Evaluation of Hydrocortisone Hemisuccinate and Fludrocortisone in ICU Patients with Sepsis: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effect of **hydrocortisone** plus **fludrocortisone** compared to placebo on a composite outcome of death or persistent organ dysfunction in adults admitted to the intensive care unit (ICU) with sepsis. Persistent organ dysfunction is defined as continued dependency on mechanical ventilation, new renal replacement therapy, or vasopressors, assessed at 90 days. This objective is clinically relevant as it aims to determine the efficacy of corticosteroid therapy in improving survival and reducing organ failure in a critically ill population with varying immune response profiles.

Secondary objectives include:

• Comparing the effect of hydrocortisone plus fludrocortisone versus placebo on 6-month mortality.
• Assessing the impact on health-related quality of life (HRQoL) at 6 months.
• Evaluating organ function at multiple time points if the patient remains in the ICU.
• Investigating the incidence of hyperglycemia and hypernatremia, defined by specific glucose and sodium levels, respectively, up to day 28.
• Monitoring secondary infections up to day 90.
• Examining gastrointestinal bleeding, defined by clinical evidence and the need for intervention.
• Assessing neurological cognitive dysfunction using the PROMIS Adult cognitive function score.
• Evaluating neuromuscular weakness using the Muscular Disability Rating Scale (MDRS).

The clinical trial involves **adult patients** admitted to the **intensive care unit (ICU)** with a proven or suspected infection as the main diagnosis. The study population includes both **male and female subjects** aged 18 years and older. Participants are selected based on their admission to the ICU with conditions such as community-acquired pneumonia-related sepsis, vasopressor dependency, septic shock, or acute respiratory distress syndrome (ARDS). The trial includes individuals who have been tested for specific biomarkers and those managed with COVID-19, provided they have available biological samples. The trial population is characterized by a diverse range of biological profiles for immune responses and corticosteroid bioactivity. The sponsor has not provided the total number of participants involved in the study. Participants are required to be affiliated with a social security system or universal health coverage. The trial also includes vulnerable populations, such as those under guardianship or curatorship, and individuals in simple emergency situations as legally defined.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **hydrocortisone** plus **fludrocortisone** versus placebo in patients admitted to the ICU with proven or suspected infection as the main diagnosis. The primary objective is to assess the impact on a composite endpoint of death or persistent organ dysfunction at 90 days. The trial will involve multiple arms and is expected to conclude by November 24, 2025, with recruitment having commenced on April 10, 2020.

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 admission due to infection, and specific biomarker testing. Following randomization, participants will receive either the active treatment or placebo. The trial includes follow-up visits to monitor outcomes such as mortality, vasopressor-free days, and mechanical ventilation-free days at intervals of 7, 14, 28 days, and 6 months. The end-of-study visit will assess the primary and secondary endpoints, including health-related quality of life and ICU readmission rates.

The expected duration of participant involvement is up to 90 days post-randomization, with conditions for early termination including withdrawal of consent or adverse events. The trial will utilize **betamethasone** ointment, **fludrocortisone** tablets, and **hydrocortisone hemisuccinate** solution for injection/infusion, with placebo counterparts for blinding. The study aims to identify the best sepsis population for corticotherapy by evaluating different biological profiles for immune responses and corticosteroid bioactivity.

The clinical trial involves the administration of **BETAMETHASONE**, which is provided in the form of an ointment. The active substance, betamethasone, is of chemical origin. The ointment is applied via **cutaneous use** with a maximum daily dose of 10 µl microlitre(s) and a total dose not exceeding 10 µl microlitre(s) over a treatment period of 1 day. Participant compliance with the application schedule is monitored to ensure adherence to the dosing regimen.

**FLUDROCORTISONE** is administered in the form of tablets, with the active substance being fludrocortisone of chemical origin. The route of administration is **oral use**. The maximum daily dose is 50 µg microgram(s), with a total dose not exceeding 350 µg microgram(s) over a 7-day treatment period. The tablets are provided in anonymized blister packs to maintain blinding, and participant adherence is monitored throughout the trial.

**HYDROCORTISONE HEMISUCCINATE** is delivered as a solution for injection or infusion, with the active substance being hydrocortisone hemisuccinate of chemical origin. The administration route is **intravenous use**. The maximum daily dose is 200 mg milligram(s), with a total dose not exceeding 1400 mg milligram(s) over a 7-day treatment period. The solution is provided in anonymized vials to ensure blinding, and compliance with the dosing schedule is closely monitored.

The trial also includes the use of a **Placebo of fludrocortisone** and a **Placebo of hydrocortisone**. These placebos are used to maintain the blinding of the study and are administered in a manner consistent with their respective active comparators. The placebo forms and routes of administration are not specified, but they are integral to the study design to ensure unbiased results.

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the 90-day organ dysfunction, ventilation, and vasopressors-free survival after randomization. This is a composite measure that includes day 90 mortality and survival free days off vasopressors and mechanical ventilation, with a Sequential Organ Failure Assessment (SOFA) score greater than 6. Secondary endpoints include mortality at 7, 14, 28 days, and 6 months, as well as vasopressor-free days, mechanical ventilation-free days, and organ dysfunction-free days. Organ dysfunction will be evaluated using the SOFA score, with dysfunction defined by a score greater than 6.

Additional secondary endpoints include health-related quality of life (HRQoL) in 6-month survivors, assessed by the EuroQol-5D (EQ-5D), the proportion of patients with decisions to withhold or withdraw active treatments, ICU and hospital length of stay, and the rate of re-admission to the ICU within 180 days post-randomization. Safety endpoints will also be monitored as per the protocol. The trial aims to compare the effects of hydrocortisone plus fludrocortisone versus placebo on these outcomes in adults in the intensive care unit (ICU) with different biological profiles for immune responses and corticosteroid bioactivity.