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Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α

Primary Purpose

Hypoxia, Normoxia, Hyperoxia

Status
Completed
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
Lipopolysaccharide
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoxia focused on measuring Oxygen, Hypoxia, Hyperoxia, Inflammation, Innate immunity

Eligibility Criteria

18 Years - 35 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Written informed consent to participate in this trial
  • Male subjects aged 18 to 35 years inclusive
  • Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory parameters

Exclusion Criteria:

  • Use of any medication(including herbal remedies and vitamin/mineral supplements) or recreational drugs within 7 days prior to profiling day
  • Smoking
  • Use of caffeine, or alcohol or within 1 day prior to profiling day
  • Previous participation in a trial where LPS was administered
  • Surgery or trauma with significant blood loss or blood donation within 3 months prior to profiling day
  • Participation in another clinical trial within 3 months prior to profiling day.
  • History, signs or symptoms of cardiovascular disease
  • An implant that in the opinion of the investigator may make invasive procedures risky for the subject due to the increased risks associated with a possible infection.
  • Subject has an implanted active cardiac device (ICD, IPG and/or CRT) Implanted active neurostimulation device
  • Subject has internal jugular vein that cannot be accessed
  • History of vaso-vagal collapse or of orthostatic hypotension
  • History of atrial or ventricular arrhythmia
  • Resting pulse rate ≤45 or ≥100 beats / min
  • Hypertension (RR systolic >160 or RR diastolic >90)
  • Hypotension (RR systolic <100 or RR diastolic <50)
  • Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block
  • Subject is diagnosed with epilepsy or history of seizures
  • Renal impairment: plasma creatinine >120 μmol/L
  • Liver function abnormality: alkaline phosphatase>230 U/L and/or ALT>90 U/L
  • Coagulation abnormalities: APTT or PT > 1.5 times the reference range
  • History of asthma
  • Immuno-deficiency CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 2 weeks before profiling day
  • Known or suspected of not being able to comply with the trial protocol - 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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Hypoxia

Hyperoxia

Normoxia

Arm Description

Subjects will be breathing an individualized mix of nitrogen and room air titrated to an oxygen saturation of 80-85%.

Subjects will be breathing 100% of oxygen

Subjects wil be breathing room air (21%)

Outcomes

Primary Outcome Measures

Plasma TNF-alpha concentration following LPS administration
Plasma TNF-α concentration after LPS administration (Area Under Curve); comparison of subjects treated with hypoxia compared to normoxia and hyperoxia compared to hypoxia

Secondary Outcome Measures

Hypoxia Inducible Factor 1 alpha in circulating leukocytes
Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymfocytes and monocytes as measured with flow cytometry
Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes
Reactive Oxygen Species in circulating leukocytes
Phagocytic function of circulating leukocytes
cytokine production after ex vivo stimulation of leukocytes
circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA)
Hemodynamic parameters
Blood pressure, heart frequency, cardiac output measurement
ventilatory response
Measures of ventilation: respiratory rate, blood gas changes
adenosine metabolism
urine and plasma adenosine,adenosine receptor mRNA, purines
alkaline phosphatase
cognitive function
neuropsychologic assessment of cognitive function
Hepcidin and iron parameters
catecholamines and cortisol
adrenaline, noradrenaline, dopamine and cortisol
Neutrophilic function
body temperature
oxygen saturation and arterial blood gas
subjective symptom scores
high sensitive troponine
iFABP
brain specific proteins
endocan
downstream targets of HIF
adrenomedullin, VEGF, EPO
heart rate variability
kidney injury markers in plasma and urine
microbiome in feces
markers of immunoparalysis
monocytic histone 3 lysine 4 trimethylation of the promotor region of pro-inflammatory genes, ex viv production of proinflammatory cytokines, HLA-DR expression on moncytes.
measures of coagulation and plateletfunction
platelet activation and platelet function, thrombin generation and other coagulation parameters, hematolocial infection profile using hematology analyser
meausures of coagulation and fibrinolysis
thrombin generation, thrombocyte function, ROTEM, plasmatic coagulation, fibrinolysis parameters

Full Information

First Posted
October 31, 2013
Last Updated
May 19, 2015
Sponsor
Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01978158
Brief Title
Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α
Official Title
Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α. A Pilot Proof of Principle Study
Study Type
Interventional

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
October 2013 (undefined)
Primary Completion Date
December 2013 (Actual)
Study Completion Date
December 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Oxygen is a widely available gas that is cheap, easy to get and extensively used in medicine. From animal studies it has become apparent that increasing or lowering the degree of oxygen in the blood, the inflammatory response can be altered. We will investigate of this is also true in humans by increasing, lowering or keeping oxygen levels normal while giving healthy subjects a short inflammatory stimulus.
Detailed Description
The primary objective of the study is to determine the effects of hyperoxia and hypoxia compared to normoxia in the human endotoxemia model on the innate immune reponse in healthy volunteers. A parallel, randomized study in healthy male volunteers. The subjects will be randomized to hypoxia, hyperoxia, or normoxia, and will all undergo experimental human endotoxemia (administration of 2 ng/kg LPS iv). In the hypoxia group: the subjects will breathe an individualized mix of nitrogen and room air for 3.5 hours using an air-tight respiratory helmet. The gas mixture will be adjusted to achieve a saturation of 80-85%. In the hyperoxia group, subjects will breathe 100% oxygen for 3.5 hours using the same respiratory helmet. In the normoxia group, subjects will breathe room air (21% oxygen, 79% nitrogen) also wearing the respiratory helmet. 1 hour after oxygen status adjustment (t=0), all subject will be administered an intravenous bolus (2ng/kg) of LPS derived from E coli O:113. 2.5 hours after LPS administration, the helmets will be removed and all subjects will breathe ambient room air. The primary study endpoint is the difference in plasma cytokines between the hypoxia and normoxia group, and between the hyperoxia and normoxia group. Secondary objectives include HIF-1α protein and mRNA, aHIF mRNA expression in circulating leukocytes, measures of ROS, leukocyte phagocytosis, and cytokine production by leukocytes stimulated ex vivo with various inflammatory stimuli, and measurement of basic hemodynamic and ventilatory parameters and temperature.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxia, Normoxia, Hyperoxia
Keywords
Oxygen, Hypoxia, Hyperoxia, Inflammation, Innate immunity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hypoxia
Arm Type
Experimental
Arm Description
Subjects will be breathing an individualized mix of nitrogen and room air titrated to an oxygen saturation of 80-85%.
Arm Title
Hyperoxia
Arm Type
Experimental
Arm Description
Subjects will be breathing 100% of oxygen
Arm Title
Normoxia
Arm Type
Active Comparator
Arm Description
Subjects wil be breathing room air (21%)
Intervention Type
Drug
Intervention Name(s)
Lipopolysaccharide
Other Intervention Name(s)
Purified LPS from Escherischa coli (O:113)
Intervention Description
LPS is used to elicit an inflammatory response in all subjects
Primary Outcome Measure Information:
Title
Plasma TNF-alpha concentration following LPS administration
Description
Plasma TNF-α concentration after LPS administration (Area Under Curve); comparison of subjects treated with hypoxia compared to normoxia and hyperoxia compared to hypoxia
Time Frame
1 day
Secondary Outcome Measure Information:
Title
Hypoxia Inducible Factor 1 alpha in circulating leukocytes
Description
Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymfocytes and monocytes as measured with flow cytometry
Time Frame
1 day
Title
Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes
Time Frame
24 hours
Title
Reactive Oxygen Species in circulating leukocytes
Time Frame
1 day
Title
Phagocytic function of circulating leukocytes
Time Frame
1 day
Title
cytokine production after ex vivo stimulation of leukocytes
Time Frame
1 day
Title
circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA)
Time Frame
1 day
Title
Hemodynamic parameters
Description
Blood pressure, heart frequency, cardiac output measurement
Time Frame
1 day
Title
ventilatory response
Description
Measures of ventilation: respiratory rate, blood gas changes
Time Frame
1 day
Title
adenosine metabolism
Description
urine and plasma adenosine,adenosine receptor mRNA, purines
Time Frame
1 day
Title
alkaline phosphatase
Time Frame
1 day
Title
cognitive function
Description
neuropsychologic assessment of cognitive function
Time Frame
1 day
Title
Hepcidin and iron parameters
Time Frame
1 day
Title
catecholamines and cortisol
Description
adrenaline, noradrenaline, dopamine and cortisol
Time Frame
1 day
Title
Neutrophilic function
Time Frame
1 day
Title
body temperature
Time Frame
1 day
Title
oxygen saturation and arterial blood gas
Time Frame
1
Title
subjective symptom scores
Time Frame
1 day
Title
high sensitive troponine
Time Frame
1 day
Title
iFABP
Time Frame
1 day
Title
brain specific proteins
Time Frame
1 day
Title
endocan
Time Frame
1 day
Title
downstream targets of HIF
Description
adrenomedullin, VEGF, EPO
Time Frame
1 day
Title
heart rate variability
Time Frame
1 day
Title
kidney injury markers in plasma and urine
Time Frame
2 days
Title
microbiome in feces
Time Frame
-1 day untill 1 week
Title
markers of immunoparalysis
Description
monocytic histone 3 lysine 4 trimethylation of the promotor region of pro-inflammatory genes, ex viv production of proinflammatory cytokines, HLA-DR expression on moncytes.
Time Frame
1 day
Title
measures of coagulation and plateletfunction
Description
platelet activation and platelet function, thrombin generation and other coagulation parameters, hematolocial infection profile using hematology analyser
Time Frame
1 day
Title
meausures of coagulation and fibrinolysis
Description
thrombin generation, thrombocyte function, ROTEM, plasmatic coagulation, fibrinolysis parameters
Time Frame
1 day

10. Eligibility

Sex
Male
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 to participate in this trial Male subjects aged 18 to 35 years inclusive Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory parameters Exclusion Criteria: Use of any medication(including herbal remedies and vitamin/mineral supplements) or recreational drugs within 7 days prior to profiling day Smoking Use of caffeine, or alcohol or within 1 day prior to profiling day Previous participation in a trial where LPS was administered Surgery or trauma with significant blood loss or blood donation within 3 months prior to profiling day Participation in another clinical trial within 3 months prior to profiling day. History, signs or symptoms of cardiovascular disease An implant that in the opinion of the investigator may make invasive procedures risky for the subject due to the increased risks associated with a possible infection. Subject has an implanted active cardiac device (ICD, IPG and/or CRT) Implanted active neurostimulation device Subject has internal jugular vein that cannot be accessed History of vaso-vagal collapse or of orthostatic hypotension History of atrial or ventricular arrhythmia Resting pulse rate ≤45 or ≥100 beats / min Hypertension (RR systolic >160 or RR diastolic >90) Hypotension (RR systolic <100 or RR diastolic <50) Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block Subject is diagnosed with epilepsy or history of seizures Renal impairment: plasma creatinine >120 μmol/L Liver function abnormality: alkaline phosphatase>230 U/L and/or ALT>90 U/L Coagulation abnormalities: APTT or PT > 1.5 times the reference range History of asthma Immuno-deficiency CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 2 weeks before profiling day Known or suspected of not being able to comply with the trial protocol - Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Pickkers, MD, PhD
Organizational Affiliation
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Intensive Care Medicine
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6500HB
Country
Netherlands

12. IPD Sharing Statement

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Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α

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