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NCT Number: NCT00916448

The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia

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.

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Key information

Conditions

Endotoxemia Bacteremia Infections Inflammation Multi Organ Dysfunction Syndrome Pathologic Processes Pathological Conditions, Signs and Symptoms Sepsis Systemic Inflammatory Response Syndrome Toxemia

Age range

18 year–35 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Atazanavir

Drug

capsules of 150 mg, 2 capsules, twice daily on 4 consecutive days

Other names: Reyataz

E. coli endotoxin

Drug

2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Registry information

Official study title

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

Important dates

Study start
2009
Primary completion
2010
Study completion
2015
First posted
Jun 9, 2009
Registry last updated
Aug 14, 2015

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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