Clinical trial NCT00249899: Efficacy of Lapaquistat Acetate Alone or Combined With High-Dose Statin Therapy in Subjects With Hypercholesterolemia
Official title: A Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat or Placebo When Co-Administered With High Dose Statin Therapy in Subjects With Primary Hypercholesterolemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hypercholesterolemia
Keywords: Hyperlipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2005-11-07
Enrollment: 649
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 lapaquistat acetate, once daily (QD), taken alone or with additional statin therapy 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 atorvastatin, rosuvastatin or simvastatin (stable statin therapy) will be more efficacious in lowering low-density lipoprotein cholesterol, compared to lapaquistat or stable statin therapy alone. Total participation time in this study is anticipated to be 24 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.
* The subject had taken the highest recommended dose of a statin for at least 4 weeks prior to Visit 1.

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.
* The subject had a known hypersensitivity or history of adverse reaction to atorvastatin, simvastatin or rosuvastatin.
* 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 24 or Final Visit
Secondary outcomes:
measure: Adverse Events
timeFrame: Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit
measure: Physical Examination
timeFrame: Week 24 or Final Visit
measure: Safety Laboratory Tests
timeFrame: Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit
measure: 12- lead Electrocardiogram assessments
timeFrame: Week 24 or Final Visit
measure: Best Corrected Visual Acuity results
timeFrame: Week 24 or Final Visit
measure: Vital Signs
timeFrame: Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit
measure: Change from Baseline in Triglycerides
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in Total Cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in High Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in Very Low Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in apolipoprotein A1
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in apolipoprotein B
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in non- High Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in high-sensitivity C-reactive protein
timeFrame: Week 24 or Final Visit
measure: Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 1.81 mmol/L (70 mg/dL)
timeFrame: Week 24 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 24 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 24 or Final Visit
Other outcomes:
Locations:
city: Santa Ana
country: United States
state: California
city: Chicago
country: United States
state: Illinois
city: Iowa City
country: United States
state: Iowa
city: Kansas City
country: United States
state: Kansas
city: Auburn
country: United States
state: Maine
city: Scarborough
country: United States
state: Maine
city: Baltimore
country: United States
state: Maryland
city: Saint Louis
country: United States
state: Missouri
city: Concord
country: United States
state: New Hampshire
city: Cincinnati
country: United States
state: Ohio
city: Houston
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Seattle
country: United States
state: Washington
city: Calgary
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Chicoutimi
country: Canada
state: Quebec
city: Laval
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Ste-Foy
country: Canada
state: Quebec
city: Bellville
country: South Africa
city: Johannesburg
country: South Africa
city: Parow
country: South Africa
city: Pretoria
country: South Africa
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.