Intravenous Vitamin C for Patients Hospitalized With COVID-19

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)

Revisions to Nonauthor Collaborator Names

“…The Original Investigation titled “Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials,” published on November 14, 2023, has been updated to fix the spelling of names in a supplement (Alessandro Belletti, Alessandra Bonaccorso, Claudia Costantino, Ashlish Dawda, Pierre-Yves Egreteau, Nasir Khoso, Sven Laudi, Juan Martin-Lazaro, Jack Richecoeur, L. Roebers, Giovanna Russelli, Patrica Thompson, and Harald Verheij are the correct spellings). This article was corrected online.…”

Vitamin C for Patients Hospitalized With COVID-19

“…In our collective clinical experience, we frequently observe patients in the intensive care unit administered this vitamin solution for 5 to 7 days. Although we recognize that the vitamin C doses in the LOVIT, LOVIT-COVID, and REMAP-CAP studies were higher, we believe there now exist concerns about the potential deleterious effect of co-administering large doses of vitamin C when the primary aim is thiamine replenishment.…”

“…To the Editor The recently published REMAP-CAP and LOVIT-COVID studies tested the hypothesis that the administration of high-dose vitamin C (ascorbic acid) increases the number of days patients are alive and free from organ support. However, these studies were terminated early when statistical triggers for harm and futility were met. In addition, the earlier LOVIT study found harm from high-dose vitamin C and a higher risk of death or persistent organ dysfunction at 28 days.…”

“…We wonder whether the REMAP-CAP and LOVIT investigators consider this risk of vitamin C exposure acceptable in the intensive care unit population? And whether a switch to a thiamine-only injectable formulation should occur forthwith?…”

Vitamin C for Patients Hospitalized With COVID-19—Reply

“…The LOVIT-COVID and REMAP-CAP harmonized randomized clinical trials and the LOVIT trial, all of which studied administration of high-dose vitamin C (200 mg/kg/d) in patients with COVID-19 infection and sepsis, respectively, do not directly address this safety question. In these trials, administration of thiamine and other vitamins was at the discretion of the clinicians.…”