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Marie-Hélène Masse
Julie Ménard
Sheila Sprague

Thanks to all Participating Centers and collaborators for engaging in this research program!

Thanks to the CCCTG for endorsing this research project.

Study Overview LOVIT

Treatment options for sepsis are limited to antimicrobials and supportive care (intravenous fluids, vasopressors, mechanical ventilation and renal replacement therapy). Recent preliminary evidence suggests that intravenous vitamin C may be the first therapy to mitigate the dysregulated cascade of events transforming an infection into sepsis. However, definitive practice changing evidence requires a large trial powered to detect a plausible, modest, and clinically important difference in mortality.

Primary Outcome
Death or persistent organ dysfunction (defined as continued dependency on mechanical ventilation, renal replacement therapy, or vasopressors) at 28 days. 

Secondary Outcomes
- Mortality and health-related quality of life at 6 months.
- Daily organ function (SOFA score days 1, 2, 3, 4, 7, 10, 14, and 28).
- Global tissue dysoxia, biomarkers for inflammation, infection, and endothelial injury on days 1, 3, 7.
- Occurrence of stage 3 acute kidney injury as defined by KDIGO criteria;
- Acute hemolysis as defined by:
             - clinician judgment of hemolysis, as recorded in the chart, OR
             - hemoglobin drop of at least 25 g/L within 24 hours of a dose of investigational product PLUS 2 of the following:
                   ▪  reticulocyte count >2 times upper limit of normal at clinical site lab;
                   ▪  haptoglobin < lower limit of normal at clinical site lab;
                   ▪  indirect (unconjugated) bilirubin >2 times upper limit of normal at clinical site lab;
                   ▪  LDH >2 times upper limit of normal at clinical site lab.
  Severe hemolysis:
             - hemoglobin < 75 g/L AND at least 2 of the above criteria AND requires 2 units of packed red blood cells.
- Hypoglycemia as defined by core lab-validated glucose levels of less than  < 3.8 mmol/L.

Study design
Parallel blinded randomized controlled trial.

Inclusion Criteria
· Patients ≥18 years old
· Admitted to ICU with proven or suspected infection as the main  diagnosis
· Currently treated with a continuous intravenous infusion of vasopressors   (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine).

Exclusion Criteria
·   > 24 hours of intensive care unit (ICU) admission
·   Known Glucose-6-phosphate dehydrogenase (G6PD) deficiency
·   Pregnancy
·   Known allergy to vitamin C
·   Known kidney stones within the past 1 year
·   Received any intravenous vitamin C during this hospitalization unless  incorporated in parenteral nutrition
·   Expected death or withdrawal of life-sustaining treatments within 48 hours
·   Previously enrolled in this study
·   Previously enrolled in a trial for which co-enrolment is not allowed (co-enrolment to be determined case   by case).

Study Intervention
Experimental arm: vitamin C 50 mg/kg every 6 hours for 96 hours.
Control arm: placebo (0.9% NaCl or dextrose 5% in water).

Web-based randomization system available 24/7. Eligible patients will be randomized in a 1:1 ratio to vitamin C or matching placebo. We will use permuted blocks of undisclosed and variable size and stratify randomization by site.

Sample Size
We will enroll a total of at least 800 patients. Sites are expected to enroll at least 1 patient per month.

Daily during ICU stay and telephone follow-up at 6 months.