Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

ACTIV-3–Therapeutics for Inpatients with COVID-19 (TICO) Study Group

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61 Scopus citations

Abstract

Background: Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to 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. Efficacy and safety analyses were done 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 and the participant follow-up is ongoing. Findings: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. 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. Funding: US National Institutes of Health (NIH) and Operation Warp Speed.

Original languageEnglish (US)
Pages (from-to)972-984
Number of pages13
JournalThe Lancet Respiratory Medicine
Volume10
Issue number10
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
We thank the members of the ACTIV-3–TICO data and safety monitoring board for their review of the protocol and their guidance based on interim reviews of the data. We also thank the participants and families whose dedication to contributing to science made this research study possible. The Division of Clinical Research at the National Institute of Allergy and Infectious Diseases funded this project. Investigators from NIH were directly involved in all aspects of this study, including study design, data collection, data analysis, data interpretation, and writing of the report. All analyses of biological material were done in a masked manner at laboratories affiliated with the funding source; data were sent to the statistical and data management center at the University of Minnesota for linkage to the trial database. Several representatives from the funding source are part of the writing group for the manuscript. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing official policies, either expressed or implied, of the National Institutes of Health or the Department of Veterans Affairs. Supported by the US 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 and the Research Triangle Institute for the Prevention and Early Treatment of Acute Lung Injury Network and the Cardiothoracic Surgical Trials Network, the US Department of Veterans Affairs, and grants from the governments of Denmark, Australia, the UK, and Singapore. The research was, in part, funded by National Institutes of Health Agreement 1OT2HL156812-01 and National Cancer Institute contract 75N91019D00024, task order number 75N91020F00039. Trial medications were donated by AstraZeneca (tixagevimab/cilgavimab) and Gilead Sciences (remdesivir).

Funding Information:
JDN, TAM, NE, and GG directly accessed and verified the underlying data. JDL, HCL, JDN, AGB, VJD, ACG, ESH, VK, and BTT were responsible for conceptualisation. All authors were responsible for the investigation and reviewing and editing the manuscript. JDN, TAM, NE, and GG were responsible for data curation. TAM, NE, and GG were responsible for formal analysis JDN, AGB, VJD, ACG, VK, BTT, and JDL were responsible for funding acquisition. JDL, HCL, JDN, AGB, VJD, ACG, ESH, VK, GM, and BTT were responsible for supervision. TLH, AAG, and RP composed the initial manuscript.

Publisher Copyright:
© 2022 Elsevier Ltd

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