TY - JOUR
T1 - Intravenous Vitamin C for Patients Hospitalized With COVID-19
T2 - Two Harmonized Randomized Clinical Trials
AU - LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators
AU - Adhikari, Neill K. J.
AU - Hashmi, Madiha
AU - Tirupakuzhi Vijayaraghavan, Bharath Kumar
AU - Haniffa, Rashan
AU - Beane, Abi
AU - Webb, Steve A.
AU - Angus, Derek C.
AU - Gordon, Anthony C.
AU - Cook, Deborah J.
AU - Guyatt, Gordon H.
AU - Berry, Lindsay R.
AU - Lorenzi, Elizabeth
AU - Mouncey, Paul R.
AU - Au, Carly
AU - Pinto, Ruxandra
AU - Ménard, Julie
AU - Sprague, Sheila
AU - Masse, Marie-H. lène
AU - Huang, David T.
AU - Heyland, Daren K.
AU - Nichol, Alistair D.
AU - McArthur, Colin J.
AU - de Man, Angelique
AU - Al-Beidh, Farah
AU - Annane, Djillali
AU - Anstey, Matthew
AU - Arabi, Yaseen M.
AU - Battista, Marie-Claude
AU - Berry, Scott
AU - Bhimani, Zahra
AU - Bonten, Marc J. M.
AU - Bradbury, Charlotte A.
AU - Brant, Emily B.
AU - Brunkhorst, Frank M.
AU - Burrell, Aidan
AU - Buxton, Meredith
AU - Cecconi, Maurizio
AU - Cheng, Allen C.
AU - Cohen, Dian
AU - Cove, Matthew E.
AU - Day, Andrew G.
AU - Derde, Lennie P. G.
AU - Detry, Michelle A.
AU - Estcourt, Lise J.
AU - Fagbodun, Elizabeth O.
AU - Fitzgerald, Mark
AU - Goossens, Herman
AU - Green, Cameron
AU - Higgins, Alisa M.
AU - Shankar-Hari, Manu
AU - Hills, Thomas E
N1 - Funding Information: 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). Funding Information: 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 Toront o (Toronto, Ontario, Canada), and the Global Coalition for Adaptive Research (San Francisco, California). Publisher Copyright: © 2023 American Medical Association. All rights reserved.
PY - 2023/11/14
Y1 - 2023/11/14
N2 - 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 ParticipantsL 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 outcomewas 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.
AB - 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 ParticipantsL 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 outcomewas 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.
KW - Ascorbic Acid/therapeutic use
KW - Bayes Theorem
KW - COVID-19
KW - Critical Illness/therapy
KW - Female
KW - Hospital Mortality
KW - Humans
KW - Male
KW - Middle Aged
KW - Randomized Controlled Trials as Topic
KW - Sepsis/drug therapy
KW - Vitamins/therapeutic use
UR - http://www.scopus.com/inward/record.url?scp=85176971549&partnerID=8YFLogxK
U2 - https://doi.org/10.1001/jama.2023.21407
DO - https://doi.org/10.1001/jama.2023.21407
M3 - Article
C2 - 37877585
SN - 0098-7484
VL - 330
SP - 1745
EP - 1759
JO - JAMA
JF - JAMA
IS - 18
ER -