The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia

Sepsis Clinical Trial

Official title:

The Effects of Atazanavir-induced Hyperbilirubinemia on the Innate Immune Response During Human Endotoxemia. A Parallel Double Blind Placebo Controlled Pilot Study.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00916448
• Other study ID #: ATV LPS study
• 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

Related Conditions & MeSH terms

• Endotoxemia
• Hyperbilirubinemia
• Inflammation
• Multi Organ Dysfunction Syndrome
• Sepsis

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