Efficacy of Lapaquistat Acetate in Subjects Currently Treated With Lipid-Lowering Therapy.

Type 2 Diabetes Clinical Trial

Official title:

A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 100 mg in Subjects With Type 2 Diabetes Currently Treated With Lipid-Lowering Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00251680
• Other study ID #: TAK-475/EC304
• Secondary ID: 2005-002316-24U1
• Status: Completed
• Phase: Phase 3
• First received: November 8, 2005
• Last updated: May 23, 2012
• Start date: October 2005
• 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 MedicineFinland: Finnish Medicines AgencyPoland: Ministry of HealthGermany: Federal Institute for Drugs and Medical DevicesSlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine the efficacy of lapaquistat acetate, once daily (QD), taken with established lipid-lowering therapy in subjects with type 2 diabetes mellitus.

Description:

Diabetes mellitus is a recognized cause of secondary dyslipidemia, and is also independently considered to be a major cardiovascular risk factor requiring aggressive lipid-lowering treatment. Type 2 diabetes accounts for 85% to 90% of diabetes worldwide. It affects about 2% of the Caucasian population in most Westernized countries, and the prevalence rises with age to 10% in those over 70 years of age. Five percent or more of young- and middle-aged adults in some Asian or Afro-Caribbean groups in the United Kingdom have this condition. Approximately 12 million Americans have type 2 diabetes, and an estimated 20 million more have some degree of glucose intolerance. The greatest cause of mortality in type 2 diabetes is atherosclerotic vascular disease and its sequelae between 75% and 80% of adult subjects with diabetes die of macrovascular complications.

Lapaquistat acetate is a squalene synthase inhibitor currently under development at Takeda for the treatment of dyslipidemia. This study will evaluate the efficacy and safety of lapaquistat acetate co-administered with an established lipid-lowering therapy including atorvastatin, simvastatin, rosuvastatin, or fenofibrate in subjects with type 2 diabetes mellitus.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 400
• 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:

• Females of childbearing potential who are sexually active must agree to use adequate contraception from screening throughout the duration of the study and for 30 days following the last dose.

• Has a documented history of dyslipidemia with or without cardiovascular risk factors but without type 1 or 2 diabetes.

• Is on a stable antidiabetic regimen, which may have included oral antidiabetic medication and/or insulin, for at least 3 months prior to Screening.

• Prior to Randomization, the participant has a mean low density lipoprotein cholesterol level greater than or equal to 100 mg/dL and less than or equal to 190 mg/dL for 2 consecutive samples.

• Prior to Randomization, the subject has mean triglyceride level greater than or equal to 400 mg/dL for 2 consecutive samples.

• Is willing and able to comply with the recommended, standardized diet.

Exclusion Criteria:

• Has annine aminotransferase or aspartate aminotransferase level greater than 1.5 times the upper limit of normal, identified during screening.

• Has a serum creatinine greater than 133 mmol/L, identified during screening.

• Has a creatine kinase greater than 3 times the upper limit of normal, identified during screening.

• Has active liver disease or jaundice.

• Has taken any bile acid sequestrants [eg, cholestyramine], and intestinal cholesterol uptake inhibitors [eg, ezetimibe]) from 30 days before Screening until study completion or any fibrates for 6 weeks before Visit 1.

• Has a previous history of cancer that has been in remission for less than 5 years prior to the first dose of study medication.

• Has an endocrine disorder, such as Cushing's syndrome, hyperthyroidism, or inappropriately treated hypothyroidism affecting lipid metabolism.

• Has a history of myocardial infarction, angina pectoris, unstable angina, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary angioplasty, coronary or peripheral arterial surgery, or multiple risk factors that confer a 10-year risk for cardiovascular heart disease greater than 20% based on Framingham risk scoring.

• Has a positive hepatitis B surface antigen or hepatitis C virus antibody test, as determined by medical history.

• Has a positive human immunodeficiency virus status or is taking antiretroviral medications, as determined by medical history and/or subject's verbal report.

• Has received any investigational medication 30 days prior to screening, or is participating in an investigational study.

• Has received lapaquistat acetate in a previous clinical study or as a therapeutic agent.

• Has a history or presence of clinically significant food allergy that would prevent adherence to the specialized 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 had inflammatory bowel disease or any other malabsorption syndrome, or has had gastric bypass or any other surgical procedure for weight loss.

• Has a history of drug abuse or a history of high alcohol intake within the previous 2 years.

• Has type 1 or 2 diabetes mellitus.

• Subject had a history of photoallergic or phototoxic reaction during treatment with a fibrate or ketoprofen.

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

• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• Lapaquistat acetate and lipid-lowering therapy
Lapaquistat acetate 50 mg, tablets, orally, once daily and stable lipid-lowering therapy for up to 24 weeks.
• Lipid-lowering therapy
Lapaquistat acetate placebo-matching tablets, tablets, orally, once daily and stable lipid-lowering therapy for up to 24 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

United States,  Czech Republic,  Estonia,  Finland,  Germany,  Poland,  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	Change from Baseline in fasting plasma Low Density Lipoprotein cholesterol		Week 24 or Final Visit	No
Secondary	Change from Baseline in Triglycerides		Week 24 or Final Visit	No
Secondary	Change from Baseline in Total Cholesterol		Week 24 or Final Visit	No
Secondary	Change from Baseline in High Density Lipoprotein cholesterol		Week 24 or Final Visit	No
Secondary	Change from Baseline in Very Low Density Lipoprotein cholesterol		Week 24 or Final Visit	No
Secondary	Change from Baseline in apolipoprotein A1		Week 24 or Final Visit	No
Secondary	Change from Baseline in apolipoprotein B		Week 24 or Final Visit	No
Secondary	Change from Baseline in non- High Density Lipoprotein cholesterol		Week 24 or Final Visit	No
Secondary	Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density Lipoprotein cholesterol		Week 24 or Final Visit	No
Secondary	Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol		Week 24 or Final Visit	No
Secondary	Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B		Week 24 or Final Visit	No
Secondary	Change from Baseline in high-sensitivity C-reactive protein		Week 24 or Final Visit	No
Secondary	Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 1.81 mmol/L (70 mg/dL)		Week 24 or Final Visit	No
Secondary	Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.59 mmol/L (100 mg/dL)		Week 24 or Final Visit	No
Secondary	Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.37 mmol/L (130 mg/dL)		Week 24 or Final Visit	No
Secondary	Best corrected visual acuity		Week 24 or Final Visit	Yes
Secondary	Adverse Events		Weeks 2, 4, 8, 12, 16, 20, and 24 or Final Visit	Yes
Secondary	Clinical Laboratory Tests		Weeks 2, 4, 8, 12, 16, 20, and 24 or Final Visit	Yes
Secondary	Vital Signs		Weeks 2, 4, 8, 12, 16, 20, and 24 or Final Visit	Yes
Secondary	12-lead Electrocardiogram		Weeks 12 and 24 or Final Visit	Yes
Secondary	Physical Examination		Week 24 or Final Visit	Yes