Among critically ill patients given vitamin C, the median number of organ-support free days was 7 versus 10 in the control group, with an adjusted OR of 0.88 (95% CI 0.73-1.06), reported Neill K. J. Adhikari, MDCM, MSc, of the Sunnybrook Health Sciences Centre in Toronto, and co-authors in JAMA.
Of patients who were not critically ill, the median number of organ-support free days was a similar 22 days in each arm, with an adjusted OR of 0.80 (95% CI 0.60-1.01).
Survival to hospital discharge in critically ill patients was 61.9% in the vitamin C group versus 64.6% in the control group. Among non-critically ill patients, survival to discharge was 85.1% and 86.6%, respectively.
For critically ill patients, the posterior probability for efficacy of vitamin C therapy was 8.6%, 91.4% for harm, and 99.9% for futility. The posterior probabilities for non-critically ill patients were 17.8% for efficacy, 82.2% for harm, and 98.1% for futility. Recruitment for the trials, which ran from 2020 through 2022, stopped in July 2022 because statistical triggers for futility and harm in the REMAP-CAP trial were reached.
“We were surprised by these results,” Adhikari wrote in an email to MedPage Today. “Although the results do not completely exclude the possibility that vitamin C is effective, they are far more consistent with vitamin C being ineffective.”
Following a single-center study in 2017 that appeared to show a significant decrease in sepsis mortality with the administration of vitamin C, hydrocortisone, and thiamine, a number of larger clinical trials showed that ultimately, there was no benefit with vitamin C in patients with sepsis. But before the results of these trials were widely known and after the start of the pandemic, interest in vitamin C as a potential treatment for COVID-19 arose, especially since COVID-19 patients had low vitamin C. A meta-analysis of nine smaller trials, the study authors wrote, suggested vitamin C might reduce hospital COVID-19 mortality.
Researchers began the current two trials separately to get more definitive results and ultimately combined their efforts into a single study encompassing 90 ICUs and 40 non-ICU hospital sites in four continents, with a unified intervention, outcome measure set, and statistical analysis plan.
Patients admitted to an ICU who received respiratory or cardiovascular organ support at randomization were classified as critically ill; all others were classified as not critically ill. The two groups (1,568 critically ill and 1,022 not critically ill) were randomized into vitamin C and control groups, which had patients combined from both initial trials. Control patients from the blinded LOVIT-COVID trial received placebo, while in the open-label REMAP-CAP, control patients received no vitamin C.
Care was at clinician discretion. Intervention group patients had 50 mg/kg of body weight of vitamin C administered intravenously every 6 hours for 96 hours, with a maximum of 16 doses given. Follow-up was in the hospital for the primary outcome, and by telephone at 6 months for other outcomes.
The primary outcome was a composite of “organ support-free days,” defined as days alive and free of respiratory and cardiovascular organ support up to day 21 and survival to hospital discharge, on an ordinal scale from -1 (death in the hospital) to 22, with higher numbers denoting faster recovery.
“From the standpoint of the bedside clinician, the results of the harmonized trial are clear: vitamin C should not be used as a treatment for hospitalized patients with COVID-19,” observed Craig Jabaley, MD, and Craig Coopersmith, MD, both of Emory University in Atlanta, in an accompanying editorial.
“Although the allure of vitamin C may continue to tempt clinicians, the results from the harmonized LOVIT-COVID and REMAP-CAP trials should lead clinicians to use therapies that have been demonstrated to be beneficial in patients with COVID-19 as opposed to one that is almost certainly ineffective and potentially harmful,” they wrote.
The researchers acknowledged limitations including combined data from two differently designed trials, fewer patients in the placebo-controlled LOVIT-COVID trial, and the possibility of differential care in the open-label REMAP-CAP study. Some data were unavailable, including individual vaccination status, vitamin C product received, and baseline vitamin C levels.
Funding for the LOVIT-COVID trial came from the Lotte and John Hecht Memorial Foundation. Nova Biomedical Canada provided glucometers, testing strips, and control solutions to trial sites that requested them.
Funding for the REMAP-CAP trial came from the Lotte and John Hecht Memorial Foundation; grants from the Platform for European Preparedness Against Re-Emerging Epidemics Consortium of the European Union, the Rapid European COVID-19 Emergency Research Response Consortium of the European Union’s Horizon 2020 Research and Innovation Programme, the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program, the National Institute for Health and Care Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland, the French Ministry of Health, the Wellcome Trust Innovations Project, the Japan Agency for Medical Research and Development; funding from the University of Pittsburgh Medical Center Learning While Doing Program, the Translational Breast Cancer Research Consortium, the Office of Health and Medical Research NSW Health, the Minderoo Foundation, the National University Health System research office, Singapore.
The researchers reported relationships with non-profit groups, academic institutions, and industry.
The editorialists had no disclosures.
Source Reference: Adhikari NKJ, et al “Intravenous vitamin C for patients hospitalized with COVID-19” JAMA 2023, DOI: 10.1001/jama.2023.21407.
Source Reference: Jabaley CS, Coopersmith CM “Vitamin C for patients with COVID-19” JAMA 2023, DOI: doi:10.1001/jama.2023.18592.