EndotoxemiaPhase 1NCT00309374
Anti-Inflammatory Effect of Statins in the Human Endotoxin Model
A Phase 1 study testing LPS 2ng/kg intravenous bolus, Simvastatin 80mg; administered daily p.o. over 5 days and Rosuvastatin 40mg; administered daily p.o. over 5 days in people with Endotoxemia, run by Medical University of Vienna at 1 site in Austria.
Trial summary
The purpose of this study is to determine the effects of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia. Read more about this study
- Who is it for?
- Ages 18 to 45 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Endotoxemia
- What is being tested?
- LPS 2ng/kg intravenous bolus, Simvastatin 80mg; administered daily p.o. over 5 days and Rosuvastatin 40mg; administered daily p.o. over 5 days
- Type of treatment
- Injection or infusion
- How many people
- 6 participants
- Where
- 1 siteAustria
- Study dates
- Mar 2006to Jul 2006
- Phase
- Phase 1
- 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 45 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Men aged between 18 and 45 years
- Nonsmokers or smokers <5 cig/d
- Body mass index between 18 and 30; respectively weight ≤ 95 kilograms
- Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant
Who cannot join
- Regular use of medication, abuse of alcoholic beverages, participation in a clinical trial in the 3 weeks preceding the study
- Evidence of hypertension, pathologic hyperglycemia, hyperlipidemia
- Treatment in the previous 3 weeks with any drug
- Symptoms of a clinically relevant illness in the 3 weeks before the first study day
- History or presence of gastrointestinal, liver or kidney disease, or other conditions known to interfere with distribution, metabolism or excretion of study drugs
- Blood donation during the previous 3 weeks
- History of hypersensitivity to the trial drug or to drugs with a similar chemical structure
Trial locations and contacts
1 site in 1 country.
Austria1 site
Medical University of Vienna, Dept. of Clinical Pharmacology
Vienna, State of Vienna
About this study
The purpose of this study is to determine the effects of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia.
Read the detailed description
The beneficial effect of lipid lowering in cardiovascular disease is well established. Statin potently reduce elevated cholesterol levels but also exert pleiotropic other effects such as improvement of inflammation-induced vascular dysfunction, upregulation of endothelial nitric oxide synthase, yield antiinflammatory and antioxidant properties and lower tissue factor (TF) expression on peripheral blood mononuclear cells (PB-MNC) in vivo. The mechanism of action for these effects remains unclear, but is already seen after short term treatment and was independent of cholesterol reduction. Following endotoxin administration to healthy humans, the systemic response includes the activation of inflammation by cytokines, mainly IL-1, IL-6, THF-α and INF-γ, activation of the clotting system with enhanced thrombin generation, and vascular dysfunction, as demonstrable by an impaired response to vasoconstrictors. Low dose endotoxemia therefore serves as an adequate model for acute inflammation and the interaction of the three systems.
The goal of this study is to determine the effect of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia and to investigate if anti-inflammatory effects are similar between two different statins. Further, we plan to study genome-wide effects on the leukocyte transcriptome induced by (i) statin pretreatment, (ii) low-dose endotoxemia, and (iii) the anti-inflammatory effects if the statins.
The study will be carried out as a randomized placebo controlled double-blind threeway crossover three period study. Subjects will receive three treatment periods (Day 1 - Day 5) in randomized order consisting of 5 days oral Simvastatin (80 mg/day), 5 days oral Rosuvastatin (40 mg/day) and 5 days adequate placebo. On Day 5 of each study period, subjects will receive LPS (2 ng/kg i.v.). Inflammatory protein expression and coagulation activation will be assessed on Day 1 and Day 5 of each period. Washout-time between treatment periods will be ≥6 weeks.
- Conditions
- Endotoxemia
- Being tested
- LPS 2ng/kg intravenous bolus, Simvastatin 80mg; administered daily p.o. over 5 days, Rosuvastatin 40mg; administered daily p.o. over 5 days
- Keywords
- LPS, Statins, leukocyte mRNA expression profiles
- Medical subject headings
- Endotoxemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LPS 2ng/kg intravenous bolusDrug
Simvastatin 80mg; administered daily p.o. over 5 daysDrug
Rosuvastatin 40mg; administered daily p.o. over 5 daysDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
monocyte CRP production
leukocyte mRNA expression profiles (human genome GeneChip arrays)
Secondary outcomes (4)
various inflammation and coagulation parameters
platelets
endothelial progenitor cells
adverse events
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Mar 2006 (estimated)
- Study startMar 2006
- Study completionJul 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for EndotoxemiaStudies of the same condition, open and under way.
- More trials run by Medical University of ViennaThe 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 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Enrolment
- 6 participants
Sponsor and investigators
- Lead sponsor
- Medical University of Vienna
- Sponsor type
- University, hospital or other
- Investigators
- Michael Wolzt, MD, Principal investigator, Medical University of Vienna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00309374
- Sponsor's protocol ID
- EK291/2005Version2.0
- Status last verified
- Jan 2007
- First submitted
- 30 Mar 2006
- Last updated
- 5 Jan 2007
- Results posted
- No
Publications
Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, Wojta J, Huber K, Minar E, Wolzt M, Kopp CW. Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation. 2005 Apr 12;111(14):1841-6. doi: 10.1161/01.CIR.0000158665.27783.0C.
PubMed 15824212Pernerstorfer T, Hollenstein U, Hansen J, Knechtelsdorfer M, Stohlawetz P, Graninger W, Eichler HG, Speiser W, Jilma B. Heparin blunts endotoxin-induced coagulation activation. Circulation. 1999 Dec 21-28;100(25):2485-90. doi: 10.1161/01.cir.100.25.2485.
PubMed 10604885Spiel AO, Mayr FB, Leitner JM, Firbas C, Sieghart W, Jilma B. Simvastatin and rosuvastatin mobilize Endothelial Progenitor Cells but do not prevent their acute decrease during systemic inflammation. Thromb Res. 2008;123(1):108-13. doi: 10.1016/j.thromres.2008.03.007. Epub 2008 Apr 22.
PubMed 18433844
Study at a glance
From the registry record, last updated by the sponsor on 5 Jan 2007. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Anti-Inflammatory Effect of Statins in the Human Endotoxin Model
- ClinicalTrials.gov ID
- NCT00309374
- Acronym / sponsor ID
- EK291/2005Version2.0
- Conditions
- Endotoxemia
- Keywords
- LPS, Statins, leukocyte mRNA expression profiles
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants
- Lead sponsor
- Medical University of ViennaUniversity, hospital or other
- Study start
- Mar 2006
- Study completion
- Jul 2006
- First posted
- 31 Mar 2006 (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.
The purpose of this study is to determine the effects of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia.
Detailed description
The beneficial effect of lipid lowering in cardiovascular disease is well established. Statin potently reduce elevated cholesterol levels but also exert pleiotropic other effects such as improvement of inflammation-induced vascular dysfunction, upregulation of endothelial nitric oxide synthase, yield antiinflammatory and antioxidant properties and lower tissue factor (TF) expression on peripheral blood mononuclear cells (PB-MNC) in vivo. The mechanism of action for these effects remains unclear, but is already seen after short term treatment and was independent of cholesterol reduction. Following endotoxin administration to healthy humans, the systemic response includes the activation of inflammation by cytokines, mainly IL-1, IL-6, THF-α and INF-γ, activation of the clotting system with enhanced thrombin generation, and vascular dysfunction, as demonstrable by an impaired response to vasoconstrictors. Low dose endotoxemia therefore serves as an adequate model for acute inflammation and the interaction of the three systems.
The goal of this study is to determine the effect of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia and to investigate if anti-inflammatory effects are similar between two different statins. Further, we plan to study genome-wide effects on the leukocyte transcriptome induced by (i) statin pretreatment, (ii) low-dose endotoxemia, and (iii) the anti-inflammatory effects if the statins.
The study will be carried out as a randomized placebo controlled double-blind threeway crossover three period study. Subjects will receive three treatment periods (Day 1 - Day 5) in randomized order consisting of 5 days oral Simvastatin (80 mg/day), 5 days oral Rosuvastatin (40 mg/day) and 5 days adequate placebo. On Day 5 of each study period, subjects will receive LPS (2 ng/kg i.v.). Inflammatory protein expression and coagulation activation will be assessed on Day 1 and Day 5 of each period. Washout-time between treatment periods will be ≥6 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Men aged between 18 and 45 years
- Nonsmokers or smokers <5 cig/d
- Body mass index between 18 and 30; respectively weight ≤ 95 kilograms
- Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant
Key exclusion criteria (7 listed)
- Regular use of medication, abuse of alcoholic beverages, participation in a clinical trial in the 3 weeks preceding the study
- Evidence of hypertension, pathologic hyperglycemia, hyperlipidemia
- Treatment in the previous 3 weeks with any drug
- Symptoms of a clinically relevant illness in the 3 weeks before the first study day
- History or presence of gastrointestinal, liver or kidney disease, or other conditions known to interfere with distribution, metabolism or excretion of study drugs
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 |
|---|---|---|
| LPS 2ng/kg intravenous bolus | Drug | – |
| Simvastatin 80mg; administered daily p.o. over 5 days | Drug | – |
| Rosuvastatin 40mg; administered daily p.o. over 5 days | Drug | – |
Primary outcome
monocyte CRP production
leukocyte mRNA expression profiles (human genome GeneChip arrays)
4 secondary outcomes
various inflammation and coagulation parameters
platelets
endothelial progenitor cells
adverse events
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 5 Jan 2007.
- Background: PubMed 15824212Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, Wojta J, Huber K, Minar E, Wolzt M, Kopp CW. Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation. 2005 Apr 12;111(14):1841-6. doi: 10.1161/01.CIR.0000158665.27783.0C.
- Background: PubMed 10604885Pernerstorfer T, Hollenstein U, Hansen J, Knechtelsdorfer M, Stohlawetz P, Graninger W, Eichler HG, Speiser W, Jilma B. Heparin blunts endotoxin-induced coagulation activation. Circulation. 1999 Dec 21-28;100(25):2485-90. doi: 10.1161/01.cir.100.25.2485.
- Derived from this study: PubMed 18433844Spiel AO, Mayr FB, Leitner JM, Firbas C, Sieghart W, Jilma B. Simvastatin and rosuvastatin mobilize Endothelial Progenitor Cells but do not prevent their acute decrease during systemic inflammation. Thromb Res. 2008;123(1):108-13. doi: 10.1016/j.thromres.2008.03.007. Epub 2008 Apr 22.
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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.
Michael Wolzt, MD principal investigator
Medical University of Vienna
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing LPS 2ng/kg intravenous bolus, Simvastatin 80mg; administered daily p.o. over 5 days and Rosuvastatin 40mg; administered daily p.o. over 5 days in people with Endotoxemia, run by Medical University of Vienna at 1 site in Austria.
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 4 inclusion and 7 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 5 Jan 2007. 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 Austria. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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?
monocyte CRP production. The study lists 2 primary outcomes in all. 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 NCT00309374, which also lists 3 linked publications.
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 5 Jan 2007.