E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Sepsis complicated by ARDS |
|
E.1.1.1 | Medical condition in easily understood language |
General and serious infection of the body |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001052 |
E.1.2 | Term | Acute respiratory distress syndrome |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
|
E.2.2 | Secondary objectives of the trial |
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 <lower limit of normal at clinical site lab; ▪indirect (unconjugated) bilirubin>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 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 representant signed consent whenever he/she is present at inclusion;
• Affiliation to a social security system or to an universal health coverage (Couverture Maladie Universelle, CMU);
• Patients under guardianship or curatorship can be included;
• Patients in case of simple emergency (legal definition) or vital emergency will be included. |
|
E.4 | Principal exclusion criteria |
• > 24 hours of intensive care unit (ICU) admission;
• Known Glucose-6-phosphate dehydrogenase (G6PD) deficiency;
• Pregnancy and breast-feeding;
• Hyperoxaluria
• Known allergy excipients of vitamin C solution; or to one of the excipients in particular methyl parhydroxybenzoate (E218) or propyl (E216)
• Treatment with Deferoxamine
• Known kidney stones within the past 1 year;
• Received any intravenous vitamin C during this hospitalization unless incorporated in parenteral nutrition (PN) in doses standard for PN;
• Expected death or withdrawal of life-sustaining treatments within 48 hours;
• Previously enrolled in this study;
• Previously enrolled in an interventional trial for which co-enrolment is not allowed (co-enrolment to be determined case by case). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Death or persistent organ dysfunction (defined as continued dependency on mechanical ventilation, renal replacement therapy, or vasopressors) at 28 days. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | 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). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
baseline days 1, 2, 3, 4, 7, 10, 14, 28 and at 6 months |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |