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

Dyslipidemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00487994
• Other study ID #: 01-04-TL-475-002
• Secondary ID: 2004-000775-34U1
• Status: Completed
• Phase: Phase 3
• First received: June 15, 2007
• Last updated: May 23, 2012
• Start date: November 2004
• Est. completion date: May 2007

Study information

• Verified date: May 2012
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCzech Republic: State Institute for Drug ControlEstonia: The State Agency of MedicineGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyLatvia: State Agency of MedicinesLithuania: State Medicine Control Agency - Ministry of HealthNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ministry of Health of the Russian FederationSlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaPeru: Ministry of HealthChile: Comisión Nacional de Investigación Científica y TecnológicaMexico: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2130
• Est. completion date: May 2007
• Est. primary completion date: May 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Dyslipidemia
• Dyslipidemias

Intervention

Drug:
• Lapaquistat acetate
Lapaquistat acetate 100 mg, tablets, orally, once daily and Atorvastatin placebo-matching capsules, orally, once daily for up to 96 weeks.
• 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.
• Atorvastatin
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

United States,  Argentina,  Chile,  Czech Republic,  Estonia,  Germany,  Hungary,  Latvia,  Lithuania,  Mexico,  Netherlands,  Peru,  Poland,  Russian Federation,  Slovakia,  South Africa,  United Kingdom, 

References & Publications (1)

Stein EA, Bays H, O'Brien D, Pedicano J, Piper E, Spezzi A. Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011 May 10;123(18):1974-85. doi: 10.1161/CIRCULATIONAHA.110.975284. Epub — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Lens Opacity Classification System findings		Weeks 24, 48, 72, and 96 or Final Visit	Yes
Primary	Best corrected visual acuity		Weeks 24, 48, 72, and 96 or Final Visit	Yes
Primary	Adverse Events		Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit	Yes
Primary	Clinical Laboratory Tests		Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit	Yes
Primary	Vital signs (blood pressure and pulse rate) and weight		Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit	Yes
Primary	12-lead Electrocardiogram		Weeks 48 and 96 or Final Visit	Yes
Primary	Physical Examination		Weeks 48 and 96 or Final Visit	Yes
Secondary	Change from Baseline in Low Density Lipoprotein cholesterol		Week 96 or Final Visit	No
Secondary	Change from Baseline in High Density Lipoprotein cholesterol		Week 96 or Final Visit	No
Secondary	Change from Baseline in Total Cholesterol		Week 96 or Final Visit	No
Secondary	Change from Baseline in Triglycerides		Week 96 or Final Visit	No
Secondary	Change from Baseline in Very Low Density Lipoprotein cholesterol		Week 96 or Final Visit	No
Secondary	Change from Baseline in Apolipoprotein A1		Week 96 or Final Visit	No
Secondary	Change from Baseline in Apolipoprotein B		Week 96 or Final Visit	No