Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial

Fang Liu, Yuan Zhu, Jing Zhang, Yiming Li, Zhiyong Peng, Fang Liu, Yuan Zhu, Jing Zhang, Yiming Li, Zhiyong Peng

Abstract

Introduction: The rapid worldwide spread of COVID-19 has caused a global health crisis. To date, symptomatic supportive care has been the most common treatment. It has been reported that the mechanism of COVID-19 is related to cytokine storms and subsequent immunogenic damage, especially damage to the endothelium and alveolar membrane. Vitamin C (VC), also known as L-ascorbic acid, has been shown to have antimicrobial and immunomodulatory properties. A high dose of intravenous VC (HIVC) was proven to block several key components of cytokine storms, and HIVC showed safety and varying degrees of efficacy in clinical trials conducted on patients with bacterial-induced sepsis and acute respiratory distress syndrome (ARDS). Therefore, we hypothesise that HIVC could be added to the treatment of ARDS and multiorgan dysfunction related to COVID-19.

Methods and analysis: The investigators designed a multicentre prospective randomised placebo-controlled trial that is planned to recruit 308 adults diagnosed with COVID-19 and transferred into the intensive care unit. Participants will randomly receive HIVC diluted in sterile water or placebo for 7 days once enrolled. Patients with a history of VC allergy, end-stage pulmonary disease, advanced malignancy or glucose-6-phosphate dehydrogenase deficiency will be excluded. The primary outcome is ventilation-free days within 28 observational days. This is one of the first clinical trials applying HIVC to treat COVID-19, and it will provide credible efficacy and safety data. We predict that HIVC could suppress cytokine storms caused by COVID-19, help improve pulmonary function and reduce the risk of ARDS of COVID-19.

Ethics and dissemination: The study protocol was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (identifiers: Clinical Ethical Approval No. 2020001). Findings of the trial will be disseminated through peer-reviewed journals and scientific conferences.

Trial registration number: NCT04264533.

Keywords: adult intensive & critical care; clinical trials; infectious diseases; respiratory infections.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Standard Protocol Items: Recommendations for Interventional Trials checklist. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, brain natriuretic peptide; BUN, blood urea nitrogen; CHOL, cholesterol; CK-MB, creatine kinase isoenzyme-MB; cysC, cystatin C; DBIL, direct bilirubin; IL-6, interleukin-6; MYO, myoglobin; PCT, procalcitonin; SCR, serum creatinine; TG, triglyceride; TBIL, total bilirubin; TnIU1tr, high sensitive troponin I. 1Markers of myocardial injury include CK-MB, MYO, TnIU1tr. 2Serum chemistry includes ALT, AST, TBIL, DBIL, CHOL, TG, Scr, BUN, CysC, BNP, PCT, cytokines.
Figure 2
Figure 2
Study flow. ICU, intensive care unit.

References

    1. Coronavirus disease 2019 (COVID-19) situation report – 153: World Health organization, 2020. Available: [Accessed 22 June 2020].
    1. Huang C, Wang Y, Li X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 2020;395:497–506. 10.1016/S0140-6736(20)30183-5
    1. Wang D, Hu B, Hu C, et al. . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020. 10.1001/jama.2020.1585. [Epub ahead of print: 07 Feb 2020].
    1. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, et al. . Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis 2020;34:101623. 10.1016/j.tmaid.2020.101623
    1. Wang Y, Zhang D, Du G, et al. . Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569–78. 10.1016/S0140-6736(20)31022-9
    1. Geleris J, Sun Y, Platt J, et al. . Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 2020;382:2411–8. 10.1056/NEJMoa2012410
    1. Cao B, Wang Y, Wen D, et al. . A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787–99. 10.1056/NEJMoa2001282
    1. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. . Cytokine release syndrome. J Immunother Cancer 2018;6:56. 10.1186/s40425-018-0343-9
    1. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39:529–39. 10.1007/s00281-017-0629-x
    1. Tu Y-F, Chien C-S, Yarmishyn AA, et al. . A review of SARS-CoV-2 and the ongoing clinical trials. Int J Mol Sci 2020;21:2657 10.3390/ijms21072657
    1. Wan S, Yi Q, Fan S, et al. . Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCp). medRxiv 2020 2020.
    1. Zhou Y, Fu B, Zheng X, et al. . Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv 2020.
    1. Xu Z, Shi L, Wang Y, et al. . Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420–2. 10.1016/S2213-2600(20)30076-X
    1. Mousavi S, Bereswill S, Heimesaat MM. Immunomodulatory and antimicrobial effects of vitamin C. Eur J Microbiol Immunol 2019;9:73–9. 10.1556/1886.2019.00016
    1. Hemilä H, Chalker E. Vitamin C can shorten the length of stay in the ICU: a meta-analysis. Nutrients 2019;11. 10.3390/nu11040708. [Epub ahead of print: 27 Mar 2019].
    1. Sauberlich HE, Packer L, Fuchs J. A history of scurvy and vitamin C. Vitamin C in Health & Disease, 1997.
    1. Carr AC, Maggini S. Vitamin C and immune function. Nutrients 2017;9. 10.3390/nu9111211. [Epub ahead of print: 03 Nov 2017].
    1. Johnston CS, Beezhold BL, Mostow B, et al. . Plasma vitamin C is inversely related to body mass index and waist circumference but not to plasma adiponectin in nonsmoking adults. J Nutr 2007;137:1757–62. 10.1093/jn/137.7.1757
    1. Johnston CS, Corte C, Swan PD. Marginal vitamin C status is associated with reduced fat oxidation during submaximal exercise in young adults. Nutr Metab 2006;3:35. 10.1186/1743-7075-3-35
    1. Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. Faseb J 1996;10:709–20. 10.1096/fasebj.10.7.8635688
    1. Härtel C, Strunk T, Bucsky P, et al. . Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes. Cytokine 2004;27:101–6. 10.1016/j.cyto.2004.02.004
    1. Chen Y, Luo G, Yuan J, et al. . Vitamin C mitigates oxidative stress and tumor necrosis factor-alpha in severe community-acquired pneumonia and LPS-induced macrophages. Mediators Inflamm 2014;2014:426740 10.1155/2014/426740
    1. Cárcamo JM, Bórquez-Ojeda O, Golde DW. Vitamin C inhibits granulocyte macrophage-colony-stimulating factor-induced signaling pathways. Blood 2002;99:3205–12. 10.1182/blood.V99.9.3205
    1. Maeng HG, Lim H, Jeong Y-J, et al. . Vitamin C enters mouse T cells as dehydroascorbic acid in vitro and does not recapitulate in vivo vitamin C effects. Immunobiology 2009;214:311–20. 10.1016/j.imbio.2008.09.003
    1. Gao Y-L, Lu B, Zhai J-H, et al. . The parenteral vitamin C improves sepsis and sepsis-induced multiple organ dysfunction syndrome via preventing cellular immunosuppression. Mediators Inflamm 2017;2017:4024672 10.1155/2017/4024672
    1. Tanaka M, Muto N, Gohda E, et al. . Enhancement by ascorbic acid 2-glucoside or repeated additions of ascorbate of mitogen-induced IgM and IgG productions by human peripheral blood lymphocytes. Jpn J Pharmacol 1994;66:451–6. 10.1254/jjp.66.451
    1. Huijskens MJAJ, Walczak M, Sarkar S, et al. . Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy 2015;17:613–20. 10.1016/j.jcyt.2015.01.004
    1. Kratzer E, Tian Y, Sarich N, et al. . Oxidative stress contributes to lung injury and barrier dysfunction via microtubule destabilization. Am J Respir Cell Mol Biol 2012;47:688–97. 10.1165/rcmb.2012-0161OC
    1. Delgado-Roche L, Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res 2020;51:384–7. 10.1016/j.arcmed.2020.04.019
    1. Jin X, Su R, Li R, et al. . Amelioration of particulate matter-induced oxidative damage by vitamin C and quercetin in human bronchial epithelial cells. Chemosphere 2016;144:459–66. 10.1016/j.chemosphere.2015.09.023
    1. Lang JD, McArdle PJ, O'Reilly PJ, et al. . Oxidant-Antioxidant balance in acute lung injury. Chest 2002;122:314S–20. 10.1378/chest.122.6_suppl.314S
    1. Fisher BJ, Kraskauskas D, Martin EJ, et al. . Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol 2012;303:L20–32. 10.1152/ajplung.00300.2011
    1. Bharara A, Grossman C, Grinnan D, et al. . Intravenous vitamin C administered as adjunctive therapy for recurrent acute respiratory distress syndrome. Case Rep Crit Care 2016;2016:1–4. 10.1155/2016/8560871
    1. Furuya A, Uozaki M, Yamasaki H, et al. . Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int J Mol Med 2008;22:541–5. 10.22038/IJBMS.2018.20714.5398
    1. Padayatty SJ, Sun H, Wang Y, et al. . Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004;140:533. 10.7326/0003-4819-140-7-200404060-00010
    1. Hemilä H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. J Intensive Care 2020;8:15. 10.1186/s40560-020-0432-y
    1. Fowler AA, Syed AA, Knowlson S, et al. . Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 2014;12:32. 10.1186/1479-5876-12-32
    1. Fowler AA, Truwit JD, Hite RD, et al. . Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA 2019;322:1261. 10.1001/jama.2019.11825
    1. Fowler Iii AA, Kim C, Lepler L, et al. . Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med 2017;6:85–90. 10.5492/wjccm.v6.i1.85
    1. Barness LA. Safety considerations with high ascorbic acid dosage. Ann N Y Acad Sci 1975;258:523–8. 10.1111/j.1749-6632.1975.tb29311.x
    1. Buehner M, Pamplin J, Studer L, et al. . Oxalate nephropathy after continuous infusion of high-dose vitamin C as an adjunct to burn resuscitation. J Burn Care Res 2016;37:e374–9. 10.1097/BCR.0000000000000233
    1. Campbell GD, Steinberg MH, Bower JD. Letter: ascorbic acid-induced hemolysis in G-6-PD deficiency. Ann Intern Med 1975;82:810. 10.7326/0003-4819-82-6-810_1
    1. Andres A, Zeier M, Eckert C. Acute kidney injury following high-dose vitamin C treatment. Dtsch Arztebl Int 2019;116:756. 10.3238/arztebl.2019.0756
    1. Fijen L, Weijmer M. Acute oxalate nephropathy due to high vitamin C doses and exocrine pancreatic insufficiency. BMJ Case Rep 2019;12. 10.1136/bcr-2019-231504. [Epub ahead of print: 19 Nov 2019].
    1. Padayatty SJ, Sun AY, Chen Q, et al. . Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 2010;5:e11414. 10.1371/journal.pone.0011414
    1. Khoshnam-Rad N, Khalili H. Safety of vitamin C in sepsis: a neglected topic. Curr Opin Crit Care 2019;25:329–33. 10.1097/MCC.0000000000000622
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. . Spirit 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7. 10.7326/0003-4819-158-3-201302050-00583
    1. Ware JH, Hamel MB. Pragmatic trials--guides to better patient care? N Engl J Med 2011;364:1685–7. 10.1056/NEJMp1103502
    1. The Guideline for COVID-19 (version 5) issued by the National health Commission of the people's Republic of China, 2020. Available: [Accessed 5 Feb 2020].
    1. Wilson MK, Baguley BC, Wall C, et al. . Review of high-dose intravenous vitamin C as an anticancer agent. Asia Pac J Clin Oncol 2014;10:22–37. 10.1111/ajco.12173
    1. The good clinical practice (GCP) issued by the National medical administration of the people's Republic of China, 2003. Available: [Accessed 6 Aug 2003].
    1. Riordan HD, Hunninghake RB, Riordan NH, et al. . Intravenous ascorbic acid: protocol for its application and use. P R Health Sci J 2003;22:287–90.
    1. Ranieri VM, Rubenfeld GD, et al. , ARDS Definition Task Force . Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307:2526–33. 10.1001/jama.2012.5669
    1. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120:c179–84. 10.1159/000339789
    1. Coronavirus disease 2019 (COVID-19) situation report – 23: World Health organization, 2020. Available: [Accessed 12 Feb 2020].
    1. Wang Y, Lin H, Lin B-W, et al. . Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann Intensive Care 2019;9:58. 10.1186/s13613-019-0532-9

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