Clinical trial NCT00817843: The PostprAndial eNdothelial Function After Combination of Ezetimibe and simvAstatin Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Metabolic Syndrome
Keywords: Postprandial hypertriglyceridemia
Metabolic syndrome
Endothelial function
Flow mediated dilatation
EndoPAT
Simvastatin
Ezetimibe
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2009-01-07
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: INCLUSION CRITERIA:

1. 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
2. Patient understands the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
3. Patient is a male or female of 18-79 years of age on the day of signing informed consent.
4. Patient is a non-smoker.
5. Patient is willing to maintain a stable diet for the duration of the study.
6. 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.
7. 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)
8. Patient has a baseline fasting LDL-C level of ≥ 100 mg/dL and \< 220 mg/dL, and TG level \< 400 mg/dL.

EXCLUSION CRITERIA:

1. Patient has a BMI \> 35.
2. Patient has hypersensitivity or intolerance to ezetimibe or simvastatin or any component of these medications, or to latex.
3. Patient routinely consumes more than 14 alcoholic drinks per week.
4. Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent.
5. 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).
6. 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
7. 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.
8. It is not possible to obtain a FMD measurement of sufficient quality at screening (Visit 1)
9. 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

Primary outcomes:
measure: Treatment Difference in (Postprandial-Fasting) FMD
timeFrame: After 6 weeks of treatment
Secondary outcomes:
measure: Postprandial Endopat Measurement
timeFrame: after 6 weeks of treatment (crossover)
measure: Preprandial Endothelial Function Measured by FMD
timeFrame: after 6 weeks of treatment (crossover)
measure: Preprandial Endopat Measurement
timeFrame: after 6 weeks of treatment (crossover)
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Hoorn
country: Netherlands
facility: Vascular Research Center Hoorn
city: Utrecht
country: Netherlands
facility: Department of Vascular Medicine UMC Utrecht
city: Waalwijk
country: Netherlands
facility: Tweesteden Ziekenhuis
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
Study officials:
affiliation: UMC Utrecht
name: Frank LJ Visseren, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Olijhoek JK, Hajer GR, van der Graaf Y, Dallinga-Thie GM, Visseren FL. The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial. J Cardiovasc Pharmacol. 2008 Aug;52(2):145-50. doi: 10.1097/FJC.0b013e31817ffe76.