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0 0.5 1 1.5 2+ Mortality, critical, day 90 -6% Improvement Relative Risk Mortality, non-critical, day 90 -8% Mortality, critical, day 28 -6% Mortality, non-critical, day 28 -6% Mortality, LOVIT-COVID cri.. 28% Mortality, LOVIT-COVID.. 28% Mortality, REMAP-CAP crit.. -16% Mortality, REMAP-CAP n.. -27% Ventilation, critical -35% Ventilation, non-critical -69% Vitamin C  LOVIT-COVID REMAP-CAP  LATE TREATMENT  RCT Is late treatment with vitamin C beneficial for COVID-19? RCT 1,560 patients in multiple countries Higher ventilation with vitamin C (p=0.038) Adhikari et al., JAMA, October 2023 Favors vitamin C Favors control

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

Adhikari et al., JAMA, doi:10.1001/jama.2023.21407, LOVIT-COVID REMAP-CAP, NCT04401150
Oct 2023  
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Very late stage (APACHE II 8 and 12 for non-critical and critical) RCT with publication delayed over a year showing higher ventilation and no significant difference in mortality with vitamin C.
Authors have combined what was to be two separate trials into one trial, however there are very large differences between the trials.
eTable 15 shows that results in LOVIT-COVID were substantially better than those in REMAP-CAP. eTable 13 shows improved survival for LOVIT-COVID and worse survival for REMAP-CAP (authors provide mortality breakdown only for hospital survival):
LOVIT-COVID shows 85% and 82% probability of superiority of vitamin C (critical and non-critical).
REMAP-CAP shows 12% and 7% probability of superiority of vitamin C.
Notably, LOVIT-COVID patients were blinded, while REMAP-CAP was open-label, introducing additional opportunity for bias on this highly politicized treatment. REMAP-CAP had more patients and dominates the combined results.
eFigure 8b also shows that the REMAP-CAP results were initially positive, switching to negative around September 2021. Authors note that they were unable to explain this reversal. The overall negative result is only due to the larger number of patients in the REMAP-CAP later time period.
Results for intubation are much worse than mortality, with statistically significant higher intubation for the treatment group. Hypothetically, if the actual risk matched other trials (~20% lower risk in meta analysis of 18 RCTs at the time), and there was something causing biased intubation of treatment patients in this mostly open-label trial, we may get the observed results whereby intubation is significantly worse due to the bias, but this has a muted effect on mortality which may reflect the change in risk due to intubation combined with that due to treatment.
Results varied dramatically over time. For example, during 22 Jan ‐ 21 Apr 2021, the probability of superiority for vitamin C was 1.0 for critical and 0.97 for non-critical (eTable 17).
There were dramatic changes in randomization proportions and in overall clinical outcomes over time, leading to potential issues and inaccuracies in the attempted adjustment for confounding by time.
The very long delay between the end of the trial and publication also raises questions.
NCT04401150 (history) (LOVIT-COVID) and NCT02735707 (history) (REMAP-CAP) (preliminary analysis, to be updated, please submit updates/corrections).
This is the 18th COVID-19 RCT for vitamin C, which collectively show efficacy with p=0.00088.
This is the 65th of 66 COVID-19 controlled studies for vitamin C, which collectively show efficacy with p=0.00000029.
risk of death, 6.4% higher, HR 1.06, p = 0.47, treatment 1,032, control 528, inverted to make HR<1 favor treatment, critical, day 90.
risk of death, 7.5% higher, HR 1.08, p = 0.56, treatment 454, control 563, inverted to make HR<1 favor treatment, non-critical, day 90.
risk of death, 6.4% higher, HR 1.06, p = 0.61, treatment 1,032, control 528, inverted to make HR<1 favor treatment, critical, day 28.
risk of death, 6.4% higher, HR 1.06, p = 0.71, treatment 454, control 563, inverted to make HR<1 favor treatment, non-critical, day 28.
risk of death, 27.5% lower, HR 0.72, p = 0.34, inverted to make HR<1 favor treatment.
risk of death, 28.1% lower, HR 0.72, p = 0.37, inverted to make HR<1 favor treatment.
risk of death, 16.3% higher, HR 1.16, p = 0.22, inverted to make HR<1 favor treatment.
risk of death, 26.6% higher, HR 1.27, p = 0.19, inverted to make HR<1 favor treatment.
risk of mechanical ventilation, 35.1% higher, HR 1.35, p = 0.04, treatment 1,032, control 528, inverted to make HR<1 favor treatment, critical.
risk of mechanical ventilation, 69.5% higher, HR 1.69, p = 0.008, treatment 454, control 563, inverted to make HR<1 favor treatment, non-critical.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Adhikari et al., 25 Oct 2023, Randomized Controlled Trial, multiple countries, peer-reviewed, 1 author, REMAP-CAP non-critical, trial NCT04401150 (history) (LOVIT-COVID REMAP-CAP).
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This PaperVitamin CAll
Intravenous Vitamin C for Patients Hospitalized With COVID-19
Simin Florescu, Delia Stanciu, Mihaela Zaharia, Alma kosa, Daniel Codreanu, Komal Fareed, Aneela Kidwai, Callum Kaye, Amanda Coutts, Lynn Mackay, Charlotte Summers, Petra Polgarova, Neda Farahi, Eleonore Fox, David Sapsford, Katherine Bongaerts, Peter Featherstone, Anthony Ng, Stephen Mcwilliam, Daniel Hawcutt, Laura Rad, Laura O’malley, Jennifer Whitbread, Dawn Jones, Rachael Dore, Paula Saunderson, Olivia Kelsall, Nicholas Cowley, Laura Wild, Jessica Thrush, Hannah Wood, Karen Austin, Adrian Donnelly, Martin Kelly, Naoise Smyth, Sinéad O’kane, Declan Mcclintock, Majella Warnock, Ryan Campbell, Edmund Mccallion, Amine azaiz, Cyril Charron, Mathieu Godement, Guillaume Geri, Antoine Vieillard-Baron, Paul Johnson, Shirley Mckenna, Joanne Hanley, Andrew Currie, Barbara Allen, Clare Mcgoldrick, Moyra Mcmaster, Ashwin Mani, Meghena Mathew, Revathi Kandeepan, Chandrashekar Vignesh, Nagarajan Ramakrishnan, Augustian James, Evangeline Elvira, Ramachandran Pratheema, Suresh Babu, Rabindrarajan Ebenezer, S Krishnamoorthy, Lakshmi Ranganathan, Manisha Ganesan, Madhu Shree, Simone Piva, Emanuele Focà, Damiano Rizzoni, Gianluca Boari, Mattia Marchesi, Magdalena Butler, Keri-Anne Cowdrey, Brittany Mason, Melissa Woolett, Eamon Duffy, Yan Chen, Hiromi Nakamuro, Caroline O’connor, Lauren West, Khaled El-Khawas, Angus Richardson, Dianne Hill, Robert Commons, Hussam Abdelkharim, Manoj Saxena, Margaret Muteithia, Kelsey Dobell-Brown, Rajeev Jha, Michael Kalogirou, Christine Ellis, Vinodh Krishnamurthy, Aibhilin O’connor, Saranya Thurairatnam, Dipak Mukherjee, Agilan Kaliappan, Mark Vertue, Anne Nicholson, Joanne Riches, Gracie Maloney, Lauren Kittridge, Amanda Solesbury, Angelo Ramos, Daniel Collins, Kathy Brickell, Liadain Reid, Michelle Smyth, Patrick Breen, Sandra Spain, Gerard Curley, Natalie Mcevoy, Pierce Geoghegan, Jennifer Clarke, Jon Silversides, Peter Mcguigan, Kathryn Ward, Aisling O’neill, Stephanie Finn, Chris Wright, Jackie Green, Érin Collins, Emmet Major, Julie Mcauley, Angus Carter, Julie Smith, Catherine Boschert, Kitty Slieker, Esther Ewalds, Arnate Sanders, Wendy Wittenberg, Heidi Geurts, Latesh Poojara, Treena Sara, Kiran Nand, Brenda Reeve, William Dechert, Barbara Phillips, Laura Oritz-Ruiz De gordoa, Marion Campbell, Filipa Dos Santos, Dan Hansen, Dee Mullan, Julia Affleck, Arif Shaikh, Andrew Murray, Mahesh Ramanan, Thuy Frakking, Jez Pinnell, Matt Robinson, Lisa Gledhill, Tracy Wood, Ritesh Sanghavi, Deepak Bhonagiri, Megan Ford, Harshel G Parikh, Bronwyn Avard, Mary Nourse, Bree Mcdonald, Natasha Edmunds, Oscar Hoiting, Marco Peters, Els Rengers, Manon Bindels, Mirjam Evers, Anton Prinssen, Matt Morgan, Jade Cole, Helen Hill, Michelle Davies, Angharad Williams, Emma Thomas, Rhys Davies, Matt Wise, Daniel Law, Patrick Grimm, Jens Soukup, Richard Wetzold, Madlen Löbel, Lisa Starke, Francois Lellouche, Patricia Lizotte, Adrien Auvet, Celine Ravry, Vanessa Creange, Anne-Helene Boivin, Amélie Barreau, Sophie Vandewoestyne, Pierre-Louis Declercq, Antoine Marchalot, Cecile Saladin, Stephanie Gelinotte, Jean-Pierre Eraldi, François Bourgerol, Marion Beuzelin, Rigaud Jean-Philippe, Franck Pourcine, Mehran Monchi, Gael Pradel, Marie-Helene Hausermann, Michel Boudineau, Thi-My-Hue Nguyen-Valat, Christophe Guitton, Remy Marnai, Marie-Helene Leroyer, Michaël Landais, Cedric Darreau, Marjorie Saint Martin, Patrice Tirot, Nicolas Chudeau, Aurélie Brasselet, Lev Volkov, Jean-Christophe Callahan, Juliette Meunier, Thomas Douillard, Elliot Le Basnier, Marion Veillard, Dominique Vivier, David Luis, Romain Mercier, Anne Sagnier, Nathalie Verrier, Cecile Caplin, Jack Richecoeu, Daniele Combaux, Shidasp Siami, Christelle Aparicio, Sarah Vautier, Asma Jeblaoui, Delphine Lemaire-Brunel, Frédérick D’aragon, Dominique Bérard, Brian Grondin-Beaudoin, Marc-André Leclair, Olivier Lesur, Michaël Mayette, Yannick Poulin, Hector Quiroz-Martinez, Charles St-Arnaud, Elaine Carbonneau, Brigitte Bolduc, Julie Bélisle, Marie-Pier Bouchard, Line Côté, Joannie Martineau, Alexandra Naisby, Louise Robert-Petit, Marie-Ève Thibault, Julie Leblond, Gaetan Plantefeve, Cécile Leparco
JAMA, doi:10.1001/jama.2023.21407
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.
Additional Information: This article was written with gratitude to and in memory of our friend and colleague, Wilma van Bentum-Puijk, MSc.
Abraham, Reinhart, Opal, Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial, JAMA, doi:10.1001/jama.290.2.238?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.21407
Angus, Berry, Lewis, The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) study: rationale and design, Ann Am Thorac Soc, doi:10.1513/AnnalsATS.202003-192SD
Attacc, ACTIV-4a Investigators, and REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2105911
Bhatt, Mehta, Adaptive designs for clinical trials, N Engl J Med, doi:10.1056/NEJMra1510061
Canner, The Coronary Drug Project: monitoring of the data for evidence of adverse or beneficial treatment effects, Control Clin Trials, doi:10.1016/0197-2456(83)90029-6
Carr, Rowe, The emerging role of vitamin C in the prevention and treatment of COVID-19, Nutrients, doi:10.3390/nu12113286
Chiscano-Camón, Ruiz-Rodriguez, Ruiz-Sanmartin, Roca, Ferrer, Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome, Crit Care, doi:10.1186/s13054-020-03249-y
Dechartres, Trinquart, Boutron, Ravaud, Influence of trial sample size on treatment effect estimates: meta-epidemiological study, BMJ, doi:10.1136/bmj.f2304
Fish, Rynne, Jennings, REMAP-CAP Immunoglobulin Domain UK Investigators. Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial, Intensive Care Med, doi:10.1007/s00134-022-06869-w
Fowler, Iii, Syed, Knowlson, Unit Nursing. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis, J Transl Med, doi:10.1186/1479-5876-12-32
Fowler, Iii, Truwit, Hite, Effect of vitamin C infusion on organ failure and biomarkers Research Original Investigation Intravenous Vitamin C for Patients Hospitalized With COVID-19 of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial, JAMA, doi:10.1001/jama.2019.11825?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.21407
Fujii, Luethi, Young, Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial, JAMA, doi:10.1001/jama.2019.22176?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.21407
Glasziou, Sanders, Hoffmann, Waste in COVID-19 research, BMJ, doi:10.1136/bmj.m1847
Granholm, Kaas-Hansen, Lange, An overview of methodological considerations regarding adaptive stopping, arm dropping, and randomization in clinical trials, J Clin Epidemiol, doi:10.1016/j.jclinepi.2022.11.002
Heyland, Muscedere, Drover, Jiang, Day et al., Persistent organ dysfunction plus death: a novel, composite outcome measure for critical care trials, Crit Care, doi:10.1186/cc10110
Higgins, Berry, Lorenzi, Writing Committee for the REMAP-CAP Investigators. Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial, JAMA, doi:10.1001/jama.2022.23257?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.21407
Horby, Lim, Emberson, Dexamethasone in hospitalized patients with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2021436
Lamontagne, Agarwal, Rochwerg, A living WHO guideline on drugs for COVID-19, BMJ, doi:10.1136/bmj.m3379
Lamontagne, Masse, Menard, Intravenous vitamin C in adults with sepsis in the intensive care unit, N Engl J Med, doi:10.1056/NEJMoa2200644
Laterre, Berry, Blemings, Effect of selepressin vs placebo on ventilator-and vasopressor-free days in patients with septic shock: the SEPSIS-ACT randomized clinical trial, JAMA, doi:10.1001/jama.2019.14607?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.21407
Olczak-Pruc, Swieczkowski, Ladny, Vitamin C supplementation for the treatment of COVID-19: a systematic review and meta-analysis, Nutrients, doi:10.3390/nu14194217
Ramanan, Tong, Kumar, Venkatesh, Geographical representation of low-and middle-income countries in randomized clinical trials for COVID-19, JAMA Netw Open, doi:10.1001/jamanetworkopen.2022.0444?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.21407
Sevransky, Rothman, Hager, Effect of vitamin C, thiamine, and hydrocortisone on ventilator-and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial, JAMA, doi:10.1001/jama.2020.24505?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.21407
Usher, The global COVID-19 treatment divide, Lancet, doi:10.1016/S0140-6736(22)00372-5
Vail, Wunsch, Pinto, Use of hydrocortisone, ascorbic acid, and thiamine in adults with septic shock, Am J Respir Crit Care Med, doi:10.1164/rccm.202005-1829OC
Vijayaraghavan, Md; Rashan, Haniffa, Beane, Phd et al., None
Wheatley, Clayton, Be skeptical about unexpected large apparent treatment effects: the case of an MRC AML12 randomization, Control Clin Trials, doi:10.1016/S0197-2456(02)00273-8
Late treatment
is less effective
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