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

NCT ID: NCT01978158

Last Updated: 2015-05-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2013-12-31

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.

Conditions

Hypoxia; Normoxia; Hyperoxia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hypoxia

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

Group Type: EXPERIMENTAL

Lipopolysaccharide

Intervention Type: DRUG

LPS is used to elicit an inflammatory response in all subjects

Hyperoxia

Subjects will be breathing 100% of oxygen

Group Type: EXPERIMENTAL

Lipopolysaccharide

Intervention Type: DRUG

LPS is used to elicit an inflammatory response in all subjects

Normoxia

Subjects wil be breathing room air (21%)

Group Type: ACTIVE_COMPARATOR

Lipopolysaccharide

Intervention Type: DRUG

LPS is used to elicit an inflammatory response in all subjects

Interventions

Lipopolysaccharide

LPS is used to elicit an inflammatory response in all subjects

Intervention Type: DRUG

Other Intervention Names

Purified LPS from Escherischa coli (O:113)

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Pickkers, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Locations

Intensive Care Medicine

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

Other Identifiers

2013-002390-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL44630.091.13

Identifier Type: OTHER

Identifier Source: secondary_id

2013/290

Identifier Type: OTHER

Identifier Source: secondary_id

OX2

Identifier Type: -

Identifier Source: org_study_id