Vascular Effects of Ezetimibe/Simvastatin and Simvastatin on Atherosclerosis

Atherosclerosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00560170
• Other study ID #: NCKUH-01/HR-95-112
• Status: Completed
• Phase: Phase 4
• First received: November 16, 2007
• Last updated: February 23, 2010
• Start date: September 2007
• Est. completion date: February 2008

Study information

• Verified date: February 2010
• Source: National Cheng-Kung University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Taiwan: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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:

1. Male or female subjects aged 40 to 80 years

2. 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)

3. LDL-cholesterol >100mg/dL (indication to treat with statin)

4. Written informed consent

5. Primary care physician authorization letter to participate in the study.

Exclusion criteria:

1. Inability to give consent

2. Pre-menopausal women

3. Current use of antibiotics, anti-inflammatory or immunosuppressant drugs

4. History of LFT >2 times the upper normal limit

5. History of myopathy / myositis or CPK > 10 times the upper normal limit

6. CPK above normal limits at study onset

7. Any evidence of inflammatory, infectious or neoplastic disease

8. History of CABG, PCI or acute ischemic syndrome in the preceding 3 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: February 2008
• Est. primary completion date: January 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

• Inclusion Criteria:

1. Male or female subjects aged 40 to 80 years

2. 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)

3. LDL-cholesterol >100mg/dL (indication to treat with statin)

4. Written informed consent

5. Primary care physician authorization letter to participate in the study.

• Exclusion criteria:

1. Inability to give consent

2. Pre-menopausal women

3. Current use of antibiotics, anti-inflammatory or immunosuppressant drugs

4. History of LFT >2 times the upper normal limit

5. History of myopathy / myositis or CPK > 10 times the upper normal limit

6. CPK above normal limits at study onset

7. Any evidence of inflammatory, infectious or neoplastic disease

8. History of CABG, PCI or acute ischemic syndrome in the preceding 3 months.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Atherosclerosis

Intervention

Drug:
• Simvastatin (Zocor)
40mg of Simvastatin (n=20) orally per-day for 28 days
• 10mg/10mg of Ezetimibe/Simvastatin (Vytorin)
10mg/10mg of Ezetimibe/Simvastatin (n=20) orally per-day for 28 days

Locations

Country	Name	City	State
Taiwan	National Cheng Kung University Hospital	Tainan

Sponsors (1)

Lead Sponsor	Collaborator
National Cheng-Kung University Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	changes in the lipid profile change and Rho-kinase expression and activity		28 days	Yes
Secondary	correlation between changes in Rho-kinase expression and activity with the changes in LDL-C, hsCRP and BAFMD		28 days	No