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 ARDS Patients.

INTERVENTION: Trade Name: LAROSCORBINE Product Name: LAROSCORBINE Pharmaceutical Form: Solution for infusion INN or Proposed INN: ASCORBIC ACID CAS Number: 89924‐69‐6 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1000‐ Pharmaceutical form of the placebo: Solution for infusion Route of administration of the placebo: Intravenous use CONDITION: Sepsis complicated by ARDS ; MedDRA version: 21.1 Level: PT Classification code 10001052 Term: Acute respiratory distress syndrome System Organ Class: 10038738 ‐ Respiratory, thoracic and mediastinal disorders Therapeutic area: Body processes [G] ‐ Immune system processes [G12] PRIMARY OUTCOME: Main Objective: 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 ICU patients. Primary end point(s): Death or persistent organ dysfunction (defined as continued dependency on mechanical ventilation, renal replacement therapy, or vasopressors) at 28 days. Secondary Objective: To compare the effect of high‐dose intravenous Vit 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) and organ dysfunction‐free days up to 28 day; 4)Global tissue dysoxia (baseline) 5)Oxygenation Index (days cf3 and if still intubated) 6)Occurrence of stage3 acute kidney injury 7)Acute hemolysis as defined by: ‐clinician judgment of hemolysis, OR ‐hemoglobin drop of at least 25g/L within 24hours of a dose of investigational product PLUS 2 of : ?reticulocyte count >2times upper limit of normal at clinical site lab; ?haptoglobin 2times upper limit of normal at clinical site lab; ?LDH>2times upper limit of normal at clinical site lab; Severe hemolysis: ‐hemoglobin<75g/L AND at least 2 of the above criteria AND requires 2 units of packed red blood cells;; 8)Hypoglycemia (glucose levels<3.8mmol/L); To assess baseline Vit C levels in participants Timepoint(s) of evaluation of this end point: 28 days SECONDARY OUTCOME: Secondary end point(s): 1) Persistent organ dysfunction‐free days in ICU, up to day 28. ; 2) Ventilation free days (VFDs) to day 28 ; 3) Mortality at 6 months. ; 4) HRQoL in 6‐month survivors assessed by the EuroQol‐5D (EQ‐5D). ; 5) Global tissue dysoxia assessed by serum lactate concentration at basemline.24 This will be assessed using liquid chromatography technique coupled with tandem mass spectrometry (LC‐MS/MS). ; 6) 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); ; 7) Organ function (including renal function) assessed by the SOFA score (Table 1) (days 1, 2, 3, 4, 7, 10, 14, and 28); ; 8) Occurrence of stage 3 acute kidney injury as defined by KDIGO criteria20 daily; ; 9) Acute hemolysis as diagnosed by the clinical site team (daily); ; 10) Hypoglycemia assessed by core lab (see section 4.5 for assessment) (during the time participants receive the 16 doses of the investigational product and for a maximum of 7 days following the last dose). Timepoint(s) of evaluation of this end point: baseline days 1, 2, 3, 4, 7, 10, 14, 28 and at 6 months INCLUSION CRITERIA: • Patients = 18 years old; • Admitted to the ICU with proven or suspected infection as the main diagnosis; • Patients with or without positive PCR test for SARS CoV2 • Currently treated with a continuous intravenous infusion of vasopressors (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine); • Currently treated with invasive mechanical ventilation • Presenting with Acute Respiratory Distress Syndrome • ARDS defined by all the following criteria: o Acute onset, i.e. within one week of an apparent clinical insult and with progression of respiratory syndrome o bilateral opacities on chest imaging not explained by other pulmonary pathologies (e.g. pleural effusion, atelectasis, nodules, etc.) o no evidence for heart failure or volume overload o PaO2/FiO2 = 300 mm Hg o PEEP = 5 cm H2O • Patient who has signed an informed and written consent whenener he/she is capable of consent, if not, Patient’s