Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency

Study Overview
=================
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).

Official Title
-----------------
Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency

Conditions
-----------------
Critical Illness Related Corticosteroids Insufficiency

Intervention / Treatment
-----------------
* Drug: Investigational products administration
* Drug: Placebo administration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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). Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>For CIRCI patients: hydrocortisone + fludrocortisone therapy. | Drug: Investigational products administration<br>* Investigational products include: Hydrocortisone hemisuccinate 50 mg: one intravenous injection every 6 hours, and 9 alpha fludrocortisone 50 μg: one tablet per day via a nasogastric tube. All treatments will be stopped after 7 days or until the patient has left the intensive care unit (whichever occurs first) without tapering off.<br>|
| Placebo Comparator: Placebo<br>For CIRCI patients: hydrocortisone placebo + fludrocortisone placebo | Drug: Placebo administration<br>* Placebos for hydrocortisone and for fludrocortisone, administered in same manner as the active drugs in the interventional arm, for 7 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of ventilator- and vasopressor-free days | number of ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) after randomisation. | at day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rates | Mortality rates at ICU and hospital discharge and at day 30, 90 and 180 after randomization | at day 30, 90 and 180 | 
| Number of days alive without vasopressors | Number of days alive without vasopressors on day 30 after randomization. | at day 30 | 
| Number of days alive free of mechanical ventilation | Number of days alive free of mechanical ventilation on day 30 after randomization. | at day 30 | 
| Number of days alive with SOFA < 4 | Number of days alive with SOFA < 4 in the 30 days after randomization | daily un to 30 days | 
| Withhold and/or withdraw proportion | Proportion of patients with a decision to withhold and/or withdraw active treatments. | up to 3 months | 
| ICU duration | Duration of stay (unit: day and minutes) at ICU. | up to 3 months | 
| duration of hospitalization of stay | Duration of hospitalization of stay. | daily up to 30 days | 
| Rate of re-admission to the ICU | Rate of re-admission to the ICU during the 30 days after randomization. | daily up to 30 days | 
| Safety endpoints - serious adverse events associated with corticosteroids | - 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. | daily up to 30 days | 
| Safety endpoints - hospital-acquired infections proportion | - Proportion of patients affected by hospital-acquired infections; | daily up to 30 days | 
| Safety endpoints - hyperglycemia | - Number of episodes of hyperglycemia during ICU stay or up to day 30, whichever occurs first; | daily up to 30 days | 
| Safety endpoints - hypernatremia | - Number of episodes of hypernatremia during ICU stay or up to day 30, whichever occurs first; | daily up to 30 days | 
| Safety endpoints - Gastroduodenal bleeding | - Gastroduodenal bleeding requiring transfusion or hemostatic treatment during ICU stay or up to day 30, whichever occurs first; | daily up to 30 days | 
| Safety endpoints - corticosteroids administration requiring | - Number of patients requiring the administration corticosteroids following the end of the administration of the experimental treatment. | daily up to 30 days | 
| Rate of ventilation and vasopressors free survival 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 CIRCI | at day 90 | 
| Renal replacement therapy (RRT)-free days | Renal replacement therapy (RRT)-free days up to Day 30 after randomisation (excluding patients on RRT for chronic renal failure at time of randomisation) | up to day 30 | 
| response to glucocorticoids | Score of cutaneous vasoconstrictor response to glucocorticoids | up to 3 months | 
| Change in quality of life | 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 | up to Day 30 and 90 | 
| Rate of ventilation | Endpoint concerning non-randomised patients: Rate of ventilation at day 30 post SYNACTHENE® test | at day 30 | 
| Vasopressors free days | Endpoint concerning non-randomised patients: Vasopressors free days at day 30 post SYNACTHENE® test | at day 30 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ICU, critical illness related corticosteroids insufficiency, hydrocortisone, fludrocortisone, survival