Anti-Inflammatory Effect of Statins in the Human Endotoxin Model

• ClinicalTrials.gov Identifier: NCT00309374
• Recruitment Status: Completed
• First Posted: March 31, 2006
• Last Update Posted: January 5, 2007
• Sponsor: Medical University of Vienna
• Information provided by: Medical University of Vienna

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Endotoxemia	Drug: 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	Phase 1

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

• Study Type: Interventional (Clinical Trial)
• Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: Anti-Inflammatory Effect of Statins in the Human Endotoxin Model
• Study Start Date: March 2006
• Study Completion Date: July 2006

Arms and Interventions

Outcome Measures

Primary Outcome Measures :

1. monocyte CRP production
2. leukocyte mRNA expression profiles (human genome GeneChip arrays)

Secondary Outcome Measures :

1. various inflammation and coagulation parameters
2. platelets
3. endothelial progenitor cells
4. adverse events

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

Austria

Medical University of Vienna, Dept. of Clinical Pharmacology

Vienna, Austria

Sponsors and Collaborators

Medical University of Vienna

Investigators

• Principal Investigator: Michael Wolzt, MD; Medical University of Vienna

More Information

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Spiel 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.

• ClinicalTrials.gov Identifier: NCT00309374
• Other Study ID Numbers: EK291/2005Version2.0
• First Posted: March 31, 2006
• Last Update Posted: January 5, 2007
• Last Verified: January 2007

Keywords provided by Medical University of Vienna:

LPS; Statins; leukocyte mRNA expression profiles

Additional relevant MeSH terms:

Endotoxemia; Bacteremia; Sepsis; Infection; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Rosuvastatin Calcium; Simvastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors