Tixagevimab/Cilgavimab for Treatment of Hospitalised COVID-19 Patients: A Randomised, Double-Blind, Phase 3 Trial

Abstract

Background: Tixagevimab/cilgavimab is a neutralising monoclonal antibody combination hypothesized to improve outcomes for hospitalised COVID-19 patients.

Methods: In a phase 3, blinded, randomised, placebo-controlled trial, adults hospitalised for COVID-19 at 81 sites on four continents were assigned to receive intravenous tixagevimab 300 mg/cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Key secondary outcomes included 90-day mortality and a composite safety outcome (death, serious adverse events, organ failure, and serious co-infection) through day 90. Efficacy and safety analyses were performed in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab/cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978.

Findings: From February 10 to September 30, 2021, 1455 patients were randomised and 1417 in the primary modified intention-to-treat population were infused with tixagevimab/cilgavimab (n=710) or placebo (n=707). By day 90, sustained recovery was achieved by 617 (87%) tixagevimab/cilgavimab and 595 (84%) placebo group participants in the full cohort (rate ratio 1.08; 95%CI, 0.97-1.20; p=0.21). Results were similar in the seronegative subgroup (rate ratio 1.14; 95%CI, 0.97-1.34; p=0.13). Mortality was lower in the tixagevimab/cilgavimab (61 [8.6%]) versus placebo (86 [12.2%]) group (hazard ratio 0.70; 95%CI, 0.50-0.97; p=0.03). The composite safety outcome occurred in 178 (25%) tixagevimab/cilgavimab and 212 (30%) placebo group participants (hazard ratio 0.83, 95%CI 0.68-1.01; p=0.06). Serious adverse events occurred in 34 (4.8%) tixagevimab/cilgavimab and 38 (5.4%) placebo group participants.

Interpretation: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab/cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.

Trial Registration: This study is registered with ClinicalTrials.gov, NCT04501978.

Funding: Supported by the U.S. Operation Warp Speed program, the National Institute of Allergy and Infectious Diseases and Leidos Biomedical Research for the INSIGHT Network, the National Heart, Lung, and Blood Institute (NHLBI) and the Research Triangle Institute for the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network and the Cardiothoracic Surgical Trials Network (CTSN), the U.S. Department of Veterans Affairs, and grants from the governments of Denmark (no. 126 from the National Research Foundation), Australia (from the National Health and Medical Research Council), the United Kingdom (MRC_UU_12023/23 from the Medical Research Council), and Singapore (COVID19RF-005 from the National Medical Research Council). The research was, in part, funded by National Institutes of Health (NIH) Agreement 1OT2HL156812-01 and National Cancer Institute (NCI) contract 75N91019D00024, task order number 75N91020F00039.

Declaration of Interest: TLH reports consulting fees from Lysovant, royalties for topic authorship, and participation on a Staphylococcus Aureus Network Adaptive Platform (SNAP) Trial Data and Safety Monitoring Board (DSMB), outside of the submitted work. AAG reports grants from US National Institutes of Health (NIH) during the conduct of the study, grants from US Centers for Disease Control (CDC), US Department of Defense (DOD), Abbvie, and Faron Pharmaceuticals, and participation on a NIH DSMB, outside of the submitted work. RP reports grants from Gilead, ViiV, and MSD and consulting fees from Gilead, ViiV, MSD, Theratechnologies, and Eli Lilly, outside of the submitted work. TAM reports grants from National Institute of Allergies and Infectious Diseases (NIAID), NIH, and Leidos, outside of the submitted work. GAG reports partial salary support from NIH through the University of Minnesota during the conduct of the study. US reports grants from ViiV, Cytodyn, NIAID, and Cardiothoracic Surgical Trial Network (CTSN), consulting fees from ViiV and Shionogi, and payment for educational events from Paratek and Shionogi, outside of the submitted work. RLG reports contracts from Regeneron, consulting fees from Gilead and GSK Pharmaceuticals, participation on advisory boards for Eli Lilly, Gilead, GSK, Johnson and Johnson, Roche/Genentech, and Kinevant Sciences, stock in AbCellera, and receipt of drugs from Gilead, outside of the submitted work. MKJ reports grants from Gilead, participation on an advisory board for Gilead, and a Board of Director position with HIV Medication Association, outside of the submitted work. LM reports payment for educational events from Merck, travel support from Merck and Gilead, and participation on an advisory board for Merck, outside of the submitted work. EM reports grants from NIAID and NIH, outside of the submitted work. KK reports grants and contracts with NIH, Regeneron, Abbott, Pfizer, Romark, and Raisonance, consulting fees from Regeneron, travel support from Sanford Guide and Burroughs Wellcome Fund, patent pending for 3D swabs, and leadership positions at Sanford Guide and Burroughs Wellcome Fund, outside of the submitted work. PEM reports grants from NHLBI and NIH during the conduct of the study and grants and contracts from NHLBI and NIH and consulting fees from Dompe, Medtronic, and Boerhinger Ingelheim, outside of the submitted work. BT reports grants from VA Cooperative Studies Program Coordinating Center during the conduct of the study and grants and consulting fees from Genentech, outside of the study. KUK reports grants from NIH during the conduct of the study. MAM reports grants from NIH, DOD, California Institute of Regenerative Medicine, Roche-Genentech, and Quantum Therapeutics and consulting fees from Novartis, Johnson and Johnson, Citius Pharmaceuticals, Pilant Therapeutics, and Gilead, outside of the submitted work. GP reports consulting fees from Menarini, Pfizer, MSD, and Gilead, payment for education events from Pfizer, MSD, Astra-Zeneca, and Gilead, and participation on advisory boards for Pfizer, Gilead, and MSD, outside of the submitted work. KNS reports consulting fees from Roche, Bristol Myers Squibb (BMS), Amgen, and MSD, outside of the submitted work. SRB reports consulting fees from Gilead, MSD, and GSK, payment for educational events from Gilead and MSD, and participation on advisory boards for Gilead, MSD, Pfizer, Roche, and ViiV, outside of the submitted work. JDC reports grants from NIH, outside of the submitted work. PC reports grants from NIH during the conduct of the study and grants from Eli Lilly, Regeneron, Gilead, consulting fees from Eli Lilly, Regeneron, and Gilead, and payment for education events from Frontier Collaborative, Physician Education Resource, Rockpointe, CME Outfitter, outside of the submitted work. DJD reports grants from NIH during the conduct of the study. DCF reports grants from NIH during the conduct of the study, grants from NIH and CDC, consulting fees from Cytovale, and participation on DSMB for Medpace, outside of the submitted work. HFG reports grants from Swiss National Science Foundation, Swiss HIV Cohort Study, Gilead, Yvonne Jacob Foundation, and NIH and participation on advisory boards for Merck, Gilead, ViiV, Janssen, and Novartis, outside of the submitted work. RDH reports grants from NHLBI, Airway Therapeutics, Incyte Corporation, and Kiniksa Pharmaceuticals and participation on a NIH DSMB outside of the submitted work. AK reports grants from United Therapeutics, Johnson & Johnson, Eli Lilly, Astra-Zeneca, and 4DMedical, outside of the submitted work. JSO reports grants from NIH during the conduct of the study. JSS reports grants from NIH during the conduct of the study. BEY reports consulting fees from Gilead and Novacyte and payment for educational events from Astra-Zeneca, Gilead, Sanofi, and Roche, outside of the submitted work. ANP reports grants from Bill and Melinda Gates Foundation (BMGF), UK Research and Innovation (UKRI), Wellcome Trust, and National Institute for Health and Care Research (NIHR) and consulting fees from BMGF, outside of the submitted work. DDM reports support from DNRF126 during the conduct of the study. MLP reports grants from Boehringer-Ingelheim, payment for authorship from Genentech and France Foundation, and travel support from Eastern Pulmonary Conference, outside of the submitted work. DS reports salary support from NIH through Axle Informatics during the conduct of the study and leadership position for EigenMed, outside of the submitted work. VN reports grants from NIH during the conduct of the study. SLP reports grants from the University of Minnesota during the conduct of the study and grants from Gilead, ViiV, Janssen, European and Developing Countries Clinical Trials Partnership (EDCTP), Medical Reserve Corps (MRC), and NIHR, and participation on a NIHR DSMB, outside of the submitted work. GT reports grants from University College London (UCL), outside of the submitted work. SMB reports grants from NIH during the conduct of the study and grants from NIH and participation on a DSMB for Hamilton, outside of the submitted work. WHS reports grants from NIH and NHLBI during the conduct of the study. BG reports grants from NIH during the conduct of the study. SS reports grants from NIH, outside of the conduct of the study. CSR reports grants from NIH during the conduct of the study. PG reports being an employee of AstraZeneca, being a full member of Academia de Medicina, Rio de Janeiro, Brazil, and stock ownership at Takeda. MTE reports being an employee of and stock ownership at AstraZeneca. AT reports being an employee of AstraZeneca. AGB reports grants from University of Minnesota, MRC, and UKRI during the conduct of the study. VJD reports grants from NIAID/NIH and contract with the University of Minnesota, outside of the conduct of the study. GM reports grants from Gilead, Abbvie, and Viiv, payment for speaking engagement from Janssen, participation on advisory boards for Astra-Zeneca and Gilead, and leadership role on Australian National COVID-19 taskforce treatments committee, outside of the conduct of the study. BTT reports grants from NHLBI and consulting fees from Bayer, Novartis, and Thetis, outside of the conduct of the study. JDN reports grants from NIH and NIAID during the conduct of the study. All other members of the writing committee declare no competing interests.

Ethical Approval: This study was approved by the following Review Boards: United States: Advarra Denmark: De Videnskabsetiske Komiteer for Region Hovedstaden Poland: Komisja Bioetyczna przy Uniwersytecie Warszawskim Spain: Hosp Universitari Germans Trias I Pujol Switzerland: Cantonal Ethics Committee Zurich Greece: Bioethic & Deontology Committee of Athens Medical School, National Organization for Medicines, and National Ethics Committee Uganda: Uganda Virus Research Institute Research Ethics Committee UK: Berkshire Research Ethics Committee Singapore: NHG Domain Specific Review Board.