Efficacy of Lapaquistat Acetate and Atorvastatin on Blood Cholesterol Levels in Subjects With Primary Hypercholesterolemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00143676
First received: August 31, 2005
Last updated: May 23, 2012
Last verified: May 2012
  Purpose

The purpose of this study is to determine the efficacy of lapaquistat acetate, once daily (QD), on lowering cholesterol in subjects already taking atorvastatin.


Condition Intervention Phase
Hypercholesterolemia
Drug: Lapaquistat acetate and atorvastatin
Drug: Atorvastatin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized Placebo-controlled Study to Evaluate the Efficacy and Safety of TAK-475 50 mg, 100 mg, or Placebo When Co-administered With Atorvastatin (10 mg to 40 mg) in Subjects With Primary 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 24 or Final Visit ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Adverse Events [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: Yes ]
  • Physical Examination [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: Yes ]
  • Safety Laboratory Tests [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: Yes ]
  • Electrocardiogram assessments [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: Yes ]
  • Best Corrected Visual Acuity results [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: Yes ]
  • Vital Signs [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: Yes ]
  • Change from Baseline in Triglycerides [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Total Cholesterol [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in High Density Lipoprotein cholesterol [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Very Low Density Lipoprotein cholesterol [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in apolipoprotein A1 [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in apolipoprotein B [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in non- High Density Lipoprotein cholesterol [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density Lipoprotein cholesterol [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in high-sensitivity C-reactive protein [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 1.813 mmol/L (70 mg/dL) [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.590 mmol/L (100 mg/dL) [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.367 mmol/L (130 mg/dL) [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]

Enrollment: 448
Study Start Date: August 2005
Study Completion Date: August 2006
Primary Completion Date: August 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lapaquistat Acetate 50 mg QD + Atorvastatin Drug: Lapaquistat acetate and atorvastatin
Lapaquistat acetate 50 mg, tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Other Names:
  • Lapaquistat
  • Lipitor
  • TAK-475
Experimental: Lapaquistat Acetate 100 mg QD + Atorvastatin Drug: Lapaquistat acetate and atorvastatin
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Other Names:
  • Lapaquistat
  • Lipitor
  • TAK475
Active Comparator: Atorvastatin Drug: Atorvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg to 40 mg stable dose for up to 24 weeks.
Other Name: Lipitor

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.

This study will assess the effects of co-administration of lapaquistat acetate with atorvastatin, the most commonly prescribed statin in the United States, on LDL-C and associated lipid variables in subjects with hypercholesterolemia. Study Participation is anticipated to be up to 24 weeks.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Female subjects of childbearing potential must not be pregnant as determined by a negative serum human chorionic gonadotropin, lactating, or planning on becoming pregnant, and agrees to use acceptable forms of contraception during the study.
  • Must have a mean low density lipoprotein cholesterol value greater than or equal to 2.590 mmol/L (100 mg/dL) for 2 consecutive samples
  • Must have a mean triglyceride value less than or equal to 4.516 mmol/L (400 mg/dL) for 2 consecutive samples.
  • Has taken a stable dose of atorvastatin (10 to 40 mg)
  • Has clinical laboratory evaluations within reference range for the testing laboratory.
  • Is willing and able to continue to comply with a standardized low-cholesterol diet.

Exclusion Criteria:

  • Has an alanine aminotransferase or aspartate aminotransferase level greater than 1.5 times the upper limit of normal, active liver disease or jaundice.
  • Has a serum creatinine level greater than 135 μmol/L (1.5 mg/dL).
  • Has a creatine phosphokinase level greater than 3 times the upper limit of normal
  • Has diabetes with a hemoglobin A1c level greater than 8% at Visit 1.
  • Has a history of cancer in remission for less than 5 years prior to the first dose of study drug.
  • Has an endocrine disorder, such as Cushing's syndrome, hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid metabolism.
  • Has a history of myocardial infarction, unstable angina, transient ischemic attacks, cerebrovascular accident, percutaneous coronary intervention, or coronary or peripheral arterial surgery.
  • Has a positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or the subject's verbal report.
  • Has a positive human immunodeficiency virus status or was taking antiretroviral medications as determined by medical history and/or the subject's verbal report.
  • Has had 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 atorvastatin.
  • Has a history or presence of clinically significant food allergy that would prevent adherence to the recommended diet.
  • Has a known homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia.
  • Has fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain.
  • Has uncontrolled hypertension
  • Has inflammatory bowel disease or any other malabsorption syndrome or has had gastric bypass or any other surgical procedure for weight loss.
  • 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 reduce life expectancy, impair successful management according to the protocol, or make the subject an unsuitable candidate to receive study drug.
  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: NCT00143676

  Hide Study Locations
Locations
United States, Alabama
Birmingham, Alabama, United States
Northport, Alabama, United States
United States, Arizona
Sierra Vista, Arizona, United States
Tucson, Arizona, United States
United States, Arkansas
Jonesboro, Arkansas, United States
Searcy, Arkansas, United States
United States, California
Anaheim, California, United States
Carmichael, California, United States
Chula Vista, California, United States
Escondido, California, United States
Pismo Beach, California, United States
Santa Rosa, California, United States
United States, Colorado
Golden, Colorado, United States
United States, Connecticut
Waterbury, Connecticut, United States
United States, Florida
Clearwater, Florida, United States
Daytona Beach, Florida, United States
Hollywood, Florida, United States
Jacksonville, Florida, United States
Jupiter, Florida, United States
Kissimmee, Florida, United States
Miami, Florida, United States
New Port Richey, Florida, United States
Ocala, Florida, United States
Pembroke Pines, Florida, United States
West Palm Beach, Florida, United States
United States, Hawaii
Honolulu, Hawaii, United States
United States, Illinois
Arlington Heights, Illinois, United States
Chicago, Illinois, United States
Peoria, Illinois, United States
United States, Indiana
Bloomington, Indiana, United States
Evansville, Indiana, United States
Indianapolis, Indiana, United States
United States, Iowa
Waterloo, Iowa, United States
United States, Kansas
Arkansas City, Kansas, United States
Kansas City, Kansas, United States
Overland Park, Kansas, United States
Wichita, Kansas, United States
United States, Kentucky
Louisville, Kentucky, United States
United States, Maine
Auburn, Maine, United States
United States, Michigan
Livonia, Michigan, United States
United States, Minnesota
Edina, Minnesota, United States
United States, Nebraska
Omaha, Nebraska, United States
United States, Nevada
Las Vegas, Nevada, United States
United States, New Jersey
Edison, New Jersey, United States
Margate, New Jersey, United States
United States, New York
New Hyde Park, New York, United States
Rochester, New York, United States
Syracuse, New York, United States
United States, North Carolina
Hickory, North Carolina, United States
Raleigh, North Carolina, United States
Statesville, North Carolina, United States
Winston-Salem, North Carolina, United States
United States, Ohio
Cincinnati, Ohio, United States
United States, Oklahoma
Tulsa, Oklahoma, United States
United States, Oregon
Medford, Oregon, United States
Portland, Oregon, United States
United States, Pennsylvania
Allentown, Pennsylvania, United States
Altoona, Pennsylvania, United States
Downingtown, Pennsylvania, United States
Sellerville, Pennsylvania, United States
Tipton, Pennsylvania, United States
United States, Rhode Island
Warwick, Rhode Island, United States
United States, South Carolina
Charleston, South Carolina, United States
Mt. Pleasant, South Carolina, United States
Simpsonville, South Carolina, United States
United States, Tennessee
Chattanooga, Tennessee, United States
Morristown, Tennessee, United States
United States, Texas
Corpus Christi, Texas, United States
Dallas, Texas, United States
Euless, Texas, United States
San Antonio, Texas, United States
The Colony, Texas, United States
United States, Utah
Ogden, Utah, United States
Salt Lake City, Utah, United States
United States, Virginia
Norfolk, Virginia, United States
Richmond, Virginia, United States
United States, Washington
Renton, Washington, United States
United States, Wisconsin
Madison, Wisconsin, United States
Sponsors and Collaborators
Takeda
Investigators
Study Director: Medical Director Takeda
  More Information

Publications:
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00143676     History of Changes
Other Study ID Numbers: 01-04-TL-475-009, U1111-1122-7783
Study First Received: August 31, 2005
Last Updated: May 23, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Takeda:
Hyperlipidemia
Dyslipidemia
Drug Therapy

Additional relevant MeSH terms:
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Atorvastatin
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 September 18, 2014