The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia

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

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Inflammation; Endotoxemia; Multi Organ Dysfunction Syndrome
• Intervention / Treatment: Drug: E. coli endotoxin; Drug: Atazanavir

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500 HB
      • Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo medication: 2 capsules taken twice daily for 4 consecutive days and thereafter infusion of 2 ng/kg E.coli endotoxin intravenously	Drug: E. coli endotoxin; 2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously
Active Comparator: Atazanavir; Atazanavir 150 mg, 2 capsules taken twice daily for 4 consecutive days and thereafter infusion of 2 ng/kg E.coli endotoxin intravenously	Drug: E. coli endotoxin; 2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously; Drug: Atazanavir; capsules of 150 mg, 2 capsules, twice daily on 4 consecutive days; Other Names: Reyataz

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Time Frame
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
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
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
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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Peter Pickkers, MD, PhD, Radboud University Nijmegen Medical Centre, The Netherlands

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: June 5, 2009
• First Submitted That Met QC Criteria: June 8, 2009
• First Posted (Estimate): June 9, 2009

Study Record Updates

• Last Update Posted (Estimate): August 14, 2015
• Last Update Submitted That Met QC Criteria: August 13, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Inflammation; Endotoxin; Oxidative Stress; Sepsis; Bilirubin; Multi organ dysfunction syndrome; Heme oxygenase
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Sepsis; Bacteremia; Toxemia; Inflammation; Endotoxemia; Hyperbilirubinemia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Atazanavir Sulfate
• Other Study ID Numbers: ATV LPS study