Anti-Inflammatory Effect of Statins in the Human Endotoxin Model

This study has been completed.
Sponsor:
Information provided by:
Medical University of Vienna
ClinicalTrials.gov Identifier:
NCT00309374
First received: March 30, 2006
Last updated: January 4, 2007
Last verified: January 2007
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: Anti-Inflammatory Effect of Statins in the Human Endotoxin Model

Resource links provided by NLM:


Further study details as provided by Medical University of Vienna:

Primary Outcome Measures:
  • monocyte CRP production
  • leukocyte mRNA expression profiles (human genome GeneChip arrays)

Secondary Outcome Measures:
  • various inflammation and coagulation parameters
  • platelets
  • endothelial progenitor cells
  • adverse events

Estimated Enrollment: 6
Study Start Date: March 2006
Estimated Study Completion Date: July 2006
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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00309374

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:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00309374     History of Changes
Other Study ID Numbers: EK291/2005Version2.0
Study First Received: March 30, 2006
Last Updated: January 4, 2007
Health Authority: Austria: Federal Ministry for Health and Women

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
Anti-Inflammatory Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014