The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia

The recruitment status of this study is unknown because the information has not been verified recently.
Verified December 2009 by Radboud University.
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by:
Radboud University
ClinicalTrials.gov Identifier:
NCT00916448
First received: June 5, 2009
Last updated: April 14, 2011
Last verified: December 2009
  Purpose

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.


Condition Intervention
Endotoxemia
Inflammation
Multi Organ Dysfunction Syndrome
Sepsis
Drug: Atazanavir
Drug: E. coli endotoxin

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: The Effects of Atazanavir-induced Hyperbilirubinemia on the Innate Immune Response During Human Endotoxemia. A Parallel Double Blind Placebo Controlled Pilot Study.

Resource links provided by NLM:


Further study details as provided by Radboud University:

Primary Outcome Measures:
  • 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. [ Time Frame: before and at several time points until 24 hrs after endotoxin administration ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine if the attenuated vascular response to endothelium dependent vasodilators and vasoconstrictors during endotoxemia can be prevented by atazanavir-induced hyperbilirubinemia. [ Time Frame: before and until 6 hours after endotoxin administration ] [ Designated as safety issue: No ]
  • To detect the effects of human endotoxemia on gastric perfusion measured by tonometry in the presence or absence of atazanavir-induced hyperbilirubinemia. [ Time Frame: Before and at several time points up to 9 hours after endotoxin administration ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: Before and at several time points up to 24 hours after endotoxin administration ] [ Designated as safety issue: No ]
  • To determine the effect of atazanavir induced hyperbilirubinemia on heme oxygenase induction and activity during human endotoxemia. [ Time Frame: before and at several time points up to 24 hours after endotoxin administration ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: May 2009
Estimated Study Completion Date: December 2011
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: Atazanavir
capsules of 150 mg, 2 capsules, twice daily on 4 consecutive days
Other Name: Reyataz
Drug: E. coli endotoxin
2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00916448

Locations
Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University
Investigators
Principal Investigator: Peter Pickkers, MD, PhD Radboud University Nijmegen Medical Centre, The Netherlands
  More Information

No publications provided

Responsible Party: P. Pickkers, MD, PhD, Radboud University Nijmegen Medical Centre
ClinicalTrials.gov Identifier: NCT00916448     History of Changes
Other Study ID Numbers: ATV LPS study
Study First Received: June 5, 2009
Last Updated: April 14, 2011
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Radboud University:
Endotoxin
Bilirubin
Inflammation
Sepsis
Multi organ dysfunction syndrome
Oxidative Stress
Heme oxygenase

Additional relevant MeSH terms:
Hyperbilirubinemia
Inflammation
Sepsis
Endotoxemia
Pathologic Processes
Infection
Systemic Inflammatory Response Syndrome
Bacteremia
Toxemia
Atazanavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2014