Comparison of Early Versus Delayed Etoposide Initiation in Severe Sporadic Hemophagocytic Lymphohistiocytosis in Intensive Care: A Randomized Trial

The primary objective of this study is to compare the effect on the evolution of **organ failures** of two initiation strategies of **etoposide** in severe **hemophagocytic lymphohistiocytosis (HLH)** in intensive care. This involves an early strategy where etoposide is initiated within 12 hours after inclusion, and a delayed strategy where this treatment is initiated only in case of unfavorable evolution after 48 hours. The clinical relevance of this objective lies in optimizing treatment timing to improve patient outcomes in severe HLH cases, potentially reducing organ failure and improving survival rates.

Secondary objectives include evaluating various clinical outcomes and treatment parameters: - **Survival** - **Duration of mechanical ventilation** - **Duration of catecholamine therapy** - **Need for renal replacement therapy** - **Length of stay in the intensive care unit** - **Length of hospital stay** - **Proportion of patients receiving etoposide treatment** - **Cumulative dose of etoposide** - **Time to initiation of etoposide treatment** - **Number of patients receiving another immunosuppressive treatment** - **Normalization of HLH-related biological abnormalities** - **Evolution of the HScore (probability score for HLH)** - **Potential side effects attributable to etoposide, such as healthcare-associated infections, incidence of neutropenia, and bleeding events** - **Evolution of the SOFA score and modified SOFA score**

The clinical trial involves participants diagnosed with **hemophagocytic lymphohistiocytosis (HLH)**, focusing on adult patients who have been admitted to an intensive care unit. The study population includes both male and female subjects, with an age range that encompasses young adults to middle-aged individuals. Participants are required to have a confirmed diagnosis of HLH, characterized by the presence of five or more Henter criteria, and must be experiencing their first episode of the condition. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include the presence of one or more organ failures, such as circulatory, respiratory, renal, or neurological complications. Lifestyle factors such as diet, physical activity, or habits are not specified as part of the selection process. The trial aims to evaluate the impact of two initiation strategies of etoposide on the progression of organ failures in severe HLH cases.

The clinical trial is designed to evaluate the efficacy of two initiation strategies of **etoposide** in patients with severe **hemophagocytic lymphohistiocytosis (HLH)** admitted to intensive care. This is a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial will commence on January 15, 2025, and is expected to conclude by January 15, 2028. Participants will be randomly assigned to either an early initiation group, where etoposide is administered within 12 hours of inclusion, or a delayed initiation group, where treatment begins only if there is an unfavorable evolution after 48 hours.

The study involves several key visits, starting with the inclusion (screening) visit, where eligibility is confirmed based on criteria such as adult age, confirmed diagnosis of HLH, and admission to intensive care with organ failures. Follow-up visits will occur regularly to monitor the progression of organ failures using the modified Sequential Organ Failure Assessment (SOFA) score, and to assess secondary endpoints such as time to death, ventilator-free days, and length of hospital stay. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced by the participants.

Participant involvement is expected to last up to 60 days, with the primary endpoint being the occurrence of an event defined as the onset or worsening of organ failures. Conditions that may lead to early termination from the study include significant adverse reactions to etoposide or withdrawal of consent by the participant. The trial aims to provide valuable insights into the optimal timing of etoposide initiation in managing severe HLH, potentially influencing future treatment protocols.

The clinical trial involves the use of **etoposide**, a chemotherapeutic agent, as the experimental medication. Etoposide is administered in the form of an intravenous (IV) injection or infusion, with a pharmaceutical form designated as PHF675. The dosing regimen for etoposide is calculated based on body surface area, with a maximum daily dose of 100 mg/m² and a total maximum dose of 450 mg over the treatment period. The maximum treatment duration is set at 7 days. The trial aims to evaluate two initiation strategies of etoposide in patients with severe sporadic hemophagocytic lymphohistiocytosis (HLH) in intensive care settings. The early strategy involves initiating etoposide within 12 hours of inclusion, while the delayed strategy commences treatment only if there is an unfavorable evolution after 48 hours.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of etoposide under the outlined conditions. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial does not involve any pediatric formulations, and etoposide is not classified as an orphan drug for this study. The chemical origin of the active substance is confirmed, and the trial is conducted under the authorization status of the product as per regulatory requirements.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is the occurrence of an event defined as the onset or worsening of organ failures, evaluated using the modified Sequential Organ Failure Assessment (SOFA) score, excluding the hematologic component. An event is characterized by an increase of at least 1 point for at least two organ systems compared to Day 0. In the delayed treatment arm, the use of rescue **etoposide** treatment or secondary aggravation during follow-up will also be considered an event.

Secondary endpoints include a variety of measures: time to death after inclusion with a maximum follow-up of 60 days, number of ventilator-free and catecholamine-free days between inclusion and Day 14, and the proportion of patients receiving at least one session of renal replacement therapy within the same timeframe. Additional secondary endpoints are the length of stay in the intensive care unit and hospital, the proportion of patients receiving a dose of **etoposide**, and the cumulative dose of **etoposide** over the first 14 days. The trial will also measure the number of days between inclusion and initiation of **etoposide** treatment, the number of patients receiving other immunosuppressive treatments during the intensive care unit stay up to Day 14, and the time from inclusion to normalization of fibrinogen, decrease in ferritin, and decrease in triglycerides during the intensive care unit stay up to Day 14. Other secondary endpoints include the HScore at Days 2, 7, and 14, the proportion of patients experiencing healthcare-associated infections, acquired neutropenia, and post-inclusion bleeding events requiring transfusion or surgical intervention, as well as the Delta SOFA at Days 2 and 5, and the maximum SOFA score.