Critical Illness Related Corticosteroids InsufficiencyPhase 3HORNbILLNCT04404400
Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency
A Phase 3 study testing Investigational products administration in people with Critical Illness Related Corticosteroids Insufficiency, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Critical Illness Related Corticosteroids Insufficiency
- What is being tested?
- Investigational products administration
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,092 participants
- Where
- 1 siteFrance
- Study dates
- 17 Feb 2022to Feb 2026
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Who cannot join
- 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
Show all 17Show fewer
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
France1 site, 1 recruiting
- Recruiting
General Intensive care Unit, Raymond Poincaré Hospital, APHP
Garches, 92380
About this study
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.
Read the 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).
- Being tested
- Investigational products administration, Placebo administration
- Keywords
- critical illness related corticosteroids insufficiency, hydrocortisone, fludrocortisone, ICU, survival
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Investigational products administrationDrug
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 administrationDrug
Placebos for hydrocortisone and for fludrocortisone, administered in same manner as the active drugs in the interventional arm, for 7 days.
| Study group | Role | What they receive |
|---|---|---|
| Active | Experimental | For CIRCI patients: hydrocortisone + fludrocortisone therapy. Receives: Drug: Investigational products administration |
| Placebo | Placebo comparator | For CIRCI patients: hydrocortisone placebo + fludrocortisone placebo Receives: Drug: Placebo administration |
What is being measured
The primary outcome is the main question the study is designed to answer.
number of ventilator- and vasopressor-free days
number of ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) after randomisation.
Measured: at day 30
Secondary outcomes (20)
Mortality rates
Mortality rates at ICU and hospital discharge and at day 30, 90 and 180 after randomization
Measured: at day 30, 90 and 180
Number of days alive without vasopressors
Number of days alive without vasopressors on day 30 after randomization.
Measured: at day 30
Number of days alive free of mechanical ventilation
Number of days alive free of mechanical ventilation on day 30 after randomization.
Measured: at day 30
Number of days alive with SOFA < 4
Number of days alive with SOFA < 4 in the 30 days after randomization
Measured: daily un to 30 days
Withhold and/or withdraw proportion
Proportion of patients with a decision to withhold and/or withdraw active treatments.
Measured: up to 3 months
ICU duration
Duration of stay (unit: day and minutes) at ICU.
Measured: up to 3 months
duration of hospitalization of stay
Duration of hospitalization of stay.
Measured: 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.
Measured: 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.
Measured: daily up to 30 days
Safety endpoints - hospital-acquired infections proportion
- Proportion of patients affected by hospital-acquired infections;
Measured: daily up to 30 days
Safety endpoints - hyperglycemia
- Number of episodes of hyperglycemia during ICU stay or up to day 30, whichever occurs first;
Measured: daily up to 30 days
Safety endpoints - hypernatremia
- Number of episodes of hypernatremia during ICU stay or up to day 30, whichever occurs first;
Measured: 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;
Measured: 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.
Measured: 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
Measured: 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)
Measured: up to day 30
response to glucocorticoids
Score of cutaneous vasoconstrictor response to glucocorticoids
Measured: 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
Measured: up to Day 30 and 90
Rate of ventilation
Endpoint concerning non-randomised patients:
Rate of ventilation at day 30 post SYNACTHENE® test
Measured: at day 30
Vasopressors free days
Endpoint concerning non-randomised patients:
Vasopressors free days at day 30 post SYNACTHENE® test
Measured: at day 30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2020
- Study start17 Feb 2022
- Primary completionFeb 2026 (estimated)
- Study completionFeb 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Critical Illness Related Corticosteroids InsufficiencyStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,092 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Nicholas HEMING, MD, PhD, Principal investigator, General Intensive care Unit, Raymond Poincaré Hospital, APHPDjillali ANNANE, MD, PhD, Study director, General Intensive care Unit, Raymond Poincaré Hospital, APHP
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04404400
- Sponsor's protocol ID
- APHP200018
- Other IDs
- 2020-003942-35
- Acronym
- HORNbILL
- Status last verified
- Apr 2025
- First submitted
- 19 May 2020
- Last updated
- 27 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 28940011Annane 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.
PubMed 29490185Heming N, Baron E, Muller G, Badie J, Preau S, Siami S, Pouplet C, Berger A, Damoisel C, Argaud L, Rigaud JP, Lambiotte F, Klouche K, Bruel C, Clere-Jehl R, Darmon M, Maizel J, Quenot JP, Robin C, Fleuriet J, Jacota M, Paoletti X, Annane D; HORNBILL consortium; CRICS-TRIGGERSEP network. HydrOcortisone and fludRocortisoNe for critical ILLness-related corticosteroid insufficiency (HORNbILL): study protocol for a multicentre randomised placebo-controlled trial. BMJ Open. 2026 Jun 17;16(6):e119187. doi: 10.1136/bmjopen-2026-119187.
PubMed 42309657
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency
- ClinicalTrials.gov ID
- NCT04404400
- Acronym / sponsor ID
- HORNbILL / APHP200018
- Keywords
- critical illness related corticosteroids insufficiency, hydrocortisone, fludrocortisone, ICU, survival
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 1,092 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 17 Feb 2022 (actual)
- Primary completion
- Feb 2026 (estimated)
- Study completion
- Feb 2026 (estimated)
- First posted
- 27 May 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Active | Experimental | Drug: Investigational products administrationFor CIRCI patients: hydrocortisone + fludrocortisone therapy. |
| Placebo | Placebo comparator | Drug: Placebo administrationFor CIRCI patients: hydrocortisone placebo + fludrocortisone placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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).
Key exclusion criteria (17 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Investigational products administrationInvestigational 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. | Drug | Active |
| Placebo administrationPlacebos for hydrocortisone and for fludrocortisone, administered in same manner as the active drugs in the interventional arm, for 7 days. | Drug | Placebo |
Primary outcome
number of ventilator- and vasopressor-free days
Time frame: at day 30
number of ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) after randomisation.
20 secondary outcomes
Mortality rates
Time frame: at day 30, 90 and 180
Number of days alive without vasopressors
Time frame: at day 30
Number of days alive free of mechanical ventilation
Time frame: at day 30
Number of days alive with SOFA < 4
Time frame: daily un to 30 days
Withhold and/or withdraw proportion
Time frame: up to 3 months
ICU duration
Time frame: up to 3 months
duration of hospitalization of stay
Time frame: daily up to 30 days
Rate of re-admission to the ICU
Time frame: daily up to 30 days
Safety endpoints - serious adverse events associated with corticosteroids
Time frame: daily up to 30 days
Safety endpoints - hospital-acquired infections proportion
Time frame: daily up to 30 days
Safety endpoints - hyperglycemia
Time frame: daily up to 30 days
Safety endpoints - hypernatremia
Time frame: daily up to 30 days
Safety endpoints - Gastroduodenal bleeding
Time frame: daily up to 30 days
Safety endpoints - corticosteroids administration requiring
Time frame: daily up to 30 days
Rate of ventilation and vasopressors free survival at day 90
Time frame: at day 90
Renal replacement therapy (RRT)-free days
Time frame: up to day 30
response to glucocorticoids
Time frame: up to 3 months
Change in quality of life
Time frame: up to Day 30 and 90
Rate of ventilation
Time frame: at day 30
Vasopressors free days
Time frame: at day 30
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2025.
- Background: PubMed 28940011Annane 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.
- Background: PubMed 29490185Annane 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.
- Derived from this study: PubMed 42309657Heming N, Baron E, Muller G, Badie J, Preau S, Siami S, Pouplet C, Berger A, Damoisel C, Argaud L, Rigaud JP, Lambiotte F, Klouche K, Bruel C, Clere-Jehl R, Darmon M, Maizel J, Quenot JP, Robin C, Fleuriet J, Jacota M, Paoletti X, Annane D; HORNBILL consortium; CRICS-TRIGGERSEP network. HydrOcortisone and fludRocortisoNe for critical ILLness-related corticosteroid insufficiency (HORNbILL): study protocol for a multicentre randomised placebo-controlled trial. BMJ Open. 2026 Jun 17;16(6):e119187. doi: 10.1136/bmjopen-2026-119187.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Nicholas HEMING, MD, PhD principal investigator
General Intensive care Unit, Raymond Poincaré Hospital, APHP
Djillali ANNANE, MD, PhD study director
General Intensive care Unit, Raymond Poincaré Hospital, APHP
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Investigational products administration in people with Critical Illness Related Corticosteroids Insufficiency, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Nicholas HEMING, MD, PhD (+ 33 1 47 10 77 78, nicholas.heming@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
number of ventilator- and vasopressor-free days (time frame: at day 30). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04404400, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2025.