Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis

Study Overview
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Brief Summary
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Main objective and primary endpoint: To compare the effect hydrocortisone plus fludrocortisone vs. placebo on a composite of death or persistent organ dysfunction - defined as continued dependency on mechanical ventilation, new renal replacement therapy, or vasopressors - assessed at 90 days on intensive care unit (ICU) adults and having different biological profiles for immune responses and corticosteroids bioactivity. Secondary objectives and endpoints: Mortality and health-related quality of life at 6 months; Daily organ function (SOFA score days 1, 2, 3, 4, 7, 10, 14, 28, and 90); Daily secondary infections (up to 90 days) Daily blood and urinary levels of glucose, sodium and potassium (up to 28 day) Daily gastroduodenal bleeding (up to 28 day) Daily cognitive function and muscles' strength (days 1 to 28, 90 and 180 days).

Detailed Description
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The potential benefits of a lower dose ( ≤ 400 mg of hydrocortisone or equivalent per day), and a longer duration at full dose ( ≥ three days) of treatment, have been investigated in numerous randomized controlled trials over the past three decades. In the past two years, guidelines for clinical practices about corticosteroids use in sepsis have been released. All but one of the guidelines, recommended against the use of corticosteroids in sepsis, except in patients with septic shock and poorly responsive to fluid replacement and vasopressor therapy. Some guidelines suggested that corticosteroids should be given as a continuous infusion rather than intermittent boluses. Corticosteroids survival benefit is not affected by age, gender, disease severity, type of infection, source of infection, or type of pathogens. There is currently no diagnostic test for CS sensitivity/resistance in sepsis. The scientific community is competing to identify markers delineating between patients who draw survival benefit from corticosteroids (CS-sensitive sepsis) and those who may be harmed (CS-resistant sepsis). In sepsis, the deregulated response may result in systemic inflammation and organs damage, or immune paresis and secondary infections. Obviously, patients with systemic inflammation may benefit from CS whereas those with immune paresis may deteriorate. The study team had have looked for an interaction between survival in response to corticosteroids and the presence of CIRCI according to the ACTH test results (cortisol increment of less than 9µg/dL). The benefits from corticosteroids were more important in patients with CIRCI in the Ger-Inf-05 trial but not in the APROCCHS trial. Thus, current sepsis guidelines suggest that the ACTH test may not reliably guide the use of corticosteroids. Indeed, this test provides information neither on corticosteroids bioactivity nor on patient's immune status, when this information should precede any corticotherapy. Recent studies suggested that a transcriptomic signature based on 100 genes may identify a subset of paediatric sepsis that had increased risk of death when exposed to corticosteroids. Another study found transcriptomic based sepsis response signatures (SRS) associated with immune paresis (SRS1) or with systemic inflammation (SRS 2). In this study, patients with a SRS 2 transcriptomic signature had significantly higher mortality when treated with hydrocortisone. Thus, we have started exploring the mechanisms of sensitivity/resistance to corticosteroids in sepsis, namely by investigating endocan, as a surrogate of patient's inflammatory status, and GILZ expression as a marker of corticosteroids bioactivity. This is a new multicentre concealed-allocation multi-arms, parallel-group, adaptive blinded randomized controlled trial. The overall objective of the trial is to determine whether different signatures of immune status and/or corticosteroids biological activity influence the responses to hydrocortisone plus fludrocortisone of adults with sepsis. To remain pragmatic, this trial has broad eligibility criteria and includes all patients admitted to the ICU with a primary diagnosis of sepsis. Patients will be randomly assigned to hydrocortisone plus fludrocortisone or placebo for 7 days, targeting 1800 patients with full follow-up up to 6 months.

Official Title
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A Multicentre Concealed-Allocation Multi-arms Blinded Randomized Controlled Trial to Identify the Best Sepsis Population for Corticotherapy

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Administration procedures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient ≥18 years old; Admitted to ICU with proven or suspected infection as the main diagnosis; Community acquired pneumonia related sepsis or vasopressors dependency (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine) or septic shock (vasopressor to maintain mean blood pressure of at least 65 mmHg and lactate levels above 2 mmol/l) or acute respiratory distress syndrome (ARDS: a- acute onset, i.e. within one week of an apparent clinical insult and with progression of respiratory syndrome, b- bilateral opacities on chest imaging not explained by other pulmonary pathologies, e.g. pleural effusion, atelectasis, nodules etc, c- no evidence for heart failure or volume overload, d- PaO2/FiO2 ≤ 300 mm Hg, - PEEP ≥ 5 cm H2O; Patients who have been tested for one or more RECORDS specific biomarkers: CIRCI Endocan GILZ DUSP-1 MDW lymphopenia Transcriptomic SRS2 Endotype B PCR COVID-19 PCR Influenza PCR other respiratory virus Cutaneous vasoconstrictor response to glucocorticoids Patient who has signed an informed and written consent whevener he/she is able of consent, if not, if not ascent from his/her representant whenever he/she is present at time of screening for inclusion; Patient affiliated to a social security system or to an universal health coverage (Couverture Maladie Universelle (CMU) in France; Patient under guardianship or curatorship will be included; Patient in case of simple emergency (legal definition) will be included; Patients managed with covid 19 and having biological samples available. Exclusion Criteria: Pregnancy; Expected death or withdrawal of life-sustaining treatments within 48 hours; Previously enrolled in this study Formal indication for corticosteroids according to most recent international guidelines Vaccination with live virus within past 6 months Hypersensitivity to hydrocortisone or fludrocortisone or (microsined betamethasone dipropionate*) or any of their excipients (spc) Women of childbearing potential not using contraception Nursing women * For patients included in this stratum, if applicable, do not apply the cream to an infected or ulcerated area

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Biomarker CIRCI neg: Corticosteroid arm<br>Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Placebo Comparator: Biomarker CIRCI neg: Placebo arm<br>Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Experimental: Biomarker endocan: Corticosteroid arm<br>Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Placebo Comparator: Biomarker endocan: Placebo arm<br>Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Experimental: Biomarker GILZ: Corticosteroid arm<br>Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Placebo Comparator: Biomarker GILZ: Placebo arm<br>Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Experimental: Biomarker CPD: Corticosteroid arm<br>Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Placebo Comparator: Biomarker CPD: Placebo arm<br>Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Experimental: Biomarker Transcriptomic SRS: Corticosteroid arm<br>Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Placebo Comparator: Biomarker Transcriptomic SRS: Placebo arm<br>Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Experimental: Biomarker Endotype B: Corticosteroid arm<br>Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|
| Placebo Comparator: Biomarker Endotype B: Placebo arm<br>Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment. | Drug: Administration procedures<br>* Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-month mortality | Patient's vital status. | Daily up to 3 months | 
| Persistent organ dysfunction | Persistent organ dysfunction (defined as continued dependency on mechanical ventilation, renal replacement therapy, or vasopressors) and with SOFA score ≤6 up to 90 days. | At baseline, 1 month and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality at 7, 14, 28 day and 6 months | Patient's vital status. | at 7, 14, 28 day and 6 months | 
| Vasopressor free days | defined as the number of days with permanent hemodynamic stability in the absence of any vasopressor agent, norepinephrine, phenylephrine, epinephrine, dopamine, vasopressine or its analogs, and soever. When a patient will die on vasopressor therapy, the corresponding vasopressor free day will be 0. | through study completion, an average of 6 month | 
| Mechanical ventilation free days | defined as the number of days with permanent appropriate oxygenation while the patients is extubated and breathing spontaneously, i.e. no need for non invasive ventilation, high flow oxygen or CPAP. Other uses of non-invasive ventilation (e.g., chronic night-time use for chronic obstructive pulmonary disease) are not counted. When a patient will die on mechanical ventilation or will be discharge home on mechanical ventilation, the corresponding mechanical ventilation free day will be 0. | through study completion, an average of 6 month | 
| Organ dysfunction free days | Organ function (including renal function) will be assessed by the SOFA score (Vincent 1996). Organ dysfunction will be defined by a SOFA score of > 6 (Annane 2018). Organ dysfunction free days are defined by the number of days with os total SOFA score of 6 or less. When a patient will die on vasopressor therapy, the corresponding vasopressor free day will be 0. | through study completion, an average of 6 month | 
| HRQoL in 6-month survivors assessed by the EuroQol-5D (EQ-5D) | This questionnaire is a standardised measure of health status developed to provide a simple, generic measure of health for clinical and economic appraisal. It is made up for two components; health state description and evaluation. The health status is measured in terms of five dimensions; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In evaluation part, the respondents evaluate their overall health status using the visual analogue scale. | at 1, 28, 90 day and 6 months | 
| Proportion of patients with a decision to withhold and/or withdraw active treatments |  | through study completion, an average of 6 month | 
| ICU and hospital length of stay |  | through study completion, an average of 6 month | 
| Rate of re-admission to the ICU during the 180 days after randomization |  | through study completion, an average of 6 month | 
| Safety endpoints: proportion of patients affected by any serious adverse events | Serious adverse events associated with corticosteroids, among the following: hospital-acquired infections, hyperglycemia, hypernatremia, neurological disorders (coma, stroke or muscle weakness, as defined below) during the 90 days after randomization. | up to 90 days | 
| Coma | Coma will be defined as a Glasgow coma score < 8 | up to 90 days | 
| Neurologic sequelae | Neurologic sequelae will be assessed according to the score on the Muscular Disability Rating Scale (MDRS), 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. | up to 90 days | 
| Proportion of patients affected by hospital-acquired infections | Proportion of patients affected by hospital-acquired infections (CTINILS. Définition des infections associées aux soins. 2007, (document in french)). | up to 90 days | 
| Number of episodes of hyperglycemia | Number of episodes of hyperglycemia (blood glucose levels >150mg/dl) during ICU stay (or up to day 90, whichever occurs first) | daily during ICU stay or up to 90 days | 
| Number of episodes of hypernatremia | Number of episodes of hypernatremia (serum sodium > 145 mmol/L) during ICU stay (or up to day 90, whichever occurs first) | daily during ICU stay or up to day 90 | 
| Glasgow coma scale at ICU and hospital discharge | Glasgow coma scale at ICU and hospital discharge | at ICU discharge and hospital discharge | 
| Number of patients with an episode of stroke | Number of patients with an episode of stroke (medical diagnosis as registered in the medical file) during ICU stay (or up to day 90, whichever occurs first) | daily during ICU stay or up to day 90 | 
| Gastroduodenal bleeding | Gastroduodenal bleeding requiring transfusion or hemostatic treatment during ICU stay (or up to day 90, whichever occurs first) | daily during ICU stay or up to day 90 | 
| Adult cognitive function score | Neurological cognitive dysfunction defined as by low score on the PROMIS (Adult cognitive function score). PROMIS (Patient-Reported Outcomes Measurement Information System): for assessment of fatigue, ability to partake in social activities, physical function, emotional distress, depression, anxiety and cognitive function. | at 1, 28, 90 day and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Corticosteroid, intensive care unit, CS-resistant Sepsis, CS-sensitive Sepsis