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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01978158
Other study ID # OX2
Secondary ID 2013-002390-21NL
Status Completed
Phase Phase 1/Phase 2
First received October 31, 2013
Last updated May 19, 2015
Start date October 2013
Est. completion date December 2013

Study information

Verified date May 2015
Source Radboud University
Contact n/a
Is FDA regulated No
Health authority Netherlands: Independent Ethics CommitteeNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 30
Est. completion date December 2013
Est. primary completion date December 2013
Accepts healthy volunteers Accepts Healthy Volunteers
Gender Male
Age group 18 Years to 35 Years
Eligibility 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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment


Related Conditions & MeSH terms


Intervention

Drug:
Lipopolysaccharide
LPS is used to elicit an inflammatory response in all subjects

Locations

Country Name City State
Netherlands Intensive Care Medicine Nijmegen Gelderland

Sponsors (1)

Lead Sponsor Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type Measure Description Time frame Safety issue
Primary Plasma TNF-alpha concentration following LPS administration Plasma TNF-a concentration after LPS administration (Area Under Curve); comparison of subjects treated with hypoxia compared to normoxia and hyperoxia compared to hypoxia 1 day No
Secondary Hypoxia Inducible Factor 1 alpha in circulating leukocytes Hypoxia Inducible Factor 1 alpha in circulating neutrophils, lymfocytes and monocytes as measured with flow cytometry 1 day No
Secondary Hypoxia Inducible Factor mRNA and anti Hypoxia Inducible Factor mRNA in circulating leukocytes 24 hours No
Secondary Reactive Oxygen Species in circulating leukocytes 1 day No
Secondary Phagocytic function of circulating leukocytes 1 day No
Secondary cytokine production after ex vivo stimulation of leukocytes 1 day No
Secondary circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA) 1 day No
Secondary Hemodynamic parameters Blood pressure, heart frequency, cardiac output measurement 1 day No
Secondary ventilatory response Measures of ventilation: respiratory rate, blood gas changes 1 day No
Secondary adenosine metabolism urine and plasma adenosine,adenosine receptor mRNA, purines 1 day No
Secondary alkaline phosphatase 1 day No
Secondary cognitive function neuropsychologic assessment of cognitive function 1 day No
Secondary Hepcidin and iron parameters 1 day No
Secondary catecholamines and cortisol adrenaline, noradrenaline, dopamine and cortisol 1 day No
Secondary Neutrophilic function 1 day No
Secondary body temperature 1 day No
Secondary oxygen saturation and arterial blood gas 1 Yes
Secondary subjective symptom scores 1 day No
Secondary high sensitive troponine 1 day No
Secondary iFABP 1 day No
Secondary brain specific proteins 1 day No
Secondary endocan 1 day No
Secondary downstream targets of HIF adrenomedullin, VEGF, EPO 1 day No
Secondary heart rate variability 1 day No
Secondary kidney injury markers in plasma and urine 2 days No
Secondary microbiome in feces -1 day untill 1 week No
Secondary 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. 1 day No
Secondary measures of coagulation and plateletfunction platelet activation and platelet function, thrombin generation and other coagulation parameters, hematolocial infection profile using hematology analyser 1 day No
Secondary meausures of coagulation and fibrinolysis thrombin generation, thrombocyte function, ROTEM, plasmatic coagulation, fibrinolysis parameters 1 day No
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