Emapalumab Treatment For Anticipated Clinical Benefit In Sepsis Driven By The Interferon-Gamma Endotype (The EMBRACE Trial)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 75
- 试验地点
- 24
- 主要终点
- Decrease of SOFA score by the end-of-treatment
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Placebo
Standard-of-care (SoC) treatment and placebo drug.
干预措施: Placebo (Drug)
Emapalumab Group 1
SoC treatment and a low dose of emapalumab.
干预措施: Emapalumab-Izsg (Drug)
Emapalumab Group 2
SoC treatment and a high dose of emapalumab.
干预措施: Emapalumab-Izsg (Drug)
结局指标
主要结局
Decrease of SOFA score by the end-of-treatment
时间窗: From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.
The study primary endpoint is the decrease of SOFA score by the end-of-treatment (EOT). This is defined as either a) at least 1.4 points decrease of mean SOFA score calculated between days 1 and EOT from SOFA score of day 0; OR b) at least 2 points decrease of SOFA at EOT from day 0.
次要结局
- The rate of serious TEAEs and non-serious TEAEs(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.)
- The number of doses required in each group to achieve the SOFA score response by the EOT.(From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.)
- The change of the SOFA score from day 0 until day 7(From enrollment (day 0) to 8 days after enrollment (day 7).)
- 28-day mortality(From enrollment to 28 days after enrollment.)
- The change of the SOFA score from 0 until day 28(From enrollment to 28 days after enrollment.)
- The change of the SOFA score from 0 until EOT(From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.)
- The pharmacokinetics of emapalumab(From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.)
- The need to stop the study drug due to drop of the number of HLA-DR receptors on CD14-monocytes.(From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.)
- The circulating concentrations of IL-6, ferritin, IFNγ and CXCL9 over the days of treatment(From enrollment to the end of treatment of the study drug for each of the study participants, ranging from 2 to 29 days.)