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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00916448
Other study ID # ATV LPS study
Secondary ID
Status Completed
Phase N/A
First received June 5, 2009
Last updated August 13, 2015
Start date May 2009
Est. completion date July 2015

Study information

Verified date July 2015
Source Radboud University
Contact n/a
Is FDA regulated No
Health authority Netherlands: Medical Ethics Review Committee (METC)
Study type Interventional

Clinical Trial Summary

Excessive inflammation, production of free radicals and vascular injury are considered the main contributors to the development of organ dysfunction in patients with severe infections and sepsis. The endogenously produced unconjugated bilirubin is one of the most powerful anti-oxidants of the human body and the administration of bilirubin in animal experiments has been shown to protect from inflammation-induced death. However, bilirubin for human administration is not yet available. Therefore, we wish to exploit one of the side effects of atazanavir, a registered drug currently used as a protease inhibitor in HIV infected patients. Atazanavir inhibits the enzyme UPD glucuronosyl transferase enzyme (UGT1A1) and therefore increases endogenously produced bilirubin levels moderately. To study the effect of hyperbilirubinemia during inflammation we will apply the human endotoxemia model. The human endotoxemia model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting. We hypothesize that atazanavir-induced hyperbilirubinemia has beneficial anti-inflammatory and vascular effects during human endotoxemia.


Recruitment information / eligibility

Status Completed
Enrollment 30
Est. completion date July 2015
Est. primary completion date March 2010
Accepts healthy volunteers Accepts Healthy Volunteers
Gender Male
Age group 18 Years to 35 Years
Eligibility Inclusion Criteria:

- Healthy male volunteers

Exclusion Criteria:

- Use of any medication or anti-oxidant vitamin supplements.

- History of allergic reaction to atazanavir.

- Smoking.

- Previous spontaneous vagal collapse.

- History, signs or symptoms of cardiovascular disease.

- (Family) history of myocardial infarction or stroke under the age of 65 years.

- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex 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 creatinin >120 µmol/l).

- Liver enzyme abnormalities or positive hepatitis serology.

- Subjects with a total bilirubin level above 15 µmol/L and a normal direct bilirubin level suggesting Gilbert Syndrome.

- Positive HIV serology or any other obvious disease associated with immune deficiency.

- Febrile illness in the week before the LPS challenge.

- Participation in a drug trial or donation of blood 3 months prior to the LPS challenge.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment


Intervention

Drug:
Atazanavir
capsules of 150 mg, 2 capsules, twice daily on 4 consecutive days
E. coli endotoxin
2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously

Locations

Country Name City State
Netherlands Radboud University Nijmegen Medical Centre 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 The effect of atazanavir-induced hyperbilirubinemia on systemic activation of the innate immune response by measurement of various cytokines induced by a lipopolysaccharide (LPS) challenge. before and at several time points until 24 hrs after endotoxin administration No
Secondary To determine if the attenuated vascular response to endothelium dependent vasodilators and vasoconstrictors during endotoxemia can be prevented by atazanavir-induced hyperbilirubinemia. before and until 6 hours after endotoxin administration No
Secondary To detect the effects of human endotoxemia on gastric perfusion measured by tonometry in the presence or absence of atazanavir-induced hyperbilirubinemia. Before and at several time points up to 9 hours after endotoxin administration No
Secondary To determine if atazanavir induced hyperbilirubinemia can attenuate subclinical renal damage (determined by several markers of acute kidney injury) known to occur during human endotoxemia. Before and at several time points up to 24 hours after endotoxin administration No
Secondary To determine the effect of atazanavir induced hyperbilirubinemia on heme oxygenase induction and activity during human endotoxemia. before and at several time points up to 24 hours after endotoxin administration No
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