Efficacy of Lapaquistat Acetate on Blood Cholesterol Levels in Treating Subjects With Hypercholesterolemia

• Double Blind: The primary objective is to evaluate the reduction in LDL-C [ Time Frame: 12 weeks ]
• Open label: Evaluate the long-term safety and lipid variables after open-label treatment [ Time Frame: 48 weeks ]

• Change from Baseline in Total Cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in Very Low Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in apolipoprotein A1 Timeframe: Week 12 or Final Visit [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in apolipoprotein B [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in non- High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in Triglycerides [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]

The purpose of the study is to determine the reduction of LDL-cholesterol level after treatment with 50 mg per day of lapaquistat acetate once daily (QD).

This study is being conducted to determine the potential of lapaquistat acetate 50 mg per day to lower LDL-C levels compared with placebo. This study is also being conducted to further evaluate the safety and tolerability of lapaquistat acetate 50 mg over a period of 12 weeks. An optional, 48-week, open-label extension will follow the 12 week, double-blind treatment period to evaluate the long-term safety and tolerability of lapaquistat acetate 50 mg/day.

• Drug: Lapaquistat acetate
  Lapaquistat acetate 50 mg, tablets, orally, once daily for up to 12 weeks.
  Other Name: TAK-475
• Drug: Placebo
  Lapaquistat acetate placebo-matching tablets, orally, once daily for up to 12 weeks.

• Experimental: Lapaquistat Acetate 50 mg QD
  Intervention: Drug: Lapaquistat acetate
• Placebo Comparator: Placebo QD
  Intervention: Drug: Placebo

Inclusion Criteria:

• Females of childbearing potential who are sexually active must agree to use adequate contraception from screening throughout the duration of the study and for 30 days following the last dose.
• Prior to Randomization, the participant has a mean low density lipoprotein cholesterol level greater than or equal to 130 mg/dL and less than or equal to 190 mg/dL for 2 consecutive samples.
• Prior to Randomization, the subject has mean triglyceride level greater than or equal to 400 mg/dL for 2 consecutive samples.
• Is willing and able to comply with the recommended, standardized diet.

Exclusion Criteria:

• Has an nine aminotransferase or aspartate aminotransferase level greater than 1.5 times the upper limit of normal, identified during screening.
• Has a serum creatinine greater than 133 mmol/L, identified during screening.
• Has a creatine kinase greater than 3 times the upper limit of normal, identified during screening.
• Has active liver disease or jaundice.
• Has taken any fibrates within 42 days of Visit 1 or any lipid-lowering therapy for at least 30 days prior to Screening.
• Has a previous history of cancer that has been in remission for less than 5 years prior to the first dose of study medication.
• Has an endocrine disorder, such as Cushing's syndrome, hyperthyroidism, or inappropriately treated hypothyroidism affecting lipid metabolism.
• Has a history of myocardial infarction, angina pectoris, unstable angina, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary angioplasty, coronary or peripheral arterial surgery, or multiple risk factors that confer a 10-year risk for cardiovascular heart disease greater than 20% based on Framingham risk scoring.
• Has a positive hepatitis B surface antigen or hepatitis C virus antibody test, as determined by medical history.
• Has a positive human immunodeficiency virus status or is taking antiretroviral medications, as determined by medical history and/or subject's verbal report.
• Has received any investigational medication 30 days prior to screening, (for drugs with a long half-life, within a period of less than 5 times the drug's half-life) or is participating in an investigational study.
• Has received lapaquistat acetate in a previous clinical study or as a therapeutic agent.
• Has a history or presence of clinically significant food allergy that would prevent adherence to the specialized 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 had inflammatory bowel disease or any other malabsorption syndrome, or has had gastric bypass or any other surgical procedure for weight loss.
• Has a history of drug abuse or a history of high alcohol intake within the previous 2 years.
• Has type 1 or 2 diabetes mellitus.