Comparison of Efficacy and Safety of Ezetimibe or Statin Monotherapy to Co-Administration of Both
Comparison of Efficacy and Safety of Ezetimibe or Statin Monotherapy to Co-Administration of Both
The purpose of this study is to compare the percent change in LDL cholesterol induced by
 ezetimibe or simvastatin monotherapy and by co-administration of both agents in Black, White
 and Hispanic men. Ezetimibe is a drug that blocks sterol absorption and simvastatin blocks
 hepatic cholesterol biosynthesis. The hypothesis to be tested is that Blacks are likely to be
 more responsive to LDL lowering by ezetimibe than statins because Blacks have a low
 production of cholesterol.
Statins effectively lower plasma LDL cholesterol levels at the lowest recommended doses, and
 subsequent doubling of the dosage results in a modest additional reduction of about ~6%. A
 large inter-individual variability in the magnitude of the LDL-lowering response is seen in
 patients taking statins, as revealed by data provided to the P.I. by Merck & Co. Inc. Mean
 reductions in plasma levels of LDL-C and the variation in response (SD) are provided for ~300
 subjects taking only simvastatin, only ezetimibe or both ezetimibe and simvastatin. The
 mechanisms responsible for this inter-individual variability in lipid-lowering response is
 not known. The effect of ethnicity on the statin-associated LDL-lowering has only been
 examined in one study. In this study, directed attempts were made to implement the NCEP
 guidelines for secondary prevention using statins. Fewer Blacks than Whites reached the goal
 of treatment for plasma LDL-C levels, despite being seen more frequently in the clinic and
 having their lipoproteins measured more often. It was proposed that this difference was due
 to lower compliance with the drug regimen among Blacks. An alternative explanation for the
 ethnic difference in response to therapy is that the effectiveness of statins differs between
 ethnic groups.

 We hypothesize that Blacks are likely to be more responsive to agents that inhibit
 cholesterol absorption and less responsive to agents that interfere with cholesterol
 synthesis. This hypothesis is also based on the results of a recent study conducted in our
 laboratory that showed lower levels of lathosterol in Blacks than in Whites. Lathosterol is a
 precursor of cholesterol and therefore it is a marker of de novo synthesis of the sterol. In
 contrast, campesterol is a plant sterol and its plasma levels are assumed to be indicators of
 sterol absorption. To directly address the study question, an intervention study that
 compares the relative efficacy of ezetimibe and simvastatin will be carried out. In this aim
 we will answer the following questions:

 -  Do Blacks, Whites and Hispanics respond differently to simvastatin and ezetimibe?

 -  Do baseline levels of noncholesterol sterols and/or the campesterol:lathosterol ratios
 predict responsiveness to cholesterol-lowering drugs?

 -  Does the low level of plasma lathosterol in Blacks reflect reduced rates of cholesterol
 synthesis secondary to increased cholesterol absorption, and is the relative
 responsiveness to the two different classes of LDL-lowering agents used in the clinical
 trial related to the balance between cholesterol absorption and synthesis in an
 individual?

 The ultimate goal is to identify genetic or metabolic indices that can be used to
 individualize cholesterol lowering therapy, allowing the most effective therapeutic regimen
 to be selected. This is particularly important if long-term lipid lowering therapy is to be
 used in individuals whose short-term cardiovascular risk is low since it would be
 particularly desirable to use the most effective drugs at the lowest doses in this setting.

 This will be a randomized, double-blind, placebo-controlled, 4-period, crossover study of 26
 weeks duration comprising a 3-day screening period; a 2-week, single-blind placebo run-in
 period; and four 6-week, double-blind treatment periods. Each individual will be randomized
 to one of the four treatment sequences. Randomization will be stratified by race
 (Black/White); both Black and White subjects will be allocated in a 1:1:1:1 ratio to the 4
 treatment sequences. The Allocation schedule will be generated at Merck and Merck will
 maintain the blinding. There are 10 required clinic visits (visit 1,2,4,5,7,8,10,11,13,14),
 and 5 telephone contacts (visit 3,6,9,12) at the mid-point of each treatment period to review
 compliance with diet, study medications, and alcohol consumption requirements. A post-study
 follow-up will also be conducted via telephone for serious adverse experience review (visit
 15). Total visits will be 15 (10 clinic and 5 telephone) Each treatment period will last
 about 6 weeks. During the screening visit, subjects will undergo a physical exam, dietary
 assessment, vital signs (blood pressure, heart rate, and respirations), and provide blood (3
 tablespoons) sample for routine chemistries (metabolic comprehensive panel), complete blood
 count, liver function tests, thyroid test, and plasma cholesterol, triglyceride and
 lipoprotein cholesterol measurement by beta-estimation) levels, and a urine sample. Subjects
 meeting eligibility criteria will be scheduled to return for Visit 2 to begin a two-week
 single-blind placebo run-in phase. At Visit 3, subjects who, by pill count, miss no more than
 two tablets of the single-blind study medication will be randomized to one of the 4 treatment
 sequences. Subjects will take 2 pills each day. Vital signs will be performed at each visit.
 A physical will be completed at the end of the study. Serum chemistry measurements, plasma
 cholesterol and triglyceride levels, lipoprotein cholesterol by beta-quantitation,
 measurement of apolipoprotein B and measurement of non-cholesterol sterols will be measured
 at all visits (3-4 tablespoons of blood will be drawn). The analyses will be repeated in a
 separate plasma sample if the data are inconsistent or needs verification. Circulating levels
 of noncholesterol sterols will be measured by gas chromatography and mass-spectrometry, a
 routine procedure in our laboratory, in the same samples. Investigators will be blinded to
 lipid/lipoprotein values after Visit 1. Hematology and urinalysis will be performed at Visits
 1 and 14. Dietary counseling will be provided during the study. Also, DNA will be extracted
 from blood samples obtained during the trial to examine genes that control cholesterol
 metabolism.
Inclusion Criteria:

 -  Black, white and hispanic males between the ages of 20 to 70 years

 -  In good general health

 -  Having a body mass index (BMI) between 20 and 35 kg/m2

 -  Plasma LDL-C concentrations greater than or equal to 130 mg/dl but less than or equal
 to 175 mg/dL

 -  TG (triglyceride) levels less than or equal to 250 mg/dL.

 Exclusion Criteria:

 -  Any condition that would be likely to render the individual unable to complete the
 study

 -  Hypersensitivity to HMG-CoA reductase inhibitors

 -  Poor mental function, drug or substance abuse, or unstable psychiatric illnesses that
 may interfere with optimal participation in the study

 -  Treatment with another investigational drug within 30 days prior to Visit 1

 -  Alcohol consumption >14 drinks per week

 -  Phytosterol/phytostanol-containing products including margarines within 2 weeks

 -  History of CHD, peripheral vascular disease, cerebrovascular disease, CHF, or
 uncontrolled arrhythmias

 -  Creatinine >1.5 mg/dL, nephrotic syndrome, or other renal disease

 -  Fasting plasma glucose (FPG) >126 mg/dL or history of diabetes

 -  Abnormal TSH

 -  Uncontrolled hypertension (systolic BP >160 mm Hg and/or diastolic BP >100 mm Hg)

 -  Known active liver diseases or elevated serum transaminases (ALT and AST >1.5 times
 the upper limit of normal)

 -  Digestive disorders or any abdominal surgery within the past 6 months

 -  Cancer within the past 5 years (except for skin cancer)

 -  HIV, HBV, or HCV positive

 -  Lipid-lowering agents: bile-acid binding resins, HMG-CoA reductase inhibitors,
 ezetimibe, niacin (>200 mg/day), cholestin, fish oil, and fibrates, or cholesterol
 absorption inhibitors (e.g., neomycin) taken within 8 weeks prior to Visit 1

 -  Medications that are potent inhibitors of CYP3A4 (cyclosporine, systemic itraconazole
 or ketoconazole, erythromycin or clarithromycin, nefazodone, verapamil, amiodarone,
 and protease inhibitors)

 -  Anti-obesity medications: orlistat or sibutramine taken within 8 weeks prior to Visit
 1

 -  Systemic corticosteroids.