Clinical trial NCT04404387: Lessening Organ Dysfunction With VITamin C in Septic ARDS
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Septic
Acute Respiratory Distress Syndrome
Keywords: Septic
Acute respiratory distress syndrome
Vitamin C
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-05-27
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Number of deceased participants or with persistent organ dysfunction
timeFrame: Both assessed at 28 days
Secondary outcomes:
measure: Vital statue at 6 months
timeFrame: at 6 months
measure: Quality of life assessement: EQ-5D-5L
timeFrame: at 6 months
measure: Daily organ function
timeFrame: Days 1, 2, 3, 4, 7, 10, 14, 28
measure: Global tissue dysoxia
timeFrame: At baseline and days 1, 3, 7
measure: Occurrence of stage 3 acute kidney injury
timeFrame: Up to day 28
measure: Acute hemolysis
timeFrame: Up to day 28
measure: Hypoglycemia
timeFrame: During the time participants receive the 16 doses of the investigational product and the 7 days following the last dose
Other outcomes:
Locations:
city: Garches
country: France
facility: Department Intensive Care Unit, Hospital Raymond Poincaré - APHP
Study officials:
affiliation: Department Intensive Care Unit, Hospital Raymond Poincaré - APHP
name: Djillali ANNANE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: