The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia

NCT ID: NCT00916448

Last Updated: 2015-08-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-05-31
• Study Completion Date: 2015-07-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

placebo medication: 2 capsules taken twice daily for 4 consecutive days and thereafter infusion of 2 ng/kg E.coli endotoxin intravenously

Group Type: PLACEBO_COMPARATOR

E. coli endotoxin

Intervention Type: DRUG

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

Atazanavir

Atazanavir 150 mg, 2 capsules taken twice daily for 4 consecutive days and thereafter infusion of 2 ng/kg E.coli endotoxin intravenously

Group Type: ACTIVE_COMPARATOR

Atazanavir

Intervention Type: DRUG

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

E. coli endotoxin

Intervention Type: DRUG

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

Interventions

Atazanavir

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

Intervention Type: DRUG

E. coli endotoxin

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

Intervention Type: DRUG

Other Intervention Names

Reyataz

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Pickkers, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Nijmegen Medical Centre, The Netherlands

Locations

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 37261364 (View on PubMed)

Other Identifiers

ATV LPS study

Identifier Type: -

Identifier Source: org_study_id