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Effect of Lapaquistat Acetate Combined With Fenofibrate on Blood Cholesterol Levels

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00813527
Recruitment Status : Completed
First Posted : December 23, 2008
Last Update Posted : May 24, 2012
Information provided by (Responsible Party):

Brief Summary:
The purpose of this study is to compare changes in cholesterol levels in patients with elevated blood cholesterol with administration of lapaquistat acetate, once daily (QD), and fenofibrate.

Condition or disease Intervention/treatment Phase
Hyperlipidemias Drug: Lapaquistat acetate and fenofibrate Drug: Fenofibrate Phase 2

Detailed Description:

Elevated plasma cholesterol (hypercholesterolemia) and various other plasma lipid imbalances (dyslipidemias) are major risk factors for coronary heart disease. It has been established that lowering the low-density lipoprotein cholesterol plasma concentration effectively reduces cardiovascular morbidity and mortality. As a result of this finding, the National Cholesterol Education Program Adult Treatment Panel III identifies control of low-density lipoprotein cholesterol as essential in 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 Adult Treatment Panel III-recommended levels of low-density lipoprotein cholesterol reduction, making it necessary to increase the dose or add an additional treatment. This in turn may result in decreased tolerability and potential safety concerns.

At higher doses, statins are associated with various myopathies ranging from rare occurrences of rhabdomyolysis and myositis to more frequent symptoms of muscle weakness, cramps, or pain; these can occur with mild or no increases in creatine kinase. Statin use also is associated with increases in liver transaminase levels. These tolerability and safety concerns may contribute to the high discontinuation rates of statins and their prescription at low, and often ineffective, doses.

TAK-475 (lapaquistat acetate) inhibits the cholesterol synthesis pathway at a different step than statins (acting on squalene synthase rather than 3-hydroxy-3-methylglutaryl coenzyme A); it does not reduce concentrations of isoprenylated intermediates believed to be responsible for the myopathies associated with statin use.

This study was conducted to determine whether lapaquistat acetate with fenofibrate has the potential to be more effective than fenofibrate by itself in lowering low-density lipoprotein cholesterol.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 213 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 or Placebo When Coadministered With Fenofibrate in Subjects With Combined Hyperlipidemia
Study Start Date : February 2006
Actual Primary Completion Date : January 2007
Actual Study Completion Date : January 2007

Resource links provided by the National Library of Medicine

Drug Information available for: Fenofibrate

Arm Intervention/treatment
Experimental: Lapaquistat Acetate 100 mg QD + Fenofibrate 145 mg QD Drug: Lapaquistat acetate and fenofibrate
Lapaquistat acetate 100 mg, tablets, orally, once daily and fenofibrate 145 mg, tablets, orally, once daily for up to 12 weeks.
Other Names:
  • Lapaquistat
  • TAK-475

Active Comparator: Fenofibrate 145 mg QD Drug: Fenofibrate
Lapaquistat acetate placebo-matching tablets, orally, once daily and fenofibrate 145 mg, tablets, orally, once daily for up to 12 weeks.
Other Names:
  • Tricor
  • Trilipix

Primary Outcome Measures :
  1. Percent change from Baseline in direct fasting plasma low-density lipoprotein cholesterol. [ Time Frame: Week 12 or Final Visit. ]

Secondary Outcome Measures :
  1. Change from baseline in calculated low-density lipoprotein cholesterol. [ Time Frame: Week 12 or Final Visit. ]
  2. Change from baseline in non- high-density lipoprotein cholesterol. [ Time Frame: Week 12 or Final Visit. ]
  3. Change from baseline in total cholesterol. [ Time Frame: Week 12 or Final Visit. ]
  4. Change from baseline in apolipoprotein B. [ Time Frame: Week 12 or Final Visit. ]
  5. Change from baseline in triglycerides. [ Time Frame: Week 12 or Final Visit. ]
  6. Change from baseline in high-density lipoprotein cholesterol. [ Time Frame: Week 12 or Final Visit. ]
  7. Change from baseline in apolipoprotein A1. [ Time Frame: Week 12 or Final Visit. ]
  8. Change from baseline in very-low-density lipoprotein cholesterol. [ Time Frame: Week 12 or Final Visit. ]
  9. Change from baseline in derived ratios including total cholesterol/high-density lipoprotein cholesterol, low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, and apolipoprotein B/ apolipoprotein Al. [ Time Frame: Week 12 or Final Visit. ]
  10. Change from baseline in high-sensitivity C-reactive protein. [ Time Frame: Week 12 or Final Visit. ]
  11. Percentage of Subjects Achieving Target Direct low-density lipoprotein cholesterol Levels. [ Time Frame: Week 12 or Final Visit. ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Women of childbearing potential must not be pregnant as determined by a negative serum human chorionic gonadotropin, not lactating, not planning on becoming pregnant between Screening and 30 days following the last dose of study medication, and agreed to use acceptable forms of contraception during the study.
  • Prior to Randomization, must have a mean low density lipoprotein cholesterol greater than or equal to 100 mg/dL (2.59 mmol/L) for 2 consecutive samples. The difference between the two individual low density lipoprotein cholesterol values not to exceed 15% of the higher value.
  • Prior to Randomization, must have mean triglycerides greater than or equal to 150 and less than or equal to 600 mg/dL (1.70 and 6.78 mmol/L, respectively) for 2 consecutive samples. The upper value for either triglycerides sample must have been less than or equal to 650 mg/dL (7.35 mmol/L).
  • Clinical laboratory evaluations (including clinical chemistry [fasted for at least 10 hours], hematology and urinalysis) within the reference range for the testing laboratory unless results deemed not clinically significant or considered within normal limits for this subject by the investigator or the sponsor.
  • Willing and able to continue to comply with a standardized low cholesterol diet.

Exclusion Criteria:

  • Alanine aminotransferase or aspartate aminotransferase level of greater than 1.5 times the upper limit of normal, active liver disease or jaundice.
  • Serum creatinine greater than 1.5 mg/dL (133 μmol/L).
  • Creatine phosphokinase greater than 3 times the upper limit of normal.
  • Diabetes with a hemoglobin A1c greater than 8 % at Visit 1.
  • Previous history of cancer in remission for less than 5 years prior to the first dose of study medication. Does not include those subjects with basal cell or stage I squamous cell carcinoma of the skin.
  • An endocrine disorder, such as Cushing's syndrome, hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid metabolism. Subjects with hypothyroidism on appropriate replacement therapy (defined as stable thyroid hormone replacement therapy at least 3 months prior to Visit 1 and thyrotropin levels less than 1.5 times the upper limit of normal) are eligible for enrollment. If thyrotropin is greater than 1.5 times upper limit of normal, a free thyroxine level is to be determined. If the free thyroxine is within normal limits for that subject, the subject may continue in the study.
  • History of myocardial infarction, unstable angina, transient ischemic attacks, cerebrovascular accident, percutaneous coronary intervention, coronary or peripheral arterial surgery (bypass graft surgery) in the 6 months prior to Visit 1.
  • Positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or subject's verbal report.
  • Positive human immunodeficiency virus status or is taking anti-retroviral medications, as determined by medical history and/or subject's verbal report.
  • Unable or unwilling to discontinue excluded medications or to continue stable doses of "stable dose" medications or required treatment with any excluded medication during the study.
  • Exposure to TAK-475 in other studies or currently is participating in another investigational study or has 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 halflife.
  • Known hypersensitivity or history of adverse reaction to any fibrate.
  • History or presence of clinically significant food allergy that would prevent adherence to the therapeutic lifestyle change (or equivalent) diet.
  • Known homozygous familial hypercholesterolemia or known Type III hyperlipoproteinemia (familial dysbetalipoproteinemia).
  • Active cholecystitis or known cholelithiasis (a fibrate risk factor).
  • Severe renal or hepatic dysfunction, including biliary cirrhosis during Run-In or at Randomization (a fibrate risk factor).
  • Fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain.
  • Uncontrolled hypertension (defined as resting diastolic blood pressure greater than100 mm Hg or resting systolic blood pressure greater than 160 mm Hg) at Visit 1.
  • Inflammatory bowel disease or any other malabsorption syndrome or has had gastric bypass or any other surgical procedure for weight loss.
  • Unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments.
  • Unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent was available.
  • History of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic drinks per day) within the past 2 years.
  • Any other serious disease or condition at Screening or at Randomization that might reduce life expectancy, impair successful management according to the protocol, or make the subject an unsuitable candidate to receive study medication.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00813527

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United States, Alabama
Huntsville, Alabama, United States
United States, Arizona
Sierra Vista, Arizona, United States
United States, California
Beverly Hills, California, United States
Long Beach, California, United States
Spring Valley, California, United States
United States, Colorado
Colorado Springs, Colorado, United States
Golden, Colorado, United States
United States, Connecticut
Waterbury, Connecticut, United States
United States, Florida
Jacksonville, Florida, United States
Kissimmee, Florida, United States
Miami, Florida, United States
Ocala, Florida, United States
Pembroke Pines, Florida, United States
Pinellas Park, Florida, United States
West Palm Beach, Florida, United States
United States, Georgia
Warner Robins, Georgia, United States
United States, Illinois
Chicago, Illinois, United States
Peoria, Illinois, United States
United States, Indiana
Indianapolis, Indiana, United States
United States, Kansas
Wichita, Kansas, United States
United States, Minnesota
Edina, Minnesota, United States
United States, Missouri
St. Louis, Missouri, United States
United States, North Carolina
Raleigh, North Carolina, United States
Winston-Salem, North Carolina, United States
United States, Ohio
Cincinnati, Ohio, United States
Columbus, Ohio, United States
United States, Oregon
Hillsboro, Oregon, United States
United States, Pennsylvania
Beaver, Pennsylvania, United States
United States, South Carolina
Goose Creek, South Carolina, United States
United States, Tennessee
Nashville, Tennessee, United States
United States, Virginia
Norfolk, Virginia, United States
Richmond, Virginia, United States
Canada, British Columbia
Coquitlam, British Columbia, Canada
Victoria, British Columbia, Canada
Canada, Ontario
London, Ontario, Canada
Toronto, Ontario, Canada
Sponsors and Collaborators
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Study Director: Senior Medical Director Takeda
Publications of Results:
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Responsible Party: Takeda Identifier: NCT00813527    
Other Study ID Numbers: 01-05-TL-475-031
U1111-1122-8178 ( Registry Identifier: WHO )
First Posted: December 23, 2008    Key Record Dates
Last Update Posted: May 24, 2012
Last Verified: May 2012
Keywords provided by Takeda:
Drug Therapy
Lipid Metabolism Disorders
Additional relevant MeSH terms:
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Lipid Metabolism Disorders
Metabolic Diseases
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents