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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Lapaquistat acetate and simvastatin; Drug: Lapaquistat acetate and simvastatin; Drug: Simvastatin

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.

• Study Type: Interventional
• Enrollment (Actual): 1362
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Abbotsford, British Columbia, Canada
    • Coquitlam, British Columbia, Canada
    • Victoria, British Columbia, Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada
  • Newfoundland and Labrador
    • Mount Pearl, Newfoundland and Labrador, Canada
    • St. John's, Newfoundland and Labrador, Canada
  • Ontario
    • Cornwall, Ontario, Canada
    • London, Ontario, Canada
    • Oakville, Ontario, Canada
    • Oshawa, Ontario, Canada
    • Thornhill, Ontario, Canada
    • Toronto, Ontario, Canada
  • Prince Edward Island
    • Cornwall, Prince Edward Island, Canada
  • Quebec
    • Mirabel, Quebec, Canada
    • Sherbrooke, Quebec, Canada
    • St. Lambert, Quebec, Canada
    • Ste-Foy, Quebec, Canada
• United States
  • Alabama
    • Huntsville, Alabama, United States
  • Arizona
    • Chandler, Arizona, United States
    • Scottsdale, Arizona, United States
    • Sierra Vista, Arizona, United States
    • Tucson, Arizona, United States
  • California
    • Beverly Hills, California, United States
    • Long Beach, California, United States
    • Sacramento, California, United States
    • Spring Valley, California, United States
  • Colorado
    • Colorado Springs, Colorado, United States
  • Florida
    • 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
  • Illinois
    • Arlington Heights, Illinois, United States
    • Chicago, Illinois, United States
    • Peoria, Illinois, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Kansas
    • Overland Park, Kansas, United States
    • Wichita, Kansas, United States
  • Kentucky
    • Louisville, Kentucky, United States
  • Minnesota
    • Edina, Minnesota, United States
  • Missouri
    • St. Louis, Missouri, United States
  • Nevada
    • Las Vegas, Nevada, United States
  • New Jersey
    • Margate City, New Jersey, United States
  • North Carolina
    • Raleigh, North Carolina, United States
    • Statesville, North Carolina, United States
    • Winston-Salem, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Columbus, Ohio, United States
    • Kettering, Ohio, United States
  • Oklahoma
    • Bartlesville, Oklahoma, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Beaver, Pennsylvania, United States
    • Downingtown, Pennsylvania, United States
    • Tipton, Pennsylvania, United States
  • South Carolina
    • Goose Creek, South Carolina, United States
  • Tennessee
    • Jackson, Tennessee, United States
    • Nashville, Tennessee, United States
  • Texas
    • San Antonio, Texas, United States
  • Virginia
    • Norfolk, Virginia, United States
    • Richmond, Virginia, United States
  • Washington
    • Lakewood, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Simvastatin	Drug: Simvastatin; Lapaquistat acetate placebo-matching tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.; Other Names: Zocor
Experimental: Lapaquistat Acetate 50 mg QD + Simvastatin	Drug: Lapaquistat acetate and simvastatin; Lapaquistat acetate 50 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.; Other Names: Zocor; TAK-475; Drug: Lapaquistat acetate and simvastatin; Lapaquistat acetate 100 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.; Other Names: Zocor; TAK-475
Experimental: Lapaquistat Acetate 100 mg QD + Simvastatin	Drug: Lapaquistat acetate and simvastatin; Lapaquistat acetate 50 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.; Other Names: Zocor; TAK-475; Drug: Lapaquistat acetate and simvastatin; Lapaquistat acetate 100 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.; Other Names: Zocor; TAK-475

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
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 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 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 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
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 the ratio of Low Density Lipoprotein cholesterol/High Density	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

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Actual): May 1, 2007
• Study Completion (Actual): May 1, 2007

Study Registration Dates

• First Submitted: February 1, 2006
• First Submitted That Met QC Criteria: February 1, 2006
• First Posted (Estimate): February 3, 2006

Study Record Updates

• Last Update Posted (Estimate): May 24, 2012
• Last Update Submitted That Met QC Criteria: May 23, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Drug Therapy; Hyperlipidemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: 01-05-TL-475-020; U1111-1122-7978 (Registry Identifier: WHO)