LOVIT is a multicentre concealed-allocation parallel-group blinded randomized controlled trial to ascertain the effect of high-dose intravenous vitamin C compared to placebo on mortality or persistent organ dysfunction at 28 days in septic intensive care unit patients. Patients with COVID-19 are considered eligible for this study.

Background. The burden of sepsis is increasing worldwide. It is the cause of 8 million global deaths each year. Currently, treatment options are limited to antimicrobials and supportive care such as intravenous fluids, vasopressors, mechanical ventilation, and renal replacement therapy. In the absence of effective therapies specifically targeting the dysregulated immune response, prolonged use of these life-sustaining therapies can be debilitating. A growing body of evidence suggesting that vitamin C, an inexpensive and readily available intervention, is potentially lifesaving in sepsis. Intravenous vitamin C may be the first therapy to mitigate the dysregulated cascade of events that leads to sepsis. If proven effective, vitamin C could be used worldwide and drastically change outcomes in high- and low-income settings alike.

Objectives. To determine whether intravenous vitamin C, compared to placebo, reduces mortality and morbidity in sepsis (induced by bacterial and viral pathogens (as COVID-19)), and compare clinical and biochemical measures of organ dysfunction, and health-related quality of life (HRQoL) at 6 months. To ascertain the volume of distribution, clearance, and plasma concentration over a course of 96 hours of intravenous vitamin C 50 mg/kg of weight every 6 hours or matching placebo (pharmacokinetic (PK) substudy).

Methods. Patients will be randomly assigned to vitamin C (intravenous, 50 mg/kg every 6h) or placebo (0.9% NaCl or dextrose 5% in water) for 96 hours. Study personnel at the clinical sites will document the composite of death or persistent organ dysfunction at day 28. Daily assessments will occur for organ function, on days 1, 3, 7 for inflammation, infection, and endothelial injury biomarkers, at baseline for vitamin C level, and at 6 months for mortality and HRQoL. The LOVIT Trial will be conducted in adult general Canadian and international intensive care units. For the PK substudy: Blood samples will be drawn around the 8th dose at time 0 and then after administration at times 1h, 2h, 4h and 6h (the 6h level will be immediately prior to the next dose). The PK substudy will be conducted with 100 participants in 3 of the 25 participating centers.

Relevance. In the context of increasing off-label use of vitamin C for sepsis and ongoing trials of vitamin C bundled with other pharmacological interventions, the LOVIT Trial will constitute a rigorous assessment of the effect of vitamin C monotherapy on patient-important outcomes.

Inclusion Criteria:

1. Admitted to the intensive care unit with proven or suspected infection as the main diagnosis;
2. Currently treated with a continuous IV infusion of vasopressors (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine).

Exclusion Criteria:

1. > 24 hours of intensive care unit admission;
2. Known Glucose-6-phosphate dehydrogenase (G6PD) deficiency;
3. Pregnancy;
4. Known allergy to vitamin C;
5. Known kidney stones within the past 1 year;
6. Received any intravenous vitamin C during this hospitalization unless incorporated in parenteral nutrition;
7. Expected death or withdrawal of life-sustaining treatments within 48 hours;
8. Previously enrolled in this study;
9. Previously enrolled in a trial with which co-enrolment is not allowed.

The LOVIT trial has broad eligibility criteria and includes patients with a primary diagnosis of sepsis of any cause (including sepsis caused by viral pathogens as COVID-19).

De-identified individual participant data collected during the LOVIT trial will be shared with researchers who provide a detailed and methodologically sound proposal, with specific aims. Data sharing will be for the purposes of medical research, with specific data elements provided to answer the research questions in the proposal, and under the auspices of the consent under which the data were originally gathered.

Data availability will commence after the publication of the primary and secondary analyses, with no anticipated end date.

Qualified researchers will need to sign a data sharing and access agreement and will need to confirm that data will only be used for the agreed upon purpose for which data access was granted. The decision to grant access will be made by the trial co-principal investigators, with involvement of the trial steering committee as needed. Proposals to access LOVIT data should be directed to the trial co-principal investigators via email: francois.lamontagne@usherbrooke.ca and neill.adhikari@utoronto.ca. Costs of preparing and providing partial datasets will be charged to requesting investigators.