Comparison of Efficacy and Safety of Ezetimibe or Statin Monotherapy to Co-Administration of Both
Condition: Cholesterol, LDL
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Ezetimibe and Simvastatin
Intervention type(s): Drug
Intervention MeSH terms: Simvastatin; Ezetimibe
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Cholesterol; LDL; Ezetimibe; Statin; Zetia; Zocor; Simvastin