Safety and Efficacy of Lapaquistat Acetate Taken Alone and With Atorvastatin in Subjects With Primary Dyslipidemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00487994
First received: June 15, 2007
Last updated: May 23, 2012
Last verified: May 2012
  Purpose

The purpose of this study is to evaluate the overall safety of Lapaquistat Acetate, once daily (QD), by itself or in combination with atorvastatin in subjects with primary dyslipidemia.


Condition Intervention Phase
Dyslipidemia
Drug: Lapaquistat acetate
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, Parallel Group Study to Evaluate the Safety, Tolerability and Efficacy of Lapaquistat Acetate Alone or Coadministered With Atorvastatin in Subjects With Primary Dyslipidemia

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Lens Opacity Classification System findings [ Time Frame: Weeks 24, 48, 72, and 96 or Final Visit ] [ Designated as safety issue: Yes ]
  • Best corrected visual acuity [ Time Frame: Weeks 24, 48, 72, and 96 or Final Visit ] [ Designated as safety issue: Yes ]
  • Adverse Events [ Time Frame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit ] [ Designated as safety issue: Yes ]
  • Clinical Laboratory Tests [ Time Frame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit ] [ Designated as safety issue: Yes ]
  • Vital signs (blood pressure and pulse rate) and weight [ Time Frame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit ] [ Designated as safety issue: Yes ]
  • 12-lead Electrocardiogram [ Time Frame: Weeks 48 and 96 or Final Visit ] [ Designated as safety issue: Yes ]
  • Physical Examination [ Time Frame: Weeks 48 and 96 or Final Visit ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Change from Baseline in Low Density Lipoprotein cholesterol [ Time Frame: Week 96 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in High Density Lipoprotein cholesterol [ Time Frame: Week 96 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Total Cholesterol [ Time Frame: Week 96 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Triglycerides [ Time Frame: Week 96 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Very Low Density Lipoprotein cholesterol [ Time Frame: Week 96 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Apolipoprotein A1 [ Time Frame: Week 96 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in Apolipoprotein B [ Time Frame: Week 96 or Final Visit ] [ Designated as safety issue: No ]

Enrollment: 2130
Study Start Date: November 2004
Study Completion Date: May 2007
Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lapaquistat Acetate 100 mg QD Drug: Lapaquistat acetate
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin placebo-matching capsules, orally, once daily for up to 96 weeks.
Other Name: TAK-475
Experimental: Lapaquistat Acetate 100 mg QD + Atorvastatin 10 mg QD Drug: Lapaquistat acetate and atorvastatin
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 weeks.
Other Names:
  • TAK-475
  • Lipitor
Active Comparator: Atorvastatin 10 mg QD Drug: Atorvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 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.

Study Participation is anticipated to be up to two years.

  Eligibility

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

Inclusion Criteria:

  • Has a confirmatory central laboratory result with low density lipoprotein cholesterol greater than or equal to 3.37 mmol/L and less than 5.69 mmol/L, and triglyceride less than 4.52 mmol/L.
  • Females of child-bearing age must have undergone surgical sterilization, hysterectomy, tubal ligation, or bilateral oophorectomy; other female subjects must have been postmenopausal.
  • Must be in good physical and mental health as determined by a physician on the basis of medical history, physical examination, and laboratory results.
  • Has a fasting low density lipoprotein cholesterol level greater than or equal to 3.37 mmol/L and less than 4.92 mmol/L, and a triglyceride value less than 4.52 mmol/L.

Exclusion Criteria:

  • Coronary Heart Disease or Coronary Heart Disease-risk factors comprised of:

    • Diabetes mellitus type 1 or 2.
    • History or presence of myocardial infarction, angina pectoris, unstable angina, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft), aortic aneurysm, transient ischemic attacks, or cerebrovascular accident.
  • A body mass index less than 15 or greater than 35.
  • A history or presence of:

    • Drug abuse or a history of alcohol abuse within the 2 years previous to screening.
    • Uncontrolled hypertension despite medical treatment
    • Thyroid disease, particularly hyperthyroidism or subjects whose thyroid replacement therapy was initiated within the previous 3 months.
    • Human immunodeficiency virus-positive status, or hepatitis B or C infection.
    • Malignancy, except subjects whose malignancy had been diagnosed as stage I basal or squamous cell carcinoma.
    • Heterozygous or homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia.
    • Fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain and/or discontinuation of statins due to myalgia.
    • Trauma to the eye or eye irradiation; glaucoma; iritis; uveitis; prior intraocular surgery, laser surgery to the iris, retinal photocoagulation, or laser trabeculoplasty; corneal opacification or other medial opacities; or had undergone LASIK refractive surgery within 6 months prior to screening.
    • A clinically significant food allergy that would prevent adherence to the specialized diet.
  • Any other serious disease or condition that might have affected life expectancy or made it difficult to successfully manage and monitor the subject according to the protocol.
  • Has a known hypersensitivity or history of adverse reaction to atorvastatin or to lapaquistat acetate.
  • Is taking part in another investigational study or had been participating in an investigational study within the 30 days prior to Screening Visit 1.
  • Has an alanine aminotransferase or aspartate aminotransferase level greater than 2 times the upper limit of normal, active liver disease, jaundice, serum creatinine greater than 135 μmol/L (1.5 mg/dL), or creatine kinase greater than 3 times the upper limit of normal.
  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: NCT00487994

  Show 129 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: Medical Director Takeda
  More Information

Publications:
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00487994     History of Changes
Other Study ID Numbers: 01-04-TL-475-002, 2004-000775-34, U1111-1122-7619
Study First Received: June 15, 2007
Last Updated: May 23, 2012
Health Authority: United States: Food and Drug Administration
Czech Republic: State Institute for Drug Control
Estonia: The State Agency of Medicine
Germany: Federal Institute for Drugs and Medical Devices
Hungary: National Institute of Pharmacy
Latvia: State Agency of Medicines
Lithuania: State Medicine Control Agency - Ministry of Health
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of the Russian Federation
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Peru: Ministry of Health
Chile: Comisión Nacional de Investigación Científica y Tecnológica
Mexico: Ministry of Health

Keywords provided by Takeda:
Hypercholesterolemia
Hyperlipidemia
Drug Therapy

Additional relevant MeSH terms:
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 August 18, 2014