The Effects of Human Endotoxemia on Functional Capacity of Hematopoietic Stem and Progenitor Cells (LPS-BM)

October 4, 2022 updated by: Radboud University Medical Center
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
12

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500 HB
        • Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 31 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: LPS group
Healthy male volunteers that will receive an intravenous administration of LPS (2ng/kg) twice.
Drug: LPS
This is a non-investigational product. LPS is used as challenge agent to achieve a controlled inflammatory state.
Other Names:
  • Lipopolysaccharide (LPS from Escherichia coli Type O11)
  • Endotoxin
Placebo Comparator: Placebo group
Healthy male volunteers that will receive an intravenous administration of placebo (NaCl 0.9%).
Drug: Placebo
Injection of NaCl 0.9%.
Other Names:
  • NaCl

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in function and transcriptional pathways
Time Frame: 15 days
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in (Genome-wide) chromatin accessibility
Time Frame: 15 days
The change in epigenomic profile (chromatin accessibility) of hematopoietic progenitor cells and blood leukocytes (using single cell ATACseq) following human endotoxemia.
15 days
Change in cellular metabolism
Time Frame: 15 days
The change in cellular metabolism of hematopoietic progenitor cells and blood leukocytes (e.g. using Seahorse analyzer, CYTOF) following human endotoxemia.
15 days
Change in macrophage activity in the brain
Time Frame: 15 days
To changes in tissue resident macrophages activity in the brain (assessed using 18F-DPA-714 labeling and PET examinations) following human endotoxemia.
15 days
Life-span of blood leukocytes during homeostasis
Time Frame: 8 days
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).
8 days
Life-span of blood leukocytes during endotoxemia
Time Frame: 8 days
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).
8 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Radboud University Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
UMC Utrecht

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 5, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 28, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 28, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 28, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 4, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 6, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 6, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 4, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL61136.091.17
  • 2017-3337 (Other Identifier: METC Oost Nederland (Ethical Board))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD 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

IPD Sharing Supporting Information Type

  • Statistical Analysis Plan (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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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