Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials
A brand-new publication is shedding much needed light on the effects of intravenous vitamin C in patients hospitalized with COVID-19.
Published yesterday in JAMA and presented at the European Society of Intensive Care Medicine in Milan, this paper reports a harmonized analysis of two clinical trials, the placebo-controlled LOVIT-COVID trial and the open-label vitamin C domain of REMAP-CAP.
“Harnessing the power of global collaboration, the harmonized REMAP-CAP and LOVIT-COVID trials have investigated vitamin C, a potential therapy for COVID-19, and have shown it to be ineffective and probably harmful,” said Dr. Neill Adhikari, co-lead investigator for the LOVIT-COVID trial and of the Vitamin C Domain of REMAP-CAP.
“The results from this trial suggest that the use of vitamin C in hospitalized COVID-19 patients should be de-adopted.” Dr. François Lamontagne, co-lead investigator of these trials, added, “The results underscore the health and economic benefits of identifying and abandoning readily available interventions that are ineffective and potentially harmful to patients.”
Through this global initiative, combining clinical trial data and recruiting patients from countries around the world, this model of research continues to produce important evidence for the clinical communities.
- News release: Global Coalition for Adaptive Research
1,568 critically ill patients (med. age 60y; 36% female) were enrolled at 90 hospitals and 1022 non-critically ill patients (med. age 62y; 42% female) were enrolled at 40 hospitals. Patients were recruited from Asia (34.7%), N. America (28.5%), Europe (27.7%), & Australia (9.2%).
Participants were randomized to vitamin C (1037 critically ill, 456 non-critically ill) or control (n=531 critically ill; 566 non-critically ill). The trials were stopped on 15 July 2022 after statistical triggers for futility and harm were met. These triggers were added after LOVIT showed that vitamin C caused harm in septic patients on a vasopressor infusion.
The primary endpoint was organ support-free days within 21 days (OSFDs, an ordinal composite outcome with in-hospital decedents assigned -1 [worst outcome] and patients surviving to discharge with no organ support assigned 22 [best outcome]), as in other REMAP-CAP domains. Among critically ill patients, median (IQR) OSFDs were 7 (-1 to 17) in the vitamin C group and 10 (-1 to 17) in the control group (adjusted OR 0.88 (95% CrI 0.73 to 1.06), with posterior probabilities of 8.6% (efficacy), 91.4% (harm), and 99.9% (futility).
Among non-critically ill patients, median (IQR) OSFDs were 22 (18 to22) in the vitamin C group and 22 (21 to 22) in the control group (adjusted OR 0.80 (95% CrI 0.60 to 1.01), with posterior probabilities of 2.9% (efficacy), 97.1% (harm), and >99.9% (futility).
Among critically ill patients, survival to hospital discharge was 61.9% for the vitamin C group vs 64.6% 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% for the vitamin C group vs 86.6% for the control group (adjusted OR, 0.86 [95%CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.
There was no firm evidence of benefit in secondary outcomes or in patient subgroups. Serious adverse events were reported in 1.8% of patients in the vitamin C group & 0.8% of patients in control. Four serious adverse events were possibly or probably related to vitamin C.
The treatment effect of vitamin C varied over time and a 10-month gap between two adaptive analyses led to more critically ill patients on vitamin C despite the lack of benefit. Treatment variation was not related to trial (LOVIT-COVID vs. REMAP-CAP), continent, or dominant SARS-CoV-2 variant.
Although the results do not exclude the possibility that vitamin C helps some hospitalized patients with COVID-19, it is far more likely that vitamin C is ineffective or harmful. These harmonized trials demonstrate the benefit and challenges of cooperation among research groups and funders addressing a common research question. Showing a potential treatment with increasing use to be ineffective is important for the health system globally.
In conclusion, 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. REMAP-CAP continues to inform the care of patients with COVID-19 and influenza.
Read the publication:
The LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators. Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials. JAMA. Published online October 25, 2023. doi:10.1001/jama.2023.21407