Vascular Effects of Ezetimibe/Simvastatin and Simvastatin on Atherosclerosis

Study Overview
=================
Brief Summary
-----------------
Multiple clinical trials, using 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins), have shown benefit in the primary and secondary prevention of atherosclerotic complications. However, till now, there is an incomplete understanding of all the mechanisms of the biologic effects of statins beyond LDL cholesterol (LDL-C) reduction, but there is accumulating evidence that the Rho-GTP/Rho-Kinase pathway (Rho/Rho-K) plays an important role and may be a strategic therapeutic target in cardiovascular diseases. With similar LDL-C reduction ability, the availability of Ezetimibe offers the potential to begin to address the question whether some of the benefits conferred by statins may accrue independently of their effects on LDL-C lowering. A better understanding of the role of the Rho/Rho-kinase signaling pathway in the pathogenesis of atherosclerosis in human is essential. Inhibition of Rho/Rho-kinase by statins may explain some of the biological beneficial effects of statins observed in clinical trials. This study aims to translate into patients important experimental discoveries regarding the initiation of inflammation in atherosclerosis in an attempt to improve upon the present treatment of cardiovascular diseases.

Detailed Description
-----------------
Study Design: A single-blind controlled trial with two arms will be conducted at National Chen-Kung University Hospital (NCKUH). We will screen subjects with stable atherosclerosis to complete enrollment of 40 subjects in the study (see inclusion and exclusion criteria section below). A central pharmacist at NCKUH will randomize the patients to 40mg or Simvastatin (n=20) or 10mg/10mg of Ezetimibe/Simvastatin (n=20) for 28 days. If the patient is already on a statin a two-week washout period will be 2 weeks prior to trial initiation. Primary Outcomes and measurement: The primary outcomes are the mean changes in the Rho-kinase expression and activity in leukocytes in response to 40mg or Simvastatin (n=20) or 10mg/10mg of Ezetimibe/Simvastatin (n=20) over 28 days. Secondary Outcomes and measurement: The secondary outcomes are the correlation between the mean changes in Rho-kinase expression and activity in leukocytes and vascular tissue with the mean changes in LDL-C, hsCRP, and BAFMD, as well as its relation with clinical characteristics. Subjects: Participants will be recruited from the ambulatory clinics at the NCKUH Clinic. Inclusion Criteria: Male or female subjects aged 40 to 80 years Documented stable atherosclerosis by angiography or vascular ultrasound (more that 20% luminal narrowing), peripheral arterial disease or type 2 diabetes mellitus (coronary heart disease (CHD) risk equivalent - Adult Treatment Program (ATP)-III guidelines) LDL-cholesterol >100mg/dL (indication to treat with statin) Written informed consent Primary care physician authorization letter to participate in the study. Exclusion criteria: Inability to give consent Pre-menopausal women Current use of antibiotics, anti-inflammatory or immunosuppressant drugs History of LFT >2 times the upper normal limit History of myopathy / myositis or CPK > 10 times the upper normal limit CPK above normal limits at study onset Any evidence of inflammatory, infectious or neoplastic disease History of CABG, PCI or acute ischemic syndrome in the preceding 3 months.

Official Title
-----------------
Rho-kinase in Patients With Atherosclerosis: Effects of Statins A Randomized Clinical Trial Comparing Ezetimibe/Simvastatin and Simvastatin

Conditions
-----------------
Atherosclerosis

Intervention / Treatment
-----------------
* Drug: Simvastatin (Zocor)
* Drug: 10mg/10mg of Ezetimibe/Simvastatin (Vytorin)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Inclusion Criteria: Male or female subjects aged 40 to 80 years Documented stable atherosclerosis by angiography or vascular ultrasound (more that 20% luminal narrowing), peripheral arterial disease or type 2 diabetes mellitus (coronary heart disease (CHD) risk equivalent - Adult Treatment Program (ATP)-III guidelines) LDL-cholesterol >100mg/dL (indication to treat with statin) Written informed consent Primary care physician authorization letter to participate in the study. Exclusion criteria: Inability to give consent Pre-menopausal women Current use of antibiotics, anti-inflammatory or immunosuppressant drugs History of LFT >2 times the upper normal limit History of myopathy / myositis or CPK > 10 times the upper normal limit CPK above normal limits at study onset Any evidence of inflammatory, infectious or neoplastic disease History of CABG, PCI or acute ischemic syndrome in the preceding 3 months.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: high dose statin<br>40mg of Simvastatin (n=20) | Drug: Simvastatin (Zocor)<br>* 40mg of Simvastatin (n=20) orally per-day for 28 days<br>* Other names: Zocor;|
| Active Comparator: combination arm<br>10mg/10mg of Ezetimibe/Simvastatin (n=20) | Drug: 10mg/10mg of Ezetimibe/Simvastatin (Vytorin)<br>* 10mg/10mg of Ezetimibe/Simvastatin (n=20) orally per-day for 28 days<br>* Other names: Vytorin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in the lipid profile change and Rho-kinase expression and activity |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| correlation between changes in Rho-kinase expression and activity with the changes in LDL-C, hsCRP and BAFMD |  | 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HMG-CoA Reductase Inhibitors, endothelial function, HMG-CoA Reductase Inhibitors on vascular protection