Determining the Fingerprint of Endotoxin Tolerance

NCT ID: NCT06801873

Last Updated: 2025-02-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 110 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-27
• Study Completion Date: 2020-08-20

Brief Summary

An explorative, prospective study in 100 healthy volunteers who will be challenged with endotoxin twice to identify SNPs and transcripts that are associated with the degree of endotoxin tolerance

Detailed Description

Sepsis remains the number one cause of death in the ICU and incident rates are rising. The focus of sepsis research has shifted away from the hyperinflammatory phase towards the detrimental role of immunosuppression, a phenomenon known as "sepsis-induced immunoparalysis". Because to a high level of heterogeneity and a lack of appropriate biomarkers, a much-warranted precision medicine approach is not possible. The identification of novel biomarkers for sepsis-induced immunoparalysis is also hampered by the extreme heterogeneity of the patient population. Experimental human endotoxemia is a highly standardized, controlled and reproducible model, which results in the development of endotoxin tolerance, an immunologic state capturing many hallmarks of sepsis-induced immunoparalysis. This study aims to identify genomic and transcriptomics biomarkers of endotoxin tolerance. Ultimately, this will lead to the identification of novel biomarkers for the early identification of patients who are prone to develop sepsis-induced immunoparalysis, and facilitate precision medicine for this highly vulnerable group. Primarily, the investigators aim to identify SNPs and transcripts that are associated with the degree of endotoxin tolerance. To increase the chances of success, the genomic and transcriptomic data obtained in vivo will be integrated with data obtained by a previously performed in vitro study. Secondary objectives include SNPs and transcripts associated with the inflammatory response, and epigenomic changes, metabolites, and proteins associated with the inflammatory response and the degree of endotoxin tolerance. Furthermore, the investigators will explore the role of gender and sex hormones in the inflammatory response and endotoxin tolerance, as well as the relationship between ex vivo and in vivo inflammatory responses. This is an explorative, prospective study in 100 healthy volunteers who will be challenged with endotoxin twice. The study takes place at the research unit of the department of Intensive Care Medicine of the Radboud University Medical Center, Nijmegen.

Conditions

Endotoxemia; Sepsis; Systemic Inflammation; Immunosuppresion

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

LPS

All healthy subjects (male/female) are challenged with endotoxin (LPS) twice.

Group Type: EXPERIMENTAL

Endotoxin (E. coli O:113, Reference Endotoxin)

Intervention Type: OTHER

Intravenous administration of 1 ng/kg (total body weight) endotoxin (Lot no. 94332B1; List Biological Laboratories, Campbell, USA). This is a non-investigational product. Endotoxin is used as challenge agent to achieve a controlled inflammatory state.

Interventions

Endotoxin (E. coli O:113, Reference Endotoxin)

Intravenous administration of 1 ng/kg (total body weight) endotoxin (Lot no. 94332B1; List Biological Laboratories, Campbell, USA). This is a non-investigational product. Endotoxin is used as challenge agent to achieve a controlled inflammatory state.

Intervention Type: OTHER

Other Intervention Names

LPS; Lipopolysaccharide

Eligibility Criteria

Inclusion Criteria

• Written informed consent
• Age ≥18 and ≤35 yrs
• Male
• Healthy (as confirmed by medical history, examination, ECG, blood sampling)

Exclusion Criteria

• Use of any medication
• Smoking
• History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema)
• Known anaphylaxis or hypersensitivity to the non-investigational products or their excipients.
• History or signs of hematological disease (bone marrow dysfunction):
• Thrombocytopenia (<150*10^9/ml) or anemia (hemoglobin < 8.0 mmol/L)
• Abnormalities in leukocyte differential counts
• History, signs or symptoms of cardiovascular disease, in particular:
• Previous spontaneous vagal collapse
• History of atrial or ventricular arrhythmia
• Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complete left bundle branch block
• Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
• Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
• Renal impairment (defined as plasma creatinine >120 μmol/l)
• Liver enzyme abnormalities (above 2x the upper limit of normal)
• Medical history of any disease associated with immune deficiency
• CRP > 20 mg/L, WBC > 12x109/L or < 4 x109/L, or clinically significant acute illness, including infections, within 3 weeks before labeling day
• Previous (participation in a study with) LPS administration
• Any vaccination within 3 months prior to labeling day
• Participation in a drug trial or donation of blood 3 months prior to labeling day
• Recent hospital admission or surgery with general anesthesia (<3 months to labeling day)
• Use of recreational drugs within 21 days prior to labeling day
• Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.
• Unwillingness to be informed about potential chance findings

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Intensive Care Medicine Deparmtent

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

Other Identifiers

2018-4983

Identifier Type: OTHER

Identifier Source: secondary_id

NL68166.091.18

Identifier Type: -

Identifier Source: org_study_id