The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells

NCT05570643 | Completed DMC

• 2 other identifiers: NL61136.091.172017-3337
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

We will investigate whether human endotoxemia induces changes in human bone marrow cells and their downstream effector cells. To comprehensively investigate underlying mechanisms behind functional and transcriptional changes in these cell types, we will use state-of-the-art systems biology techniques, including single cell transcriptomics (epi)genetics, and metabolomics.

Conditions

Sepsis, Endotoxemia, Immunosuppression

Keywords

Sepsis, immunosuppression, systemic inflammation, human endotoxemia, bone marrow stem and progenitor cells, myelopoiesis, monocytes, transciptomics

Outcome Measures

Primary Outcomes (1)

• Change in function and transcriptional pathways

  The change in function and transcriptional pathways (gene expression) of hematopoietic progenitor cells and blood leukocytes (using various functional assays and single cell RNAseq) following human endotoxemia.

  15 days

Secondary Outcomes (5)

• Change in (Genome-wide) chromatin accessibility

  15 days

• Change in cellular metabolism

  15 days

• Change in macrophage activity in the brain

  15 days

• Life-span of blood leukocytes during homeostasis

  8 days

• Life-span of blood leukocytes during endotoxemia

  8 days

Study Arms (2)

LPS group

EXPERIMENTAL

Healthy male volunteers that will receive an intravenous administration of LPS (2ng/kg) twice.

Drug: LPS

Placebo group

PLACEBO COMPARATOR

Healthy male volunteers that will receive an intravenous administration of placebo (NaCl 0.9%).

Drug: Placebo

Interventions

LPS DRUG

This is a non-investigational product. LPS is used as challenge agent to achieve a controlled inflammatory state.

Also known as: Lipopolysaccharide (LPS from Escherichia coli Type O11), Endotoxin

LPS group

Placebo DRUG

Injection of NaCl 0.9%.

Also known as: NaCl

Placebo group

Eligibility Criteria

• Age: 18 Years - 35 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Radboud University Medical Center: lead
• UMC Utrecht: collaborator

Study Sites (1)

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

MeSH Terms

Conditions

Sepsis; Endotoxemia

Interventions

Lipopolysaccharides; Endotoxins

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bacteremia; Toxemia

Intervention Hierarchy (Ancestors)

Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens; Biological Factors; Bacterial Toxins; Toxins, Biological

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: LPS is a non-investigational product and will only be used as a challenge agent to induce systemic inflammation. Since the effects op LPS-induced systemic inflammation are profound, no masking will be required.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: An pilot study to explore the effects of a LPS-challenge on functional capacity and gene expression of human stem and hematopoietic progenitor cells and blood leukocytes. Subjects will be allocated to a LPS group (n=8 healthy volunteers) that will be challenged with endotoxin twice, or to a placebo group (n=4) who will undergo the same study procedures but receive a placebo challenge (NaCl 0.9%).

Study Record Dates

• First Submitted: September 28, 2022
• First Posted: October 6, 2022
• Study Start: January 5, 2018
• Primary Completion: June 28, 2018
• Study Completion: June 28, 2018
• Last Updated: October 6, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, ANALYTIC CODE
• Access Criteria: Bulk RNA-seq and scRNA-seq data for this study can be downloaded from GEO database (https://www.ncbi.nlm.nih.gov/geo/) with the accession number: GSE212093. Codes used to perform the data analysis related to this study are available at https://github.com/fkeramati/LPS-SI

Locations

NL (1)