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Efficacy of Lapaquistat Acetate Alone or Combined With Rosuvastatin in Subjects With Hypercholesterolemia

Primary Purpose

Hypercholesterolemia

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Lapaquistat acetate and rosuvastatin
Lapaquistat acetate and rosuvastatin
Rosuvastatin
Sponsored by
Takeda
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypercholesterolemia focused on measuring Hyperlipidemia, Drug Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Woman of childbearing potential can not to be pregnant, lactating, not planning on becoming pregnant, and agree to use acceptable forms of contraception throughout the course of the study. Prior to Randomization, has a low-density lipoprotein cholesterol level mean greater than or equal to 3.37 mmol/L and less than or equal to 5.70 mmol/L. Prior to Randomization, has a mean triglyceride level less than or equal to 4.52 mmol/L (400 mg/dL). Has clinical laboratory evaluations including clinical chemistry, hematology, and urinalysis within the defined reference range. Participant is taking a stable dose of rosuvastatin (10 or 20 mg) for at least 4 weeks prior to Screening. Exclusion Criteria: Has an alanine aminotransferase or aspartate aminotransferase level of greater than 1.5 times the upper limit of normal, active liver disease or jaundice. Has a serum creatinine of greater than 133 μmol/L. Has a creatine kinase greater than 3 times the upper limit of normal. Has type 1 or 2 diabetes mellitus. Has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication. Has an endocrine disorder, such as Cushing syndrome, hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid metabolism. Has a history of myocardial infarction, angina pectoris, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary revascularization or multiple factors that conferred a 10-year risk for coronary heart disease greater than 20% based on Framingham risk scoring. Has a positive hepatitis B surface antigen, or antibody to hepatitis C virus, as determined by medical history and/or subject's verbal report. Has a positive human immunodeficiency virus status or was taking antiretroviral medications, as determined by medical history. Has exposure to lapaquistat acetate in other studies, was participating in another investigational study, or had 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 half-life. The subject had a known hypersensitivity or history of adverse reaction rosuvastatin. Has a history or presence of clinically significant food allergy that would prevent adherence to the recommended diet. Has a known heterozygous or homozygous familial hypercholesterolemia or known Type III hyperlipoproteinemia (familial dysbetalipoproteinemia). Has fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain. Has uncontrolled hypertension Has inflammatory bowel disease, any other malabsorption syndrome, or had gastric bypass or any other surgical procedure for weight loss. Is unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments. Has a history of drug abuse or a history of alcohol abuse within the past 2 years. Has any other serious disease or condition that might reduced life expectancy, impaired successful management according to the protocol, or make the participant an unsuitable candidate to receive study medication.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Lapaquistat Acetate 50 mg QD + Rosuvastatin

Lapaquistat Acetate 100 mg QD + Rosuvastatin

Rosuvastatin

Arm Description

Outcomes

Primary Outcome Measures

Change from Baseline in Low Density Lipoprotein cholesterol

Secondary Outcome Measures

Adverse Events
Physical Examination
Safety Laboratory Tests
12- lead Electrocardiogram assessments
Best Corrected Visual Acuity results
Vital Signs
Change from Baseline in Triglycerides
Change from Baseline in Total Cholesterol
Change from Baseline in High Density Lipoprotein cholesterol
Change from Baseline in Very Low Density Lipoprotein cholesterol
Change from Baseline in apolipoprotein A1
Change from Baseline in apolipoprotein B
Change from Baseline in non- High Density Lipoprotein cholesterol
Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density
Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol
Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B
Change from Baseline in high-sensitivity C-reactive protein
Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 1.81 mmol/L (70 mg/dL)
Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.59 mmol/L (100 mg/dL)
Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.37 mmol/L (130 mg/dL)

Full Information

First Posted
November 4, 2005
Last Updated
May 23, 2012
Sponsor
Takeda
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1. Study Identification

Unique Protocol Identification Number
NCT00249912
Brief Title
Efficacy of Lapaquistat Acetate Alone or Combined With Rosuvastatin in Subjects With Hypercholesterolemia
Official Title
A Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 50 mg, 100 mg or Placebo When Coadministered With Rosuvastatin 10 mg or 20 mg in Subjects With Primary Hypercholesterolemia
Study Type
Interventional

2. Study Status

Record Verification Date
May 2012
Overall Recruitment Status
Completed
Study Start Date
October 2005 (undefined)
Primary Completion Date
April 2007 (Actual)
Study Completion Date
April 2007 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Takeda

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate lapaquistat acetate, once daily (QD), taken alone or with rosuvastatin on cholesterol levels in treating patients with elevated cholesterol.
Detailed Description
Elevated plasma cholesterol (hypercholesterolemia) and various other plasma lipid imbalances (dyslipidemias) are major risk factors for coronary heart disease. Patients with hypercholesterolemia have elevated low-density lipoprotein cholesterol, which leads to atherosclerotic deposition of cholesterol in the arterial walls. As identified by the National Cholesterol Education Program Adult Treatment Panel III, lowering the low-density lipoprotein cholesterol plasma concentration effectively reduces cardiovascular morbidity and mortality and is essential for 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 ATP III-recommended levels of low-density lipoprotein cholesterol reduction, making it necessary to increase the dose or add an additional treatment. Dose increases of statins in turn may result in decreased tolerability and potential safety concerns which contribute to the high discontinuation rates of statins and their prescription at low, and often ineffective, doses. The purpose of this study is to determine whether administration of lapaquistat acetate co-administered with rosuvastatin will be more efficacious in lowering low-density lipoprotein cholesterol, compared to lapaquistat or rosuvastatin alone. Total participation time in this study is anticipated to be 24 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypercholesterolemia
Keywords
Hyperlipidemia, Drug Therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
415 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lapaquistat Acetate 50 mg QD + Rosuvastatin
Arm Type
Experimental
Arm Title
Lapaquistat Acetate 100 mg QD + Rosuvastatin
Arm Type
Experimental
Arm Title
Rosuvastatin
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Lapaquistat acetate and rosuvastatin
Other Intervention Name(s)
TAK-475, Crestor
Intervention Description
Lapaquistat acetate 50 mg, tablets, orally, once daily and stable Rosuvastatin therapy (10 or 20 mg) for up to 24 weeks.
Intervention Type
Drug
Intervention Name(s)
Lapaquistat acetate and rosuvastatin
Other Intervention Name(s)
TAK-475, Crestor
Intervention Description
Lapaquistat acetate 100 mg, tablets, orally, once daily and stable Rosuvastatin therapy (10 or 20 mg) for up to 24 weeks.
Intervention Type
Drug
Intervention Name(s)
Rosuvastatin
Other Intervention Name(s)
Crestor
Intervention Description
Lapaquistat acetate placebo-matching tablets, orally, once daily and stable Rosuvastatin therapy (10 or 20 mg) for up to 24 weeks.
Primary Outcome Measure Information:
Title
Change from Baseline in Low Density Lipoprotein cholesterol
Time Frame
Week 24 or Final Visit
Secondary Outcome Measure Information:
Title
Adverse Events
Time Frame
Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit
Title
Physical Examination
Time Frame
Week 24 or Final Visit
Title
Safety Laboratory Tests
Time Frame
Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit
Title
12- lead Electrocardiogram assessments
Time Frame
Week 24 or Final Visit
Title
Best Corrected Visual Acuity results
Time Frame
Week 24 or Final Visit
Title
Vital Signs
Time Frame
Weeks: 2, 4, 8, 12, 16, 20, and 24 or Final Visit
Title
Change from Baseline in Triglycerides
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in Total Cholesterol
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in High Density Lipoprotein cholesterol
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in Very Low Density Lipoprotein cholesterol
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in apolipoprotein A1
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in apolipoprotein B
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in non- High Density Lipoprotein cholesterol
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B
Time Frame
Week 24 or Final Visit
Title
Change from Baseline in high-sensitivity C-reactive protein
Time Frame
Week 24 or Final Visit
Title
Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 1.81 mmol/L (70 mg/dL)
Time Frame
Week 24 or Final Visit
Title
Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.59 mmol/L (100 mg/dL)
Time Frame
Week 24 or Final Visit
Title
Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.37 mmol/L (130 mg/dL)
Time Frame
Week 24 or Final Visit

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Woman of childbearing potential can not to be pregnant, lactating, not planning on becoming pregnant, and agree to use acceptable forms of contraception throughout the course of the study. Prior to Randomization, has a low-density lipoprotein cholesterol level mean greater than or equal to 3.37 mmol/L and less than or equal to 5.70 mmol/L. Prior to Randomization, has a mean triglyceride level less than or equal to 4.52 mmol/L (400 mg/dL). Has clinical laboratory evaluations including clinical chemistry, hematology, and urinalysis within the defined reference range. Participant is taking a stable dose of rosuvastatin (10 or 20 mg) for at least 4 weeks prior to Screening. Exclusion Criteria: Has an alanine aminotransferase or aspartate aminotransferase level of greater than 1.5 times the upper limit of normal, active liver disease or jaundice. Has a serum creatinine of greater than 133 μmol/L. Has a creatine kinase greater than 3 times the upper limit of normal. Has type 1 or 2 diabetes mellitus. Has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication. Has an endocrine disorder, such as Cushing syndrome, hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid metabolism. Has a history of myocardial infarction, angina pectoris, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary revascularization or multiple factors that conferred a 10-year risk for coronary heart disease greater than 20% based on Framingham risk scoring. Has a positive hepatitis B surface antigen, or antibody to hepatitis C virus, as determined by medical history and/or subject's verbal report. Has a positive human immunodeficiency virus status or was taking antiretroviral medications, as determined by medical history. Has exposure to lapaquistat acetate in other studies, was participating in another investigational study, or had 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 half-life. The subject had a known hypersensitivity or history of adverse reaction rosuvastatin. Has a history or presence of clinically significant food allergy that would prevent adherence to the recommended diet. Has a known heterozygous or homozygous familial hypercholesterolemia or known Type III hyperlipoproteinemia (familial dysbetalipoproteinemia). Has fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain. Has uncontrolled hypertension Has inflammatory bowel disease, any other malabsorption syndrome, or had gastric bypass or any other surgical procedure for weight loss. Is unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments. Has a history of drug abuse or a history of alcohol abuse within the past 2 years. Has any other serious disease or condition that might reduced life expectancy, impaired successful management according to the protocol, or make the participant an unsuitable candidate to receive study medication.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
City
Birmingham
State/Province
Alabama
Country
United States
City
Haleyville
State/Province
Alabama
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United States
City
Mobile
State/Province
Alabama
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United States
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Scottsdale
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Arizona
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United States
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Long Beach
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California
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United States
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Mission Viejo
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California
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Orange
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California
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Redondo Beach
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Rolling Hills Estates
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San Diego
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United States
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Torrance
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Tustin
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Avon
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Connecticut
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United States
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Bristol
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Connecticut
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De Land
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Ft. Lauderdale
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Hialeah
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Jacksonville
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Jupiter
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Melbourne
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Miami
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Naples
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Ocala
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Pembroke Pines
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Plantation
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Hayden Lake
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Idaho
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Meridian
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Idaho
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Arlington Heights
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Illinois
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Aurora
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Illinois
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Chicago
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Illinois
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Peoria
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Indianapolis
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Indiana
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Iowa City
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Iowa
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Kansas City
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Kansas
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Witchita
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Louisville
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Kentucky
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Thibodaux
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Louisiana
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Auburn
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Maine
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Haverhill
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Massachusetts
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Benzonia
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Detroit
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Kansas City
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St. Louis
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Missoula
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Montana
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Concord
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New Hampshire
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West Seneca
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New York
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Raleigh
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North Carolina
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Statesville
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Winstom-Salem
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Grand Forks
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North Dakota
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Akron
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Ohio
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Cincinnati
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Ohio
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Columbus
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Ohio
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Kettering
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Ohio
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Tulsa
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Oklahoma
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Eugene
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Oregon
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Portland
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Oregon
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Lansdale
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Pennsylvania
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Philadelphia
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Pittsburgh
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Pennsylvania
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Scotland
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Pennsylvania
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Cranston
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Rhode Island
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Anderson
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South Carolina
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Bristol
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Tennessee
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Cordova
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Tennessee
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Kingsport
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Tennessee
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Austin
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Texas
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Dallas
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Texas
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Houston
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Texas
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McKinney
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Midland
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Texas
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San Antonio
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Texas
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Salt Lake City
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Utah
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City
Burke
State/Province
Virginia
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United States
City
Norfolk
State/Province
Virginia
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Richmond
State/Province
Virginia
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Weber City
State/Province
Virginia
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Bellevue
State/Province
Washington
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Burien
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Washington
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Edmonds
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Washington
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Seattle
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Washington
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Spokane
State/Province
Washington
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Calgary
State/Province
Alberta
Country
Canada
City
Portage La Prairie
State/Province
Manitoba
Country
Canada
City
London
State/Province
Ontario
Country
Canada
City
Oakville
State/Province
Ontario
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Canada
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Oshawa
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Ontario
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Canada
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Thornhill
State/Province
Ontario
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Canada
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Toronto
State/Province
Ontario
Country
Canada
City
Chicoutimi
State/Province
Quebec
Country
Canada
City
St. Jerome
State/Province
Quebec
Country
Canada
City
Ste-Foy
State/Province
Quebec
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
21518985
Citation
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 2011 Apr 25.
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Efficacy of Lapaquistat Acetate Alone or Combined With Rosuvastatin in Subjects With Hypercholesterolemia

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