Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial.

Background Tixagevimab and cilgavimab (AZD7442) are two monoclonal antibodies developed by AstraZeneca for the pre-exposure prophylaxis and treatment of patients infected by SARS-CoV-2. Its effectiveness and safety in patients hospitalized with COVID-19 was not known at the outset of this trial. Methods DisCoVeRy is a phase 3, adaptive, multicentre, randomized, controlled trial conducted in 63 sites in Europe. Participants were randomly assigned (1:1) to receive placebo or tixagevimab-cilgavimab in addition to standard of care. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale. Several clinical, virological, immunological and safety endpoints were also assessed. Findings Due to slow enrolment, recruitment was stopped on July 1st, 2022. The antigen positive modified intention-to-treat population (mITT) was composed of 173 participants randomized to tixagevimab-cilgavimab (n=91) or placebo (n=82), 91.9% (159/173) with supplementary oxygen, and 47.4% (82/173) previously vaccinated at inclusion. There was no significant difference in the distribution of the WHO ordinal scale at day 15 between the two groups (odds ratio (OR) 0.93, 95%CI [0.54-1.61]; p=0.81) nor in any clinical, virological or safety secondary endpoints. In the global mITT (n=226), neutralization antibody titers were significantly higher in the tixagevimab-cilgavimab group/patients compared to placebo at day 3 (Least-square mean differences (LSMD) 1.44, 95% Confidence interval (CI) [1.20-1.68]; p < 10-23) and day 8 (LSMD 0.91, 95%CI [0.64-1.18]; p < 10-8) and it was most important for patients infected with a pre-omicron variant, both at day 3 (LSMD 1.94, 95% CI [1.67-2.20], p < 10-25) and day 8 (LSMD 1.17, 95% CI [0.87-1.47], p < 10-9), with a significant interaction (p < 10-7 and p=0.01 at days 3 and 8, respectively). Interpretation There were no significant differences between tixagevimab-cilgavimab and placebo in clinical endpoints, however the trial lacked power compared to prespecified calculations. Tixagevimab-cilgavimab was well tolerated, with low rates of treatment related events. ### Competing Interest Statement M.H. reports grants from The Belgian Center for Knowledge (KCE), the Fonds Erasme-COVID-Université Libre de Bruxelles and the EU-Horizon program, for the submitted work; and has received support for attending meetings from Pfizer; support for participation on an advisory board for therapeutics on COVID-19; and support for leadership for the Belgian guidelines on therapeutics for COVID-19 and acting as a treasurer for the Belgian Society of Clinical Microbiology and Infectious Diseases. R.G. reports consulting fees from Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, Abbvie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankvo; lecture fees from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, Abbvie, Gilead, and Daiichi Sankvo; support for attending meetings from Roche, Amgen, Janssen, AstraZeneca, Novartis, Merck Sharp & Dohme, Celgene, Gilead, Bristol Myers Squibb, Abbvie, and Daiichi Sankvo; participation in a Data Safety and Monitoring Board for Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, Abbvie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankyo; research grants from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, Abbvie, Gilead, and Daiichi Sankyo. J.-A.P. reports consulting fees from Pfizer, Merck Sharp & Dohme, and Janssen-Cilag; lecture fees from Pfizer; and support for attending meetings from Pfizer. D.C. reports grants and lecture fees from Janssen and lecture fees from Gilead, outside the submitted work. C.B. reports participation in a Data Safety and Monitoring Board for 4Living Biotech; and consulting fees from Da Volterra and Mylan Pharmaceuticals, outside the submitted work. F.M. reports grants and consulting fees from Da Volterra, grants from Sanofi, and consulting fees from Ipsen, outside the submitted work. All other authors declare no competing interests. ### Clinical Trial NCT04315948 ### Funding Statement This work received funding from several sources: the European Commission (EU-Response, Grant 101015736), the DIM One Health Ile-de-France (R20117HD) and Astra-Zeneca. We thank all participants who consented to enroll in the trial, as well as all study and site staff whose indispensable assistance made the conduct of the DisCoVeRy trial possible (all listed in the appendix, pp 27-36) ### 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: Ethics committee of the BASG (Bundesamt fur Sicherheit im Gesundheitswesen), Austria, gave ethical approval for this work. Ethics committee of the FAMHP (Federal Agency for Medicines and Health Products), Belgium, gave ethical approval for this work. Ethics committee of the SUKL (Statni Ustav Pro Kontrolu Leciv), Czech Republic, gave ethical approval for this work. Ethics committee of the ANSM (Agence nationale de securite du medicament et des produits de sante), France, gave ethical approval for this work. Ethics committee of the National Organization for Medicines, Greece, gave ethical approval for this work. Ethics committee of the National Institute of Pharmacy and Nutrition (OGYEI), Hungary, gave ethical approval for this work. Ethics committee of the HPRA (Health Products Regulatory Authority), Ireland, gave ethical approval for this work. Ethics committee of the CNER (Comite National d Ethique de Recherche, ministere de la sante), Luxembourg, gave ethical approval for this work. Ethics committee of the NOMA (Norwegian Medical Products Agency), Norway, gave ethical approval for this work. Ethics committee of the Komisja Bioetyczna Przy Uniwersytecie Medycznym W Lodzi, Poland, gave ethical approval for this work. Ethics committee of the Infarmed (National Authority of Medicines and Health Products), Portugal, gave ethical approval for this work. Ethics committee of the SULK (Statni ustav pro kontrolu leciv), Slovakia, gave ethical approval for this work. Ethics committee of the AEMPS (Agencia Espanola de Medicamentos y Productos Sanitarios), Spain, gave 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes With publication, deidentified, individual participant data that underlie this Article, along with a data dictionary describing variables in the dataset, will be made available to researchers whose proposed purpose of use is approved by the DisCoVeRy Steering Committee. To request the dataset, please address directly to the corresponding author (florence.ader@chu-lyon.fr) or to the sponsor's representative (helene.esperou@inserm.fr) to obtain a data access form. All requests will be evaluated by the Trial Management Team and the DisCoVeRy Steering Committee. For accepted requests, data will be shared after signing a data transfer agreement with the study sponsor. Data will be shared directly or through access on the INSERM repository. Related documents, such as the study protocol, statistical analysis plan, and informed consent form, will be made available (with publication) on request to the corresponding author or to the sponsor's representative. The data will be open access for the informed consent form, protocol, and statistical analysis plan.