Effect of Lapaquistat Acetate Combined With Fenofibrate on Blood Cholesterol Levels
Information source: Takeda
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hyperlipidemias
Intervention: Lapaquistat acetate and fenofibrate (Drug); Fenofibrate (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: Takeda Official(s) and/or principal investigator(s): Senior Medical Director, Study Director, Affiliation: Takeda
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.
Clinical Details
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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Percent change from Baseline in direct fasting plasma low-density lipoprotein cholesterol.
Secondary outcome: Change from baseline in calculated low-density lipoprotein cholesterol.Change from baseline in non- high-density lipoprotein cholesterol. Change from baseline in total cholesterol. Change from baseline in apolipoprotein B. Change from baseline in triglycerides. Change from baseline in high-density lipoprotein cholesterol. Change from baseline in apolipoprotein A1. Change from baseline in very-low-density lipoprotein cholesterol. 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. Change from baseline in high-sensitivity C-reactive protein. Percentage of Subjects Achieving Target Direct low-density lipoprotein cholesterol Levels.
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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.
Locations and Contacts
Huntsville, Alabama, United States
Sierra Vista, Arizona, United States
Coquitlam, British Columbia, Canada
Victoria, British Columbia, Canada
Beverly Hills, California, United States
Long Beach, California, United States
Spring Valley, California, United States
Colorado Springs, Colorado, United States
Golden, Colorado, United States
Waterbury, Connecticut, United States
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
Warner Robins, Georgia, United States
Chicago, Illinois, United States
Peoria, Illinois, United States
Indianapolis, Indiana, United States
Wichita, Kansas, United States
Edina, Minnesota, United States
St. Louis, Missouri, United States
Raleigh, North Carolina, United States
Winston-Salem, North Carolina, United States
Cincinnati, Ohio, United States
Columbus, Ohio, United States
London, Ontario, Canada
Toronto, Ontario, Canada
Hillsboro, Oregon, United States
Beaver, Pennsylvania, United States
Goose Creek, South Carolina, United States
Nashville, Tennessee, United States
Norfolk, Virginia, United States
Richmond, Virginia, United States
Additional Information
Starting date: February 2006
Last updated: May 23, 2012
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