Efficacy of Lapaquistat Acetate Alone or Combined With Simvastatin in Subjects With Hypercholesterolemia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate lapaquistat acetate, once daily (QD), taken alone or with simvastatin on cholesterol levels in treating patients with elevated cholesterol.

Detailed Description
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Elevated plasma cholesterol (hypercholesterolemia) and various other plasma lipid imbalances (dyslipidemias) are major risk factors for coronary heart disease. Patients with hypercholesterolemia have elevated low-density lipoprotein cholesterol, which leads to atherosclerotic deposition of cholesterol in the arterial walls. As identified by the National Cholesterol Education Program Adult Treatment Panel III, lowering the low-density lipoprotein cholesterol plasma concentration effectively reduces cardiovascular morbidity and mortality and is essential for the prevention and management of coronary heart disease. Currently, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are the first-line monotherapies prescribed to reduce low-density lipoprotein cholesterol, after diet and therapeutic lifestyle change. However, low doses of statins often fail to produce the ATP III-recommended levels of low-density lipoprotein cholesterol reduction, making it necessary to increase the dose or add an additional treatment. Dose increases of statins in turn may result in decreased tolerability and potential safety concerns which contribute to the high discontinuation rates of statins and their prescription at low, and often ineffective, doses. The purpose of this study is to determine whether administration of lapaquistat acetate co-administered with simvastatin will be more efficacious in lowering low-density lipoprotein cholesterol, compared to lapaquistat or simvastatin alone. Total participation time in this study is anticipated to be 19 weeks.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled Factorial Study to Evaluate the Efficacy and Safety of Lapaquistat and Simvastatin Alone and in Combination in Subjects With Hypercholesterolemia

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Lapaquistat acetate and simvastatin
* Drug: Lapaquistat acetate and simvastatin
* Drug: Simvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Woman of childbearing potential can not to be pregnant, lactating, not planning on becoming pregnant, and agree to use acceptable forms of contraception throughout the course of the study. Prior to Randomization, has a low-density lipoprotein cholesterol level mean greater than or equal to 3.37 mmol/L and less than or equal to 5.70 mmol/L. Prior to Randomization, has a mean triglyceride level less than or equal to 4.52 mmol/L (400 mg/dL). Has clinical laboratory evaluations including clinical chemistry, hematology, and urinalysis within the defined reference range. Exclusion Criteria: Has an alanine aminotransferase or aspartate aminotransferase level of greater than 1.5 times the upper limit of normal, active liver disease or jaundice. Has a serum creatinine of greater than 133 μmol/L. Has a creatine kinase greater than 3 times the upper limit of normal. Has type 1 or 2 diabetes mellitus. Has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication. 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 factors that conferred a 10-year risk for coronary heart disease greater than 20% based on Framingham risk scoring. Has a positive hepatitis B surface antigen, or antibody to hepatitis C virus, as determined by medical history and/or subject's verbal report. Has a positive human immunodeficiency virus status or was taking antiretroviral medications, as determined by medical history. Has exposure to lapaquistat acetate in other studies, was participating in another investigational study, or had participated in an investigational study within the past 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 known hypersensitivity or history of adverse reaction to simvastatin. Has a known hypersensitivity or history of adverse reaction to simvastatin. Has a history or presence of clinically significant food allergy that would prevent adherence to the recommended 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, any other malabsorption syndrome, or had gastric bypass or any other surgical procedure for weight loss. Is unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments. Has a history of drug abuse or a history of alcohol abuse within the past 2 years. Has any other serious disease or condition that might reduced life expectancy, impaired successful management according to the protocol, or make the participant an unsuitable candidate to receive study medication.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapaquistat Acetate 50 mg QD + Simvastatin<br> | Drug: Lapaquistat acetate and simvastatin<br>* Lapaquistat acetate 50 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.<br>* Other names: Zocor;|
| Experimental: Lapaquistat Acetate 100 mg QD + Simvastatin<br> | Drug: Lapaquistat acetate and simvastatin<br>* Lapaquistat acetate 100 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.<br>* Other names: Zocor;|
| Active Comparator: Simvastatin<br> | Drug: Simvastatin<br>* Lapaquistat acetate placebo-matching tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.<br>* Other names: Zocor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Low Density Lipoprotein cholesterol |  | Week 12 or Final Visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | Weeks: 2, 4, 8, and 12 or Final Visit | 
| Physical Examination |  | Week 12 or Final Visit | 
| Safety Laboratory Tests |  | Weeks: 2, 4, 8, and 12 or Final Visit | 
| 12- lead Electrocardiogram assessments |  | Week 12 or Final Visit | 
| Best Corrected Visual Acuity results |  | Week 12 or Final Visit | 
| Vital Signs |  | Weeks: 2, 4, 8, and 12 or Final Visit | 
| Change from Baseline in Triglycerides |  | Week 12 or Final Visit | 
| Change from Baseline in Total Cholesterol |  | Week 12 or Final Visit | 
| Change from Baseline in High Density Lipoprotein cholesterol |  | Week 12 or Final Visit | 
| Change from Baseline in Very Low Density Lipoprotein cholesterol |  | Week 12 or Final Visit | 
| Change from Baseline in apolipoprotein A1 |  | Week 12 or Final Visit | 
| Change from Baseline in apolipoprotein B |  | Week 12 or Final Visit | 
| Change from Baseline in non- High Density Lipoprotein cholesterol |  | Week 12 or Final Visit | 
| Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density |  | Week 12 or Final Visit | 
| Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol |  | Week 12 or Final Visit | 
| Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B |  | Week 12 or Final Visit | 
| Change from Baseline in high-sensitivity C-reactive protein |  | Week 12 or Final Visit | 
| Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.59 mmol/L (100 mg/dL) |  | Week 12 or Final Visit | 
| Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.37 mmol/L (130 mg/dL) |  | Week 12 or Final Visit | 
| Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 4.14 mmol/L (160 mg/dL) |  | Week 12 or Final Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperlipidemia, Drug Therapy