Abstract
Introduction
Impairment of the hypothalamic–pituitary–adrenal axis during critical illness, called Critical Illness-Related Corticosteroid Insufficiency (CIRCI), is frequent. There is no standard treatment for CIRCI. This trial aims to determine whether, through biomarker enrichment using CIRCI criteria, hydrocortisone and fludrocortisone, compared with placebo, improve organ dysfunction-free survival in critically ill patients.
Methods and analysis
French multicentre, placebo-controlled, double-blind superiority trial that will randomly assign adults with CIRCI to receive a 7-day course of hydrocortisone and fludrocortisone or their placebo. Randomisation (1:1) will be stratified by centre and presence or absence of acute respiratory distress syndrome. The primary outcome, number of ventilator-free and vasopressor-free days within 30 days (deaths assigned zero days) after randomisation, will be analysed using a Bayesian model. Patients who do not suffer from CIRCI will be followed up for 90 days.
Ethics and dissemination
The protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Ouest I, France no 2021T1-11) on 23 September 2021. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals.
Trial registration number
Keywords: INTENSIVE & CRITICAL CARE, Adrenal disorders, Adult intensive & critical care
STRENGTHS AND LIMITATIONS OF THIS STUDY.
Test hydrocortisone and fludrocortisone in the intensive care unit using a biomarker-enrichment strategy (Critical Illness-Related Corticosteroid Insufficiency (CIRCI), as defined by current international guidelines).
Rigorous methodology, including a double-blind, placebo-controlled, multicentre design.
Patients without CIRCI will be followed up, allowing for comparisons between the CIRCI and non-CIRCI populations.
Bayesian statistics will be employed to analyse results.
Introduction
Intensive care units (ICU) treat the sickest patients.1,3 ICU-mortality for ventilator and/or vasopressor dependent ICU patients is approximately 30%.4,6 Excessive or persistent systemic inflammation correlates with disease severity and may lead to tissue destruction and disease progression.7 8 The hypothalamic–pituitary–adrenal (HPA) axis plays a key role in regulating systemic inflammation.9 10 Under physiological conditions, activation of the HPA axis leads to increased cortisol secretion and translocation of the glucocorticoid receptor into the nucleus. Critical illness may be associated with an imbalance between systemic inflammation and HPA axis activation in a condition called Critical Illness-Related Corticosteroid Insufficiency (CIRCI).11 CIRCI is associated with altered CRH/ACTH (corticotropin releasing hormone/adrenocorticotropic hormone) synthesis, adrenal steroidogenesis, peripheral corticosteroid metabolism and tissue resistance to glucocorticoids.12 The reported prevalence of CIRCI in the ICU ranges between 20% and 60%.13 The combination of hydrocortisone and fludrocortisone reduced mortality and organ failure in septic shock regardless of the presence of CIRCI.6 14 15 Corticosteroids increased the number of ventilator-free days in acute respiratory distress syndrome (ARDS)16 and probably reduce mortality in severe community-acquired pneumonia.17,19 Corticosteroids exhibit a largely favourable safety profile, are inexpensive and readily available in low- and middle-income countries (LMICs). To date, there is no evidence to support the use of corticosteroids in patients with CIRCI.20 The hypothesis of this trial is that in this biomarker enriched population (biological definition of CIRCI) the combination of hydrocortisone and fludrocortisone will improve organ failure-free survival in critically ill patients.
Methods and analysis
Study design and oversight
Patients included in this study will be screened for CIRCI. Patients positive for CIRCI will then be randomised with a 1:1 allocation ratio to receive hydrocortisone and fludrocortisone or their respective placebos. The protocol and qualification of all investigators were approved by the Ethics Committee (Comité de Protection des Personnes, Ouest I, France, no 2021T1-11), on 23 September 2021 and by the ANSM (Agence nationale de sécurité du médicament et des produits de santé, the French medicines agency) on 23 March 2021.
Inclusion in the trial started on 17 February 2022 in 19 centres in France. Participating centres included centres within the CRICS-TRIGGERSEP network, in order to ensure adequate patient enrolment. The first patient was included on 17 February 2022. The last patient was included on 20 May 2025. Follow-up of the last patient is expected to be completed on 17 November 2025. Database management and cleaning activities are planned for the first half of 2026. Data analysis is expected during the third quarter of 2026. Informed written consent will be obtained prior to any act related to the study. Consent from a legally authorised representative will be sought (France, art. L 1122–1 CSP) whenever patients are unable to provide consent. Whenever the patient is unable to consent and in the absence of a legally authorised representative, the ethics committee allowed consent to be waived. Deferred consent or consent of a legally authorised representative will be obtained by an investigator for the continuation of the study procedures and utilisation of the patient’s data and biological samples. A data safety and monitoring board (DSMB), including intensive care medicine, endocrinology and methodology experts, was set up before recruitment of the first patient. DSMB members have full access to the raw data of the trial and meet regularly. Data monitoring is performed by the sponsor (Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Saclay Ouest Clinical Research Unit). The sponsor has full access to patients’ charts and checks for the accuracy of all data recorded in the electronic case report form (eCRF). Data management is performed by the sponsor. A code is assigned to each participant and keep the linking key separate, enabling analysis to be carried out without revealing names or contact details. The Biological Resource Centre of the Raymond Poincaré Hospital (AP-HP) provides centres with sample kits for collecting biological material and centralises sample storage. A central pharmacy (General Agency of Equipment and Health Products/Agence Générale des Equipements et Produits de Santé) labels study drugs and ships them to participating centres. Unused drugs are destroyed by the local pharmacist. This trial is registered at ClinicalTrials.gov under number NCT04404400.
Study participants: inclusion and exclusion criteria, screening for CIRCI, conduct of the trial.
The recruitment and randomisation process is described in figure 1.
Figure 1. Study flow chart describing the process of recruitment and randomisation. CIRCI, critical illness-related corticosteroid insufficiency.
Inclusion criteria
ICU patients aged ≥18 years will be eligible for inclusion in the trial if they meet all of the following criteria: (1) SOFA score ≥4 for at least 6 consecutive hours21; (2) Informed written consent obtained from the patient, a legally authorised representative, or through an emergency procedure (online supplemental file 1) and (3) affiliation to the French social security or benefiting from universal health coverage.
Exclusion criteria
Patients will not be eligible for the trial if they meet at least one of the following criteria: (1) expected death or withdrawal of life-sustaining treatments within 48 hours (moribund patients); (2) suspected or proven acute adrenal insufficiency (basal cortisol <5 µg/dL or peak cortisol <18 µg/dL)22 23; (3) chronic adrenal insufficiency; (4) concomitant treatment that inhibits cortisol production; (5) septic shock (Sepsis-3 definition)24; (6) active tuberculosis or fungal infection; (7) active viral hepatitis or active infection with herpes viruses; (8) hypersensitivity to hydrocortisone, fludrocortisone, cosyntropin or any of their excipients; (9) formal indication for corticosteroids or substitutive hydrocortisone for any reason (eg, oxygen-dependent COVID-19 pneumonia); (10) current treatment by more than 15 mg/day of prednisone (or equivalent) for more than 30 days; (11) diabetic ketoacidosis or hyperglycaemic hyperosmolar syndrome; (12) pregnant or breastfeeding woman; (13) previously enrolled in this study; (14) participation in another interventional study that focuses on CIRCI and/or corticosteroids and/or that addresses a similar primary endpoint and (15) adults with a legally appointed guardian or tutor.
Initial study visit
After obtaining informed consent, a study visit is performed in order to collect (1) patient demographics; (2) the date and reason of ICU admission and the patient’s location before admission: home, hospital or long-term care facility; (3) severity of illness (Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score; (4) pre-existing conditions: Knaus score25 and Mac Cabe class26; (5) date of initiation of mechanical ventilation and of vasopressors; (6) presence of ARDS27; (7) measurement of serum total cortisol, immediately before and 30 and 60 min after intravenous injection of 250 μg of cosyntropin, performed any time during the day; (8) blood samples for central laboratory (9) and a skin vasoconstrictor response to glucocorticoids will be performed in a subgroup of patients.28 29
CIRCI definition
CIRCI was defined as a change in baseline cortisol at 60 min of <9 µg/dL after cosyntropin (250 µg) administration or a random plasma cortisol of <10 µg/dL.20
Follow-up
Follow-up will differ depending on the presence or absence of CIRCI. Patients suffering from CIRCI will be randomised to receive hydrocortisone and fludrocortisone or their placebos. In patients without CIRCI (ie, screened but not randomised patients), minimal characteristics for sample description and data for the assessment of their endpoint (at 30 and 90 days after cosyntropin test, through telephone calls) will be collected.
Outcomes
The primary outcome will be the number of ventilator-free and vasopressor-free days up to day 30, defined as days from randomisation to 30 days, during which the patient is alive, free of mechanical ventilation, and free of treatment with intravenous vasopressors.30 Any patient who dies within 30 days will be assigned zero days. After mechanical ventilation and vasopressors are weaned, if either is restarted before day 30 for more than 60 min within a 24-hour period, the intervening days will not count as being ventilator or vasopressor-free. Transient use of mechanical ventilation or vasopressors during and up to 3 hours after surgery or a bedside procedure (eg, haemodialysis) will be exempt. Vasopressor therapy is defined as the intravenous administration of any dose of norepinephrine, phenylephrine, dopamine, epinephrine, vasopressin or terlipressin. Mechanical ventilation is defined as invasive mechanical ventilation via endotracheal tube (including tracheostomy) or non-invasive ventilation with >5 cmH2O continuous positive airway pressure and >5 cmH2O pressure support when deployed to avoid intubation. Chronic use of non-invasive ventilation (eg, chronic night-time use for chronic obstructive pulmonary disease) will not be counted.
Secondary endpoints include: (1) Mortality rates at ICU and hospital discharge and at day 30, 90 and 180 after randomisation. (2) Number of days alive and free of vasopressors on day 30 after randomisation. Patients who die before weaning from vasopressors will be considered as having 0 vasopressor-free days. (3) Number of days alive and free of mechanical ventilation on day 30 after randomisation. Patients who die before weaning from mechanical ventilation will be considered as having 0 ventilator-free days. (4) Number of days alive and free of organ dysfunction (defined as SOFA <4) in the 30 days after randomisation. (5) Proportion of patients with a decision to withhold and/or withdraw active treatments. (6) Renal replacement therapy (RRT)-free days up to Day 30 after randomisation (excluding patients on RRT for chronic renal failure at time of randomisation). Patients who die before weaning from RRT will be considered as having 0 RRT-free days. (7) Number of 30-day ICU-free days. (8) ICU and hospital length of stay. (9) Rate of re-admission to the ICU during the 30 days after randomisation. (10) Cutaneous vasoconstrictor response to glucocorticoids (before administration of the corticoid treatment at study or placebo).28 (11) Health-related quality of life, based on the EuroQol group’s 5-Dimension 5-Level (EQ-5D-5L) questionnaire, at day 30 and 90 after randomisation (12). Safety endpoints include (1) Coma defined as a Glasgow coma scale <8. (2) Neurologic sequelae assessed by the Muscular Disability Rating Scale, with a score of 1 indicating no deficit, 2 minor deficit with no functional disability, 3 distal motor deficit, 4 mild-to-moderate proximal motor deficit, and 5 severe proximal motor deficit. (3) Proportion of patients affected by hospital-acquired infections. (4) Number of episodes of hyperglycaemia (blood glucose levels >150 mg/dL) during ICU stay (or up to day 30, whichever occurs first). (5) Number of episodes of hypernatraemia (serum sodium >145 mmol/L) during ICU stay (or up to day 30, whichever occurs first). (6) Glasgow coma scale at ICU and hospital discharge. (7) Number of patients with an episode of stroke (medical diagnosis as registered in the medical file) during ICU stay (or up to day 30, whichever occurs first). (8) Gastroduodenal bleeding requiring transfusion or haemostatic treatment during the ICU stay (or up to day 30, whichever occurs first). (9) Number of patients requiring the administration of corticosteroids following the end of the administration of the experimental treatment.
The secondary endpoints for subjects devoid of CIRCI are the number of ventilation and vasopressors-free days at day 30 after screening and all cause 90-day mortality after screening (assessed using the same definition as for the primary endpoint).
Randomisation
The period from inclusion to randomisation must not exceed 72 hours. This time window was chosen to allow investigators sufficient time to obtain the results of the cosynoptrin test. Sites were encouraged to randomise eligible patients as soon as possible. A computer process is used to generate block-randomisation sequences in a 1:1 ratio, independently of healthcare staff, research personnel, participants or the data analyst. Randomisation is stratified by centre and by the presence or not of ARDS. Randomisation will be centralised and performed through an internet-based central service running 24/7 embedded in the eCRF. Healthcare staff, research personnel, participants, and the data analyst are all blinded to treatment allocation. Only the central pharmacist is unblinded. Unblinding will be requested for any reason considered essential by the investigating physician, in a situation where the clinical condition of the patient warrants knowing whether or not he/she received hydrocortisone or fludrocortisone. Unblinding requests are to be sent to and managed by the sponsor.
Interventions
Investigational medicinal products
Investigational medicinal products are packaged in numbered boxes, labelled for this study according to Good Manufacturing Practices, under the responsibility of the central pharmacist. Each numbered box is allocated to a patient following randomisation and contains enough corticosteroids or placebo to treat one patient for 7 days. Each numbered box contains 30 vials of hydrocortisone 100 mg or placebo and 1 blister of 10 tablets of fludrocortisone 50 µg or placebo. Hydrocortisone hemisuccinate (SERB, Paris, France) or its placebo is administered as 50 mg intravenous bolus every 6 hours for 7 days. Fludrocortisone or its placebo (HAC Pharma, Caen, France) is administered as a 50 µg tablet via a nasogastric tube once a day in the morning, for 7 days. Placebo vial or tablets have similar aspects, tastes and colours to the active drug.
Forbidden interventions
Corticosteroids, whatever the dose and the route (except local administration), are not allowed. If an unavoidable indication for corticosteroids occurs after randomisation (eg, new onset autoimmune disease), the patient should be treated by open label corticosteroids; study treatments are to be suspended to avoid the administration of unnecessarily high doses of corticosteroids. Short-duration administration of open-labelled corticosteroids is allowed to prevent post-extubation laryngeal oedema. Continuous infusion of neuromuscular blocking agents is to be avoided when possible.
Biobanking and cutaneous vasoconstrictor response to glucocorticoids
Blood samples will be drawn, and serum will be stocked for later use, before randomisation and on day 7. Cutaneous vasoconstrictor response to glucocorticoids is assessed in a subgroup of patients (before administration of the corticoid treatment at study or placebo). The cutaneous vasoconstrictor response to glucocorticoids has been previously described.28 Briefly, 30 µg/mL betamethasone is applied to the skin on the inside of the forearm, before administration of any investigational medicinal product. The degree of skin blanching is assessed after 12 hours of exposure with a score ranging from 0 to 4: 0 no skin blanching, 1 skin blanching is less than 50% of the area of application, 2 skin blanching is more than 50% of the area of application, 3 if blanching recovers the whole area of application and 4 if blanching expands beyond the area of application. A score of 2 or less indicates resistance to corticosteroids. A photograph of the forearm restricted to the tested skin area is recorded.
Statistical analysis
We hypothesised that the effect size (difference in the number of ventilator- and vasopressor-free days within 30 days after randomisation between the randomisation arms) will be of 2 ventilator-free and vasopressor-free days30; the SE of the number of ventilator-free and vasopressor-free days within 30 days after randomisation is anticipated to be 10 (12; 35). We assumed that the 30-days mortality rate in ICU will be 20%. The outcomes are modelled using a zero-inflated distribution to account for excess in 0 due to patients who would die before hospital discharge. For patients alive at discharge, the number of ventilator-free and vasopressor-free days is assumed to follow an inverse binomial distribution with overdispersion parameter. A logistic model will be set up for the mortality rate. Prior distribution for the intercept and the treatment effect will be taken as normal; hyper-parameters for the intercept are mean=0.2 (to match the expected 20% mortality rate) and prior mean=0 for the treatment effect parameter. Diffuse priors are selected with variance for the 2 parameters of 0.0001.
The trial is designed using a flexible Bayesian approach to have an 80% posterior probability that one arm is superior to the other one if the actual mean difference is 2 days; it has a 5% posterior probability of superiority if the mean difference is 0 day under the assumptions that the death rates are similar and equal to 20% in both arms and that the overdispersion is similar in both arms with a SE of 10. We assumed smaller effects would not be considered clinically significant. A maximum of 1092 randomised patients (546/group) will be needed. Inclusions will continue until 1092 patients are randomised or the trial is prematurely stopped at an interim analysis due to one arm having a 90% probability of success compared with the other arm.
Three interim analyses equally spaced are designed using a Bayesian framework to calculate the probability of difference between the two arms on both the primary endpoint and the mortality rate, overall and in predefined subgroups. Due to the Bayesian computation, interim analyses will not be associated with type I error rates. Each analysis of the posterior predictive probability (posterior probability for a new patient) will be accompanied by its 95% credibility interval. Sensitivity analysis for several priors will be computed. The DSMB will review those results and provide recommendations regarding the continuation or the interruption of the trial. It will carefully consider situations where:
the probability that one arm is superior to the other one exceeds 95% whatever the investigated sensitivity analyses.
the probability that the mortality rate is larger in one arm than in the other one exceeds 90%.
The primary analysis will be performed according to the intention to treat procedure.
Patients’ characteristics will be described and compared according to the nature of the variable. Continuous variables will be expressed as mean, median, SD and IQR for the whole population and separately for each of the two arms and for the group of subjects devoid of CIRCI. Categorical variables will be expressed as number and percentage, for the whole population and separately for each of the two arms and for the group of subjects devoid of CIRCI. For randomised patients, the distributions of outcomes will be compared between the two arms using the Student’s t-test (or a nonparametric Wilcoxon rank-sum test if necessary) for continuous variables, and χ2 test (or Fisher exact test if necessary) for categorical variables.
In non-randomised patients (ICU adults devoid of CIRCI), the rate of ventilator and vasopressor-free survival at day 90 and day 180 post SYNACTHENE test will be calculated.
Data will be analysed by using the R language (V.3.0 R Foundation for Statistical Computing, Vienna Austria. http://www.R-project.org/), within the Clinical Research Unit AP-HP Paris Saclay Ouest.
Role of the sponsor and funding source
The sponsor and funding source has no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Ethics and dissemination
The trial was funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique (PHRC) (contract number PHRC-19-0173) and by France 2030 programme (ANR-23-IAHU-0004). The protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Ouest I, France, no 2021T1-11), on 23 September 2021 and by the ANSM (Agence nationale de sécurité du médicament et des produits de santé, the French medicines agency) on 23 March 2021. Trial results will be disseminated at relevant conferences and published in peer-reviewed journals.
Patient and public involvement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.
Discussion
HORNBILL is the first multicentre, placebo-controlled, randomised controlled trial aimed at assessing whether in a biomarker enriched population, hydrocortisone and fludrocortisone improve organ dysfunction-free days. Corticosteroids exhibit anti-inflammatory properties10 and in septic shock are consistently found to reduce the reliance on vasopressors.6 14 Corticosteroids have already demonstrated a benefit on mortality in septic shock,14 severe community-acquired pneumonia,19 in oxygen dependent COVID-1931 and on ventilation free survival in ARDS.16 Additional conditions commonly found in the ICU may also benefit from corticosteroids. We chose to enrich our study population by (1) including the sickest patients into this trial, that is, those hospitalised in the ICU with evidence of organ dysfunction and (2) identifying patients with an abnormal biological response to a cosyntropin test.
Advantages of corticosteroids include their inexpensive nature, wide availability including in LMICs as well as a largely positive safety profile. Other positive aspects of this trial are the continued follow-up of non-CIRCI patients. This population without CIRCI will potentially serve as an additional external control population to evaluate prognostic impact.
We must acknowledge some limits to the current trial including the fact that corticosteroids are widely administered in multiple conditions in the ICU and therefore that equipoise might be challenging in select conditions. To mitigate this issue, we excluded patients with septic shock from the current study. Excluding septic shock while improving equipoise, narrows generalisability and may preferentially remove the subgroup most likely to benefit. second, cortisol dosing may not always be available in participating centres. Third, the usefulness of an ACTH stimulation test compared with basal cortisol levels has been questioned, an international task force in charge of producing CIRCI guidelines could not agree on the best biological definition of CIRCI.20 Additionally, the definition of CIRCI is guideline-based, not evidence-based. Biological thresholds defined in guidelines are vulnerable to bias.32 This trial may decrease the overall burden in non-septic critical illness by offering an additional treatment.
Supplementary material
Acknowledgements
We thank the staff of the Clinical Research Unit AP-HP Paris Saclay Ouest involved in the project: Nawal Derridj-Ait Younes, Nabil Beghoul, Yohann Goldberg, Hind Benharrats, Gokula Ajeenthiravasan, Alexandre Alvarez. We thank the staff of the ‘Département des Essais Cliniques de l’établissement pharmaceutique de l’AGEPS’ for their involvement in ensuring the provision of the investigational medicinal products necessary for this study.
Footnotes
Funding: This trial is funded by the French Ministry of Health: Programme Hospitalier de Recherche Clinique National (PHRC-19-0173) and the France 2030 programme (ANR-23-IAHU-0004).
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2026-119187).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Collaborators: Collaborators: The HORNBILL consortium, Rania Bounab, Pierre Moine, Virginie Maxime, Ségolène Jourdier, Tarik Hissem, Sivanthiny Sivanandamoorthy, Matthieu Henry-Lagarrigue, Laureen Guillemin, Gwenhael Colin, Marine Jacquier, François Philippart, François Barbier, Armelle Mathonnet, Maxime Desgrouas, Mai-Anh Nay, Marie Skarzynski, Toufik Kamel, Mélanie Faure, Hélène Messet-Charriere, Thierry Boulain, Cindy Lage, Amine Boukraa, Magda Cantineau Harim, Mathilde Tuffier, Jean-Michel Constantin, Mona Assefi, Noemie Clavieras, Natacha Sybel Kapandji, Agnès Murat, Florian Blanchard, Sylvain Malfroy, Chaouki Mezher, Hakim Slimani, Pierre-Louis Declercq, Virginie Lemiale, Alexis Lambour, Marie-Line Harlay, Martin Cour, Neven Stevic, Marion Provent, Eddine Bendiab, Noémie Besnard, Ines Gueguen, Nicolas Dognon, Côme Bureau, Patrick Girardie, Asaël Berger.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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