Clinical trial NCT04404400: Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency
Official title: Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Critical Illness Related Corticosteroids Insufficiency
Keywords: critical illness related corticosteroids insufficiency
hydrocortisone
fludrocortisone
ICU
survival
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-05-27
Enrollment: 1092
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 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).

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.

Primary outcomes:
measure: number of ventilator- and vasopressor-free days
timeFrame: at day 30
Secondary outcomes:
measure: Mortality rates
timeFrame: at day 30, 90 and 180
measure: Number of days alive without vasopressors
timeFrame: at day 30
measure: Number of days alive free of mechanical ventilation
timeFrame: at day 30
measure: Number of days alive with SOFA < 4
timeFrame: daily un to 30 days
measure: Withhold and/or withdraw proportion
timeFrame: up to 3 months
measure: ICU duration
timeFrame: up to 3 months
measure: duration of hospitalization of stay
timeFrame: daily up to 30 days
measure: Rate of re-admission to the ICU
timeFrame: daily up to 30 days
measure: Safety endpoints - serious adverse events associated with corticosteroids
timeFrame: daily up to 30 days
measure: Safety endpoints - hospital-acquired infections proportion
timeFrame: daily up to 30 days
measure: Safety endpoints - hyperglycemia
timeFrame: daily up to 30 days
measure: Safety endpoints - hypernatremia
timeFrame: daily up to 30 days
measure: Safety endpoints - Gastroduodenal bleeding
timeFrame: daily up to 30 days
measure: Safety endpoints - corticosteroids administration requiring
timeFrame: daily up to 30 days
measure: Rate of ventilation and vasopressors free survival at day 90
timeFrame: at day 90
measure: Renal replacement therapy (RRT)-free days
timeFrame: up to day 30
measure: response to glucocorticoids
timeFrame: up to 3 months
measure: Change in quality of life
timeFrame: up to Day 30 and 90
measure: Rate of ventilation
timeFrame: at day 30
measure: Vasopressors free days
timeFrame: at day 30
Other outcomes:
Locations:
city: Garches
country: France
facility: General Intensive care Unit, Raymond Poincaré Hospital, APHP
Study officials:
affiliation: General Intensive care Unit, Raymond Poincaré Hospital, APHP
name: Nicholas HEMING, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: General Intensive care Unit, Raymond Poincaré Hospital, APHP
name: Djillali ANNANE, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers S, Russell JA, Van den Berghe G. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2017 Dec;43(12):1751-1763. doi: 10.1007/s00134-017-4919-5. Epub 2017 Sep 21.
citation: Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, Francois B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohe J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E; CRICS-TRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716.