Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency (HORNbILL)

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.

Study Overview

• Status: Recruiting
• Conditions: Critical Illness Related Corticosteroids Insufficiency
• Intervention / Treatment: Drug: Investigational products administration; Drug: Placebo administration

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).

• Study Type: Interventional
• Enrollment (Estimated): 1092
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Nicholas HEMING, MD, PhD; Phone Number: + 33 1 47 10 77 78; Email: nicholas.heming@aphp.fr
• Study Contact Backup: Name: Djillali ANNANE, MD, PhD; Phone Number: + 33 1 47 10 77 78; Email: djillali.annane@aphp.fr

Study Locations

• France
  • Garches, France, 92380
    • Recruiting
    • General Intensive care Unit, Raymond Poincaré Hospital, APHP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active; For CIRCI patients: hydrocortisone + fludrocortisone therapy.	Drug: Investigational products administration; 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.
Placebo Comparator: Placebo; For CIRCI patients: hydrocortisone placebo + fludrocortisone placebo	Drug: Placebo administration; Placebos for hydrocortisone and for fludrocortisone, administered in same manner as the active drugs in the interventional arm, for 7 days.

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
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
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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Nicholas HEMING, MD, PhD, General Intensive care Unit, Raymond Poincaré Hospital, APHP; Study Director: Djillali ANNANE, MD, PhD, General Intensive care Unit, Raymond Poincaré Hospital, APHP

Publications and helpful links

General Publications

• 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. Erratum In: Intensive Care Med. 2018 Feb 23;:
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2022
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: May 19, 2020
• First Submitted That Met QC Criteria: May 25, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Estimated): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: survival; ICU; hydrocortisone; fludrocortisone; critical illness related corticosteroids insufficiency
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: APHP200018; 2020-003942-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No