Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency
- Conditions
- Critical Illness Related Corticosteroids Insufficiency
- Interventions
- Drug: Investigational products administrationDrug: Placebo administration
- Registration Number
- NCT04404400
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
The study aims at assessing the efficacy and the safety of hydrocortisone combined with fludrocortisone compared to placebo in ICU adults with critical illness related corticosteroid insufficiency.
- Detailed Description
The hypothalamic-pituitary-adrenal axis together with the noradrenergic/vasopressinergic system are the main systems of host response to stress. In 2008 the scientific community described a syndrome called critical illness related corticosteroids insufficiency (CIRCI) in which body homeostasis is lost owing to insufficient cortisol production or bioactivity in tissues. Recent updates of international guidelines have spelled out the pathophysiology, diagnosis and management of CIRCI. The prevalence of CIRCI varies according to case mix and severity of illness. The combination of hydrocortisone and fludrocortisone improved outcomes in septic shock, a condition often complicated with CIRCI. However, there is insufficient evidence on the efficacy of corticosteroids in patients with CIRCI and without septic shock. The hypothesis of the study is that the hydrocortisone-fludrocortisone association will improve ventilation and vasopressor free survival in ICU patients with Critical illness related Corticosteroid Insufficiency.
Patients with a SOFA score ≥ 4 will be screened for CIRCI. Patients suffering from CIRCI will be randomized to receive hydrocortisone and fludrocortisone or their placebo. Patients without CIRCI will receive standard of care and will be followed up during 90 days (cohort-observational study).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1092
- Adult (≥ 18 years);
- Hospitalized in an intensive care unit;
- SOFA score ≥ 4, for at least 6 consecutive hours;
- Informed written consent from patient or from legally authorized next of kin, or emergency deferred consent;
- Affiliation to a social security system or to a universal health coverage (Couverture Maladie Universelle, CMU).
- Any suspected or proven acute adrenal insufficiency (As defined in international guidelines; basal cortisol < 5 μg/dL or peak (60) cortisol <18 μg/dL)
- Expected death or withdrawal of life-sustaining treatments within 48 hours
- Known chronic adrenal insufficiency
- Concomitant treatment that inhibits cortisol production
- Septic shock (Singer Jama 2016)
- Active tuberculosis or fungal infection
- Active viral hepatitis or active infection with herpes viruses
- Hypersensitivity or contraindication to hydrocortisone, fludrocortisone or Synacthène® or any of their excipients ( SmPC)
- Patient needing either anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason (Such as those suffering from COVID-19 pneumonia requiring oxygen therapy).
- Current treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30 days
- Diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome
- Pregnant or breastfeeding woman
- Moribund patient
- Previously enrolled in this study
- Participation to another interventional study that focuses on CIRCI and/or corticoid drugs and/or that addresses a similar primary endpoint as Hornbill ( ventilator- and vasopressor-free survival )
- Patient under guardianship or tutorship
Note: Included patients for whom acute adrenal insufficiency would be detected in the Synacthen ® test performed as part of the research for the diagnosis of CIRCI will not be randomized since they should be treated by corticosteroids.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Active Investigational products administration For CIRCI patients: hydrocortisone + fludrocortisone therapy. Placebo Placebo administration For CIRCI patients: hydrocortisone placebo + fludrocortisone placebo
- Primary Outcome Measures
Name Time Method number of ventilator- and vasopressor-free days at day 30 number of ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) after randomisation.
- Secondary Outcome Measures
Name Time Method Withhold and/or withdraw proportion up to 3 months Proportion of patients with a decision to withhold and/or withdraw active treatments.
duration of hospitalization of stay daily up to 30 days Duration of hospitalization of stay.
Safety endpoints - hospital-acquired infections proportion daily up to 30 days - Proportion of patients affected by hospital-acquired infections;
Safety endpoints - hyperglycemia daily up to 30 days - Number of episodes of hyperglycemia during ICU stay or up to day 30, whichever occurs first;
Mortality rates at day 30, 90 and 180 Mortality rates at ICU and hospital discharge and at day 30, 90 and 180 after randomization
Safety endpoints - corticosteroids administration requiring daily up to 30 days - Number of patients requiring the administration corticosteroids following the end of the administration of the experimental treatment.
Rate of ventilation at day 30 Endpoint concerning non-randomised patients:
Rate of ventilation at day 30 post SYNACTHENE® testresponse to glucocorticoids up to 3 months Score of cutaneous vasoconstrictor response to glucocorticoids
Number of days alive free of mechanical ventilation at day 30 Number of days alive free of mechanical ventilation on day 30 after randomization.
Number of days alive with SOFA < 4 daily un to 30 days Number of days alive with SOFA \< 4 in the 30 days after randomization
Safety endpoints - hypernatremia daily up to 30 days - Number of episodes of hypernatremia during ICU stay or up to day 30, whichever occurs first;
Safety endpoints - Gastroduodenal bleeding daily up to 30 days - Gastroduodenal bleeding requiring transfusion or hemostatic treatment during ICU stay or up to day 30, whichever occurs first;
Change in quality of life up to Day 30 and 90 Change in utility, based on the EuroQol group's 5-dimension 5-level (EQ-5D-5L) questionnaire, up to Day 30 and 90 after randomisation
Number of days alive without vasopressors at day 30 Number of days alive without vasopressors on day 30 after randomization.
ICU duration up to 3 months Duration of stay (unit: day and minutes) at ICU.
Rate of re-admission to the ICU daily up to 30 days Rate of re-admission to the ICU during the 30 days after randomization.
Safety endpoints - serious adverse events associated with corticosteroids daily up to 30 days - Proportion of patients affected by any serious adverse events associated with corticosteroids, among the following: hospital-acquired infections, hyperglycemia, hypernatremia, neurological disorders (coma, stroke or muscle weakness) during the 30 days after randomization.
Rate of ventilation and vasopressors free survival at day 90 at day 90 Secondary endpoint concerning screened but non-randomised patients:
Rate of ventilation and vasopressors free survival at day 90 in subjects devoid of CIRCIRenal replacement therapy (RRT)-free days up to day 30 Renal replacement therapy (RRT)-free days up to Day 30 after randomisation (excluding patients on RRT for chronic renal failure at time of randomisation)
Vasopressors free days at day 30 Endpoint concerning non-randomised patients:
Vasopressors free days at day 30 post SYNACTHENE® test
Trial Locations
- Locations (1)
General Intensive care Unit, Raymond Poincaré Hospital, APHP
🇫🇷Garches, France