Hydrocortisone and Fludrocortisone for Critical Illness-related Corticosteroid Insufficiency

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Not possible to specify

Trial duration

17 Feb 2022 → 9 Nov 2025

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

French Health Ministry

External identifiers

EU CT number

2024-516021-32-00

EudraCT number

2020-003942-35

ClinicalTrials.gov

NCT04404400

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Diagnosis

To assess the efficacy on ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) post randomization of hydrocortisone combined with fludrocortisone compared to placebo in ICU adults with critical illness related corticosteroid insufficiency.

Secondary objectives 12

1. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on Mortality at ICU and hospital discharge, and at 30 days, 90 days and 180 days after randomization
2. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on number of vasopressor-free days 30 days after randomization
3. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on Number of ventilator-free days 30 days after randomization
4. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on Kidney replacement therapy-free days at 30 days after randomization
5. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on Number of 30-day intensive care unit (ICU)–free days
6. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on organ dysfunction up to day 30 after randomisation
7. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on ICU and hospital length of stay
8. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on Rate of ICU re-admission during the 30 days after randomization
9. To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with critical illness related corticosteroid insufficiency on Health-related quality of life
10. To assess the cutaneous vasoconstrictor response to glucocorticoids in a subgroup of patients.
11. To assess serious adverse events associated with corticosteroids, including hospital acquired infections (using the WHO definition), metabolic disorders (hyperglycemia and hypernatremia), neurological disorders including coma, stroke and muscle weakness, and gastroduodenal bleeding at day 30 after randomization.
12. To assess ventilation and vasopressors free days in ICU adults devoid of critical illness related corticosteroid insufficiency, at day 30 post SYNACTHENE® test and all-cause mortality at day 90 post SYNACTHENE® test.

Conditions and MedDRA coding

Critically ill patients suffering from CIRCI

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Adult (≥18 years)
2. Hospitalized in an intensive care unit
3. SOFA score (SOFA; Sequential Organ Failure Assessment) ≥4, for at least 6 consecutive hours
4. Informed written consent from patient or from legally authorized trusted person or next of kin, if present at time of inclusion. When a patient is unable to be informed, and no legally authorized trusted person or next of kin is present, the patient may still be included (emergency procedure), and patient’s, or, where appropriate, the legally authorized trusted person or next of kin’s, deferred consent needs to be obtained as soon as possible (Article L1122-1-3; Public Health Code).
5. Affiliation to a social security system or to an universal health coverage (Couverture Maladie Universelle, CMU)

Exclusion criteria 17

1. Any suspected or proven acute adrenal insufficiency (As defined in international guidelines; basal cortisol < 5 μg/dl or peak (T60) cortisol <18 μg/dL)
2. Expected death or withdrawal of life-sustaining treatments within 48 hours
3. Known chronic adrenal insufficiency
4. Concomitant treatment that inhibits cortisol production
5. Septic shock (Singer Jama 2016)
6. Active tuberculosis or fungal infection
7. Active viral hepatitis or active infection with herpes viruses
8. Hypersensitivity to hydrocortisone, fludrocortisone or Synacthène® or any of their excipients (SmPC)
9. Patient needing either anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason (Such as those suffering from COVID-19 pneumonia requiring oxygen therapy)
10. Current treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30days
11. Diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome
12. Pregnant or breastfeeding woman
13. Moribund patient
14. Previously enrolled in this study
15. Participation to another interventional study that focuses on CIRCI and/or corticoid drugs and/or that adresses a similar primary endpoint as Hornbill (survival or use of vasopressors or of mechanical ventilation)
16. Patient under guardianship or tutorship
17. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary end point is the number of ventilator- and vasopressor-free days up to day 30, defined as days from randomisation to 30 days thereafter, during which the patient is alive, free of mechanical ventilation, and free of treatment with intravenous vasopressors.

Secondary endpoints 13

1. Mortality rates at ICU and hospital discharge and at day 30, 90 and 180 after randomization
2. Number of days alive without vasopressors on day 30 after randomization. Patients who die before vasopressor weaning will be considered as having 0 vasopressor free days.
3. Number of days alive free of mechanical ventilation on day 30 after randomization. Patients who die before mechanical ventilation weaning will be considered as having 0 ventilator free days.
4. Proportion of patients with a decision to withhold and/or withdraw active treatments
5. Renal replacement therapy (RRT)-free days up to Day 30 after randomisation (excluding patients on RRT for chronic renal failure at time of randomisation)
6. Number of days alive with SOFA <4 in the 30 days after randomization
7. Number of 30-day intensive care unit (ICU)–free days
8. ICU and hospital length of stay
9. Rate of re-admission to the ICU during the 30 days after randomization
10. Score of cutaneous vasoconstrictor response to glucocorticoids (before administration of the corticoid treatment at study or placebo)
11. 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
12. Safety endpoints
13. Secondary endpoint concerning non-randomised patients: - Ventilation and vasopressors free days at day 30 post SYNACTHENE® test and all cause 90 day mortality post SYNACTHENE® test (assessed using the same definition as for the primary endpoint: see section 4.1.1 of protocol) in subjects devoid of CIRCI.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Nicholas HEMING Coordinator

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Nicholas HEMING Coordinator

Locations

1 EU/EEA country · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications