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
  Purpose

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.


Condition Intervention Phase
Hypercholesterolemia
Drug: Lapaquistat acetate and simvastatin
Drug: Simvastatin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Change from Baseline in Low Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 1362
Study Start Date: March 2006
Study Completion Date: May 2007
Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lapaquistat Acetate 50 mg QD + Simvastatin 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
Experimental: Lapaquistat Acetate 100 mg QD + Simvastatin 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
Active Comparator: Simvastatin Drug: Simvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and stable dose of simvastatin for up to 12 weeks.
Other Name: Zocor

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00286481

  Show 67 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: Medical Director Takeda
  More Information

Publications:
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00286481     History of Changes
Other Study ID Numbers: 01-05-TL-475-020, U1111-1122-7978
Study First Received: February 1, 2006
Last Updated: May 23, 2012
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Mexico: Federal Commission for Protection Against Health Risks
Chile: Instituto de Salud Pública de Chile
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs

Keywords provided by Takeda:
Hyperlipidemia
Drug Therapy

Additional relevant MeSH terms:
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014