Back to resultsThe Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells (LPS-BM)
Primary Purpose
Sepsis, Endotoxemia, Immunosuppression
Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
LPS
Placebo
Sponsored by
About this trial
This is an interventional other trial for Sepsis, Endotoxemia, Immunosuppression focused on measuring Sepsis, immunosuppression, systemic inflammation, human endotoxemia, bone marrow stem and progenitor cells, myelopoiesis, monocytes, transciptomics
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.
Sites / Locations
- Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
LPS group
Placebo group
Arm Description
Healthy male volunteers that will receive an intravenous administration of LPS (2ng/kg) twice.
Healthy male volunteers that will receive an intravenous administration of placebo (NaCl 0.9%).
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Change in (Genome-wide) chromatin accessibility
The change in epigenomic profile (chromatin accessibility) of hematopoietic progenitor cells and blood leukocytes (using single cell ATACseq) following human endotoxemia.
Change in cellular metabolism
The change in cellular metabolism of hematopoietic progenitor cells and blood leukocytes (e.g. using Seahorse analyzer, CYTOF) following human endotoxemia.
Change in macrophage activity in the brain
To changes in tissue resident macrophages activity in the brain (assessed using 18F-DPA-714 labeling and PET examinations) following human endotoxemia.
Life-span of blood leukocytes during homeostasis
To assessment of the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans at homeostasis (using Deuterium labeling).
Life-span of blood leukocytes during endotoxemia
To determine the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans during human endotoxemia (using Deuterium labeling).
Full Information
NCT ID
NCT05570643
First Posted
September 28, 2022
Last Updated
October 4, 2022
Sponsor
Radboud University Medical Center
Collaborators
UMC Utrecht
1. Study Identification
Unique Protocol Identification Number
NCT05570643
Brief Title
The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells
Acronym
LPS-BM
Official Title
The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells
Study Type
Interventional
2. Study Status
Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
January 5, 2018 (Actual)
Primary Completion Date
June 28, 2018 (Actual)
Study Completion Date
June 28, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
Collaborators
UMC Utrecht
4. Oversight
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.
Yes
Data Monitoring Committee
Yes
5. Study Description
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.
Detailed Description
In the present study, we want to further elucidate the mechanisms behind systemic inflammation and endotoxin tolerance in vivo in humans by focusing on functional changes in hematopoietic stem and progenitor cells. Healthy male volunteers will be challenged with endotoxin to evoke a transient systemic inflammatory response. To evaluate the responses over time, blood and bone marrow aspirates will be collected at multiple timepoints. To comprehensively investigate underlying mechanisms behind functional changes, we will use state-of-the-art systems biology techniques, including single cell transcriptomics, epigenetics (e..g. scATACseq), and metabolomic. As such, this study will yield a comprehensive insight into inflammatory signaling in the different compartments of the body and will thereby improve our understanding of systemic inflammation, endotoxin tolerance,and sepsis, possibly revealing new therapeutic targets to improve sepsis outcome.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sepsis, Endotoxemia, Immunosuppression
Keywords
Sepsis, immunosuppression, systemic inflammation, human endotoxemia, bone marrow stem and progenitor cells, myelopoiesis, monocytes, transciptomics
7. Study Design
Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
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%).
Masking
None (Open Label)
Masking Description
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.
Allocation
Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
LPS group
Arm Type
Experimental
Arm Description
Healthy male volunteers that will receive an intravenous administration of LPS (2ng/kg) twice.
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
Healthy male volunteers that will receive an intravenous administration of placebo (NaCl 0.9%).
Intervention Type
Drug
Intervention Name(s)
LPS
Other Intervention Name(s)
Lipopolysaccharide (LPS from Escherichia coli Type O11), Endotoxin
Intervention Description
This is a non-investigational product. LPS is used as challenge agent to achieve a controlled inflammatory state.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
NaCl
Intervention Description
Injection of NaCl 0.9%.
Primary Outcome Measure Information:
Title
Change in function and transcriptional pathways
Description
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.
Time Frame
15 days
Secondary Outcome Measure Information:
Title
Change in (Genome-wide) chromatin accessibility
Description
The change in epigenomic profile (chromatin accessibility) of hematopoietic progenitor cells and blood leukocytes (using single cell ATACseq) following human endotoxemia.
Time Frame
15 days
Title
Change in cellular metabolism
Description
The change in cellular metabolism of hematopoietic progenitor cells and blood leukocytes (e.g. using Seahorse analyzer, CYTOF) following human endotoxemia.
Time Frame
15 days
Title
Change in macrophage activity in the brain
Description
To changes in tissue resident macrophages activity in the brain (assessed using 18F-DPA-714 labeling and PET examinations) following human endotoxemia.
Time Frame
15 days
Title
Life-span of blood leukocytes during homeostasis
Description
To assessment of the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans at homeostasis (using Deuterium labeling).
Time Frame
8 days
Title
Life-span of blood leukocytes during endotoxemia
Description
To determine the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans during human endotoxemia (using Deuterium labeling).
Time Frame
8 days
10. Eligibility
Sex
Male
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Facility Information:
Facility Name
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6500 HB
Country
Netherlands
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Single cell transcriptional/gene expression data will be shared.
IPD Sharing 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
Learn more about this trial
The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells
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