Efficacy of Lapaquistat Acetate Co-Administered With Current Lipid-Lowering Treatment on Blood Cholesterol Levels in Subjects With Homozygous Familial Hypercholesterolemia
|Hypercholesterolemia||Drug: Lapaquistat acetate and current lipid-lowering treatment Drug: Current lipid-lowering treatment||Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Double-blind, Placebo-controlled, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 or Placebo When Co-administered With Current Lipid-lowering Therapy in Subjects With Homozygous Familial Hypercholesterolemia.|
- Change from Baseline in Low Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in calculated Low Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in non- High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in Triglycerides [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in Total Cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in Very Low Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in apolipoprotein A1 [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in apolipoprotein B [ Time Frame: Week 12 or Final Visit ]
- Lipoprotein cholesterol/High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B [ Time Frame: Week 12 or Final Visit ]
- Change from Baseline in high-sensitivity C-reactive protein [ Time Frame: Week 12 or Final Visit ]
|Study Start Date:||November 2005|
|Study Completion Date:||March 2007|
|Primary Completion Date:||March 2007 (Final data collection date for primary outcome measure)|
Experimental: Lapaquistat Acetate QD
(and current lipid-lowering treatment)
Drug: Lapaquistat acetate and current lipid-lowering treatment
Cohort 1: Weight is less than 50 kg:
Lapaquistat acetate 50 mg, tablets, orally, once daily and current lipid-lowering treatment for up to 12 weeks.
Cohort 2: Weight is more than 50 kg:
Lapaquistat acetate 100 mg, tablets, orally, once daily and current lipid-lowering treatment for up to 12 weeks.
|Placebo Comparator: Current lipid-lowering treatment||
Drug: Current lipid-lowering treatment
Lapaquistat acetate placebo-matching tablets, orally, once daily and current lipid-lowering treatment for up to 12 weeks.
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.
Takeda Global Research and Development Center, Inc. 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.
This study will evaluate the efficacy of lapaquistat acetate coadministered with ongoing lipid-lowering therapy in treating subjects with homozygous familial hypercholesterolemia. The effect on LDL-C and other lipid parameters, as well as the safety and tolerability of lapaquistat acetate compared to a placebo will be evaluated during a 12-week double-blind treatment period. The long-term safety of lapaquistat acetate treatment in this population will be evaluated during an open-label extension period. Study Participation is anticipated to be up to 3 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00263081
|United States, Ohio|
|Cincinnati, Ohio, United States|
|Columbus, Ohio, United States|
|Manchester, United Kingdom|
|Study Director:||Medical Director||Takeda|