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. 2023 Nov 14;330(18):1745-1759.
doi: 10.1001/jama.2023.21407.

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

LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators; Neill K J Adhikari  1   2 , Madiha Hashmi  3 , Bharath Kumar Tirupakuzhi Vijayaraghavan  4   5 , Rashan Haniffa  6   7 , Abi Beane  6   7 , Steve A Webb  8   9 , Derek C Angus  10   11 , Anthony C Gordon  12   13 , Deborah J Cook  14   15   16 , Gordon H Guyatt  16 , Lindsay R Berry  17 , Elizabeth Lorenzi  17 , Paul R Mouncey  18 , Carly Au  18 , Ruxandra Pinto  1 , Julie Ménard  19 , Sheila Sprague  20 , Marie-Hélène Masse  19 , David T Huang  21 , Daren K Heyland  22 , Alistair D Nichol  8   23   24   25 , Colin J McArthur  26 , Angelique de Man  27 , Farah Al-Beidh  28 , Djillali Annane  29   30 , Matthew Anstey  31   32 , Yaseen M Arabi  33   34 , Marie-Claude Battista  19 , Scott Berry  17 , Zahra Bhimani  35 , Marc J M Bonten  36   37 , Charlotte A Bradbury  38 , Emily B Brant  39 , Frank M Brunkhorst  40 , Aidan Burrell  25   41 , Meredith Buxton  42 , Maurizio Cecconi  43   44 , Allen C Cheng  45   46 , Dian Cohen  47   48 , Matthew E Cove  49 , Andrew G Day  50 , Lennie P G Derde  37   51 , Michelle A Detry  17 , Lise J Estcourt  52   53 , Elizabeth O Fagbodun  54 , Mark Fitzgerald  17 , Herman Goossens  55 , Cameron Green  8 , Alisa M Higgins  8 , Thomas E Hills  56 , Christopher Horvat  39 , Nao Ichihara  57 , Devachandran Jayakumar  58 , Salmaan Kanji  59   60 , Muhammad Nasir Khoso  61 , Patrick R Lawler  62   63   64 , Roger J Lewis  17 , Edward Litton  65 , John C Marshall  66 , Daniel F McAuley  67   68 , Anna McGlothlin  17 , Shay P McGuinness  56   69   70 , Zoe K McQuilten  71 , Bryan J McVerry  72 , Srinivas Murthy  73 , Rachael L Parke  56   69   74 , Jane C Parker  23 , Luis Felipe Reyes  75   76 , Kathryn M Rowan  18 , Hiroki Saito  77 , Nawal Salahuddin  78 , Marlene S Santos  79 , Christina T Saunders  17 , Christopher W Seymour  39 , Manu Shankar-Hari  80   81 , Timo Tolppa  82 , Tony Trapani  70 , Alexis F Turgeon  83   84 , Anne M Turner  56 , Andrew A Udy  70   85 , Frank L van de Veerdonk  86 , Ryan Zarychanski  87 , François Lamontagne  19   88
Collaborators, Affiliations

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

LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators et al. JAMA. .

Erratum in

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Haniffa reported receiving grants from Wellcome Trust, Medical Research Council Africa, and International COVID-19 Data Alliance. Dr Webb reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the Medical Research Future Fund. Dr Gordon reported receiving personal fees from AstraZeneca, Janssen, Novartis, and 30 Respiratory (all fees paid to institution). Dr L. Berry reported receiving grants and being an employee of Berry Consultants. Dr Lorenzi reported being an employee of Berry Consultants. Dr Nichol reported receiving grants from the European Commission. Dr de Man reported receiving grants from the Netherlands Organisation of Health Research. Dr S. Berry reported being part owner of Berry Consultants. Dr Bradbury reported receiving personal fees from Bristol Myers Squibb, Pfizer, Bayer, Amgen, Lilly, Sobi, Sanofi, Novartis, and Janssen. Dr Cecconi reported receiving personal fees from Edwards Lifesciences, Directed Systems, and GE Healthcare. Dr Cove reported receiving grants from National University Health System; receiving personal fees from Baxter, Medtronic, B Braun, and Jafron; and holding a patent for the removal of carbon dioxide via dialysis. Dr Derde reported receiving grants from the European Commission and serving as a member of the international advisory board for Sepsis Canada. Dr Detry reported receiving grants from the European Commission and the Global Coalition for Adaptive Research and being a director and senior statistical scientist at Berry Consultants. Dr Fitzgerald reported receiving grants from the European Commission and the Global Coalition for Adaptive Research. Dr Higgins reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the Medical Research Future Fund. Dr Horvat reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Lawler reported receiving personal fees from the American College of Cardiology and McGraw Hill. Dr Lewis reported being a senior medical scientist at Berry Consultants. Dr Marshall reported receiving personal fees from AM Pharma and Matisse. Dr McAuley reported receiving grants from Innovate UK, Northern Ireland Health and Social Care, the Medical Research Council, and Wellcome Trust; receiving personal fees from Bayer, GSK, Boehringer Ingelheim, Novartis, Eli Lilly, Vir Biotechnology, Aptarion, Aviceda, and Direct Biologics; holding a patent for an anti-inflammatory treatment (issued to Queen’s University Belfast) for a novel treatment for inflammatory disease; and being the co-director of research for the Intensive Care Society and the program director for the National Institute for Health and Care Research/Medical Research Council Efficacy and Mechanism Evaluation. Dr McGlothlin reported receiving grants from the European Commission and the Global Coalition for Adaptive Research. Dr McVerry reported receiving grants from the Pittsburgh Foundation and the National Institutes of Health and receiving personal fees from Boehringer Ingelheim, Synairgen, and BioAegis. Dr Parke reported receiving grants from Fisher and Paykel Healthcare Ltd. Dr Reyes reported receiving grants from Merck Sharp & Dohme and Pfizer and receiving personal fees from GSK. Dr Rowan reported receiving grants from the European Commission. Dr Saunders reported receiving grants from the European Commission and the Global Coalition for Adaptive Research. Dr Seymour reported receiving grants from the National Institutes of Health and personal fees from Beckman Coulter and Inotrem, Inc. Dr Shankar-Hari reported receiving grants from the Chief Scientist Office Scotland, the National Institute for Health and Care Research (Efficacy and Mechanism Evaluation and Health Technology Assessment programs), the Medical Research Council, and the Huo Foundation. Dr Udy reported nonfinancial support from Integra Lifesciences. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Patients Through the Harmonized Trial Including the LOVIT-COVID Trial and the Vitamin C Domain of the REMAP-CAP Trial
Additional details appear in eFigures 2-3 in Supplement 1. ICU indicates intensive care unit. aMay have been excluded for more than 1 reason. bOf these 7800 adults, 7212 were used for covariate adjustment. cOne additional participant had missing primary outcome data.
Figure 2.
Figure 2.. Critically Ill Patients in the Harmonized Trial of Vitamin C vs Control for Those Hospitalized With COVID-19
A, The curves that rise more slowly indicate a more favorable distribution in the number of days alive and free of organ support. B, Red represents worse outcomes and blue represents better outcomes. The median adjusted proportional odds ratio from the primary analysis was 0.88 (95% credible interval, 0.73-1.06), yielding a posterior probability of 8.6% for vitamin C being superior to control. C, In the vitamin C group, 415 of 1032 patients died (40.2%) and, in the control group, 200 of 528 patients died (37.9%); the denominators exclude censored patients. Data were not available for 8 patients who were censored prior to 90 days.
Figure 3.
Figure 3.. Patients Who Were Not Critically Ill in the Harmonized Trial of Vitamin C vs Control for Those Hospitalized With COVID-19
A, The curves that rise more slowly indicate a more favorable distribution in the number of days alive and free of organ support. B, Red represents worse outcomes and blue represents better outcomes. The median adjusted proportional odds ratio from the primary analysis was 0.80 (95% credible interval, 0.60-1.01), yielding a posterior probability of 2.9% for vitamin C being superior to control. C, In the vitamin C group, 84 of 454 patients died (18.5%) and, in the control group, 97 of 563 patients died (17.2%); the denominators exclude censored patients. Data were not available for 4 patients who were censored prior to 90 days.
See this image and copyright information in PMC

Comment in

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