Evaluation of Emapalumab in Patients with Interferon-Gamma Driven Sepsis: A Randomized, Placebo-Controlled Trial

The primary objective of the EMBRACE trial is to evaluate the efficacy of **emapalumab**, a monoclonal antibody that neutralizes interferon-gamma (IFNγ) activity, in improving outcomes for patients with sepsis driven by the IFNγ endotype, known as IFNγ-Drive Sepsis (IDS). This endotype is present in approximately 20% of sepsis patients and is associated with a 28-day mortality rate of 40 to 43%, independent of infection type, comorbidities, organ dysfunctions, and isolated pathogens. The study aims to determine if emapalumab can reduce this mortality risk, thereby offering a potential therapeutic benefit for this specific patient subgroup. Additionally, the trial seeks to identify the optimal dosing regimen of emapalumab for managing IDS.

The clinical trial focuses on patients diagnosed with **sepsis** as defined by the Sepsis-3 criteria. The study population includes adults aged 18 years and older, encompassing both male and female participants. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on their diagnosis of community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, intra-abdominal infection, acute pyelonephritis, primary bloodstream infection, or viral respiratory infections. Additionally, participants must have serological documentation of the IDS endotype, characterized by detectable blood levels of IFNγ and CXCL9 exceeding 2,200 pg/ml. The trial includes individuals who are willing to use effective contraceptive methods during and after the study period, and excludes those with sepsis-induced immunoparalysis. The study population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **emapalumab**, a monoclonal antibody, in treating sepsis driven by the interferon-gamma endotype (IDS). This is a **randomized**, **double-blind**, and **controlled** trial, with a primary objective to assess whether emapalumab can improve outcomes in patients with IDS. The trial is set to commence recruitment in September 2024 and is expected to conclude by September 2026. The study will involve adult participants diagnosed with sepsis as defined by the Sepsis-3 criteria, with serological documentation of IDS. Participants will be randomly assigned to receive either emapalumab or a placebo, administered via intravenous infusion.

The trial will consist of several key visits, starting with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria, such as age, diagnosis, and serological markers. Following the screening, participants will undergo regular follow-up visits to monitor their health status and response to the treatment. The primary endpoint is the decrease in the Sequential Organ Failure Assessment (SOFA) score by the end of treatment, which is defined as either a significant reduction in the mean SOFA score or a decrease of at least two points from baseline. The end-of-study visit will occur at the conclusion of the treatment period, which is a maximum of 28 days.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as necessary to assess outcomes. Conditions that may lead to early termination from the study include the development of sepsis-induced immunoparalysis or failure to meet the primary endpoint criteria. The trial aims to identify the optimal dosing regimen of emapalumab for managing IDS, with the ultimate goal of reducing the high mortality rate associated with this specific endotype of sepsis.

The clinical trial involves the administration of **emapalumab**, a monoclonal antibody designed to neutralize **interferon-gamma** (IFNγ) activity. Emapalumab is provided as a **solution for injection** and is administered via **intravenous infusion**. The dosing regimen for emapalumab is calculated based on body weight, with a maximum daily dose of 10 mg/kg and a total maximum dose of 37 mg/kg over the treatment period. The treatment duration is set for a maximum of 28 days. Emapalumab is not formulated for pediatric use and is designated as an orphan drug under the identifier EU/3/10/749.

In addition to the experimental treatment, the study utilizes **Sodium Chloride Injection** as a comparator. This solution, with a concentration of 0.9% w/v, is also administered via **intravenous infusion**. The maximum daily volume of sodium chloride administered is 250 ml, with a total maximum volume of 2250 ml over the 28-day treatment period. Sodium chloride serves as a standard **inorganic compound** and is not designated as an orphan drug. The pharmaceutical form of sodium chloride is a **solution for injection**, and it is not specifically formulated for pediatric use.

Efficacy in the clinical trial titled "EMAPALUMAB TREATMENT FOR ANTICIPATED CLINICAL BENEFIT IN SEPSIS DRIVEN BY THE INTERFERON-GAMMA ENDOTYPE (THE EMBRACE TRIAL)" will be assessed primarily through the evaluation of the Sequential Organ Failure Assessment (SOFA) score. The primary endpoint is defined as a decrease in the SOFA score by the end-of-treatment (EOT). This is quantified as either a reduction of at least 1.4 points in the mean SOFA score calculated between days 1 and EOT from the SOFA score of day 0, or a decrease of at least 2 points in the SOFA score at EOT from day 0. Patients who do not survive until the EOT are considered as not meeting the primary endpoint. The EOT is determined as the day the study drug treatment concludes for each participant, with the SOFA score decrease being evaluated on day 28 for those requiring dosing by day 27.