Safety and Efficacy of Lapaquistat Acetate Taken Alone and With Atorvastatin in Subjects With Primary Dyslipidemia
NCT ID: NCT00487994
Last Updated: 2012-05-24
Study Results
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Basic Information
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COMPLETED
PHASE3
2130 participants
INTERVENTIONAL
2004-11-30
2007-05-31
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.
Study Participation is anticipated to be up to two years.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Lapaquistat Acetate 100 mg QD
Lapaquistat acetate
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin placebo-matching capsules, orally, once daily for up to 96 weeks.
Lapaquistat Acetate 100 mg QD + Atorvastatin 10 mg QD
Lapaquistat acetate and atorvastatin
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 weeks.
Atorvastatin 10 mg QD
Atorvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 weeks.
Interventions
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Lapaquistat acetate
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin placebo-matching capsules, orally, once daily for up to 96 weeks.
Lapaquistat acetate and atorvastatin
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 weeks.
Atorvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 weeks.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Females of child-bearing age must have undergone surgical sterilization, hysterectomy, tubal ligation, or bilateral oophorectomy; other female subjects must have been postmenopausal.
* Must be in good physical and mental health as determined by a physician on the basis of medical history, physical examination, and laboratory results.
* Has a fasting low density lipoprotein cholesterol level greater than or equal to 3.37 mmol/L and less than 4.92 mmol/L, and a triglyceride value less than 4.52 mmol/L.
Exclusion Criteria
* Diabetes mellitus type 1 or 2.
* History or presence of myocardial infarction, angina pectoris, unstable angina, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft), aortic aneurysm, transient ischemic attacks, or cerebrovascular accident.
* A body mass index less than 15 or greater than 35.
* A history or presence of:
* Drug abuse or a history of alcohol abuse within the 2 years previous to screening.
* Uncontrolled hypertension despite medical treatment
* Thyroid disease, particularly hyperthyroidism or subjects whose thyroid replacement therapy was initiated within the previous 3 months.
* Human immunodeficiency virus-positive status, or hepatitis B or C infection.
* Malignancy, except subjects whose malignancy had been diagnosed as stage I basal or squamous cell carcinoma.
* Heterozygous or homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia.
* Fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain and/or discontinuation of statins due to myalgia.
* Trauma to the eye or eye irradiation; glaucoma; iritis; uveitis; prior intraocular surgery, laser surgery to the iris, retinal photocoagulation, or laser trabeculoplasty; corneal opacification or other medial opacities; or had undergone LASIK refractive surgery within 6 months prior to screening.
* A clinically significant food allergy that would prevent adherence to the specialized diet.
* Any other serious disease or condition that might have affected life expectancy or made it difficult to successfully manage and monitor the subject according to the protocol.
* Has a known hypersensitivity or history of adverse reaction to atorvastatin or to lapaquistat acetate.
* Is taking part in another investigational study or had been participating in an investigational study within the 30 days prior to Screening Visit 1.
* Has an alanine aminotransferase or aspartate aminotransferase level greater than 2 times the upper limit of normal, active liver disease, jaundice, serum creatinine greater than 135 μmol/L (1.5 mg/dL), or creatine kinase greater than 3 times the upper limit of normal.
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
Mobile, Alabama, United States
Northport, Alabama, United States
Chandler, Arizona, United States
Phoenix, Arizona, United States
Sierra Vista, Arizona, United States
Jonesboro, Arkansas, United States
Little Rock, Arkansas, United States
Anaheim, California, United States
Rancho Cucamonga, California, United States
Santa Rosa, California, United States
Golden, Colorado, United States
Coral Gables, Florida, United States
Fort Myers, Florida, United States
Jacksonville, Florida, United States
Sarasota, Florida, United States
West Palm Beach, Florida, United States
Dunwoody, Georgia, United States
Boise, Idaho, United States
Idaho Falls, Idaho, United States
Arlington Heights, Illinois, United States
Chicago, Illinois, United States
Elk Grove Village, Illinois, United States
Evansville, Indiana, United States
Indianapolis, Indiana, United States
Waterloo, Iowa, United States
Kansas City, Kansas, United States
Overland Park, Kansas, United States
Louisville, Kentucky, United States
New Orleans, Louisiana, United States
Flint, Michigan, United States
Edina, Minnesota, United States
St Louis, Missouri, United States
Omaha, Nebraska, United States
Ship Bottom, New Jersey, United States
Rochester, New York, United States
Syracuse, New York, United States
Charlotte, North Carolina, United States
Statesville, North Carolina, United States
Wilmington, North Carolina, United States
Winston-Salem, North Carolina, United States
Cincinnati, Ohio, United States
Tulsa, Oklahoma, United States
Philadelphia, Pennsylvania, United States
Tipton, Pennsylvania, United States
Anderson, South Carolina, United States
Mt. Pleasant, South Carolina, United States
Simpsonville, South Carolina, United States
Cordova, Tennessee, United States
Morristown, Tennessee, United States
Corpus Christi, Texas, United States
Dallas, Texas, United States
Fort Worth, Texas, United States
Houston, Texas, United States
Plano, Texas, United States
San Antonio, Texas, United States
Temple, Texas, United States
Texarkana, Texas, United States
Norfolk, Virginia, United States
Richmond, Virginia, United States
Lakewood, Washington, United States
Buenos Aires, , Argentina
Córdoba, , Argentina
La Plata, , Argentina
Morón, , Argentina
Pilar, , Argentina
Rosario, , Argentina
Salta, , Argentina
Santa Fe, , Argentina
Santiago, , Chile
Brno, , Czechia
Olomouc, , Czechia
Prague, , Czechia
Tartu, , Estonia
Berlin, , Germany
Freiburg im Breisgau, , Germany
Görlitz, , Germany
Hamburg, , Germany
Mannheim, , Germany
Mönchengladbach, , Germany
Munich, , Germany
Schwerin, , Germany
Budapest, , Hungary
Debrecen, , Hungary
Esztergom, , Hungary
Győr, , Hungary
Gyula, , Hungary
Kecskemét, , Hungary
Warszawa, , Hungary
Riga, , Latvia
Kaunas, , Lithuania
Vilnius, , Lithuania
Vilnius-21, , Lithuania
Distrito Federal, , Mexico
Guadalajara, , Mexico
Jalisco, , Mexico
Mexico City, , Mexico
San Luis Potosí City, , Mexico
Zapopan, , Mexico
Es Velp, , Netherlands
Groningen, , Netherlands
Leiden, , Netherlands
Rotterdam, , Netherlands
Zoetermeer, , Netherlands
Lima, , Peru
Bialystok, , Poland
Bydgoszcz, , Poland
Gdansk, , Poland
Gorzów Wielkopolski, , Poland
Grudziądz, , Poland
Płońsk, , Poland
Torun, , Poland
Wroclaw, , Poland
Włocławek, , Poland
Moscow, , Russia
Saint Petersburg, , Russia
Saratov, , Russia
Komárno, , Slovakia
Košice, , Slovakia
Levice, , Slovakia
Cape Town, , South Africa
Johannesburg, , South Africa
Parow, , South Africa
Western Cape, , South Africa
Truro, Cornwall, United Kingdom
Blackpool, Lancashire, United Kingdom
Bolton, Lancashire, United Kingdom
Guildford, Surrey, United Kingdom
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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2004-000775-34
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
U1111-1122-7619
Identifier Type: REGISTRY
Identifier Source: secondary_id
01-04-TL-475-002
Identifier Type: -
Identifier Source: org_study_id
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