Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE)(P02578AM3)(COMPLETED)

• Proportion of subjects with a reduction in ultrasound-determined average carotid artery IMT between baseline and endpoint. [ Time Frame: 24 months ]
• Change in ultrasound-determined maximum carotid artery IMT on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ]
• Proportion of subjects developing new carotid artery plaques between baseline and endpoint. [ Time Frame: 24 months ]
• Change in ultrasound-determined average carotid artery plus average common femoral artery IMT on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ]

The purpose of the study is to determine whether ezetimibe plus simvastatin will be more effective than simvastatin alone in preventing progression of atherosclerosis of the inner layer of the carotid artery.

• Atherosclerosis
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

• Drug: ezetimibe (plus simvastatin)
  oral tablets; ezetimibe 10 mg (plus simvastatin 80 mg) once daily for 24 months
  Other Names:

  • ZETIA
  • VYTORIN
  • SCH 58235
  • SCH 465981
• Drug: placebo (plus simvastatin)
  tablets; placebo to match ezetimibe 10 mg (plus simvastatin 80 mg) once daily for 24 months

• Experimental: EZ/Simva
  Intervention: Drug: ezetimibe (plus simvastatin)
• Placebo Comparator: Placebo/Simva
  Intervention: Drug: placebo (plus simvastatin)

• Kastelein JJ, Sager PT, de Groot E, Veltri E. Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia. Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. Am Heart J. 2005 Feb;149(2):234-9.
• Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3;358(14):1431-43. Epub 2008 Mar 30.

Inclusion Criteria:

• Genotype-confirmed heterozygous familial hypercholesterolemia with written documentation of the genetic diagnosis at the time of screening and LDL-C >=210 mg/dL (5.43 mmol/L), or clinical diagnosis of heterozygous familial hypercholesterolemia, defined as LDL-C >=210 mg/dL (5.43 mmol/L) and at least one of the following:

  • tendinous xanthoma
  • child <18 years of age with hypercholesterolemia (LDL-C >159 mg/dL (4.11 mmol/L)
  • has a sibling with hypercholesterolemia (LDL-C >190 mg/dL [4.91 mmol/L]) and tendinous xanthoma
  • family history with an LDL-C value distribution pattern compatible with dominant autosomal transmission and at least one relative presenting fasting total cholesterol values >348 mg/dL (9.0 mmol/L) after exclusion of secondary causes of dyslipidemia
• LDL-C >=210 mg/dL (5.43 mmol/L) 1 week before randomization
• plasma triglyceride level <=400 mg/dL (4.52 mmol/L)

Exclusion Criteria:

• pregnancy or any other situation, condition, or illness that, in the opinion of the investigator, may interfere with optimal participation in the study
• presence of an apolipoprotein B gene mutation with confirmed absence of an LDL receptor mutation in either allele
• undergoing LDL-apheresis or plasma apheresis
• unsuitable plaque or artery morphology
• use of certain drugs, foods, or other agents known to alter cholesterol levels or to cause pharmacokinetic interactions with either ezetimibe or simvastatin