All Studies Meta Analysis

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, NCT04401150

Oct 2023

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Vitamin C for COVID-19

6th treatment shown to reduce risk in September 2020, now with p = 0.00000002 from 73 studies, recognized in 12 countries.

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

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 112 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 here1,2.

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.

See also Hemilä et al. which shows that the poor results may be explained by a rebound effect due to the abrupt termination of treatment after 4 days.

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.

Although the 28% lower mortality is not statistically significant, it is consistent with the significant 20% lower mortality [10‑28%] from meta analysis of the 44 mortality results to date.

This is the 20th of 21 COVID-19 RCTs for vitamin C, which collectively show efficacy with p=0.0012.

This is the 67th of 73 COVID-19 controlled studies for vitamin C, which collectively show efficacy with p=0.00000002 (1 in 50 million).

Important missing comments or errors? Let us know.

risk of death, 27.8% lower, HR 0.72, p = 0.19, treatment 190, control 194, combined.

risk of death, 27.5% lower, HR 0.72, p = 0.34, treatment 84, control 97, inverted to make HR<1 favor treatment, LOVIT-COVID critical.

risk of death, 28.1% lower, HR 0.72, p = 0.37, treatment 106, control 97, inverted to make HR<1 favor treatment, LOVIT-COVID non-critical.

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

risk of death, 26.6% higher, HR 1.27, p = 0.19, inverted to make HR<1 favor treatment, REMAP-CAP 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

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.

3. Hemilä et al., Rebound effect explains the divergence in survival after 5 days in a controlled trial on vitamin C for COVID-19 patients, Frontiers in Medicine, doi:10.3389/fmed.2024.1391346.frontiersin.org, doi.org.

Adhikari et al., 25 Oct 2023, Double Blind Randomized Controlled Trial, multiple countries, peer-reviewed, 82 authors, dosage 50mg/kg qid days 1-4, trial NCT04401150 (history) (LOVIT-COVID).

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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{ 'indexed': {'date-parts': [[2024, 3, 19]], 'date-time': '2024-03-19T09:42:08Z', 'timestamp': 1710841328447}, 'reference-count': 30, 'publisher': 'American Medical Association (AMA)', 'issue': '18', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'published-print': {'date-parts': [[2023, 11, 14]]}, 'abstract': 'ImportanceThe efficacy of vitamin C for ' 'hospitalized patients with COVID-19 is ' 'uncertain.ObjectiveTo ' 'determine whether vitamin C improves outcomes for patients with ' 'COVID-19.Design, Setting, and ' 'ParticipantsTwo 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.InterventionsPatients ' '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 ' 'MeasuresThe 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.ResultsEnrollment 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 ' 'RelevanceIn 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 ' 'RegistrationClinicalTrials.gov Identifiers: NCT04401150 ' '(LOVIT-COVID) and NCT02735707 ' '(REMAP-CAP)', 'DOI': '10.1001/jama.2023.21407', 'type': 'journal-article', 'created': { 'date-parts': [[2023, 10, 25]], 'date-time': '2023-10-25T12:30:56Z', 'timestamp': 1698237056000}, 'page': '1745', 'source': 'Crossref', 'is-referenced-by-count': 7, 'title': 'Intravenous Vitamin C for Patients Hospitalized With COVID-19', 'prefix': '10.1001', 'volume': '330', 'author': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials ' 'Group, and the REMAP-CAP Investigators', 'sequence': 'first', 'affiliation': []}, { 'given': 'Simin\xa0', 'family': 'Florescu', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Delia', 'family': 'Stanciu', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Mihaela\xa0', 'family': 'Zaharia', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Alma', 'family': '\xa0Kosa', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Daniel', 'family': 'Codreanu', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Komal', 'family': 'Fareed', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Aneela', 'family': 'Kidwai', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Callum', 'family': 'Kaye', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Amanda', 'family': 'Coutts', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Lynn', 'family': 'MacKay', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Charlotte', 'family': 'Summers', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Petra\xa0', 'family': 'Polgarova', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Neda', 'family': 'Farahi', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP 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'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Stephen', 'family': 'McWilliam', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Daniel', 'family': 'Hawcutt', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Laura', 'family': 'Rad', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Laura', 'family': 'O’Malley', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP 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' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Allen', 'family': 'Cheng', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Matthew', 'family': 'Cove', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Lennie', 'family': 'Derde', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Lise', 'family': 'Escourt', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Herman', 'family': 'Goossens', 'sequence': 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'given': 'Roland', 'family': 'van\xa0Kimmenade', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'David', 'family': 'Harrison', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Alisa', 'family': 'Higgins', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Lamprini', 'family': 'Lampro', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Alexina', 'family': 'Mason', 'sequence': 'additional', 'affiliation': [ { 'name': 'The 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Investigators'}]}, { 'given': 'Cain', 'family': 'Harland', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Audrey', 'family': 'Shearer', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Jess', 'family': 'Wren', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Giles', 'family': 'Clermont', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Daniel', 'family': 'Ricketts', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Fathima', 'family': 'Fazla', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Himasha', 'family': 'Muvindi', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Pramodya', 'family': 'Ishani', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Aasiyah', 'family': 'Rashan', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Ishara\xa0', 'family': 'Udayanga', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Michelle', 'family': 'Detry', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Mark', 'family': 'Fitzgerald', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Roger', 'family': 'Lewis', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Anna', 'family': 'McGlothlin', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Christina', 'family': 'Saunders', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Lindsay', 'family': 'Berry', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Elizabeth', 'family': 'Lorenzi', 'sequence': 'additional', 'affiliation': [ { 'name': 'The LOVIT-COVID Investigators, on behalf of the Canadian ' 'Critical Care Trials Group, and the REMAP-CAP Investigators'}]}, { 'given': 'Neill K. J.', 'family': 'Adhikari', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, Sunnybrook Health Sciences ' 'Centre, Toronto, Ontario, Canada'}, { 'name': 'Interdepartmental Division of Critical Care Medicine, University ' 'of Toronto, Toronto, Ontario, Canada'}]}, { 'given': 'Madiha', 'family': 'Hashmi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, Ziauddin University, ' 'Karachi, Pakistan'}]}, { 'given': 'Bharath Kumar', 'family': 'Tirupakuzhi Vijayaraghavan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, Apollo Hospitals, Chennai, ' 'India'}, {'name': 'George Institute for Global Health India, New Delhi'}]}, { 'given': 'Rashan', 'family': 'Haniffa', 'sequence': 'additional', 'affiliation': [ { 'name': 'Centre for Inflammation Research, Institute for Regeneration and ' 'Repair, University of Edinburgh, Edinburgh, Scotland'}, { 'name': 'Mahidol Oxford Tropical Medicine Research Unit, Bangkok, ' 'Thailand'}]}, { 'given': 'Abi', 'family': 'Beane', 'sequence': 'additional', 'affiliation': [ { 'name': 'Centre for Inflammation Research, Institute for Regeneration and ' 'Repair, University of Edinburgh, Edinburgh, Scotland'}, { 'name': 'Mahidol Oxford Tropical Medicine Research Unit, Bangkok, ' 'Thailand'}]}, { 'given': 'Steve A.', 'family': 'Webb', 'sequence': 'additional', 'affiliation': [ { 'name': 'Australian and New Zealand Intensive Care Research Centre, ' 'School of Public Health and Preventive Medicine, Monash ' 'University, Melbourne, Australia'}, {'name': 'St John of God Health Care, Perth, Australia'}]}, { 'given': 'Derek C.', 'family': 'Angus', 'sequence': 'additional', 'affiliation': [ { 'name': 'University of Pittsburgh Medical Center, Pittsburgh, ' 'Pennsylvania'}, {'name': 'University of Pittsburgh, Pittsburgh, Pennsylvania'}]}, { 'given': 'Anthony C.', 'family': 'Gordon', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Anaesthetics, Pain Medicine, and Intensive Care, ' 'Imperial College London, London, England'}, { 'name': 'St Mary’s Hospital, Imperial College Healthcare NHS Trust, ' 'London, England'}]}, { 'given': 'Deborah J.', 'family': 'Cook', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, McMaster University, Hamilton, Ontario, ' 'Canada'}, { 'name': 'Department of Critical Care, St Joseph’s Healthcare Hamilton, ' 'Hamilton, Ontario, Canada'}, { 'name': 'Department of Health Research Methods, Evidence, and Impact, ' 'McMaster University, Hamilton, Ontario, Canada'}]}, { 'given': 'Gordon H.', 'family': 'Guyatt', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Health Research Methods, Evidence, and Impact, ' 'McMaster University, Hamilton, Ontario, Canada'}]}, { 'given': 'Lindsay R.', 'family': 'Berry', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Elizabeth', 'family': 'Lorenzi', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Paul R.', 'family': 'Mouncey', 'sequence': 'additional', 'affiliation': [ { 'name': 'Intensive Care National Audit and Research Centre, London, ' 'England'}]}, { 'given': 'Carly', 'family': 'Au', 'sequence': 'additional', 'affiliation': [ { 'name': 'Intensive Care National Audit and Research Centre, London, ' 'England'}]}, { 'given': 'Ruxandra', 'family': 'Pinto', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, Sunnybrook Health Sciences ' 'Centre, Toronto, Ontario, Canada'}]}, { 'given': 'Julie', 'family': 'Ménard', 'sequence': 'additional', 'affiliation': [ { 'name': 'Research Centre of the Centre Hospitalier Universitaire de ' 'Sherbrooke, Sherbrooke, Quebec, Canada'}]}, { 'given': 'Sheila', 'family': 'Sprague', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Surgery, McMaster University, Hamilton, Ontario, ' 'Canada'}]}, { 'given': 'Marie-Hélène', 'family': 'Masse', 'sequence': 'additional', 'affiliation': [ { 'name': 'Research Centre of the Centre Hospitalier Universitaire de ' 'Sherbrooke, Sherbrooke, Quebec, Canada'}]}, { 'given': 'David T.', 'family': 'Huang', 'sequence': 'additional', 'affiliation': [ { 'name': 'School of Medicine, University of Pittsburgh, Pittsburgh, ' 'Pennsylvania'}]}, { 'given': 'Daren K.', 'family': 'Heyland', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, Queen’s University, ' 'Kingston, Ontario, Canada'}]}, { 'given': 'Alistair D.', 'family': 'Nichol', 'sequence': 'additional', 'affiliation': [ { 'name': 'Australian and New Zealand Intensive Care Research Centre, ' 'School of Public Health and Preventive Medicine, Monash ' 'University, Melbourne, Australia'}, { 'name': 'Faculty of Medicine, Nursing, and Health Sciences, Monash ' 'University, Clayton, Australia'}, {'name': 'University College Dublin, Dublin, Ireland'}, {'name': 'Alfred Health, Melbourne, Australia'}]}, { 'given': 'Colin J.', 'family': 'McArthur', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, Auckland City Hospital, ' 'Auckland, New Zealand'}]}, { 'given': 'Angelique', 'family': 'de Man', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Intensive Care Medicine, Amsterdam University ' 'Medical Centers, Amsterdam, the Netherlands'}]}, { 'given': 'Farah', 'family': 'Al-Beidh', 'sequence': 'additional', 'affiliation': [{'name': 'Imperial College London, London, England'}]}, { 'given': 'Djillali', 'family': 'Annane', 'sequence': 'additional', 'affiliation': [ { 'name': 'UVSQ University Paris Saclay, Institut-Hospitalo Universitaire ' 'Prometheus, Paris, France'}, { 'name': 'Médecine Intensive-Réanimation, Hôpital Raymond-Poincaré, ' 'Garches, France'}]}, { 'given': 'Matthew', 'family': 'Anstey', 'sequence': 'additional', 'affiliation': [ {'name': 'Sir Charles Gairdner Hospital, Nedlands, Australia'}, {'name': 'University of Western Australia, Perth'}]}, { 'given': 'Yaseen M.', 'family': 'Arabi', 'sequence': 'additional', 'affiliation': [ { 'name': 'King Saud bin Abdulaziz University for Health Sciences, Riyadh, ' 'Saudi Arabia'}, { 'name': 'King Abdullah International Medical Research Center, Riyadh, ' 'Saudi Arabia'}]}, { 'given': 'Marie-Claude', 'family': 'Battista', 'sequence': 'additional', 'affiliation': [ { 'name': 'Research Centre of the Centre Hospitalier Universitaire de ' 'Sherbrooke, Sherbrooke, Quebec, Canada'}]}, { 'given': 'Scott', 'family': 'Berry', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Zahra', 'family': 'Bhimani', 'sequence': 'additional', 'affiliation': [ { 'name': 'St Michael’s Hospital, Unity Health Toronto, Toronto, Ontario, ' 'Canada'}]}, { 'given': 'Marc J. M.', 'family': 'Bonten', 'sequence': 'additional', 'affiliation': [ { 'name': 'Julius Center for Health Sciences and Primary Care, University ' 'Medical Center Utrecht, Utrecht, the Netherlands'}, { 'name': 'European Clinical Research Alliance on Infectious Diseases, ' 'Utrecht, the Netherlands'}]}, { 'given': 'Charlotte A.', 'family': 'Bradbury', 'sequence': 'additional', 'affiliation': [{'name': 'University of Bristol, Bristol, England'}]}, { 'given': 'Emily B.', 'family': 'Brant', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, School of Medicine, ' 'University of Pittsburgh, Pittsburgh, Pennsylvania'}]}, { 'given': 'Frank M.', 'family': 'Brunkhorst', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Anaesthesiology and Intensive Care Medicine, Jena ' 'University Hospital, Jena, Germany'}]}, { 'given': 'Aidan', 'family': 'Burrell', 'sequence': 'additional', 'affiliation': [ {'name': 'Alfred Health, Melbourne, Australia'}, { 'name': 'Australian and New Zealand Intensive Care Research Centre, ' 'Department of Epidemiology and Preventive Medicine, Monash ' 'University, Melbourne, Australia'}]}, { 'given': 'Meredith', 'family': 'Buxton', 'sequence': 'additional', 'affiliation': [{'name': 'Global Coalition for Adaptive Research, Larkspur, California'}]}, { 'given': 'Maurizio', 'family': 'Cecconi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Milan, ' 'Italy'}, {'name': 'IRCCS Humanitas Research Hospital, Milan, Italy'}]}, { 'given': 'Allen C.', 'family': 'Cheng', 'sequence': 'additional', 'affiliation': [ { 'name': 'Monash Infectious Disease, Monash Health and School of Clinical ' 'Sciences, Monash University, Clayton, Australia'}, { 'name': 'School of Public Health and Preventive Medicine, Monash ' 'University, Melbourne, Australia'}]}, { 'given': 'Dian', 'family': 'Cohen', 'sequence': 'additional', 'affiliation': [ {'name': 'Bishop’s University, Sherbrooke, Quebec, Canada'}, {'name': 'Massawippi Valley Foundation, Ayer’s Cliff, Quebec, Canada'}]}, { 'given': 'Matthew E.', 'family': 'Cove', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, Yong Loo Lin School of Medicine, ' 'National University of Singapore, Singapore'}]}, { 'given': 'Andrew G.', 'family': 'Day', 'sequence': 'additional', 'affiliation': [ { 'name': 'Kingston Health Sciences Centre and Queen’s University, ' 'Kingston, Ontario, Canada'}]}, { 'given': 'Lennie P. G.', 'family': 'Derde', 'sequence': 'additional', 'affiliation': [ { 'name': 'European Clinical Research Alliance on Infectious Diseases, ' 'Utrecht, the Netherlands'}, { 'name': 'Intensive Care Centre, University Medical Centre Utrecht, ' 'Utrecht, the Netherlands'}]}, { 'given': 'Michelle A.', 'family': 'Detry', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Lise J.', 'family': 'Estcourt', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Haematology, NHS Blood and Transplant, Bristol, ' 'England'}, { 'name': 'Radcliffe Department of Medicine, University of Oxford, Oxford, ' 'England'}]}, { 'given': 'Elizabeth O.', 'family': 'Fagbodun', 'sequence': 'additional', 'affiliation': [ { 'name': 'Imperial Clinical Trials Unit, Imperial College London, London, ' 'England'}]}, { 'given': 'Mark', 'family': 'Fitzgerald', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Herman', 'family': 'Goossens', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Medical Microbiology, University of Antwerp, ' 'Antwerp, Belgium'}]}, { 'given': 'Cameron', 'family': 'Green', 'sequence': 'additional', 'affiliation': [ { 'name': 'Australian and New Zealand Intensive Care Research Centre, ' 'School of Public Health and Preventive Medicine, Monash ' 'University, Melbourne, Australia'}]}, { 'given': 'Alisa M.', 'family': 'Higgins', 'sequence': 'additional', 'affiliation': [ { 'name': 'Australian and New Zealand Intensive Care Research Centre, ' 'School of Public Health and Preventive Medicine, Monash ' 'University, Melbourne, Australia'}]}, { 'given': 'Thomas E.', 'family': 'Hills', 'sequence': 'additional', 'affiliation': [{'name': 'Medical Research Institute of New Zealand, Wellington'}]}, { 'given': 'Nao', 'family': 'Ichihara', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Cardiovascular Surgery, School of Medicine, Jikei ' 'University, Tokyo, Japan'}]}, { 'given': 'Devachandran', 'family': 'Jayakumar', 'sequence': 'additional', 'affiliation': [{'name': 'Dr Kamakshi Memorial Hospital Apollo, Chennai, India'}]}, { 'given': 'Salmaan', 'family': 'Kanji', 'sequence': 'additional', 'affiliation': [ {'name': 'Ottawa Hospital, Ottawa, Ontario, Canada'}, {'name': 'Ottawa Hospital Research Institute, Ottawa, Ontario, Canada'}]}, { 'given': 'Muhammad Nasir', 'family': 'Khoso', 'sequence': 'additional', 'affiliation': [{'name': 'South City Hospital, Karachi, Pakistan'}]}, { 'given': 'Patrick R.', 'family': 'Lawler', 'sequence': 'additional', 'affiliation': [ {'name': 'University Health Network, Toronto, Ontario, Canada'}, {'name': 'University of Toronto, Toronto, Ontario, Canada'}, {'name': 'McGill University Health Centre, Montreal, Quebec, Canada'}]}, { 'given': 'Roger J.', 'family': 'Lewis', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Edward', 'family': 'Litton', 'sequence': 'additional', 'affiliation': [ { 'name': 'Fiona Stanley Hospital, Department of Intensive Care Unit, ' 'University of Western Australia, Perth'}]}, { 'given': 'John C.', 'family': 'Marshall', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Surgery, University of Toronto, Toronto, Ontario, ' 'Canada'}]}, { 'given': 'Daniel F.', 'family': 'McAuley', 'sequence': 'additional', 'affiliation': [ {'name': 'Queen’s University of Belfast, Belfast, Northern Ireland'}, { 'name': 'Centre for Infection and Immunity, Royal Victoria Hospital, ' 'Belfast, Northern Ireland'}]}, { 'given': 'Anna', 'family': 'McGlothlin', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Shay P.', 'family': 'McGuinness', 'sequence': 'additional', 'affiliation': [ {'name': 'Medical Research Institute of New Zealand, Wellington'}, { 'name': 'Auckland City Hospital, Cardiothoracic and Vascular Intensive ' 'Care Unit, Auckland, New Zealand'}, { 'name': 'Australian and New Zealand Intensive Care Research Centre, ' 'Monash University, Melbourne, Australia'}]}, { 'given': 'Zoe K.', 'family': 'McQuilten', 'sequence': 'additional', 'affiliation': [{'name': 'Monash University, Monash Health, Clayton, Australia'}]}, { 'given': 'Bryan J.', 'family': 'McVerry', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of Pittsburgh, Pittsburgh, ' 'Pennsylvania'}]}, { 'given': 'Srinivas', 'family': 'Murthy', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Pediatrics, University of British Columbia, ' 'Vancouver, Canada'}]}, { 'given': 'Rachael L.', 'family': 'Parke', 'sequence': 'additional', 'affiliation': [ {'name': 'Medical Research Institute of New Zealand, Wellington'}, { 'name': 'Auckland City Hospital, Cardiothoracic and Vascular Intensive ' 'Care Unit, Auckland, New Zealand'}, { 'name': 'School of Nursing, University of Auckland, Auckland, New ' 'Zealand'}]}, { 'given': 'Jane C.', 'family': 'Parker', 'sequence': 'additional', 'affiliation': [ { 'name': 'Faculty of Medicine, Nursing, and Health Sciences, Monash ' 'University, Clayton, Australia'}]}, { 'given': 'Luis Felipe', 'family': 'Reyes', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Infectious Diseases, Universidad de La Sabana, ' 'Chia, Colombia'}, { 'name': 'Department of Critical Care Medicine, Clinica Universidad de La ' 'Sabana, Chia, Colombia'}]}, { 'given': 'Kathryn M.', 'family': 'Rowan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Intensive Care National Audit and Research Centre, London, ' 'England'}]}, { 'given': 'Hiroki', 'family': 'Saito', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Emergency and Critical Care Medicine, St Marianna ' 'University Yokohama Seibu Hospital, Yokohama, Japan'}]}, { 'given': 'Nawal', 'family': 'Salahuddin', 'sequence': 'additional', 'affiliation': [ { 'name': 'National Institute of Cardiovascular Diseases, Karachi, ' 'Pakistan'}]}, { 'given': 'Marlene S.', 'family': 'Santos', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care, St Michael’s Hospital, Toronto, ' 'Ontario, Canada'}]}, { 'given': 'Christina T.', 'family': 'Saunders', 'sequence': 'additional', 'affiliation': [{'name': 'Berry Consultants LLC, Austin, Texas'}]}, { 'given': 'Christopher W.', 'family': 'Seymour', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Critical Care Medicine, School of Medicine, ' 'University of Pittsburgh, Pittsburgh, Pennsylvania'}]}, { 'given': 'Manu', 'family': 'Shankar-Hari', 'sequence': 'additional', 'affiliation': [ { 'name': 'Institute for Regeneration and Repair, University of Edinburgh, ' 'Edinburgh, Scotland'}, {'name': 'Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, Scotland'}]}, { 'given': 'Timo', 'family': 'Tolppa', 'sequence': 'additional', 'affiliation': [{'name': 'National Intensive Care 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Centre, ' 'Monash University, Melbourne, Australia'}, { 'name': 'Department of Intensive Care and Hyperbaric Medicine, Alfred ' 'Hospital, Melbourne, Australia'}]}, { 'given': 'Frank L.', 'family': 'van de Veerdonk', 'sequence': 'additional', 'affiliation': [ { 'name': 'Internal Medicine, Radboud University Medical Center, Nijmegen, ' 'the Netherlands'}]}, { 'given': 'Ryan', 'family': 'Zarychanski', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Internal Medicine, University of Manitoba, ' 'Winnipeg, Canada'}]}, { 'given': 'François', 'family': 'Lamontagne', 'sequence': 'additional', 'affiliation': [ { 'name': 'Research Centre of the Centre Hospitalier Universitaire de ' 'Sherbrooke, Sherbrooke, Quebec, Canada'}, { 'name': 'Department of Medicine, Université de Sherbrooke, Sherbrooke, ' 'Quebec, Canada'}]}], 'member': '10', 'reference': [ { 'key': 'joi230127r2', 'doi-asserted-by': 'publisher', 'first-page': 'm3379', 'DOI': '10.1136/bmj.m3379', 'article-title': 'A 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among patients with ' 'septic shock: the VITAMINS randomized clinical trial.', 'volume': '323', 'author': 'Fujii', 'year': '2020', 'journal-title': 'JAMA'}, { 'issue': '8', 'key': 'joi230127r6', 'doi-asserted-by': 'publisher', 'first-page': '742', 'DOI': '10.1001/jama.2020.24505', 'article-title': 'Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and ' 'vasopressor-free days in patients with sepsis: the VICTAS randomized ' 'clinical trial.', 'volume': '325', 'author': 'Sevransky', 'year': '2021', 'journal-title': 'JAMA'}, { 'issue': '25', 'key': 'joi230127r7', 'doi-asserted-by': 'publisher', 'first-page': '2387', 'DOI': '10.1056/NEJMoa2200644', 'article-title': 'Intravenous vitamin C in adults with sepsis in the intensive care unit.', 'volume': '386', 'author': 'Lamontagne', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'issue': '11', 'key': 'joi230127r9', 'doi-asserted-by': 'publisher', 'first-page': '3286', 'DOI': '10.3390/nu12113286', 'article-title': 'The emerging role of vitamin C in the prevention and treatment of ' 'COVID-19.', 'volume': '12', 'author': 'Carr', 'year': '2020', 'journal-title': 'Nutrients'}, { 'issue': '1', 'key': 'joi230127r10', 'doi-asserted-by': 'publisher', 'first-page': '522', 'DOI': '10.1186/s13054-020-03249-y', 'article-title': 'Vitamin C levels in patients with SARS-CoV-2-associated acute ' 'respiratory distress syndrome.', 'volume': '24', 'author': 'Chiscano-Camón', 'year': '2020', 'journal-title': 'Crit Care'}, { 'issue': '19', 'key': 'joi230127r11', 'doi-asserted-by': 'publisher', 'first-page': '4217', 'DOI': '10.3390/nu14194217', 'article-title': 'Vitamin C supplementation for the treatment of COVID-19: a systematic ' 'review and meta-analysis.', 'volume': '14', 'author': 'Olczak-Pruc', 'year': '2022', 'journal-title': 'Nutrients'}, { 'issue': '7', 'key': 'joi230127r12', 'doi-asserted-by': 'publisher', 'first-page': '879', 'DOI': '10.1513/AnnalsATS.202003-192SD', 'article-title': 'The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for ' 'Community-acquired Pneumonia) study: rationale and design.', 'volume': '17', 'author': 'Angus', 'year': '2020', 'journal-title': 'Ann Am Thorac Soc'}, { 'issue': '8', 'key': 'joi230127r13', 'doi-asserted-by': 'publisher', 'first-page': '693', 'DOI': '10.1056/NEJMoa2021436', 'article-title': 'Dexamethasone in hospitalized patients with Covid-19.', 'volume': '384', 'author': 'Horby', 'year': '2021', 'journal-title': 'N Engl J Med'}, { 'issue': '9', 'key': 'joi230127r14', 'doi-asserted-by': 'publisher', 'first-page': '790', 'DOI': '10.1056/NEJMoa2105911', 'article-title': 'Therapeutic anticoagulation with heparin in noncritically ill patients ' 'with Covid-19.', 'volume': '385', 'author': 'ATTACC, ACTIV-4a Investigators, and REMAP-CAP Investigators', 'year': '2021', 'journal-title': 'N Engl J Med'}, { 'issue': '9', 'key': 'joi230127r15', 'doi-asserted-by': 'publisher', 'first-page': '777', 'DOI': '10.1056/NEJMoa2103417', 'article-title': 'Therapeutic anticoagulation with heparin in critically ill patients ' 'with Covid-19.', 'volume': '385', 'author': 'REMAP-CAP, ACTIV-4a, and ATTACC Investigators', 'year': '2021', 'journal-title': 'N Engl J Med'}, { 'issue': '1', 'key': 'joi230127r16', 'doi-asserted-by': 'publisher', 'first-page': '39', 'DOI': '10.1001/jama.2022.23257', 'article-title': 'Long-term (180-day) outcomes in critically ill patients with COVID-19 ' 'in the REMAP-CAP randomized clinical trial.', 'volume': '329', 'author': 'Higgins', 'year': '2023', 'journal-title': 'JAMA'}, { 'issue': '2', 'key': 'joi230127r17', 'doi-asserted-by': 'publisher', 'first-page': 'R98', 'DOI': '10.1186/cc10110', 'article-title': 'Persistent organ dysfunction plus death: a novel, composite outcome ' 'measure for critical care trials.', 'volume': '15', 'author': 'Heyland', 'year': '2011', 'journal-title': 'Crit Care'}, { 'issue': '8', 'key': 'joi230127r18', 'doi-asserted-by': 'publisher', 'first-page': 'e192', 'DOI': '10.1016/S1473-3099(20)30483-7', 'article-title': 'A minimal common outcome measure set for COVID-19 clinical research.', 'volume': '20', 'author': 'WHO Working Group on the Clinical Characterisation and Management of COVID-19 ' 'Infection', 'year': '2020', 'journal-title': 'Lancet Infect Dis'}, { 'issue': '13', 'key': 'joi230127r19', 'doi-asserted-by': 'publisher', 'first-page': '1261', 'DOI': '10.1001/jama.2019.11825', 'article-title': '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.', 'volume': '322', 'author': 'Fowler', 'year': '2019', 'journal-title': 'JAMA'}, { 'issue': '11', 'key': 'joi230127r20', 'doi-asserted-by': 'publisher', 'first-page': '1525', 'DOI': '10.1007/s00134-022-06869-w', 'article-title': 'Coronavirus disease 2019 subphenotypes and differential treatment ' 'response to convalescent plasma in critically ill adults: secondary ' 'analyses of a randomized clinical trial.', 'volume': '48', 'author': 'Fish', 'year': '2022', 'journal-title': 'Intensive Care Med'}, { 'key': 'joi230127r21', 'doi-asserted-by': 'publisher', 'first-page': 'f2304', 'DOI': '10.1136/bmj.f2304', 'article-title': 'Influence of trial sample size on treatment effect estimates: ' 'meta-epidemiological study.', 'volume': '346', 'author': 'Dechartres', 'year': '2013', 'journal-title': 'BMJ'}, { 'issue': '15', 'key': 'joi230127r22', 'doi-asserted-by': 'publisher', 'first-page': '1476', 'DOI': '10.1001/jama.2019.14607', 'article-title': 'Effect of selepressin vs placebo on ventilator- and vasopressor-free ' 'days in patients with septic shock: the SEPSIS-ACT randomized clinical ' 'trial.', 'volume': '322', 'author': 'Laterre', 'year': '2019', 'journal-title': 'JAMA'}, { 'issue': '4', 'key': 'joi230127r23', 'doi-asserted-by': 'publisher', 'first-page': '467', 'DOI': '10.1016/0197-2456(83)90029-6', 'article-title': 'The Coronary Drug Project: monitoring of the data for evidence of ' 'adverse or beneficial treatment effects.', 'volume': '4', 'author': 'Canner', 'year': '1983', 'journal-title': 'Control Clin Trials'}, { 'issue': '2', 'key': 'joi230127r24', 'doi-asserted-by': 'publisher', 'first-page': '238', 'DOI': '10.1001/jama.290.2.238', 'article-title': 'Efficacy and safety of tifacogin (recombinant tissue factor pathway ' 'inhibitor) in severe sepsis: a randomized controlled trial.', 'volume': '290', 'author': 'Abraham', 'year': '2003', 'journal-title': 'JAMA'}, { 'issue': '1', 'key': 'joi230127r25', 'doi-asserted-by': 'publisher', 'first-page': '66', 'DOI': '10.1016/S0197-2456(02)00273-8', 'article-title': 'Be skeptical about unexpected large apparent treatment effects: the ' 'case of an MRC AML12 randomization.', 'volume': '24', 'author': 'Wheatley', 'year': '2003', 'journal-title': 'Control Clin Trials'}, { 'issue': '1', 'key': 'joi230127r26', 'doi-asserted-by': 'publisher', 'first-page': '65', 'DOI': '10.1056/NEJMra1510061', 'article-title': 'Adaptive designs for clinical trials.', 'volume': '375', 'author': 'Bhatt', 'year': '2016', 'journal-title': 'N Engl J Med'}, { 'key': 'joi230127r27', 'doi-asserted-by': 'publisher', 'first-page': '45', 'DOI': '10.1016/j.jclinepi.2022.11.002', 'article-title': 'An overview of methodological considerations regarding adaptive ' 'stopping, arm dropping, and randomization in clinical trials.', 'volume': '153', 'author': 'Granholm', 'year': '2023', 'journal-title': 'J Clin Epidemiol'}, { 'key': 'joi230127r28', 'doi-asserted-by': 'publisher', 'first-page': '32', 'DOI': '10.1186/1479-5876-12-32', 'article-title': 'Phase I safety trial of intravenous ascorbic acid in patients with ' 'severe sepsis.', 'volume': '12', 'author': 'Fowler', 'year': '2014', 'journal-title': 'J Transl Med'}, { 'issue': '2', 'key': 'joi230127r29', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jamanetworkopen.2022.0444', 'article-title': 'Geographical representation of low- and middle-income countries in ' 'randomized clinical trials for COVID-19.', 'volume': '5', 'author': 'Ramanan', 'year': '2022', 'journal-title': 'JAMA Netw Open'}, { 'key': 'joi230127r30', 'doi-asserted-by': 'publisher', 'first-page': 'm1847', 'DOI': '10.1136/bmj.m1847', 'article-title': 'Waste in COVID-19 research.', 'volume': '369', 'author': 'Glasziou', 'year': '2020', 'journal-title': 'BMJ'}, { 'key': 'joi230127r1', 'unstructured': 'World Health Organization. COVID-19 dashboard. Accessed March 30, 2023. ' 'https://covid19.who.int/'}, { 'key': 'joi230127r8', 'unstructured': 'World Health Organization. A coordinated global research roadmap: 2019 ' 'novel coronavirus. Published March 12, 2020. Accessed October 6, 2023. ' 'https://www.who.int/publications/m/item/a-coordinated-global-research-roadmap'}], 'container-title': 'JAMA', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://jamanetwork.com/journals/jama/articlepdf/2811212/jama_adhikari_2023_oi_230127_1702498690.6766.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 12, 26]], 'date-time': '2023-12-26T16:01:42Z', 'timestamp': 1703606502000}, 'score': 1, 'resource': {'primary': {'URL': 'https://jamanetwork.com/journals/jama/fullarticle/2811212'}}, 'subtitle': ['Two Harmonized Randomized Clinical Trials'], 'short-title': [], 'issued': {'date-parts': [[2023, 11, 14]]}, 'references-count': 30, 'journal-issue': {'issue': '18', 'published-print': {'date-parts': [[2023, 11, 14]]}}, 'URL': 'http://dx.doi.org/10.1001/jama.2023.21407', 'relation': {}, 'ISSN': ['0098-7484'], 'subject': ['General Medicine'], 'container-title-short': 'JAMA', 'published': {'date-parts': [[2023, 11, 14]]}}

Late treatment
is less effective

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