Emapalumab Treatment for Anticipated Clinical Benefit in Sepsis Driven by the Interferon-Gamma Endotype (the Embrace Trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hellenic Institute For The Study Of Sepsis

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02], Diseases [C] - Bacterial Infections and Mycoses [C01], Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

12 Mar 2025 → ongoing

Decision date (initial)

2024-10-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Dose response, Pharmacogenomic, Pharmacokinetic

In a recent analysis of 5,503 patients with sepsis meeting the Sepsis-3 definitions and coming from Germany, Greece and Italy randomized into one discovery set and one validation set, it was found that one endotype driven by IFNγ (interferon-gamma) (IFNγ-Drive Sepsis, IDS) is prevailing in almost 20% of patients. The presence of IDS is an independent risk for 28-day mortality irrespective of the type of infection, comorbidities, organ dysfunctions and the isolated pathogen. 28-day mortality is 40 to 43%. The EMBRACE trial investigates if treatment with emapalumab, a monoclonal antibody which neutralizes IFNγ activity, may improve the outcome of patients with sepsis driven by the IDS endotype. EMBRACE also aims to identify the best dosing regimen of emapalumab for the management of IDS.

Conditions and MedDRA coding

SEPSIS

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Provide written informed consent
2. Adults (≥18 years) of male or female sex
3. 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.
4. 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.
5. 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.
6. 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
7. 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 assay.

Exclusion criteria 15

1. 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
2. Vaccination with any live or attenuated live vaccine (other than BCG) the last 12 weeks before screening
3. Known allergy or hypersensitivity reactions to emapalumab
4. Patients living with the human immunodeficiency virus (HIV)
5. Patients with stage IV solid or hematologic malignancy
6. Known active infection by the hepatitis B virus, by the hepatitis C virus and by cytomegalovirus
7. Patients with neutropenia (less than 1,000 neutrophils/mm3)
8. Patients transplanted for solid organ or stem cells
9. Pregnancy or lactation
10. Participation in any other interventional trial the last 28 days prior to day 0
11. 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
12. 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
13. 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.
14. Vaccination the last 12 weeks before screening with BCG vaccine
15. Body weight more than 125 kg

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. Patients dying before the EOT are considered not meeting the primary endpoint. EOT is defined as the day of end of treatment of the study drug for each of the study participants. For patients requiring dosing by day 27, the decrease of the SOFA score is evaluated on day 28.

Secondary endpoints 2

1. The number of doses required in each group to achieve the SOFA score response by the EOT
2. 28-day mortality

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hellenic Institute For The Study Of Sepsis

Sponsor organisation

Hellenic Institute For The Study Of Sepsis

Address

Michalakopoulou 88

City

Athens

Postcode

115 28

Country

Greece

Scientific contact point

Organisation

Hellenic Institute For The Study Of Sepsis

Contact name

President of the Board

Public contact point

Organisation

Hellenic Institute For The Study Of Sepsis

Contact name

President of the Board

Sponsor responsibilities

Article 77 compliance

Hellenic Institute For The Study Of Sepsis

Contact point sponsor

Hellenic Institute For The Study Of Sepsis

Article 77 implementation

Hellenic Institute For The Study Of Sepsis

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications