Clinical trial NCT00487994: Safety and Efficacy of Lapaquistat Acetate Taken Alone and With Atorvastatin in Subjects With Primary Dyslipidemia
Official title: A Double-Blind, Randomized, Parallel Group Study to Evaluate the Safety, Tolerability and Efficacy of Lapaquistat Acetate Alone or Coadministered With Atorvastatin in Subjects With Primary Dyslipidemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Dyslipidemia
Keywords: Hypercholesterolemia
Hyperlipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2007-06-19
Enrollment: 2130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the overall safety of Lapaquistat Acetate, once daily (QD), by itself or in combination with atorvastatin in subjects with primary dyslipidemia.

Detailed description: According to the World Health Organization, CHD is now the leading cause of death worldwide. In 2001, CHD caused 7.2 million deaths and estimates for 2020 indicate that annual CHD deaths will increase to 11.1 million. These statistics suggest that improved options are needed to treat hypercholesterolemia and dyslipidemia.

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.

Eligibility criteria: Inclusion Criteria:

* Has a confirmatory central laboratory result with low density lipoprotein cholesterol greater than or equal to 3.37 mmol/L and less than 5.69 mmol/L, and triglyceride less than 4.52 mmol/L.
* 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:

* Coronary Heart Disease or Coronary Heart Disease-risk factors comprised of:

  * 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.

Primary outcomes:
measure: Lens Opacity Classification System findings
timeFrame: Weeks 24, 48, 72, and 96 or Final Visit
measure: Best corrected visual acuity
timeFrame: Weeks 24, 48, 72, and 96 or Final Visit
measure: Adverse Events
timeFrame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit
measure: Clinical Laboratory Tests
timeFrame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit
measure: Vital signs (blood pressure and pulse rate) and weight
timeFrame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit
measure: 12-lead Electrocardiogram
timeFrame: Weeks 48 and 96 or Final Visit
measure: Physical Examination
timeFrame: Weeks 48 and 96 or Final Visit
Secondary outcomes:
measure: Change from Baseline in Low Density Lipoprotein cholesterol
timeFrame: Week 96 or Final Visit
measure: Change from Baseline in High Density Lipoprotein cholesterol
timeFrame: Week 96 or Final Visit
measure: Change from Baseline in Total Cholesterol
timeFrame: Week 96 or Final Visit
measure: Change from Baseline in Triglycerides
timeFrame: Week 96 or Final Visit
measure: Change from Baseline in Very Low Density Lipoprotein cholesterol
timeFrame: Week 96 or Final Visit
measure: Change from Baseline in Apolipoprotein A1
timeFrame: Week 96 or Final Visit
measure: Change from Baseline in Apolipoprotein B
timeFrame: Week 96 or Final Visit
Other outcomes:
Locations:
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city: Evansville
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state: Indiana
city: Indianapolis
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state: Iowa
city: Kansas City
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state: Kansas
city: Overland Park
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state: Kansas
city: Louisville
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state: Kentucky
city: New Orleans
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state: Louisiana
city: Flint
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state: Michigan
city: Edina
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state: Minnesota
city: St. Louis
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state: Missouri
city: Omaha
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state: Nebraska
city: Ship Bottom
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state: New Jersey
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city: Syracuse
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state: New York
city: Charlotte
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state: North Carolina
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state: North Carolina
city: Winston-Salem
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state: North Carolina
city: Cincinatti
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city: Tulsa
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state: Oklahoma
city: Philadelphia
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state: Pennsylvania
city: Tipton
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state: Pennsylvania
city: Anderson
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state: South Carolina
city: Mt. Pleasant
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state: South Carolina
city: Simpsonville
country: United States
state: South Carolina
city: Cordova
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state: Tennessee
city: Morristown
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state: Tennessee
city: Corpus Christi
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state: Texas
city: Dallas
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state: Texas
city: Fort Worth
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city: Houston
country: United States
state: Texas
city: Plano
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city: San Antonio
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city: Temple
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city: Texarkana
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state: Texas
city: Norfolk
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state: Virginia
city: Richmond
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state: Virginia
city: Lakewood
country: United States
state: Washington
city: Buenos Aires
country: Argentina
city: Ciudad Autonoma de Buenos Aires
country: Argentina
city: Cordoba
country: Argentina
city: La Plata
country: Argentina
city: Moron
country: Argentina
city: Pilar
country: Argentina
city: Rosario
country: Argentina
city: Salta
country: Argentina
city: Santa Fe
country: Argentina
city: Santiago de Chile
country: Chile
city: Brno
country: Czech Republic
city: Olomouc
country: Czech Republic
city: Praha
country: Czech Republic
city: Tartu
country: Estonia
city: Berlin
country: Germany
city: Freiburg
country: Germany
city: Görlitz
country: Germany
city: Hamburg
country: Germany
city: Mannheim
country: Germany
city: Munich
country: Germany
city: Mönchengladbach
country: Germany
city: Schwerin
country: Germany
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Esztergom
country: Hungary
city: Gyula
country: Hungary
city: Győr
country: Hungary
city: Kecskemét
country: Hungary
city: Warszawa
country: Hungary
city: Riga
country: Latvia
city: Kaunas
country: Lithuania
city: Vilnius-21
country: Lithuania
city: Vilnius
country: Lithuania
city: Distrito Federal
country: Mexico
city: Guadalajara
country: Mexico
city: Jalisco
country: Mexico
city: Mexico City
country: Mexico
city: San Luis Potosi
country: Mexico
city: Zapopan
country: Mexico
city: Es Velp
country: Netherlands
city: Groningen
country: Netherlands
city: Leiden
country: Netherlands
city: Rotterdam
country: Netherlands
city: Zoetermeer
country: Netherlands
city: Lima
country: Peru
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Gdansk
country: Poland
city: Gorzow Wielkopolski
country: Poland
city: Grudziadz
country: Poland
city: Plonsk
country: Poland
city: Torun
country: Poland
city: Wloclawek
country: Poland
city: Wroclaw
country: Poland
city: Moscow
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Saratov
country: Russian Federation
city: Komárno
country: Slovakia
city: Kosice
country: Slovakia
city: Levice
country: Slovakia
city: Cape Town
country: South Africa
city: Johannesburg
country: South Africa
city: Parow
country: South Africa
city: Western Cape
country: South Africa
city: Truro
country: United Kingdom
state: Cornwall
city: Blackpool
country: United Kingdom
state: Lancashire
city: Bolton
country: United Kingdom
state: Lancashire
city: Guildford
country: United Kingdom
state: Surrey
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.