Safety and Efficacy of Lapaquistat Acetate Taken Alone and With Atorvastatin in Subjects With Primary Dyslipidemia
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|ClinicalTrials.gov Identifier: NCT00487994|
Recruitment Status : Completed
First Posted : June 19, 2007
Last Update Posted : May 24, 2012
|Condition or disease||Intervention/treatment||Phase|
|Dyslipidemia||Drug: Lapaquistat acetate Drug: Lapaquistat acetate and atorvastatin Drug: Atorvastatin||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||2130 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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|
|Study Start Date :||November 2004|
|Actual Primary Completion Date :||May 2007|
|Actual Study Completion Date :||May 2007|
|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.
|Active Comparator: Atorvastatin 10 mg QD||
Lapaquistat acetate placebo-matching tablets, orally, once daily and Atorvastatin 10 mg, capsules, orally, once daily for up to 96 weeks.
Other Name: Lipitor
- Lens Opacity Classification System findings [ Time Frame: Weeks 24, 48, 72, and 96 or Final Visit ]
- Best corrected visual acuity [ Time Frame: Weeks 24, 48, 72, and 96 or Final Visit ]
- Adverse Events [ Time Frame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit ]
- Clinical Laboratory Tests [ Time Frame: Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 or Final Visit ]
- 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 ]
- 12-lead Electrocardiogram [ Time Frame: Weeks 48 and 96 or Final Visit ]
- Physical Examination [ Time Frame: Weeks 48 and 96 or Final Visit ]
- Change from Baseline in Low Density Lipoprotein cholesterol [ Time Frame: Week 96 or Final Visit ]
- Change from Baseline in High Density Lipoprotein cholesterol [ Time Frame: Week 96 or Final Visit ]
- Change from Baseline in Total Cholesterol [ Time Frame: Week 96 or Final Visit ]
- Change from Baseline in Triglycerides [ Time Frame: Week 96 or Final Visit ]
- Change from Baseline in Very Low Density Lipoprotein cholesterol [ Time Frame: Week 96 or Final Visit ]
- Change from Baseline in Apolipoprotein A1 [ Time Frame: Week 96 or Final Visit ]
- Change from Baseline in Apolipoprotein B [ Time Frame: Week 96 or Final Visit ]
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 ClinicalTrials.gov identifier (NCT number): NCT00487994
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|Study Director:||Medical Director||Takeda|