Anti-Inflammatory Effect of Statins in the Human Endotoxin Model

Endotoxemia Clinical Trial

Official title:

Anti-Inflammatory Effect of Statins in the Human Endotoxin Model

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00309374
• Other study ID #: EK291/2005Version2.0
• Status: Completed
• Phase: Phase 1
• First received: March 30, 2006
• Last updated: January 4, 2007
• Start date: March 2006
• Est. completion date: July 2006

Study information

• Verified date: January 2007
• Source: Medical University of Vienna
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Federal Ministry for Health and Women
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: July 2006
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Endotoxemia

Intervention

Drug:
• LPS 2ng/kg intravenous bolus

• Simvastatin 80mg; administered daily p.o. over 5 days

• Rosuvastatin 40mg; administered daily p.o. over 5 days

Locations

Country	Name	City	State
Austria	Medical University of Vienna, Dept. of Clinical Pharmacology	Vienna

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Vienna

Country where clinical trial is conducted

Austria, 

References & Publications (2)

Pernerstorfer 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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	monocyte CRP production
Primary	leukocyte mRNA expression profiles (human genome GeneChip arrays)
Secondary	various inflammation and coagulation parameters
Secondary	platelets
Secondary	endothelial progenitor cells
Secondary	adverse events