Clinical trial NCT06694701: Emapalumab Treatment For Anticipated Clinical Benefit In Sepsis Driven By The Interferon-Gamma Endotype (The EMBRACE Trial)
Official title: Emapalumab Treatment For Anticipated Clinical Benefit In Sepsis Driven By The Interferon-Gamma Endotype (The EMBRACE Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Sepsis
Keywords: Severe infections
IFNγ
IFNγ-Drive Sepsis
emapalumab
interferon-gamma
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2024-11-19
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: EMBRACE is a double-blind, randomized, placebo-controlled, phase IIa study that will be conducted in multiple Intensive Care Units (ICUs) and departments of Internal Medicine across Greece. It aims to investigate if treatment with emapalumab, a monoclonal antibody which blocks IFNγ, may improve the outcome of patients with sepsis driven by the IDS (endotype of IFNγ-driven sepsis) endotype. EMBRACE also aims to identify the best dosing regimen of emapalumab for the management of IDS.

Detailed description: The EMBRACE trial aims to generate proof-of-concept if treatment with emapalumab, a monoclonal antibody which blocks IFNγ signaling, may improve the outcome of patients with sepsis driven by the IDS endotype. In EMBRACE, two different dose regimens of emapalumab are administered in order to: a) investigate which dose regimen may provide most of efficacy in the decrease of SOFA score, a new endpoint for sepsis suggested already by others; b) investigate which dose regimen better attains the pharmacodynamic goal of emapalumab defined as the decrease of blood CXCL9; and c) compare the efficacy of the two dose regimens with placebo treated patients.

Eligibility criteria: Inclusion Criteria:

* Provide written informed consent
* Adults (≥18 years) of male or female sex
* Diagnosis of community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), intrabdominal infection (IAI), acute pyelonephritis (AP), primary bloodstream infection (BSI) and viral respiratory infections.
* Sepsis defined by the Sepsis-3 definitions. This is defined as any new infection which is accompanied by an increase of the total baseline SOFA score by at least 2 points. The total baseline SOFA score is calculated by the medical comorbidities and by the evaluation of clinical variables before the sepsis episode in the case of hospital-acquired sepsis. In the case of patients with unknown baseline SOFA score, sepsis is defined as any new infection accompanied by total SOFA score 2 or more.
* Willingness to use effective contraceptive methods during the period from the start of the study drug to 6 months after the administration of the last dose of the study drug, in patients of reproductive age.
* Serological documentation of IDS defined as detectable blood IFNγ and CXCL9 more than 2,200 pg/ml. IFNγ and CXCL9 are measured in the central study lab by an enzyme immunosorbent assay.
* Absence of sepsis-induced immunoparalysis (SII). This is defined as ≥8000 of HLA-DR receptors on CD45/CD14-monocytes measured by flow-cytometry in the central lab using the BD™ fluorescence assay9.

Exclusion Criteria:

* Body weight more than 104 kg
* Intake of any other biological during the last 30 days prior screening except for the intake of anakinra or tocilizumab for patients with active infection by SARS-CoV-2
* Intake of any Janus kinase inhibitors during the last 30 days prior screening except for the intake of baricitinib for patients with active infection by SARS-CoV-2
* Known active infection by Mycobacterium tuberculosis or other mycobacteria. These patients may be enrolled in the trial if treatment against infection by Mycobacterium tuberculosis or other mycobacteria has been initiated
* Known active infection by VZV (varicella zoster virus) or by Histoplasma capsulatum or by Leishmania spp. These patients may be enrolled in the trial if treatment against infection by VZV or Histoplasma capsulatum has been initiated
* Known active infection by the hepatitis B virus, by the hepatitis C virus and by cytomegalovirus
* Vaccination the last 12 weeks before screening with BCG vaccine
* Vaccination with any live or attenuated live vaccine (other than BCG) the last 12 weeks before screening
* Known allergy or hypersensitivity reactions to emapalumab
* Patients living with the human immunodeficiency virus (HIV)
* Patients with stage IV solid or hematologic malignancy
* Patients with neutropenia (less than 1,000 neutrophils/mm3)
* Patients transplanted for solid organ or stem cells
* Pregnancy or lactation
* Participation in any other interventional trial the last 28 days prior to day 1

Primary outcomes:
measure: Decrease of SOFA score by the end-of-treatment
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
Secondary outcomes:
measure: The rate of serious TEAEs and non-serious TEAEs
timeFrame: From enrollment to the end of observation of each of the study participants, which is 120 days plus or minus 3 days, after each participant's enrollment.
measure: The number of doses required in each group to achieve the SOFA score response by the EOT.
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The change of the SOFA score from day 0 until day 7
timeFrame: From enrollment (day 0) to 8 days after enrollment (day 7).
measure: 28-day mortality
timeFrame: From enrollment to 28 days after enrollment.
measure: The change of the SOFA score from 0 until day 28
timeFrame: From enrollment to 28 days after enrollment.
measure: The change of the SOFA score from 0 until EOT
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The pharmacokinetics of emapalumab
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The need to stop the study drug due to drop of the number of HLA-DR receptors on CD14-monocytes.
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The circulating concentrations of IL-6, ferritin, IFNγ and CXCL9 over the days of treatment
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
Other outcomes:
measure: Comparison between the three groups of treatment for the proteomic profile over treatment
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The comparisons between the three groups of treatment for the change of the transcriptomic profile over treatment
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The diagnostic performance of the point-of-care SepsisLoop for SII compared to the absolute count of HLA-DR receptor on CD45/CD14-monocytes.
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The clinical data and bedside biomarker levels at screening for the potential development of a diagnostic tool classifying the study population into IDS
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
measure: The prognostic biomarker levels at screening classifying the Sepsis population in different subgroups
timeFrame: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
Locations:
city: Elefsina
country: Greece
facility: 1st Department of Internal Medicine, Thriasio Elefsis General Hospital
state: Attiki
city: Kifissia
country: Greece
facility: Clinic of Intensive Care and Pulmonary Diseases, Aghioi Anargyroi Kifissia General Oncologic Hospital
state: Attiki
city: Heraklion
country: Greece
facility: Intensive Care Unit, Herakleion University General Hospital
state: Crete
city: Alexandroupolis
country: Greece
facility: Intensive Care Unit, Alexandroupolis University General Hospital
city: Athens
country: Greece
facility: 3rd University Department of Internal Medicine, Sotiria Chest Diseases Athens General Hospital
city: Athens
country: Greece
facility: 4th Department of Internal Medicine, ATTIKON University General Hospital
city: Athens
country: Greece
facility: Intensive Care Unit I, KAT Attica General Hospital
city: Athens
country: Greece
facility: Intensive Care Unit of 1st University Department Respiratory Medicine, Sotiria Chest Diseases Athens General Hospital
city: Athens
country: Greece
facility: Intensive Care Unit of Center for Respiratory Failure, Sotiria Chest Diseases Athens General Hospital
city: Athens
country: Greece
facility: Intensive Care Unit, Asklipieio Voulas General Hospital
city: Athens
country: Greece
facility: Intensive Care Unit, Ippokrateio Athens General Hospital
city: Athens
country: Greece
facility: Intensive Care Unit, Korgialeneio-Benakeio HRC Athens General Hospital
city: Athens
country: Greece
facility: Intensive Care Unit, Laiko Athens General Hospital
city: Athens
country: Greece
facility: New Multivalent Intensive Care Unit, Sotiria Chest Diseases Athens General Hospital
city: Athens
country: Greece
facility: Ηigh Dependency Unit of Department of Clinical Therapeutics, Alexandra Athens General Hospital
city: Patras
country: Greece
facility: Intensive Care Unit, Patras University General Hospital
city: Thessaloniki
country: Greece
facility: 1st Intensive Care Unit, G. Papanikolaou Thessaloniki General Hospital
city: Thessaloniki
country: Greece
facility: Department of Anesthesiology and Intensive Care, AHEPA Thessaloniki University General Hospital
city: Thessaloniki
country: Greece
facility: Intensive Care Unit, 424 General Military Training Hospital
city: Thessaloniki
country: Greece
facility: Intensive Care Unit, Aghios Dimitrios Thessaloniki General Hospital
city: Thessaloniki
country: Greece
facility: Intensive Care Unit, G. Gennimatas Thessaloniki General Hospital
city: Thessaloniki
country: Greece
facility: Intensive Care Unit, Ippokrateio Thessaloniki General Hospital
city: Thessaloniki
country: Greece
facility: Intensive Care Unit, Papageorgiou Thessaloniki General Hospital
city: Thessaloniki
country: Greece
facility: Intensive Care Unit, Theageneio Thessaloniki Cancer Hospital
Study officials:
affiliation: Hellenic Institute for the Studies of Sepsis
name: Evangelos Giamarellos-Bourboulis
role: STUDY_CHAIR
References: