Evaluation of Recombinant Human Interferon Gamma 1b in Post-Aggressive Immunosuppression in ICU Patients: A Randomized Double-Blind Controlled Trial

The primary objective of this study is to evaluate the efficacy of subcutaneous administration of **recombinant human interferon gamma 1-b** (IFNy) in improving the number of days alive without mechanical ventilation at day 28 (or upon leaving intensive care) compared with a placebo. This is specifically targeted at patients admitted to intensive care with a high severity score (SOFA of the first 24 hours post-admission ≥ 6) and a biological criterion of immunosuppression (mHLA-DR < 8000 AB/C) measured between days 5 and 10 of their admission. The clinical relevance of this objective lies in potentially reducing the duration of mechanical ventilation, which is a critical factor in patient recovery and resource allocation in intensive care units.

Secondary objectives include:

• Evaluating the efficacy of IFNy in correcting post-aggressive immunosuppression (PAIS)-defining biological abnormalities, specifically the re-ascension of mHLA-DR above 8,000 AB/C, between patients treated with recombinant interferon gamma 1-b versus placebo.
• Assessing the kinetics of plasma inflammatory parameters and leucocyte count depending on the randomization arm.
• Comparing mortality rates at day 28 and day 90 post-randomization.
• Comparing the incidence of nosocomial infections during ICU stay, defined according to the criteria of the International Sepsis Forum Consensus Conference.
• Comparing the number of days alive without antibiotic use at day 28 post-randomization.
• Comparing the length of stay in intensive care.
• Comparing organ failure score (SOFA) kinetics between the treatment and placebo groups.

The clinical trial involves participants diagnosed with **post-aggressive immunosuppression**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a Sequential Organ Failure Assessment (SOFA) score of 6 or higher within the first 24 hours post-admission to intensive care and must be mechanically ventilated at the time of inclusion, excluding those on non-invasive ventilation or high-flow nasal oxygen. Additionally, a biological criterion of immunosuppression, specifically an mHLA-DR level of less than 8,000 AB/C, must be measured between the 5th and 10th day after admission to the intensive care unit. The trial does not involve a vulnerable population, and all participants must be affiliated with a social security scheme and provide written consent through a relative or trusted person. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **recombinant human interferon gamma 1-b** in patients experiencing post-aggressive immunosuppression in intensive care units. This study is a randomized, double-blind, controlled trial with a Bayesian approach, comparing the active treatment against a placebo. The trial is expected to commence recruitment on July 1, 2024, and conclude by October 1, 2027. Participants will be involved in the study for a maximum treatment period of three days, with the primary endpoint being the number of days alive without mechanical ventilation on day 28 post-randomization or upon discharge from intensive care, whichever occurs first.

Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as age (≥18 years), a SOFA score of ≥6 within the first 24 hours post-admission, and specific immunosuppression markers. Following randomization, participants will receive either the active treatment or placebo subcutaneously. Follow-up visits will occur on days 0, 1, 2, 3, 7, and 28, or at discharge if earlier, to monitor the evolution of mHLA-DR and inflammation markers, as well as to assess secondary endpoints like mortality rates and incidence of nosocomial infections. The end-of-study visit will coincide with the final assessment on day 28 or at discharge.

Participant involvement is expected to last up to 28 days, with conditions for early termination including withdrawal of consent, adverse events, or any situation deemed necessary by the investigator for the participant's safety. The trial's methodology ensures rigorous data collection and analysis, contributing valuable insights into the treatment of post-aggressive immunosuppression in critically ill patients.

The clinical trial involves the administration of **Sodium Chloride** as a **solution for infusion**. This experimental medication is utilized in the study as a placebo. The pharmaceutical form is a solution, and it is administered via infusion. The maximum daily dose is 0.5 ml, with a total maximum dose of 1.5 ml over a treatment period of up to 3 days. The solution is not a pediatric formulation and is classified under chemical origin. The administration of Sodium Chloride is monitored to ensure compliance with the dosing schedule.

The experimental treatment in the trial is **IMUKIN**, which contains **Recombinant Human Interferon Gamma 1b**. This medication is provided as a **solution for injection** and is administered subcutaneously. The maximum daily dose is 0.1 mg, with a total maximum dose of 0.3 mg over a treatment period of up to 3 days. IMUKIN is not formulated for pediatric use and is derived from a specified substance group. The administration of IMUKIN is carefully monitored to ensure adherence to the dosing regimen and to evaluate its efficacy in improving the number of days alive without mechanical ventilation in patients with post-aggressive immunosuppression in intensive care units.

The efficacy of the clinical trial titled "INFINITY - Effect of interferon gamma as a treatment for post-aggressive immunosuppression in intensive care units, a randomized Bayesian double-blind controlled trial versus placebo" will be assessed using several primary and secondary endpoints. The primary endpoint is the number of days alive without mechanical ventilation on day 28 after randomization or upon discharge from intensive care if this occurs before the 28th day. This endpoint will provide a direct measure of the treatment's impact on patient recovery and respiratory independence.

Secondary endpoints include the evolution and kinetics of **mHLA-DR** and inflammation markers (such as IL-1, IL-2, IL-6, IL-8, TNFa) measured at specific time points: D0, D1, D2, D3, D7, and D28, or at discharge from intensive care if earlier. These measurements will be compared between patients treated with recombinant human interferon gamma 1-b and those receiving a placebo. Additional secondary endpoints include the mortality rate at D28 and D90, the incidence of nosocomial infections during the ICU stay, the number of days alive without antibiotics assessed on day 28, and the kinetics of the SOFA score assessed at inclusion and during the 7 days following inclusion. These endpoints will provide comprehensive data on the treatment's efficacy in improving clinical outcomes and reducing complications associated with immunosuppression in intensive care patients.