Effect of Lapaquistat Acetate on Blood Cholesterol Levels in Subjects With Elevated Cholesterol

A Double-blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 100 mg Versus Placebo in Subjects With Primary Hypercholesterolemia

The purpose of this study is to determine if patients with elevated cholesterol, but not taking any other lipid medication, could lower their cholesterol with administration of lapaquistat acetate, once daily (QD).

This study will evaluate the efficacy and safety of TAK-475 (lapaquistat acetate) compared to placebo in subjects with primary hypercholesterolemia. Subjects who have signed the informed consent will undergo necessary evaluations to determine eligibility for a dietary run-in phase. Subjects who meet randomization criteria will enter treatment with one of the following randomized treatments: lapaquistat acetate or placebo.

Inclusion Criteria:

• Female participants of childbearing potential cannot be been pregnant, lactating and are not planning on becoming pregnant and agrees to use acceptable forms of contraception throughout the course of this study.
• Must have a mean low-density lipoprotein cholesterol values between 3.367 and 5.689 mmol/L, inclusive, from 2 consecutive samples taken at least 1 week apart with the difference between the 2 values not exceeding 15% of the higher value.
• Must have a triglyceride value of 4.516 mmol/L or less from 2 consecutive samples taken at least 1 week apart with the upper value from either sample being 5.081 mmol/L or less.
• Has clinical laboratory evaluations within the reference ranges for the testing laboratory unless the results were deemed not clinically significant by the investigator or sponsor.
• Is willing and able to maintain a standardized low-cholesterol diet.

Exclusion Criteria:

• Has an alanine aminotransferase or aspartate aminotransferase level greater than 1.5 times the upper limit of normal, active liver disease or jaundice.
• Has a serum creatinine level greater than 135 μmol/L.
• Has a creatine phosphokinase value greater than three times the upper limit of normal.
• Has diabetes mellitus type 1 or 2.
• Has a history of cancer that had been in remission for less than 5 years prior to the first dose of study drug. This criterion did not include subjects with basal cell or stage I squamous cell carcinoma of the skin.
• Has an endocrine disorder, such as Cushing syndrome, hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid metabolism.
• Has a history of myocardial infarction, angina pectoris, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary revascularization or multiple risk factors that present a 10-year risk for CHD of greater than 20%, based on Framingham risk scoring.
• Has a positive hepatitis B surface antigen or hepatitis C virus antibody, as determined by medical history and/or participant's verbal report.
• Has a positive human immunodeficiency virus test result or was taking antiretroviral medications, as determined by medical history and/or subject's verbal report.
• Is unable or unwilling to discontinue excluded medications or to continue stable doses of "stable dose" medications or would require treatment with any excluded medication during the study.
• Has had exposure to lapaquistat acetate in other studies or was participating or enrolled in another investigational study within the previous 30 days or, for drugs with a long half-life, within a period of less than 5 times the drug's half-life.
• Has a history or presence of a clinically significant food allergy that would prevent adherence to the therapeutic lifestyle change (or equivalent) diet.
• Has a known heterozygous or homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia (familial dysbetalipoproteinemia).
• Has fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain.
• Has uncontrolled hypertension.
• Has inflammatory bowel disease or any other malabsorption syndrome or had gastric bypass or any other surgical procedure for weight loss.
• Has a history of drug abuse or alcohol abuse within the past 2 years.
• Has any other serious disease or condition at Run-In or at Randomization that might reduce life expectancy, impair successful management according to the protocol, or make the subject an unsuitable candidate to receive study drug.