Determining the Fingerprint of Endotoxin Tolerance (100LPS)

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

Study Overview

• Status: Completed
• Conditions: Sepsis; Endotoxemia; Systemic Inflammation; Immunosuppresion
• Intervention / Treatment: Other: Endotoxin (E. coli O:113, Reference Endotoxin)

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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Intensive Care Medicine Deparmtent

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LPS; All healthy subjects (male/female) are challenged with endotoxin (LPS) twice.	Other: 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.; Other Names: LPS; Lipopolysaccharide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SNPs	Single-nucleotide polymorphisms (SNPs)	1 hour before the first LPS administration
Monocyte transcriptomes	Genome-wide differential mRNA expression of monocytes obtained before and 4 hours after the first endotoxin challenge	1 hour before and 4 hours after the first LPS administration
Endotoxin tolerance	Difference in plasma cytokine concentration profiles upon the first and second endotoxin challenge (including but not limited to TNFα, IL-6, IL-8, and IL-10 all in pg/mL).	From 1 hour before the first LPS challenge until 6 hours after the second LPS challenge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gender		Enrollment
Sex hormones	Blood concentrations of estradiol, estrone and testosterone (in pmol/L) and testosteron (in nmol/L)	1 hour before the first LPS administration

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2019
• Primary Completion (Actual): February 20, 2020
• Study Completion (Actual): August 20, 2020

Study Registration Dates

• First Submitted: January 10, 2025
• First Submitted That Met QC Criteria: January 24, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Immunosuppression; Systemic inflammation; Sepsis; Genomics; Transcriptomics; endotoxin tolerance; Human endotoxemia
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Bacteremia; Toxemia; Inflammation; Endotoxemia
• Other Study ID Numbers: NL68166.091.18; 2018-4983 (Other Identifier: METC Oost Nederland (Ethical Review Board))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Omics data such as SNP/transcriptional/metabolomics data will be shared.
• IPD Sharing Access Criteria: RNA-seq data for this study will become available on GEO database.
• IPD Sharing Supporting Information Type: SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No