RESUMEN
BACKGROUND: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. OBJECTIVE: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. METHODS: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. RESULTS: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. CONCLUSIONS: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36261.
RESUMEN
BACKGROUND: Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. METHODS: LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. DISCUSSION: This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. TRIAL REGISTRATION: clinicaltrials.gov, NCT03680274, first posted 21 September 2018.