Efficacy of Lapaquistat Acetate Alone or Combined With Simvastatin in Subjects With Hypercholesterolemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00286481
First received: February 1, 2006
Last updated: May 23, 2012
Last verified: May 2012

February 1, 2006
May 23, 2012
March 2006
May 2007   (final data collection date for primary outcome measure)
Change from Baseline in Low Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
The primary endpoint will be change in fasting LDL-C at the end of study.
Complete list of historical versions of study NCT00286481 on ClinicalTrials.gov Archive Site
  • Adverse Events [ Time Frame: Weeks: 2, 4, 8, and 12 or Final Visit ] [ Designated as safety issue: Yes ]
  • Physical Examination [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: Yes ]
  • Safety Laboratory Tests [ Time Frame: Weeks: 2, 4, 8, and 12 or Final Visit ] [ Designated as safety issue: Yes ]
  • 12- lead Electrocardiogram assessments [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: Yes ]
  • Best Corrected Visual Acuity results [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: Yes ]
  • Vital Signs [ Time Frame: Weeks: 2, 4, 8, and 12 or Final Visit ] [ Designated as safety issue: Yes ]
  • Change from Baseline in Triglycerides [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Total Cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Very Low Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in apolipoprotein A1 [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in apolipoprotein B [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in non- High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in high-sensitivity C-reactive protein [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.59 mmol/L (100 mg/dL) [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.37 mmol/L (130 mg/dL) [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
  • Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 4.14 mmol/L (160 mg/dL) [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]
Not Provided
Not Provided
Not Provided
 
Efficacy of Lapaquistat Acetate Alone or Combined With Simvastatin in Subjects With Hypercholesterolemia
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

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Hypercholesterolemia
  • Drug: Lapaquistat acetate and simvastatin
    Lapaquistat acetate 50 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.
    Other Names:
    • TAK-475
    • Zocor
  • Drug: Lapaquistat acetate and simvastatin
    Lapaquistat acetate 100 mg, tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.
    Other Names:
    • TAK-475
    • Zocor
  • Drug: Simvastatin
    Lapaquistat acetate placebo-matching tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.
    Other Name: Zocor
  • Experimental: Lapaquistat Acetate 50 mg QD + Simvastatin
    Intervention: Drug: Lapaquistat acetate and simvastatin
  • Experimental: Lapaquistat Acetate 100 mg QD + Simvastatin
    Intervention: Drug: Lapaquistat acetate and simvastatin
  • Active Comparator: Simvastatin
    Intervention: Drug: Simvastatin
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
1362
May 2007
May 2007   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada
 
NCT00286481
01-05-TL-475-020, U1111-1122-7978
No
Takeda
Takeda
Not Provided
Study Director: Medical Director Takeda
Takeda
May 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP