The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia

NCT00916448 | Completed DMC

• 1 other identifier: ATV LPS study
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Endotoxemia; Inflammation; Multi Organ Dysfunction Syndrome; Sepsis

Keywords

Endotoxin; Bilirubin; Inflammation; Sepsis; Multi organ dysfunction syndrome; Oxidative Stress; Heme oxygenase

Outcome Measures

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.

  before and at several time points until 24 hrs after endotoxin administration

Secondary Outcomes (4)

• 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

Study Arms (2)

Placebo

PLACEBO COMPARATOR

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

Atazanavir

ACTIVE COMPARATOR

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; Drug: E. coli endotoxin

Interventions

Atazanavir DRUG

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

Also known as: Reyataz

Atazanavir

E. coli endotoxin DRUG

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

Atazanavir; Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male volunteers

You may not qualify if:

• 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.

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

Related Publications (1)

• Dorresteijn MJ, Dekker D, Zwaag J, Heemskerk S, Roelofs HMJ, Smits P, van der Hoeven JG, Wagener FADTG, Pickkers P. Atazanavir-induced unconjugated hyperbilirubinemia prevents vascular hyporeactivity during experimental human endotoxemia. Front Immunol. 2023 May 16;14:1176775. doi: 10.3389/fimmu.2023.1176775. eCollection 2023.

  PMID: 37261364 DERIVED

MeSH Terms

Conditions

Endotoxemia; Inflammation; Sepsis

Interventions

Atazanavir Sulfate; endotoxin, Escherichia coli

Condition Hierarchy (Ancestors)

Bacteremia; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Peter Pickkers, MD, PhD

  Radboud University Nijmegen Medical Centre, The Netherlands

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2009
• First Posted: June 9, 2009
• Study Start: May 1, 2009
• Primary Completion: March 1, 2010
• Study Completion: July 1, 2015
• Last Updated: August 14, 2015

Record last verified: 2015-07

Locations

NL (1)