The primary objective of the study aims to compare the effect of high-dose intravenous vitamin C vs. placebo on a composite of death or persistent organ dysfunction - defined as continued dependency on mechanical ventilation, new renal replacement therapy, or vasopressors - assessed at 28 days on intensive care unit (ICU) patients.

As secondary objectives, the study aims:

• To compare the effect of high-dose intravenous vitamin C vs. placebo on:

  1. 6-month mortality;

  2. 6-month HRQoL;

  3. organ function (days 1, 2, 3, 4, 7, 10, 14, and 28 if in ICU);

  4. global tissue dysoxia (at baseline);

  5. oxygenation Index (FiO2 x Mean Airway Pressure/PaO2) (days 1, 2, 3, 4, 7, 10, 14, and 28 if in ICU, and if still intubated);

  6. occurrence of stage 3 acute kidney injury as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria20;

  7. 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;
       • lactate dehydrogenase (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;

  8. hypoglycemia as defined as core lab-validated glucose levels of less than < 3.8 mmol/L.

• To assess baseline vitamin C levels in study participants (before the first dose of investigational product).

Treatment options for sepsis complicated by ARDS 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.

The study LOVIT will be conducted simultaneously in Canada (country of coordination), France, the United States of America, the United Kingdom and Australia/New Zealand.The data from each country will be merged with the aim of reaching 4,000 patients globally (roughly 800 patients per country). Thus, in the context of increasing off-label use of vitamin C for sepsis and ongoing trials of vitamin C bundled with other pharmacological interventions, this study will constitute a rigorous assessment of the effect of vitamin C monotherapy on patient-important outcomes. Moreover, the French LOVIT-ARDS, part of LOVIT, will provide additional information on the specific subgroup of patients with sepsis and ARDS.

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

The study will enroll a total of at least 770 patients. Sites are expected to enroll at least 1or 2 patients per month. By enrolling 385 evaluable patients per arm, the study will have 80% power to detect a 10% absolute risk reduction (from 50% to 40%, which corresponds to a 20% relative risk reduction).

Follow-up in the study for each patient: daily during ICU stay and telephone follow-up at 6 months.

Inclusion Criteria:

• Patients ≥18 years;
• 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);
• Presenting with Acute Respiratory Distress Syndrome
• Patient who has signed an informed and written consent, whenever he/she is capable of consent, if not ascent from his/her representant whenever he/she is present at time of screening for inclusion
• Affiliation to a social security system or to an universal health coverage (Couverture Maladie Universelle, CMU).
• Patients under guardianship or curatorship will be included.
• Patients in case of simple emergency (legal definition) will be included.

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).