Evaluation of Hydrocortisone and Fludrocortisone Efficacy in Critically Ill Patients with Corticosteroid Insufficiency: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of hydrocortisone combined with fludrocortisone compared to placebo in increasing the number of ventilator- and vasopressor-free days within 30 days post-randomization in ICU adults with critical illness-related corticosteroid insufficiency (CIRCI). This is clinically relevant as it aims to improve patient outcomes by potentially reducing the need for mechanical ventilation and vasopressor support, which are critical interventions in the management of critically ill patients.

Secondary objectives include assessing the efficacy of the treatment on various clinical outcomes:

• Mortality at ICU and hospital discharge, and at 30, 90, and 180 days after randomization.
• Number of vasopressor-free days 30 days after randomization.
• Number of ventilator-free days 30 days after randomization.
• Kidney replacement therapy-free days at 30 days after randomization.
• Number of 30-day ICU-free days.
• Organ dysfunction up to day 30 after randomization.
• ICU and hospital length of stay.
• Rate of ICU re-admission during the 30 days after randomization.
• Health-related quality of life.
• Cutaneous vasoconstrictor response to glucocorticoids in a subgroup of patients.
• Serious adverse events associated with corticosteroids, including hospital-acquired infections, metabolic disorders, neurological disorders, and gastroduodenal bleeding at day 30 after randomization.
• Ventilation and vasopressors free days in ICU adults devoid of CIRCI, at day 30 post SYNACTHENE® test and all-cause mortality at day 90 post SYNACTHENE® test.

The clinical trial involves **critically ill patients** suffering from critical illness-related corticosteroid insufficiency (CIRCI). The study population includes both male and female adults aged 18 years and older, who are hospitalized in an intensive care unit. Participants are required to have a Sequential Organ Failure Assessment (SOFA) score of 4 or higher for at least six consecutive hours. The trial population is selected based on these criteria, and informed consent is obtained from the patient or a legally authorized representative. The sponsor has not provided the total number of participants. The study includes individuals affiliated with a social security system or universal health coverage. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The population is considered vulnerable due to their critical health status.

The clinical trial is designed to evaluate the efficacy of **hydrocortisone** combined with **fludrocortisone** compared to placebo in adults with critical illness-related corticosteroid insufficiency (CIRCI) in an intensive care unit (ICU) setting. This is a randomized, double-blind, controlled trial with a primary endpoint of assessing the number of ventilator- and vasopressor-free days within 30 days post-randomization. The trial is expected to run from February 2022 to August 2026, with participant involvement lasting up to 30 days post-randomization.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), ICU hospitalization, and a SOFA score of ≥4 for at least 6 consecutive hours. Informed consent is required, with provisions for emergency inclusion if necessary. Following randomization, participants will receive either the active treatment or placebo, with follow-up visits scheduled to monitor outcomes and collect data on primary and secondary endpoints, including mortality rates and ICU length of stay.

The end-of-study visit will occur 30 days after randomization, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience adverse events, withdraw consent, or if the investigator deems it necessary for safety reasons. The trial's design ensures rigorous data collection and analysis to determine the treatment's impact on CIRCI in critically ill patients.

The clinical trial involves the administration of **Tetracosactide**, a synthetic peptide used to assess adrenal function. It is administered as an **intravenous injection** with a maximum daily dose of 250 µg. The pharmaceutical form is identified as PHF00231MIG. The treatment period is limited to one day, ensuring a controlled and precise evaluation of its effects. Participant compliance is monitored through direct observation of the administration process.

**Betamethasone** is included in the study as a non-experimental treatment. It is applied via **cutaneous use** with a maximum daily dose of 10 µl. The pharmaceutical form is PHF00017MIG. The treatment duration is one day, and compliance is ensured by instructing participants on proper application techniques and verifying adherence through follow-up assessments.

The trial also incorporates a **placebo** for fludrocortisone, which serves as a control to evaluate the efficacy of the active treatments. The placebo is administered without a specified pharmaceutical form or route, ensuring blinding and maintaining the integrity of the study design. The placebo is used for a maximum treatment period of seven days.

**Fludrocortisone acetate** is administered as an **oral** treatment with a maximum daily dose of 50 µg and a total dose of 350 µg over a seven-day period. The pharmaceutical form is PHF00245MIG. The product is blinded in a neutral blister with specific labeling to maintain study integrity. Compliance is monitored through pill counts and participant diaries.

**Hydrocortisone hemisuccinate** is provided as a **powder for injection** with a maximum daily dose of 200 mg and a total dose of 1400 mg over seven days. The product is blinded in a neutral bottle with research-specific labeling. It is administered via **intravenous use**, and compliance is ensured through direct observation and documentation of each administration.

The efficacy of the treatment in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the number of ventilator- and vasopressor-free days up to day 30 post-randomization. This is defined as the number of days during which the patient is alive, free of mechanical ventilation, and free of treatment with intravenous vasopressors within the 30-day period following randomization.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of efficacy. These include mortality rates at ICU and hospital discharge, as well as at day 30, 90, and 180 after randomization. Additional secondary endpoints are the number of days alive without vasopressors and free of mechanical ventilation on day 30 after randomization, the proportion of patients with a decision to withhold and/or withdraw active treatments, and renal replacement therapy (RRT)-free days up to day 30 after randomization. Other measures include the number of days alive with a SOFA score less than 4 in the 30 days after randomization, the number of 30-day ICU-free days, ICU and hospital length of stay, and the rate of re-admission to the ICU during the 30 days after randomization.

Additional assessments involve the score of cutaneous vasoconstrictor response to glucocorticoids, changes in utility based on the EuroQol group's 5-dimension 5-level (EQ-5D-5L) questionnaire up to day 30 and 90 after randomization, and safety endpoints. For non-randomized patients, secondary endpoints include 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.