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

Adhikari et al., JAMA, doi:10.1001/jama.2023.21407, REMAP-CAP, NCT04401150

Oct 2023

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Vitamin C for COVID-19

6th treatment shown to reduce risk in September 2020

^*, now known with p = 0.000000087 from 70 studies, recognized in 11 countries.

Lower risk for mortality, ICU admission, hospitalization, and recovery.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19early.org

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. The results for each source trial are shown separately here Adhikari, Adhikari (B).

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). 50mg/kg vitamin C administered intravenously over 30-60 minutes every 6 hours for 4 days.

This is the 19th of 21 COVID-19 RCTs for vitamin C, which collectively show efficacy with p=0.0012.

This is the 66th of 70 COVID-19 controlled studies for vitamin C, which collectively show efficacy with p=0.000000087 (1 in 11 million).

1. Adhikari et al., Intravenous Vitamin C for Patients Hospitalized With COVID-19 Two Harmonized Randomized Clinical Trials, JAMA, doi:10.1001/jama.2023.21407.jamanetwork.com, doi.org.

2. Adhikari (B) et al., Intravenous Vitamin C for Patients Hospitalized With COVID-19 Two Harmonized Randomized Clinical Trials, JAMA, doi:10.1001/jama.2023.21407.jamanetwork.com, doi.org.

Important missing comments or errors? Let us know.

risk of death, 19.5% higher, HR 1.19, p = 0.08, treatment 1,303, control 903, combined.

risk of death, 16.3% higher, HR 1.16, p = 0.22, treatment 953, control 434, inverted to make HR<1 favor treatment, REMAP-CAP critical.

risk of death, 26.6% higher, HR 1.27, p = 0.19, treatment 350, control 469, inverted to make HR<1 favor treatment, REMAP-CAP non-critical.

risk of death, 27.5% lower, HR 0.72, p = 0.34, inverted to make HR<1 favor treatment, LOVIT-COVID critical.

risk of death, 28.1% lower, HR 0.72, p = 0.37, inverted to make HR<1 favor treatment, LOVIT-COVID non-critical.

risk of death, 6.4% higher, HR 1.06, p = 0.47, treatment 1,032, control 528, inverted to make HR<1 favor treatment, combined trials, 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, combined trials, 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, combined trials, 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 mechanical ventilation, 35.1% higher, HR 1.35, p = 0.04, treatment 1,032, control 528, inverted to make HR<1 favor treatment, combined trials, 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, combined trials, 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, 82 authors, trial NCT04401150 (history) (REMAP-CAP).

This Paper Vitamin C All

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.

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Late treatment
is less effective

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