EndotoxemiaNCT00916448
The Effects of Atazanavir-induced Hyperbilirubinemia During Human Endotoxemia
A study testing Atazanavir and E. coli endotoxin in people with Endotoxemia and Inflammation, run by Radboud University Medical Center at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Endotoxemia, Inflammation, Multi Organ Dysfunction Syndrome
- What is being tested?
- Atazanavir and E. coli endotoxin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteNetherlands
- Study dates
- May 2009to Jul 2015
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy male volunteers
Who cannot join
- 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.
Show all 15Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, 6500 HB
About this study
Official title: The Effects of Atazanavir-induced Hyperbilirubinemia on the Innate Immune Response During Human Endotoxemia. A Parallel Double Blind Placebo Controlled Pilot Study.
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
- Being tested
- Atazanavir, E. coli endotoxin
- Keywords
- Endotoxin, Bilirubin, Inflammation, Sepsis, Multi organ dysfunction syndrome, Oxidative Stress, Heme oxygenase
- Medical subject headings
- Endotoxemia, Inflammation, Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtazanavirDrug
Also called Reyataz
capsules of 150 mg, 2 capsules, twice daily on 4 consecutive days
E. coli endotoxinDrug
2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Drug: Atazanavir; Drug: E. coli endotoxin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: before and at several time points up to 24 hours after endotoxin administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2009 (estimated)
- Study startMay 2009
- Primary completionMar 2010
- Study completionJul 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for EndotoxemiaStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Peter Pickkers, MD, PhD, Principal investigator, Radboud University Nijmegen Medical Centre, The Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00916448
- Sponsor's protocol ID
- ATV LPS study
- Status last verified
- Jul 2015
- First submitted
- 5 Jun 2009
- Last updated
- 14 Aug 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 37261364
Study at a glance
From the registry record, last updated by the sponsor on 14 Aug 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Atazanavir-induced Hyperbilirubinemia on the Innate Immune Response During Human Endotoxemia. A Parallel Double Blind Placebo Controlled Pilot Study.
- ClinicalTrials.gov ID
- NCT00916448
- Acronym / sponsor ID
- ATV LPS study
- Conditions
- Endotoxemia, Inflammation, Multi Organ Dysfunction Syndrome, Sepsis
- Keywords
- Endotoxin, Bilirubin, Inflammation, Sepsis, Multi organ dysfunction syndrome, Oxidative Stress, Heme oxygenase
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- May 2009
- Primary completion
- Mar 2010 (actual)
- Study completion
- Jul 2015 (actual)
- First posted
- 9 Jun 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: E. coli endotoxinplacebo medication: 2 capsules taken twice daily for 4 consecutive days and thereafter infusion of 2 ng/kg E.coli endotoxin intravenously |
| Atazanavir | Active comparator | Drug: Atazanavir, Drug: E. coli endotoxinAtazanavir 150 mg, 2 capsules taken twice daily for 4 consecutive days and thereafter infusion of 2 ng/kg E.coli endotoxin intravenously |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Healthy male volunteers
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AtazanavirAlso: Reyatazcapsules of 150 mg, 2 capsules, twice daily on 4 consecutive days | Drug | Atazanavir |
| E. coli endotoxin2 ng/kg E. coli reference endotoxin 11:H 10:K negative intravenously | Drug | Atazanavir, Placebo |
Primary outcome
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
4 secondary outcomes
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
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
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
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Aug 2015.
- Derived from this study: PubMed 37261364Dorresteijn 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Pickkers, MD, PhD principal investigator
Radboud University Nijmegen Medical Centre, The Netherlands
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Atazanavir and E. coli endotoxin in people with Endotoxemia and Inflammation, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Aug 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00916448, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2015.