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Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19., Methods: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28., Results: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19., Conclusions: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile., Competing Interests: Conflict of interest: J. Patel, D. Bass, A. Cahn, K. Davy, S. Fernandes, A. Gupta, K. Hanrott, D. Inman, E. Jarvis, D. Lakshminarayanan, S. Mukherjee, C. O'Shea, L. Schifano, J.E. Smith, R. Williamson and M. Layton are shareholders and/or employees of GSK. A. Beishuizen, X. Bocca Ruiz, H. Boughanmi, H. Colombo, G.J. Criner, J. de-Miguel-Díez, P.A. Doreski, B. François, T. Hatlen, J.D. Isaacs, N. Kostina, T. Kropotina, J-C. Lacherade, P. Martinez-Ayala, C. McEvoy, F. Meziani, M. Monchi, R. Muñoz-Bermúdez, G. Plantefeve, L.E. Schwab, Z. Shahid, M. Shirano, E. Sprinz, C. Summers, N. Terzi and Y. Trefilova were investigators in the OSCAR trial, which was funded by GSK. X. Bocca Ruiz has served as a clinical trial investigator for AstraZeneca and Zambon. B. François reports consultancy fees with GSK, Enlivex, Inotrem, Takeda, Aridis, Transgene, AM-Pharma, Asahi-Kasai and Biomérieux within the past 36 months. R. Muñoz-Bermúdez has participated on an advisory board for GSK. J.D. Isaacs has received research funding from GSK, Janssen and Pfizer, and personal fees from AbbVie, BMS, Gilead, Roche and UCB, all outside the submitted work, as well as support for event attendance from Eli Lilly and Gilead. A. Beishuizen has received consultancy fees from GSK. C. McEvoy has received research funding from the National Institutes of Health, US Department of Defense, Patient-Centered Outcomes Research Institute, GSK and AstraZeneca. C. Summers’ institution has received research funding from GSK, AstraZeneca, the Wellcome Trust, The Medical Research Council and National Institute for Health Research to support her work outside the area of the submitted manuscript. C. Summers has received personal fees from AbbVie, Roche and GSK. G.J. Criner has received research grants from ALung Technologies Inc., American College of Radiology, American Lung Associations, AstraZeneca, BioScale Inc., Boehringer Ingelheim, BREATH Therapeutics Inc., COPD Foundation, Coridea/ZIDAN, Corvus, Dr Karen Burns of St Michael's Hospital, Fisher & Paykel Healthcare Ltd, Galapagos NV, GSK, Kinevent, Lungpacer Medical Inc., National Heart Lung and Blood Institute, Nurvaira Inc., Patient-Centered Outcomes Research Institute, Pulmonary Fibrosis Foundation, PulmonX, Respironics Inc., Respivant Sciences, Spiration Inc., Steward St Elizabeth's Medical Center of Boston Inc. and Veracyte Inc.; and received personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Broncus Medical, CSA Medical, EOLO Medical, Gala Therapeutics, GSK, Helios Medical, Ion, Merck, Medtronic, Mereo BioPharma, NGM Biopharmaceuticals, Novartis, Olympus, PulmonX, Respironics Inc., Respivant Sciences, The Implementation Group and Verona Pharma. J. Neisen is an employee and shareholder of AstraZeneca, and a shareholder and former employee of GSK. L.E. Schwab reports holding shares in Johnson & Johnson and BMS, and participated on the Holy Cross Health Institutional Review Board. Z. Shahid has received research funding from Karyopharm. M. Shirano is an investigator in separate trials funded by Roche and AstraZeneca, and has received payment for lectures from Gilead Sciences. E. Sprinz participates on a data safety monitoring board/advisory board for, and has received consulting fees and honoraria from, GSK, Janssen and Gilead. M.A. Tidswell received a fee for serving on the independent data monitoring committee for this study, as well as for serving on a data safety monitoring board/advisory board for Spectral Diagnostics Inc., ReAlta Life Sciences Inc., Celltrion Inc., AstraZeneca and Molecular Partners AG. Additionally, M.A. Tidswell has held a research contract with Edesa Biotech Research Inc., RevImmune SAS, Spectral Diagnostics, Beyond Air Inc., National Institutes of Health and National Heart, Lung, and Blood Institute. D. Wyncoll received a fee for serving on the independent data monitoring committee for this study, has served as a study adjudicator for AstraZeneca, and reports consulting fees and/or honoraria from Gilead and Shionogi. J. de-Miguel-Díez, H. Boughanmi, J-C. Lacherade, P. Martinez-Ayala, T. Hatlen, G. Plantefeve, N. Terzi, M. Shirano, N. Kostina, T. Kropotina, Y. Trefilova and M. Monchi have no other conflicts of interest to declare., (Copyright ©The authors 2023.)