Evaluation of Ruxolitinib Combined with Standard Care in Reversing Organ Failure in Critically Ill Adults with Acquired Hemophagocytic Syndrome in ICU

The primary objective of this study is to demonstrate that **ruxolitinib**, when used in conjunction with standard care, may more effectively reverse organ failure, as indicated by the SOFA score, compared to standard care alone in critically ill patients with acquired hemophagocytic syndrome (HS). This is clinically relevant as it addresses the potential for improved management of organ failure in a severe and life-threatening condition.

Secondary objectives include:

• To demonstrate that ruxolitinib may improve overall survival in critically ill HS patients.
• To demonstrate that ruxolitinib may reverse clinical manifestations such as temperature and SOFA score, as well as biological manifestations including ferritin level, CD25 soluble receptor dosage, fibrinogen level, triglycerides level, hemoglobin level, white blood cells count, and platelets count related to HS.
• To analyze the impact of ruxolitinib on biological inflammatory markers, including IL2, IL6, IL10, IL12, GM-CSF, IFN gamma, and TNF alpha.
• To demonstrate the safety of ruxolitinib in critically ill HS patients.

The clinical trial involves **adult patients** over the age of 18 who are admitted to participating intensive care units (ICUs). The study population includes both male and female subjects, with a focus on those who are critically ill and have been diagnosed with acquired **hemophagocytic syndrome** (HS), regardless of etiology. Participants are selected based on their admission to the ICU and the need for symptomatic treatment of HS related to organ failure, as indicated by a Sequential Organ Failure Assessment (SOFA) score of 4 or higher. The trial population is considered vulnerable, and informed consent is required, either directly from the patient or from a family member or trustworthy person if the patient's condition does not allow for written consent. In emergency situations, consent will be obtained as soon as the patient's condition permits. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the trial data. Women of childbearing potential are required to use highly effective contraception during the study and for one day after treatment. The trial aims to assess the efficacy of ruxolitinib in conjunction with standard care in reversing organ failure in this patient population.

The clinical trial is designed to evaluate the efficacy of **ruxolitinib** in combination with standard care for critically ill patients with acquired hemophagocytic syndrome (HS). This is a randomized, double-blind, controlled trial with a primary objective to assess whether ruxolitinib can improve organ failure outcomes, as measured by the Sequential Organ Failure Assessment (SOFA) score, compared to standard care alone. The trial is set to run from October 16, 2023, to October 16, 2025, with an estimated duration of 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (over 18 years), diagnosis of acquired HS, and a SOFA score of 4 or higher. Following the screening, participants will be randomized to receive either ruxolitinib or a placebo, alongside standard care. The trial includes multiple follow-up visits to monitor the primary endpoint, which is survival with a decrease in SOFA score by at least 3 points at day 7. Secondary endpoints include overall survival, changes in temperature, SOFA score, and various biological markers related to HS.

The expected length of participant involvement is up to 28 days, corresponding to the maximum treatment period for ruxolitinib. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or any significant protocol deviations. The end-of-study visit will assess the final outcomes and collect data on the safety and efficacy of the treatment regimen. This trial is conducted under strict ethical guidelines, ensuring informed consent is obtained from all participants or their legal representatives.

The clinical trial involves the administration of **Ruxolitinib**, marketed as Jakavi 5 mg tablets, as the experimental medication. Ruxolitinib is a **Janus Associated Kinases (tyrosine Kinases) inhibitor** and is provided in tablet form. The maximum daily dose is 20 mg, with a total maximum dose of 560 mg over a treatment period of 28 days. The route of administration is oral. This medication is used in conjunction with standard-of-care therapy to assess its efficacy in reversing organ failure in critically ill patients with acquired hemophagocytic syndrome.

**Methylprednisolone**, containing the active substances **lidocaine hydrochloride monohydrate** and **methylprednisolone acetate**, is used as an auxiliary treatment. It is administered via intravenous infusion. The pharmaceutical form is coded as PHF00243MIG. The maximum daily and total dose is 2 mg/kg, with a treatment period of up to 1 day. This medication is classified under the ATC code H02AB04.

**Etoposide** is another auxiliary treatment in the trial, provided as an injectable solution. The pharmaceutical form is coded as PHF675. The maximum daily dose is 150 mg/m², with a total maximum dose of 450 mg/m² over a treatment period of 3 days. Etoposide is classified under the ATC code L01CB01.

**Dexamethasone**, with the active substance **betamethasone sodium phosphate Ph. Eur**, is also used as an auxiliary treatment. It is administered through other unspecified routes, with a pharmaceutical form coded as PHF00231MIG. The maximum daily and total dose is 40 mg, with a treatment period of up to 1 day. This medication is classified under the ATC code H02AB02.

All medications used in this trial are of chemical origin and are not formulated for pediatric use. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is defined as survival with a decrease in the Sequential Organ Failure Assessment (**SOFA**) score by at least 3 points at day 7. This endpoint is designed to evaluate the effectiveness of the treatment in reversing organ failure in critically ill patients with acquired hemophagocytic syndrome (HS).

Secondary endpoints include overall survival in critically ill HS patients, as well as various clinical and biological manifestations related to HS. These manifestations encompass temperature, SOFA score, and biological markers such as ferritin level, CD25 soluble receptor dosage, fibrinogen level, triglycerides level, hemoglobin level, white blood cell count, and platelet count. Additionally, the trial will analyze biological inflammatory markers, including IL2, IL6, IL10, IL12, GM-CSF, IFN gamma, and TNF alpha. The safety of ruxolitinib in critically ill HS patients will also be evaluated as part of the secondary endpoints.

The efficacy parameters will be measured and collected at specified timepoints, with the primary endpoint being assessed at day 7. The use of validated scales and laboratory tests will ensure the accuracy and reliability of the data collected. The analysis of these parameters will provide insights into the potential benefits of ruxolitinib in conjunction with standard care for patients with acquired HS in the intensive care unit (ICU).