Efficacy of Lapaquistat Acetate and Atorvastatin on Blood Cholesterol Levels in Subjects With Primary Hypercholesterolemia
NCT ID: NCT00143676
Last Updated: 2012-05-24
Study Results
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Basic Information
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COMPLETED
PHASE3
448 participants
INTERVENTIONAL
2005-08-31
2006-08-31
Brief Summary
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Detailed Description
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The balance among cholesterol synthesis, dietary intake, and degradation is normally adequate to maintain healthy cholesterol plasma levels. However, in patients with hypercholesterolemia, elevated low-density lipoprotein cholesterol leads to atherosclerotic deposition of cholesterol in the arterial walls. Consequently, in this population it has been established that lowering low-density lipoprotein cholesterol plasma concentrations effectively reduces cardiovascular morbidity and mortality. The National Cholesterol Education Program Adult Treatment Panel III has therefore identified control of low-density lipoprotein cholesterol as essential in the prevention and management of CHD. Additional lipid risk factors designated by National Cholesterol Education Program Adult Treatment Panel III include elevated triglycerides, elevated non-high-density lipoprotein cholesterol (atherogenic lipoproteins), and low levels of high-density lipoprotein cholesterol. Lipoproteins rich in triglycerides, such as very-low-density lipoprotein cholesterol, appear to contribute to atherosclerosis, whereas the apparent protective effect of high-density lipoprotein cholesterol, which is likely related to high-density lipoprotein cholesterol-facilitated transport of cholesterol away from atherosclerotic deposits, may be limited at low high-density lipoprotein cholesterol concentrations.
Initial dietary and lifestyle measures taken to control dyslipidemia are often inadequate, and most patients require pharmacologic intervention. Currently, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line monotherapies most often prescribed to reduce low-density lipoprotein cholesterol, after diet and therapeutic lifestyle change. However, with statin monotherapy, many patients fail to reach National Cholesterol Education Program Adult Treatment Panel III recommended levels of low-density lipoprotein cholesterol reduction. As a result, the statin dosage must be increased or an additional treatment added to achieve treatment goals. Increasing the statin dosage may result in decreased tolerability and potential safety concerns, contributing to the high discontinuation rates of statins and their prescription at low and often ineffective doses. Further, although the effectiveness of increasing the dose varies among the statins, in general, doubling of the dose above the minimum effective dose has been found to decrease serum low-density lipoprotein cholesterol by only an additional 6 percent.
TGRD is developing an orally active squalene synthase inhibitor, TAK-475 (lapaquistat acetate) for the treatment of dyslipidemia. Lapaquistat acetate inhibits the biosynthesis of cholesterol by inhibiting the enzyme squalene synthase, which catalyzes the conversion of farnesyl diphosphate to squalene-a precursor in the final steps of cholesterol production.
This study will assess the effects of co-administration of lapaquistat acetate with atorvastatin, the most commonly prescribed statin in the United States, on LDL-C and associated lipid variables in subjects with hypercholesterolemia. Study Participation is anticipated to be up to 24 weeks.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Lapaquistat Acetate 50 mg QD + Atorvastatin
Lapaquistat acetate and atorvastatin
Lapaquistat acetate 50 mg, tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Lapaquistat Acetate 100 mg QD + Atorvastatin
Lapaquistat acetate and atorvastatin
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Atorvastatin
Atorvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Interventions
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Lapaquistat acetate and atorvastatin
Lapaquistat acetate 50 mg, tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Lapaquistat acetate and atorvastatin
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Atorvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Must have a mean low density lipoprotein cholesterol value greater than or equal to 2.590 mmol/L (100 mg/dL) for 2 consecutive samples
* Must have a mean triglyceride value less than or equal to 4.516 mmol/L (400 mg/dL) for 2 consecutive samples.
* Has taken a stable dose of atorvastatin (10 to 40 mg)
* Has clinical laboratory evaluations within reference range for the testing laboratory.
* Is willing and able to continue to comply with a standardized low-cholesterol diet.
Exclusion Criteria
* Has a serum creatinine level greater than 135 μmol/L (1.5 mg/dL).
* Has a creatine phosphokinase level greater than 3 times the upper limit of normal
* Has diabetes with a hemoglobin A1c level greater than 8% at Visit 1.
* Has a history of cancer in remission for less than 5 years prior to the first dose of study drug.
* Has an endocrine disorder, such as Cushing's syndrome, hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid metabolism.
* Has a history of myocardial infarction, unstable angina, transient ischemic attacks, cerebrovascular accident, percutaneous coronary intervention, or coronary or peripheral arterial surgery.
* Has a positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or the subject's verbal report.
* Has a positive human immunodeficiency virus status or was taking antiretroviral medications as determined by medical history and/or the subject's verbal report.
* Has had 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 atorvastatin.
* Has a history or presence of clinically significant food allergy that would prevent adherence to the recommended diet.
* Has a known homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia.
* Has fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain.
* Has uncontrolled hypertension
* Has 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 alcohol abuse within the past 2 years.
* Has any other serious disease or condition that might reduce life expectancy, impair successful management according to the protocol, or make the subject an unsuitable candidate to receive study drug.
18 Years
ALL
No
Sponsors
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Takeda
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Director
Role: STUDY_DIRECTOR
Takeda
Locations
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Birmingham, Alabama, United States
Northport, Alabama, United States
Sierra Vista, Arizona, United States
Tucson, Arizona, United States
Jonesboro, Arkansas, United States
Searcy, Arkansas, United States
Anaheim, California, United States
Carmichael, California, United States
Chula Vista, California, United States
Escondido, California, United States
Pismo Beach, California, United States
Santa Rosa, California, United States
Golden, Colorado, United States
Waterbury, Connecticut, United States
Clearwater, Florida, United States
Daytona Beach, Florida, United States
Hollywood, Florida, United States
Jacksonville, Florida, United States
Jupiter, Florida, United States
Kissimmee, Florida, United States
Miami, Florida, United States
New Port Richey, Florida, United States
Ocala, Florida, United States
Pembroke Pines, Florida, United States
West Palm Beach, Florida, United States
Honolulu, Hawaii, United States
Arlington Heights, Illinois, United States
Chicago, Illinois, United States
Peoria, Illinois, United States
Bloomington, Indiana, United States
Evansville, Indiana, United States
Indianapolis, Indiana, United States
Waterloo, Iowa, United States
Arkansas City, Kansas, United States
Kansas City, Kansas, United States
Overland Park, Kansas, United States
Wichita, Kansas, United States
Louisville, Kentucky, United States
Auburn, Maine, United States
Livonia, Michigan, United States
Edina, Minnesota, United States
Omaha, Nebraska, United States
Las Vegas, Nevada, United States
Edison, New Jersey, United States
Margate City, New Jersey, United States
New Hyde Park, New York, United States
Rochester, New York, United States
Syracuse, New York, United States
Hickory, North Carolina, United States
Raleigh, North Carolina, United States
Statesville, North Carolina, United States
Winston-Salem, North Carolina, United States
Cincinnati, Ohio, United States
Tulsa, Oklahoma, United States
Medford, Oregon, United States
Portland, Oregon, United States
Allentown, Pennsylvania, United States
Altoona, Pennsylvania, United States
Downingtown, Pennsylvania, United States
Sellerville, Pennsylvania, United States
Tipton, Pennsylvania, United States
Warwick, Rhode Island, United States
Charleston, South Carolina, United States
Mt. Pleasant, South Carolina, United States
Simpsonville, South Carolina, United States
Chattanooga, Tennessee, United States
Morristown, Tennessee, United States
Corpus Christi, Texas, United States
Dallas, Texas, United States
Euless, Texas, United States
San Antonio, Texas, United States
The Colony, Texas, United States
Ogden, Utah, United States
Salt Lake City, Utah, United States
Norfolk, Virginia, United States
Richmond, Virginia, United States
Renton, Washington, United States
Madison, Wisconsin, United States
Countries
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References
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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.
Other Identifiers
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U1111-1122-7783
Identifier Type: REGISTRY
Identifier Source: secondary_id
01-04-TL-475-009
Identifier Type: -
Identifier Source: org_study_id
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