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Cited by 55Vitamin C and Antioxidants ResearchCOVID-19 Clinical Research StudiesClinical Nutrition and Gastroenterology

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

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The LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators, Florescu, Simin, Stanciu, Delia, Zaharia, Mihaela, Kosa, Alma, Codreanu, Daniel, Fareed, Komal, Kidwai, Aneela +2377 more·2023·JAMA
DOI 10.1001/jama.2023.21407PMC PMC10600726
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Abstract

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 Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP)

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  • In pulmonary arterial hypertension, inhaled treprostinil has been shown to enhance exercise capacity and quality-of-life measures.

    “The addition of inhaled treprostinil, a prostacyclin vasodilator that is primarily used in the treatment of pulmonary arterial hypertension has been shown to improve exercise capacity and quality of life measures among patients with pulmonary arterial hypertension [120].”

    From Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF) (2024) · cites this paper as [120]

    The Patients section describes adults hospitalized with COVID-19, and the trial examines intravenous vitamin C. Searches for inhaled treprostinil, pulmonary arterial hypertension, exercise capacity, and quality of life found no passage addressing the cited claim. The indexed copy is not marked as truncated. (LLM, conf=0.78)

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The LOVIT-COVID Investigators, O. B. O. T. C. C. C. T. G., Florescu, S., Stanciu, D., Zaharia, M., Kosa, A., Codreanu, D., Fareed, K., Kidwai, A., Kaye, C., Coutts, A., MacKay, L., Summers, C., Polgarova, P., Farahi, N., Fox, E., Sapsford, D., Bongaerts, K., Featherstone, P., Ng, A., McWilliam, S., Hawcutt, D., Rad, L., O’Malley, L., Whitbread, J., Jones, D., Dore, R., Saunderson, P., Kelsall, O., Cowley, N., Wild, L., Thrush, J., Wood, H., Austin, K., Donnelly, A., Kelly, M., Smyth, N., O’Kane, S., McClintock, D., Warnock, M., Campbell, R., McCallion, E., Azaiz, A., Charron, C., Godement, M., Geri, G., Vieillard-Baron, A., Johnson, P., McKenna, S., Hanley, J., Currie, A., Allen, B., McGoldrick, C., McMaster, M., Mani, A., Mathew, M., Kandeepan, R., Vignesh, C., Ramakrishnan, N., James, A., Elvira, E., Pratheema, R., Babu, S., Ebenezer, R., Krishnamoorthy, S., Ranganathan, L., Ganesan, M., Shree, M., Piva, S., Focà, E., Rizzoni, D., Boari, G., Marchesi, M., Butler, M., Cowdrey, K.-A., Mason, B., Woolett, M., Duffy, E., Chen, Y., Nakamuro, H., O’Connor, C., West, L., El-Khawas, K., Richardson, A., Hill, D., Commons, R., Abdelkharim, H., Saxena, M., Muteithia, M., Dobell-Brown, K., Jha, R., Kalogirou, M., Ellis, C., Krishnamurthy, V., O’Connor, A., Thurairatnam, S., Mukherjee, D., Kaliappan, A., Vertue, M., Nicholson, A., Riches, J., Maloney, G., Kittridge, L., Solesbury, A., Ramos, A., Collins, D., Brickell, K., Reid, L., Smyth, M., Breen, P., Spain, S., Curley, G., McEvoy, N., Geoghegan, P., Clarke, J., Silversides, J., McGuigan, P., Ward, K., O’Neill, A., Finn, S., Wright, C., Green, J., Collins, É., Major, E., McAuley, J., Carter, A., Smith, J., Boschert, C., Slieker, K., Ewalds, E., Sanders, A., Wittenberg, W., Geurts, H., Poojara, L., Sara, T., Nand, K., Reeve, B., Dechert, W., Phillips, B., Oritz-Ruiz de Gordoa, L., Campbell, M., Dos Santos, F., Hansen, D., Mullan, D., Affleck, J., Shaikh, A., Murray, A., Ramanan, M., Frakking, T., Pinnell, J., Robinson, M., Gledhill, L., Wood, T., Sanghavi, R., Bhonagiri, D., Ford, M., Parikh, H. 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F., Rowan, K., Saito, H., Santos, M., Seymour, C., Shankar-Hari, M., Turgeon, A., Turner, A., Webb, S., Zarychanski, R., McEldrew, R., KC, S., Tolppa, T., Rashan, S., Singh, V., van Bentum-Puijk, W., Brugman, C., Groeneveld, E., Jafarzadeh, M., Jongenelen, I., Keijzer-Timmers, N., Kester, E., Koelink, M., Okundaye, C., Parker, L., Patil, S., Peters, S., Rietveld, I., Sayada, S., Smit, A., van Amerongen, R., Vermont - van der Staaij, J., Doran, P., Anjum, A., Au, C., Lane, J.-B., Fagboden, E., Barton, F., Charles, W., Miller, L., Parry-Billings, K., Peters, S., Richards-Belle, A., Saull, M., Sprinckmoller, S., Wiley, D., Darnell, R., Stronach, L., Wada, A., Beqaj, B., Forbes, A., Green, C., Heritier, S., Hills, T., McEldrew, B., McQuilten, Z., Trapani, T., Manoharan, V., Dondrop, A. M., Bin Hasan, M. S., Jayakumar, D., Kalla, I., Murray, L., Siika, W., Brunkhorst, F., Ehrmann, S., Povoa, P., Horvat, C., Doi, Y., Fujitani, S., Honda, H., Jindai, K., Kamata, K., Kato, H., Kunishima, H., Nakazono, K., Shintani, A., Yamagishi, Y., Yamashita, C., Beasley, R., Daneman, N., Fowler, R., McGloughlin, S., Paterson, D., Hullegie, S., Litton, E., Murphy, S., Venkatesh, B., de Jong, M., Uyeki, T., Baillie, K., Netea, M., Orr, K., Patanwala, A., Tong, S., Cooper, N., Galea, J., Ogungbenro, K., Patawala, A., Tong, S., Youngstein, T., Carrier, M., Fergusson, D., Goligher, E., Hunt, B., Kumar, A., Laffan, M., Lother, S., Middledorp, S., Neal, M., Stanworth, S., Anstey, M., de Man, A., Udy, A., Abraham, J., Arnold, D., Begin, P., Charlewood, R., Chasse, M., Cooper, J., Coyne, M., Daly, J., Estcourt, L., Gosbell, I., Harvala-Simmonds, H., Hills, T., MacLennan, S., McDyer, J., Menon, D., Pridee, N., Roberts, D., Thomas, H., Tinmouth, A., Triulzi, D., Walsh, T., Wood, E., Calfee, C., O’Kane, C., Shyamsundar, M., Sinha, P., Thompson, T., Young, I., Ferguson, N., Hodgson, C., Neto, A., Orford, N., Phua, J., Baron, R., Epelman, S., Ezekowitz, J., Frankfurter, C., Gommans, F., Kwan, Y., Kim, E., Leaf, D., Owen, D., Pollock, K., Puskarich, M., Vaduganathan, M., van Kimmenade, R., Harrison, D., Higgins, A., Lampro, L., Mason, A., Mila de la Fuente, G., Leffelaar, E., Schotsman, J., Boyd, C., Harland, C., Shearer, A., Wren, J., Clermont, G., Ricketts, D., Fazla, F., Muvindi, H., Ishani, P., Rashan, A., Udayanga, I., Detry, M., Fitzgerald, M., Lewis, R., McGlothlin, A., Saunders, C., Berry, L., Lorenzi, E., Adhikari, N. 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M., Saito, H., Salahuddin, N., Santos, M. S., Saunders, C. T., Seymour, C. W., Shankar-Hari, M., Tolppa, T., Trapani, T., Turgeon, A. F., Turner, A. M., Udy, A. A., van de Veerdonk, F. L., Zarychanski, R., & Lamontagne, F.
Affiliations
  • Canadian Critical Care Trials Group (CA)
  • The LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators
  • Université de Versailles Saint-Quentin-en-Yvelines (FR)
  • Jena University Hospital (DE)
  • Monash Health (AU)
  • University of Pittsburgh (US)
  • Medical Research Institute of New Zealand (NZ)
  • Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  • Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, Scotland
  • Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
  • University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • Division of Anaesthetics, Pain Medicine, and Intensive Care, Imperial College London, London, England
  • Berry Consultants LLC, Austin, Texas
  • Intensive Care National Audit and Research Centre, London, England
  • Research Centre of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
  • School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • Department of Critical Care Medicine, Queen’s University, Kingston, Ontario, Canada
  • Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand
  • King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
  • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
  • University of Bristol, Bristol, England
  • Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • Bishop's University (CA)
  • Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • Kingston Health Sciences Centre and Queen’s University, Kingston, Ontario, Canada
  • European Clinical Research Alliance on Infectious Diseases, Utrecht, the Netherlands
  • Department of Haematology, NHS Blood and Transplant, Bristol, England
  • Berry Consultants, LLC (United States) (US)
  • Medical Research Institute of New Zealand, Wellington
  • University Health Network (CA)
  • University Health Network, Toronto, Ontario, Canada
  • Department of Surgery, University of Toronto, Toronto, Ontario, Canada
  • Queen’s University of Belfast, Belfast, Northern Ireland
  • Monash University, Monash Health, Clayton, Australia
  • Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • Faculty of Medicine, Nursing, and Health Sciences, Monash University, Clayton, Australia
  • Department of Critical Care, St Michael’s Hospital, Toronto, Ontario, Canada
  • Department of Anesthesiology and Critical Care, Université Laval, Quebec City, Quebec, Canada
  • Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia
  • Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2023-11-14
Volume
330
Issue
18
Pages
1745
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2023.21407
PMC
PMC10600726
OpenAlex
W4387931382
Cited by
55
References
28
Citations by year
2026: 9 · 2025: 20 · 2024: 24 · 2023: 2
FWCI
9.60
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
  • Research Portal (Queen's University Belfast) (publishedVersion, other-oa)
  • Explore Bristol Research (publishedVersion, cc-by)
  • Intellectum (Universidad de La Sabana) (submittedVersion, cc-by-nc-nd)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion)
  • Deakin Research Online (Deakin University)
Funders
  • Université Laval
  • Johns Hopkins University
  • University of Pittsburgh
  • Alder Hey Children's NHS Foundation Trust
  • McGill University
  • NHS Blood and Transplant
  • Ottawa Hospital Research Institute
  • Royal Devon and Exeter NHS Foundation Trust
  • McMaster University
  • Université de Sherbrooke
  • Middlesex University
  • Health Research Board (CTN-2021-010, KTA-2022-032)
  • Royal Marsden NHS Foundation Trust
  • Lotte and John Hecht Memorial Foundation
  • McGill University Health Centre
  • Swansea Bay University Health Board
  • Mylan
  • Tribhuvan University
  • University of Alberta
  • National Institute for Health and Care Research (COVID-19, COVID-19-RECPLAS, NIHR205101)
  • Imperial College London
  • King's College London
  • University of Oxford
  • European Commission (602525, FP7‐HEALTH‐2013‐INNOVATION‐1, FP7-HEALTH-2013INNOVATION, 101003589, COVID-19, HEALTH-2013)
  • University of Sussex
  • Intensive Care Society
  • Monash University
  • James Cook University
  • Radboud Universiteit
  • Queen's University
  • Universitair Ziekenhuis Gent
  • University of Toronto
  • Royal Adelaide Hospital
  • Universiteit Gent
  • Centre Hospitalier Universitaire de Québec
  • Université de Montréal
  • Radboud Universitair Medisch Centrum
  • Universiteit Antwerpen
  • Jikei University School of Medicine
  • Universidad de La Sabana
  • Minderoo Foundation
  • Fiona Stanley Hospital
  • Goddard Space Flight Center
  • Medical Center, University of Pittsburgh
  • Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval
  • Canadian Institutes of Health Research (COVID-19, 158584)
  • Medical Research Council (COVID-19)
  • National Health and Medical Research Council
  • Health Research Council of New Zealand (16/631)
  • St. George's, University of London
  • NIHR Imperial Biomedical Research Centre
  • National Heart, Lung, and Blood Institute (T32HL007563)
  • National Institute of General Medical Sciences (R35GM119519)
  • FP7 Health (602525)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
Keywords
vitamin C, intravenous vitamin C, COVID-19 pandemic, hospitalized patients, critically ill patients, intensive care unit, organ support, survival, futility, trial termination
MeSH terms
COVID-19, Ascorbic Acid, Bayes Theorem, Female, Humans, Male, Middle Aged, Vitamins, Randomized Controlled Trials as Topic, Critical Illness, Hospital Mortality, Sepsis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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