Intravenous Vitamin C for Patients Hospitalized With COVID-19Two Harmonized Randomized Clinical Trials

Question  Does vitamin C administered intravenously to patients hospitalized with COVID-19 improve organ support–free days (composite outcome of in-hospital mortality and days alive and free of intensive care unit–based respiratory and cardiovascular support) up to day 21?

Findings  In 2 prospectively harmonized randomized clinical trials, the use of vitamin C vs control (placebo or no vitamin C) yielded posterior probabilities for efficacy of 8.6% among 1568 critically ill patients and 2.9% among 1022 patients who were not critically ill regarding the odds of improvement for organ support–free days.

Meaning  Among hospitalized patients with COVID-19, there was a low probability that vitamin C improved organ support–free days.

Importance  The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.

Objective  To determine whether vitamin C improves outcomes for patients with COVID-19.

Design, Setting, and Participants  Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents.

Interventions  Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses).

Main Outcomes and Measures  The primary outcome was a composite of organ support–free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from –1 organ support–free days for patients experiencing in-hospital death to 22 organ support–free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support–free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility.

Results  Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support–free days was 7 (IQR, −1 to 17 days) for the vitamin C group vs 10 (IQR, −1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support–free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.

Conclusions and Relevance  In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support–free days and hospital survival.

Trial RegistrationClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP)

Accepted for Publication: October 2, 2023.

Published Online: October 25, 2023. doi:10.1001/jama.2023.21407

Corresponding Authors: Neill K. J. Adhikari, MDCM, MSc, Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada (neill.adhikari@utoronto.ca) and François Lamontagne, MD, MSc, Faculty of Medicine and Health Sciences, Division of Internal Medicine, Université de Sherbrooke, 3001 12th Ave N, Sherbrooke, QC J1H 5N4, Canada (francois.lamontagne@usherbrooke.ca).

The LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators: Neill K. J. Adhikari, MDCM, MSc; Madiha Hashmi, MD; Bharath Kumar Tirupakuzhi Vijayaraghavan, MD; Rashan Haniffa, PhD; Abi Beane, PhD; Steve A. Webb, MD, PhD; Derek C. Angus, MD, MPH; Anthony C. Gordon, MBBS, MD; Deborah J. Cook, MD, MSc; Gordon H. Guyatt, MD, MSc; Lindsay R. Berry, PhD; Elizabeth Lorenzi, PhD; Paul R. Mouncey, MSc; Carly Au, BSc; Ruxandra Pinto, PhD; Julie Ménard, PhD; Sheila Sprague, PhD; Marie-Hélène Masse, MSc; David T. Huang, MD, PhD; Daren K. Heyland, MD, MSc; Alistair D. Nichol, MD, PhD; Colin J. McArthur, MD, MSc; Angelique de Man, MD, PhD; Farah Al-Beidh, PhD; Djillali Annane, MD, PhD; Matthew Anstey, MBBS, MPH; Yaseen M. Arabi, MD; Marie-Claude Battista, PhD; Scott Berry, PhD; Zahra Bhimani, MPH; Marc J. M. Bonten, MD, PhD; Charlotte A. Bradbury, MBChB, PhD; Emily B. Brant, MD, MS; Frank M. Brunkhorst, MD, PhD; Aidan Burrell, MBBS, PhD; Meredith Buxton, PhD, MPH; Maurizio Cecconi, MD; Allen C. Cheng, MD, PhD; Dian Cohen, BA (Hons); Matthew E. Cove, MD; Andrew G. Day, MSc; Lennie P. G. Derde, MD, PhD; Michelle A. Detry, PhD; Lise J. Estcourt, MBChB, PhD; Elizabeth O. Fagbodun, MSc; Mark Fitzgerald, PhD; Herman Goossens, MD, PhD; Cameron Green, MSc; Alisa M. Higgins, PhD; Thomas E. Hills, MBBS, PhD; Nao Ichihara, MD, MPH, PhD; Devachandran Jayakumar, MS, MSc; Salmaan Kanji, PharmD; Muhammad Nasir Khoso, MBBS; Patrick R. Lawler, MD, MPH; Roger J. Lewis, MD, PhD; Edward Litton, MD, PhD; John C. Marshall, MD; Daniel F. McAuley, MD; Anna McGlothlin, PhD; Shay P. McGuinness, MBChB; Zoe K. McQuilten, MBBS, PhD; Bryan J. McVerry, MD; Srinivas Murthy, MD, MHSc; Rachael L. Parke, RN, MHSc, PhD; Jane C. Parker, BN; Luis Felipe Reyes, MD, PhD; Kathryn M. Rowan, PhD; Hiroki Saito, MD, PhD; Nawal Salahuddin, MD; Marlene S. Santos, MD, MSHS; Christina T. Saunders, PhD; Christopher W. Seymour, MD, MSc; Manu Shankar-Hari, MD, PhD; Timo Tolppa, BMBS, BSc; Tony Trapani, RN; Alexis F. Turgeon, MD, MSc; Anne M. Turner, MPH; Andrew A. Udy, MD, MSc; Frank L. van de Veerdonk, MD, PhD; Ryan Zarychanski, MD, MSc; François Lamontagne, MD, MSc.

Affiliations of The LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators: Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Adhikari, Pinto); Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada (Adhikari); Department of Critical Care Medicine, Ziauddin University, Karachi, Pakistan (Hashmi); Department of Critical Care Medicine, Apollo Hospitals, Chennai, India (Tirupakuzhi Vijayaraghavan); George Institute for Global Health India, New Delhi (Tirupakuzhi Vijayaraghavan); Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, Scotland (Haniffa, Beane); Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand (Haniffa, Beane); Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia (Webb, Nichol, Green, Higgins); St John of God Health Care, Perth, Australia (Webb); University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Angus); University of Pittsburgh, Pittsburgh, Pennsylvania (Angus); Division of Anaesthetics, Pain Medicine, and Intensive Care, Imperial College London, London, England (Gordon); St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, England (Gordon); Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Cook); Department of Critical Care, St Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada (Cook); Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada (Cook, Guyatt); Berry Consultants LLC, Austin, Texas (L. R. Berry, Lorenzi, S. Berry, Detry, Fitzgerald, Lewis, McGlothlin, Saunders); Intensive Care National Audit and Research Centre, London, England (Mouncey, Au); Research Centre of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada (Ménard, Masse, Battista, Lamontagne); Department of Surgery, McMaster University, Hamilton, Ontario, Canada (Sprague); School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Huang); Department of Critical Care Medicine, Queen’s University, Kingston, Ontario, Canada (Heyland); Faculty of Medicine, Nursing, and Health Sciences, Monash University, Clayton, Australia (Nichol, Parker); University College Dublin, Dublin, Ireland (Nichol); Alfred Health, Melbourne, Australia (Nichol, Burrell); Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand (McArthur); Department of Intensive Care Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands (de Man); Imperial College London, London, England (Al-Beidh); UVSQ University Paris Saclay, Institut-Hospitalo Universitaire Prometheus, Paris, France (Annane); Médecine Intensive-Réanimation, Hôpital Raymond-Poincaré, Garches, France (Annane); Sir Charles Gairdner Hospital, Nedlands, Australia (Anstey); University of Western Australia, Perth (Anstey); King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia (Arabi); King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Arabi); St Michael’s Hospital, Unity Health Toronto, Toronto, Ontario, Canada (Bhimani); Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands (Bonten); European Clinical Research Alliance on Infectious Diseases, Utrecht, the Netherlands (Bonten, Derde); University of Bristol, Bristol, England (Bradbury); Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Brant, Seymour); Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany (Brunkhorst); Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (Burrell); Global Coalition for Adaptive Research, Larkspur, California (Buxton); Department of Biomedical Sciences, Humanitas University, Milan, Italy (Cecconi); IRCCS Humanitas Research Hospital, Milan, Italy (Cecconi); Monash Infectious Disease, Monash Health and School of Clinical Sciences, Monash University, Clayton, Australia (Cheng); School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia (Cheng); Bishop’s University, Sherbrooke, Quebec, Canada (Cohen); Massawippi Valley Foundation, Ayer’s Cliff, Quebec, Canada (Cohen); Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Cove); Kingston Health Sciences Centre and Queen’s University, Kingston, Ontario, Canada (Day); Intensive Care Centre, University Medical Centre Utrecht, Utrecht, the Netherlands (Derde); Department of Haematology, NHS Blood and Transplant, Bristol, England (Estcourt); Radcliffe Department of Medicine, University of Oxford, Oxford, England (Estcourt); Imperial Clinical Trials Unit, Imperial College London, London, England (Fagbodun); Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium (Goossens); Medical Research Institute of New Zealand, Wellington (Hills, McGuinness, Parke, Turner); Department of Cardiovascular Surgery, School of Medicine, Jikei University, Tokyo, Japan (Ichihara); Dr Kamakshi Memorial Hospital Apollo, Chennai, India (Jayakumar); Ottawa Hospital, Ottawa, Ontario, Canada (Kanji); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (Kanji); South City Hospital, Karachi, Pakistan (Khoso); University Health Network, Toronto, Ontario, Canada (Lawler); University of Toronto, Toronto, Ontario, Canada (Lawler); McGill University Health Centre, Montreal, Quebec, Canada (Lawler); Fiona Stanley Hospital, Department of Intensive Care Unit, University of Western Australia, Perth (Litton); Department of Surgery, University of Toronto, Toronto, Ontario, Canada (Marshall); Queen’s University of Belfast, Belfast, Northern Ireland (McAuley); Centre for Infection and Immunity, Royal Victoria Hospital, Belfast, Northern Ireland (McAuley); Auckland City Hospital, Cardiothoracic and Vascular Intensive Care Unit, Auckland, New Zealand (McGuinness, Parke); Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia (McGuinness, Trapani, Udy); Monash University, Monash Health, Clayton, Australia (McQuilten); Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (McVerry); Department of Pediatrics, University of British Columbia, Vancouver, Canada (Murthy); School of Nursing, University of Auckland, Auckland, New Zealand (Parke); Department of Infectious Diseases, Universidad de La Sabana, Chia, Colombia (Reyes); Department of Critical Care Medicine, Clinica Universidad de La Sabana, Chia, Colombia (Reyes); Intensive Care National Audit and Research Centre, London, England (Rowan); Department of Emergency and Critical Care Medicine, St Marianna University Yokohama Seibu Hospital, Yokohama, Japan (Saito); National Institute of Cardiovascular Diseases, Karachi, Pakistan (Salahuddin); Department of Critical Care, St Michael’s Hospital, Toronto, Ontario, Canada (Santos); Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, Scotland (Shankar-Hari); Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, Scotland (Shankar-Hari); National Intensive Care Surveillance, Colombo, Sri Lanka (Tolppa); Department of Anesthesiology and Critical Care, Université Laval, Quebec City, Quebec, Canada (Turgeon); Population Health and Optimal Health Practices Research Unit, Departments of Traumatology, Emergency Medicine, and Critical Care Medicine, Université Laval Research Center, CHU de Québec-Université Laval, Quebec City, Quebec, Canada (Turgeon); Department of Intensive Care and Hyperbaric Medicine, Alfred Hospital, Melbourne, Australia (Udy); Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (van de Veerdonk); Department of Internal Medicine, University of Manitoba, Winnipeg, Canada (Zarychanski); Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada (Lamontagne).

Author Contributions: Drs Adhikari and Lamontagne had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Adhikari and Lamontagne are joint first and senior authors.

Concept and design: Adhikari, Webb, Angus, Gordon, Cook, Guyatt, L. Berry, Lorenzi, Sprague, Huang, Heyland, McArthur, de Man, Anstey, S. Berry, Bhimani, Bonten, Brunkhorst, Cecconi, Cheng, Cohen, Derde, Estcourt, Goossens, Hills, Kanji, Khoso, Lewis, Litton, McAuley, McQuilten, Murthy, Parke, Rowan, Seymour, Shankar-Hari, Trapani, Turgeon, Udy, Lamontagne.

Acquisition, analysis, or interpretation of data: Adhikari, Hashmi, Tirupakuzhi Vijayaraghavan, Haniffa, Beane, Webb, Angus, Gordon, Cook, Guyatt, L. Berry, Lorenzi, Mouncey, Au, Pinto, Ménard, Sprague, Masse, Huang, Nichol, McArthur, Al-Beidh, Annane, Arabi, Battista, S. Berry, Bradbury, Brant, Brunkhorst, Burrell, Buxton, Cecconi, Cheng, Cove, Day, Derde, Detry, Fagbodun, Fitzgerald, Green, Higgins, Hills, Ichihara, Jayakumar, Kanji, Khoso, Lawler, Lewis, Litton, Marshall, McAuley, McGlothlin, McGuinness, McVerry, Parker, Reyes, Rowan, Saito, Salahuddin, Santos, Saunders, Seymour, Shankar-Hari, Tolppa, Turgeon, Turner, van de Veerdonk, Zarychanski, Lamontagne.

Drafting of the manuscript: Adhikari, Tirupakuzhi Vijayaraghavan, Gordon, Sprague, Huang, Heyland, Bhimani, Cecconi, McAuley, Murthy, Shankar-Hari, Lamontagne.

Critical review of the manuscript for important intellectual content: Adhikari, Hashmi, Tirupakuzhi Vijayaraghavan, Haniffa, Beane, Webb, Angus, Gordon, Cook, Guyatt, L. Berry, Lorenzi, Mouncey, Au, Pinto, Ménard, Sprague, Masse, Huang, Heyland, Nichol, McArthur, de Man, Al-Beidh, Annane, Anstey, Arabi, Battista, S. Berry, Bonten, Bradbury, Brant, Brunkhorst, Burrell, Buxton, Cecconi, Cheng, Cohen, Cove, Day, Derde, Detry, Estcourt, Fagbodun, Fitzgerald, Goossens, Green, Higgins, Hills, Ichihara, Jayakumar, Kanji, Khoso, Lawler, Lewis, Litton, Marshall, McAuley, McGlothlin, McGuinness, McQuilten, McVerry, Parke, Parker, Reyes, Rowan, Saito, Salahuddin, Santos, Saunders, Seymour, Shankar-Hari, Tolppa, Trapani, Turgeon, Turner, Udy, van de Veerdonk, Zarychanski, Lamontagne.

Statistical analysis: L. Berry, Lorenzi, Pinto, S. Berry, Day, Detry, Fitzgerald, Khoso, Lewis, McGlothlin, Saunders, Lamontagne.

Obtained funding: Adhikari, Webb, Gordon, Masse, Heyland, Nichol, McArthur, Annane, Bonten, Burrell, Buxton, Cheng, Cove, Derde, Goossens, Higgins, Hills, Ichihara, Litton, Marshall, McAuley, McGuinness, Murthy, Rowan, Saito, Shankar-Hari, Turgeon, Lamontagne.

Administrative, technical, or material support: Adhikari, Hashmi, Tirupakuzhi Vijayaraghavan, Beane, Webb, Angus, Gordon, Cook, Mouncey, Au, Pinto, Ménard, Sprague, Masse, Nichol, McArthur, de Man, Al-Beidh, Battista, Bhimani, Brant, Brunkhorst, Buxton, Cheng, Derde, Green, Higgins, Ichihara, Jayakumar, Kanji, Khoso, McAuley, McGuinness, McQuilten, Parker, Rowan, Saito, Santos, Shankar-Hari, Tolppa, Trapani, Turner, Zarychanski, Lamontagne.

Supervision: Adhikari, Angus, Gordon, Guyatt, Ménard, Nichol, Arabi, S. Berry, Burrell, Cecconi, Derde, Hills, Kanji, Khoso, Lewis, McAuley, Murthy, Reyes, Rowan, Seymour, Lamontagne.

Conflict of Interest Disclosures: Dr Haniffa reported receiving grants from Wellcome Trust, Medical Research Council Africa, and International COVID-19 Data Alliance. Dr Webb reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the Medical Research Future Fund. Dr Gordon reported receiving personal fees from AstraZeneca, Janssen, Novartis, and 30 Respiratory (all fees paid to institution). Dr L. Berry reported receiving grants and being an employee of Berry Consultants. Dr Lorenzi reported being an employee of Berry Consultants. Dr Nichol reported receiving grants from the European Commission. Dr de Man reported receiving grants from the Netherlands Organisation of Health Research. Dr S. Berry reported being part owner of Berry Consultants. Dr Bradbury reported receiving personal fees from Bristol Myers Squibb, Pfizer, Bayer, Amgen, Lilly, Sobi, Sanofi, Novartis, and Janssen. Dr Cecconi reported receiving personal fees from Edwards Lifesciences, Directed Systems, and GE Healthcare. Dr Cove reported receiving grants from National University Health System; receiving personal fees from Baxter, Medtronic, B Braun, and Jafron; and holding a patent for the removal of carbon dioxide via dialysis. Dr Derde reported receiving grants from the European Commission and serving as a member of the international advisory board for Sepsis Canada. Dr Detry reported receiving grants from the European Commission and the Global Coalition for Adaptive Research and being a director and senior statistical scientist at Berry Consultants. Dr Fitzgerald reported receiving grants from the European Commission and the Global Coalition for Adaptive Research. Dr Higgins reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the Medical Research Future Fund. Dr Lawler reported receiving personal fees from the American College of Cardiology and McGraw Hill. Dr Lewis reported being a senior medical scientist at Berry Consultants. Dr Marshall reported receiving personal fees from AM Pharma and Matisse. Dr McAuley reported receiving grants from Innovate UK, Northern Ireland Health and Social Care, the Medical Research Council, and Wellcome Trust; receiving personal fees from Bayer, GSK, Boehringer Ingelheim, Novartis, Eli Lilly, Vir Biotechnology, Aptarion, Aviceda, and Direct Biologics; holding a patent for an anti-inflammatory treatment (issued to Queen’s University Belfast) for a novel treatment for inflammatory disease; and being the co-director of research for the Intensive Care Society and the program director for the National Institute for Health and Care Research/Medical Research Council Efficacy and Mechanism Evaluation. Dr McGlothlin reported receiving grants from the European Commission and the Global Coalition for Adaptive Research. Dr McVerry reported receiving grants from the Pittsburgh Foundation and the National Institutes of Health and receiving personal fees from Boehringer Ingelheim, Synairgen, and BioAegis. Dr Parke reported receiving grants from Fisher and Paykel Healthcare Ltd. Dr Reyes reported receiving grants from Merck Sharp & Dohme and Pfizer and receiving personal fees from GSK. Dr Rowan reported receiving grants from the European Commission. Dr Saunders reported receiving grants from the European Commission and the Global Coalition for Adaptive Research. Dr Seymour reported receiving grants from the National Institutes of Health and personal fees from Beckman Coulter and Inotrem, Inc. Dr Shankar-Hari reported receiving grants from the Chief Scientist Office Scotland, the National Institute for Health and Care Research (Efficacy and Mechanism Evaluation and Health Technology Assessment programs), the Medical Research Council, and the Huo Foundation. Dr Udy reported nonfinancial support from Integra Lifesciences. No other disclosures were reported.

Funding/Support: The LOVIT-COVID trial was funded by the Lotte and John Hecht Memorial Foundation, which also supported the REMAP-CAP trial via a subcontract. Nova Biomedical Canada, Ltd provided glucometers, testing strips, and control solutions (StatStrip Express) to trial sites that requested them in the LOVIT-COVID trial. The vitamin C that was used by the LOVIT-COVID sites (all in Canada) was purchased from Mylan. The REMAP-CAP trial was funded by FP7-health-2013-innovation-1 grant 602525 from the Platform for European Preparedness Against Re-Emerging Epidemics Consortium of the European Union, grant 101003589 from the Rapid European COVID-19 Emergency Research Response Consortium of the European Union’s Horizon 2020 Research and Innovation Programme, grant APP1101719 from the Australian National Health and Medical Research Council, grant 16/631 from the Health Research Council of New Zealand, grant 158584 from the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program, funding from the National Institute for Health and Care Research (NIHR) and the NIHR Imperial Biomedical Research Centre, grant CTN 2014-012 from the Health Research Board of Ireland, funding from the University of Pittsburgh Medical Center Learning While Doing Program, funding from the Translational Breast Cancer Research Consortium, grant PHRC-20-0147 from the French Ministry of Health, funding from the Office of Health and Medical Research NSW Health, funding from the Minderoo Foundation, grant 215522 from the Wellcome Trust Innovations Project, grants 20fk0108526h0001, 21fk0108591h0001, and 22fk0108528h0001 from the Japan Agency for Medical Research and Development, and funding from the National University Health System research office, Singapore. The sponsor for the LOVIT-COVID trial was the Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke. The REMAP-CAP trial has 4 regional nonprofit sponsors: Monash University (Melbourne, Australia), Utrecht Medical Center (Utrecht, the Netherlands), Unity Health Toronto (Toronto, Ontario, Canada), and the Global Coalition for Adaptive Research (San Francisco, California).

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The entire list of the LOVIT-COVID Investigators and the REMAP-CAP Investigators appears in Supplement 3.

Disclaimer: Dr Angus is a Senior Editor, Dr Lewis is a Statistical Editor, and Dr Seymour is an Associate Editor of JAMA but were not involved in any of the decisions regarding review of the manuscript or its acceptance.

Meeting Presentation: Presented in part at the European Society of Intensive Care Medicine; October 25, 2023; Milan, Italy.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the trial patients and their caregivers; the clinicians; the research, pharmacy, and laboratory staff members; and the trial and data coordinators; the National Institute for Health and Care Research Clinical Research Network, the University of Pittsburgh Medical Center Health System Health Services Division, and the Direction de la Recherche Clinique et de l’Innovation de l’AP-HP for their support of participant recruitment; the Unité de Recherche Clinique et Épidémiologique of the Centre de Recherche du CHU de Sherbrooke for providing support in the conduct of the LOVIT-COVID trial; the Canadian Critical Care Trials Group, including Bram Rochwerg, MD, MSc, for his uncompensated review of the manuscript; and the uncompensated members of the data and safety monitoring boards (LOVIT-COVID: Andreas Laupacis, MD, MSc, Lauren Griffith, PhD, and Scott Halpern, MD, PhD; REMAP-CAP: Victoria Manax, MD, Jason Connor, PhD, Alexandre Cavalcanti, MD, PhD, Simon Finfer, MBBS, DrMed, Simon Gates, PhD, Adrienne Randolph, MD, MSc, John Reynolds, PhD, and Tom van der Poll, MD, PhD).

Additional Information: This article was written with gratitude to and in memory of our friend and colleague, Wilma van Bentum-Puijk, MSc.