The PostprAndial eNdothelial Function After Combination of Ezetimibe and simvAstatin Study

Study Overview
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Brief Summary
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The purpose of this study is to investigate whether low-dose simvastatin in combination with ezetimibe in comparison to high-dose simvastatin alone, has a beneficial effect on the function of the endothelium after an oral fat load in patients with metabolic syndrome.

Detailed Description
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Metabolic syndrome is defined as a group of cardiovascular risk factors and is mainly driven by the epidemic of obesity. High blood lipid levels after a meal may be an important risk factor for cardiovascular disease. In this study we will investigate whether simvastatin in combination with ezetimibe vs. simvastatin alone, has a beneficial effect on the lipid levels after a meal, but more importantly, whether we can measure a difference in function of the endothelium. In a small pilot study we already found that the combination had a beneficial effect in comparison with simvastatin alone. Now we want to solidify these findings in a larger study.

Official Title
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Multicenter,Double Blind,Randomized, 2-period, Crossover Study to Compare Ezetimibe/Simvastatin (10mg/10 mg) Combination Tablet Versus Simvastatin 80mg Tablet on Postprandial Arterial Endothelial Function in Patients With Metabolic Syndrome

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Simvastatin/Ezetimibe


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patient has a diagnosis of metabolic syndrome according to the modified 2005 AHA/NHLBI Scientific Statement with at least: - Abdominal obesity defined as: *Males: waist circumference >102cm Females: waist circumference >88cm and two of the following 4 other criteria: - Triglycerides>150 mg/dL - HDL Cholesterol Males: HDL-C<40 mg/dL Females:HDL-C<50 mg/dL - Blood pressure Systolic Blood Pressure ≥130 mmHg or Diastolic Blood Pressure ≥85 mmHg Fasting glucose ≥ 100 mg/dL Patient understands the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent. Patient is a male or female of 18-79 years of age on the day of signing informed consent. Patient is a non-smoker. Patient is willing to maintain a stable diet for the duration of the study. Patient is a postmenopausal female who is not receiving hormone therapy (including cyclic and non-cyclical hormone replacement therapy or any estrogen antagonist/agonist). Postmenopausal status is defined as (1) no menses for ≥1 year but <3 years and confirmed by FSH levels elevated into the postmenopausal range (as defined by the designated laboratory) or (2) no menses for at least 3 years. Patient is naïve to lipid-lowering therapy. Naïve is defined as not being treated with a statin, a fibrate or ezetimibe for 3 months before Visit 1 (Week -2) Patient has a baseline fasting LDL-C level of ≥ 100 mg/dL and < 220 mg/dL, and TG level < 400 mg/dL. EXCLUSION CRITERIA: Patient has a BMI > 35. Patient has hypersensitivity or intolerance to ezetimibe or simvastatin or any component of these medications, or to latex. Patient routinely consumes more than 14 alcoholic drinks per week. Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent. Patient has a smoking history > 10 pack-years (1 pack-year = at least 20 cigarettes per day for a year) OR patient who has smoked within 3 months prior to Visit 1 (Week -2). Patient has exclusionary laboratory values at Visit 1 (Week -2) as listed in the table below: liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) > 1.5 X ULN with no active liver disease Serum glucose > 7.0 mmol/L Creatine kinase(CK)> 2 X ULN Albumin:creatinine ratio > 34 TSH <0.3 mcIU/mL or > 5.0 mcIU/mL Patient has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might confound the results of the study, or interfere with the patient's participation for the full duration of the study, such that it is not in the best interest of the patient to participate. It is not possible to obtain a FMD measurement of sufficient quality at screening (Visit 1) Patient has congestive heart failure, atherosclerotic vascular disease or acute or chronic coronary heart disease. 13. Patient has had a partial ileal bypass, gastric bypass, gastric banding, celiac disease or other significant intestinal malabsorption. 15. Patient has untreated and uncontrolled hypertension with systolic blood pressure >160 mm Hg or diastolic >100 mm Hg at Visit 1 (Week -2). (Patients with untreated hypertension and with office BP at Visit 1 and Visit 2 averaging 160/100 or less can be enrolled). Patients using blood pressure-lowering medication are excluded. 16. Patient has estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 based on the 4-variable MDRD 17. Patient has uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins at Visit 1 (Week -2). 18. Patient has diabetes mellitus defined as a history of diabetes or fasting serum glucose > 126 mg/dL. For the full exclusion criteria, please check the protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Simva 80mg then Simvai/Eze10/10mg<br>First 6 weeks of Simvastatin 80mg, then 6 weeks of Simvastatin/Ezetimibe 10/10mg after 6 weeks of placebo washout | Drug: Simvastatin<br>* 6 weeks of treatment with simvastatin 80 mg<br>* Other names: Simvastatin (Zocor);Drug: Simvastatin/Ezetimibe<br>* 6 weeks of treatment with simvastatin 10 mg / ezetimibe 10 mg combination<br>* Other names: Simvastatin/Ezetimibe (Zetia);|
| Experimental: First Simva/Eze 10/10mg then Simva 80mg<br>First 6 weeks of Simvastatin/Ezetimibe 10/10mg, then 6 weeks of Simvastatin 80mg after 6 weeks of placebo washout | Drug: Simvastatin<br>* 6 weeks of treatment with simvastatin 80 mg<br>* Other names: Simvastatin (Zocor);Drug: Simvastatin/Ezetimibe<br>* 6 weeks of treatment with simvastatin 10 mg / ezetimibe 10 mg combination<br>* Other names: Simvastatin/Ezetimibe (Zetia);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Difference in (Postprandial-Fasting) FMD | A comparison of the postprandial minus fasting change in FMD under treatment with simvastatin 80 mg versus simvastatin 10/10 mg | After 6 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postprandial Endopat Measurement |  | after 6 weeks of treatment (crossover) | 
| Preprandial Endothelial Function Measured by FMD |  | after 6 weeks of treatment (crossover) | 
| Preprandial Endopat Measurement |  | after 6 weeks of treatment (crossover) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postprandial hypertriglyceridemia, Metabolic syndrome, Endothelial function, Flow mediated dilatation, EndoPAT, Simvastatin, Ezetimibe