Early administration of vitamin C in patients with sepsis or septic shock in emergency departments: a multicenter, double-blind, randomized controlled trial: the C-EASIE trial

Background: Sepsis and septic shock are associated with high mortality and morbidity despite adequate standard care. Vitamin C deficiency is a common, potentially reversible, contributor to morbidity and mortality in sepsis. Previous studies have shown mixed and conflicting results. Our study aimed to determine the potential benefit of early administration (within 6 h after admission) of vitamin C in patients with sepsis or septic shock. Methods: This was a phase 3b prospective, multicenter, double-blinded, randomized placebo-controlled trial. Participants were enrolled in the Emergency Departments of 8 hospitals throughout Belgium. Patients were randomized to receive 1.5 g of vitamin C, or matching placebo, every 6 h for 4 days. The primary outcome was the average post-baseline patient Sequential Organ Failure Assessment (SOFA) score on day 2 to 5. Key secondary outcomes were the maximum SOFA score, 28-day mortality and length of ICU and hospital stay. Results: A total of 300 patients were recruited between June 4th, 2021, and August 19th, 2023. 292 patients, of which 147 were assigned to the vitamin C and 145 to the placebo group, completed the trial and were included in the analysis. The primary outcome (vitamin C, 1.98; placebo, 2.19) was 8.7% lower in the vitamin C group, but not significantly (ratio 0.91, 95% CI 0.77 to 1.08, P = 0.30). In a planned subgroup analysis, patients with a baseline SOFA score of 6 or above had a significant lower average post-baseline SOFA score in the vitamin C group (ratio 0.76, 95% CI 0.86 to 0.99, P = 0.042). Findings were similar in the two groups regarding secondary outcomes and adverse events, except for a lower probability of being on renal replacement therapy in the vitamin C group of the per protocol analysis (ratio 0.28, 95% CI 0.078 to 1.0, P = 0.05). Conclusions: Early treatment with vitamin C did not result in a statistically significant reduction in organ dysfunction. Therefore, this study does not support the use of vitamin C in sepsis patients. Trial registration: ClinicalTrials.gov Identifier: NCT04747795. Registered 4 February 2021. © The Author(s) 2025.