Clinical trial NCT00286481: Efficacy of Lapaquistat Acetate Alone or Combined With Simvastatin in Subjects With Hypercholesterolemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Keywords: Hyperlipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2006-02-03
Enrollment: 1362
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change from Baseline in Low Density Lipoprotein cholesterol
timeFrame: Week 12 or Final Visit
Secondary outcomes:
measure: Adverse Events
timeFrame: Weeks: 2, 4, 8, and 12 or Final Visit
measure: Physical Examination
timeFrame: Week 12 or Final Visit
measure: Safety Laboratory Tests
timeFrame: Weeks: 2, 4, 8, and 12 or Final Visit
measure: 12- lead Electrocardiogram assessments
timeFrame: Week 12 or Final Visit
measure: Best Corrected Visual Acuity results
timeFrame: Week 12 or Final Visit
measure: Vital Signs
timeFrame: Weeks: 2, 4, 8, and 12 or Final Visit
measure: Change from Baseline in Triglycerides
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in Total Cholesterol
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in High Density Lipoprotein cholesterol
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in Very Low Density Lipoprotein cholesterol
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in apolipoprotein A1
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in apolipoprotein B
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in non- High Density Lipoprotein cholesterol
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B
timeFrame: Week 12 or Final Visit
measure: Change from Baseline in high-sensitivity C-reactive protein
timeFrame: Week 12 or Final Visit
measure: Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.59 mmol/L (100 mg/dL)
timeFrame: Week 12 or Final Visit
measure: Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.37 mmol/L (130 mg/dL)
timeFrame: Week 12 or Final Visit
measure: Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 4.14 mmol/L (160 mg/dL)
timeFrame: Week 12 or Final Visit
Other outcomes:
Locations:
city: Huntsville
country: United States
state: Alabama
city: Chandler
country: United States
state: Arizona
city: Scottsdale
country: United States
state: Arizona
city: Sierra Vista
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Beverly Hills
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Sacramento
country: United States
state: California
city: Spring Valley
country: United States
state: California
city: Colorado Springs
country: United States
state: Colorado
city: Hialeah
country: United States
state: Florida
city: Hollywood
country: United States
state: Florida
city: Jacksonville
country: United States
state: Florida
city: Jupiter
country: United States
state: Florida
city: Kissimmee
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Ocala
country: United States
state: Florida
city: Pembroke Pines
country: United States
state: Florida
city: Pinellas Park
country: United States
state: Florida
city: Stuart
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Arlington Heights
country: United States
state: Illinois
city: Chicago
country: United States
state: Illinois
city: Peoria
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Overland Park
country: United States
state: Kansas
city: Wichita
country: United States
state: Kansas
city: Louisville
country: United States
state: Kentucky
city: Edina
country: United States
state: Minnesota
city: St. Louis
country: United States
state: Missouri
city: Las Vegas
country: United States
state: Nevada
city: Margate City
country: United States
state: New Jersey
city: Raleigh
country: United States
state: North Carolina
city: Statesville
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Kettering
country: United States
state: Ohio
city: Bartlesville
country: United States
state: Oklahoma
city: Portland
country: United States
state: Oregon
city: Beaver
country: United States
state: Pennsylvania
city: Downingtown
country: United States
state: Pennsylvania
city: Tipton
country: United States
state: Pennsylvania
city: Goose Creek
country: United States
state: South Carolina
city: Jackson
country: United States
state: Tennessee
city: Nashville
country: United States
state: Tennessee
city: San Antonio
country: United States
state: Texas
city: Norfolk
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Lakewood
country: United States
state: Washington
city: Abbotsford
country: Canada
state: British Columbia
city: Coquitlam
country: Canada
state: British Columbia
city: Victoria
country: Canada
state: British Columbia
city: Winnipeg
country: Canada
state: Manitoba
city: Mount Pearl
country: Canada
state: Newfoundland and Labrador
city: St. John's
country: Canada
state: Newfoundland and Labrador
city: Cornwall
country: Canada
state: Ontario
city: London
country: Canada
state: Ontario
city: Oakville
country: Canada
state: Ontario
city: Oshawa
country: Canada
state: Ontario
city: Thornhill
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Cornwall
country: Canada
state: Prince Edward Island
city: Mirabel
country: Canada
state: Quebec
city: Sherbrooke
country: Canada
state: Quebec
city: St. Lambert
country: Canada
state: Quebec
city: Ste-Foy
country: Canada
state: Quebec
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.