The primary objective of the study is to determine the effect of atazanavir-induced hyperbilirubinemia on systemic activation of the innate immune response induced by human endotoxemia.Secondary objectives are:- To determine if the vascular…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
- Decreased and nonspecific blood pressure disorders and shock
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is the concentration of circulating cytokines after
LPS in the absence or presence of atazanavir-induced hyperbilirubinemia.
Secondary outcome
Secondary study parameters include:
- Endothelial function after LPS administration in the absence or presence of
atazanavir-induced hyperbilirubinemia
- Gastric perfusion after LPS administration in the absence or presence of
atazanavir-induced hyperbilirubinemia
- Subclinical renal impairment after LPS administration in the absence or
presence of atazanavir-induced hyperbilirubinemia
- HO-1 activity after LPS administration in the absence or presence of
atazanavir-induced hyperbilirubinemia
Background summary
Excessive inflammation, production of free radicals and vascular injury are
considered the main contributors to the development of organ dysfunction during
sepis. 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, which is currently used
as a protease inhibitor in HIV-1 infected patients. Atazanavir inhibits UGT1A1
and therefore increases endogenously produced bilirubin levels moderately. We
wish to study the anti-inflammatory and vascular effects of Atazanavir-induced
hyperbilirubinemia using 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.
Study objective
The primary objective of the study is to determine the effect of
atazanavir-induced hyperbilirubinemia on systemic activation of the innate
immune response induced by human endotoxemia.
Secondary objectives are:
- To determine if the vascular hyporeactive response to endothelium dependent
vasodilators and vasoconstrictors can be prevented by atazanavir-induced
hyperbilirubinemia.
- To determine whether gastric perfusion is reduced during humane endotoxemia
and whether this effect can be reduced by atazanavir induced-hyperbilirubinemia.
- To determine if subclinical renal damage can be modulated by
atazanavir-induced hyperbilirubinemia.
- To determine the effects of atazanavir-induced hyperbilirubinemia on HO-1
activity after endotoxemia.
Study design
Double blinded placebo controlled parallel intervention study in healthy human
volunteers during experimental endotoxemia.
Intervention
Subjects will receive atazanavir (four day treatment with 300 mg twice daily
n=10) or placebo (n=10). Pre-hydration will be performed by infusion of 1.5 L
2.5% glucose/0.45% saline solution in 1 hour before LPS administration. LPS
derived from E coli O:113 will be injected (2 ng/kg iv.).
Study burden and risks
A medical interview and physical examination are part of this study. Atazanavir
will cause a mild and completely reversible hyperbilirubinemia. Other side
effects tend to be mild (see for further information the SPC provided with the
study protocol).
The administration of LPS induces flu-like symptoms for approximately 4 hrs. In
total, approximately 350 ml blood will be drawn during each LPS experiment and
urine will be collected.
To measure gastrointestinal perfusion a 16F nasogastric tube will be inserted.
This can cause mild discomfort at the time of insertion.
The subjects will not benefit directly from participation to the study. A
subject fee is provided.
Geert Grooteplein-zuid 10
6525 GA Nijmegen
NL
Geert Grooteplein-zuid 10
6525 GA Nijmegen
NL
Listed location countries
Age
Inclusion criteria
Age >= 18 and <= 35 yrs
Male
Healthy
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 mmHg)
- 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 umol/l suggesting Gilbert Syndrome.
- Positive HIV serology
- 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-010705-36-NL |
| CCMO | NL27052.091.09 |
| Other | volgt |