-6736(22)00519-0. Epub 2022 May 2.
• Results Hites M, Massonnaud CR, Lapique EL, Belhadi D, Jamard S, Goehringer F, Danion F, Reignier J, de Castro N, Garot D, Lacombe K, Tolsma V, Faure E, Malvy D, Staub T, Courjon J, Cazenave-Roblot F, Dyrhol Riise AM, Leturnier P, Martin-Blondel G, Roger C, Akinosoglou K, Moing VL, Piroth L, Sellier P, Lescure X, Troseid M, Clevenbergh P, Dalgard O, Gallien S, Gousseff M, Loubet P, Vardon-Bounes F, Visee C, Belkhir L, Botelho-Nevers E, Cabie A, Kotanidou A, Lanternier F, Rouveix-Nordon E, Silva S, Thiery G, Poignard P, Carcelain G, Diallo A, Mercier N, Terzic V, Bouscambert-Duchamp M, Gaymard A, Trabaud MA, Destras G, Josset L, Billard N, Han TH, Guedj J, Couffin-Cadiergues S, Dechanet A, Delmas C, Esperou H, Fougerou-Leurent C, Mestre SL, Metois A, Noret M, Bally I, Dergan-Dylon S, Tubiana S, Kalif O, Bergaud N, Leveau B, Eustace J, Greil R, Hajdu E, Halanova M, Paiva JA, Piekarska A, Rodriguez Bano J, Tonby K, Trojanek M, Tsiodras S, Unal S, Burdet C, Costagliola D, Yazdanpanah Y, Peiffer-Smadja N, Mentre F, Ader F; DisCoVeRy study group. Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial. J Infect. 2024 Mar;88(3):106120. doi: 10.1016/j.jinf.2024.106120. Epub 2024 Feb 16. No abstract available.
• Results Terzic V, Miantezila Basilua J, Billard N, de Gastines L, Belhadi D, Fougerou-Leurent C, Peiffer-Smadja N, Mercier N, Delmas C, Ferrane A, Dechanet A, Poissy J, Esperou H, Ader F, Hites M, Andrejak C, Greil R, Paiva JA, Staub T, Tacconelli E, Burdet C, Costagliola D, Mentre F, Yazdanpanah Y, Diallo A; DisCoVeRy Study Group. Cardiac Adverse Events and Remdesivir in Hospitalized Patients With COVID-19: A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial. Clin Infect Dis. 2024 Aug 16;79(2):382-391. doi: 10.1093/cid/ciae170.
• Results Massonnaud CR, Peiffer-Smadja N, Poignard P, Jamard S, Goehringer F, Danion F, Reignier J, de Castro N, Garot D, Lapique EL, Lacombe K, Tolsma V, Faure E, Malvy D, Staub T, Courjon J, Cazenave-Roblot F, Dyrhol Riise AM, Leturnier P, Martin-Blondel G, Roger C, Akinosoglou K, Le Moing V, Piroth L, Sellier P, Lescure X, Troseid M, Clevenbergh P, Dalgard O, Gallien S, Gousseff M, Loubet P, Vardon-Bounes F, Visee C, Belkhir L, Botelho-Nevers E, Cabie A, Kotanidou A, Lanternier F, Rouveix-Nordon E, Silva S, Thiery G, Carcelain G, Diallo A, Mercier N, Terzic V, Bouscambert-Duchamp M, Gaymard A, Destras G, Josset L, Belhadi D, Billard N, Guedj J, Han TH, Couffin-Cadiergues S, Dechanet A, Delmas C, Esperou H, Fougerou-Leurent C, Le Mestre S, Metois A, Noret M, Bally I, Dergan-Dylon S, Tubiana S, Kalif O, Bergaud N, Leveau B, Eustace J, Greil R, Hajdu E, Halanova M, Paiva JA, Piekarska A, Bano JR, Tonby K, Trojanek M, Tsiodras S, Unal S, Burdet C, Costagliola D, Yazdanpanah Y, Mentre F, Ader F, Hites M; DisCoVeRy study group. Efficacy, safety, pharmacokinetics, immunogenicity, and serum neutralizing activity of AZD7442 (tixagevimab-cilgavimab) in patients hospitalized with COVID-19: long-term results from the DisCoVeRy trial. Clin Microbiol Infect. 2026 Apr;32(4):618-628. doi: 10.1016/j.cmi.2025.12.014. Epub 2025 Dec 20.
• Grundeis F, Ansems K, Dahms K, Thieme V, Metzendorf MI, Skoetz N, Benstoem C, Mikolajewska A, Griesel M, Fichtner F, Stegemann M. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev. 2023 Jan 25;1(1):CD014962. doi: 10.1002/14651858.CD014962.pub2.
• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• Ansems K, Grundeis F, Dahms K, Mikolajewska A, Thieme V, Piechotta V, Metzendorf MI, Stegemann M, Benstoem C, Fichtner F. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD014962. doi: 10.1002/14651858.CD014962.
• Taccone FS, Gorham J, Vincent JL. Hydroxychloroquine in the management of critically ill patients with COVID-19: the need for an evidence base. Lancet Respir Med. 2020 Jun;8(6):539-541. doi: 10.1016/S2213-2600(20)30172-7. Epub 2020 Apr 15. No abstract available.

Drugs

Indications