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

NCT ID: NCT00286481

Last Updated: 2012-05-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1362 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-03-31
• Study Completion Date: 2007-05-31

Brief Summary

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

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.

Conditions

Hypercholesterolemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Lapaquistat Acetate 50 mg QD + Simvastatin

Group Type: EXPERIMENTAL

Lapaquistat acetate and simvastatin

Intervention Type: DRUG

Lapaquistat acetate 50 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.

Lapaquistat Acetate 100 mg QD + Simvastatin

Group Type: EXPERIMENTAL

Lapaquistat acetate and simvastatin

Intervention Type: DRUG

Lapaquistat acetate 100 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.

Simvastatin

Group Type: ACTIVE_COMPARATOR

Simvastatin

Intervention Type: DRUG

Lapaquistat acetate placebo-matching tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.

Interventions

Lapaquistat acetate and simvastatin

Lapaquistat acetate 50 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.

Intervention Type: DRUG

Lapaquistat acetate and simvastatin

Lapaquistat acetate 100 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.

Intervention Type: DRUG

Simvastatin

Lapaquistat acetate placebo-matching tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.

Intervention Type: DRUG

Other Intervention Names

TAK-475; Zocor; TAK-475; Zocor; Zocor

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

Huntsville, Alabama, United States

Chandler, Arizona, United States

Scottsdale, Arizona, United States

Sierra Vista, Arizona, United States

Tucson, Arizona, United States

Beverly Hills, California, United States

Long Beach, California, United States

Sacramento, California, United States

Spring Valley, California, United States

Colorado Springs, Colorado, United States

Hialeah, Florida, United States

Hollywood, Florida, United States

Jacksonville, Florida, United States

Jupiter, Florida, United States

Kissimmee, Florida, United States

Miami, Florida, United States

Ocala, Florida, United States

Pembroke Pines, Florida, United States

Pinellas Park, Florida, United States

Stuart, Florida, United States

West Palm Beach, Florida, United States

Arlington Heights, Illinois, United States

Chicago, Illinois, United States

Peoria, Illinois, United States

Indianapolis, Indiana, United States

Overland Park, Kansas, United States

Wichita, Kansas, United States

Louisville, Kentucky, United States

Edina, Minnesota, United States

St Louis, Missouri, United States

Las Vegas, Nevada, United States

Margate City, New Jersey, United States

Raleigh, North Carolina, United States

Statesville, North Carolina, United States

Winston-Salem, North Carolina, United States

Cincinnati, Ohio, United States

Columbus, Ohio, United States

Kettering, Ohio, United States

Bartlesville, Oklahoma, United States

Portland, Oregon, United States

Beaver, Pennsylvania, United States

Downingtown, Pennsylvania, United States

Tipton, Pennsylvania, United States

Goose Creek, South Carolina, United States

Jackson, Tennessee, United States

Nashville, Tennessee, United States

San Antonio, Texas, United States

Norfolk, Virginia, United States

Richmond, Virginia, United States

Lakewood, Washington, United States

Abbotsford, British Columbia, Canada

Coquitlam, British Columbia, Canada

Victoria, British Columbia, Canada

Winnipeg, Manitoba, Canada

Mount Pearl, Newfoundland and Labrador, Canada

St. John's, Newfoundland and Labrador, Canada

Cornwall, Ontario, Canada

London, Ontario, Canada

Oakville, Ontario, Canada

Oshawa, Ontario, Canada

Thornhill, Ontario, Canada

Toronto, Ontario, Canada

Cornwall, Prince Edward Island, Canada

Mirabel, Quebec, Canada

Saint-Lambert, Quebec, Canada

Sherbrooke, Quebec, Canada

Ste-Foy, Quebec, Canada

Countries

United States; Canada

References

Stein EA, Bays H, O'Brien D, Pedicano J, Piper E, Spezzi A. Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011 May 10;123(18):1974-85. doi: 10.1161/CIRCULATIONAHA.110.975284. Epub 2011 Apr 25.

Reference Type: RESULT

PMID: 21518985 (View on PubMed)

Other Identifiers

U1111-1122-7978

Identifier Type: REGISTRY

Identifier Source: secondary_id

01-05-TL-475-020

Identifier Type: -

Identifier Source: org_study_id