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

Hypoxia Clinical Trial

Official title:

Effects of Oxygen Status on Endotoxemia Induced Inflammation and Hypoxia Inducible Factor-1α. A Pilot Proof of Principle Study

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

• Endotoxemia
• Hyperoxia
• Hypoxia
• Inflammation
• Normoxia

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