Clinical trial NCT00251680: Efficacy of Lapaquistat Acetate in Subjects Currently Treated With Lipid-Lowering Therapy.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes
Keywords: Hyperlipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2005-11-10
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change from Baseline in fasting plasma Low Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
Secondary outcomes:
measure: Change from Baseline in Triglycerides
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in Total Cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in High Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in Very Low Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in apolipoprotein A1
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in apolipoprotein B
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in non- High Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in the ratio of Low Density Lipoprotein cholesterol/High Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in the ratio of Total Cholesterol/High Density Lipoprotein cholesterol
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in the ratio of apolipoprotein A1/apolipoprotein B
timeFrame: Week 24 or Final Visit
measure: Change from Baseline in high-sensitivity C-reactive protein
timeFrame: Week 24 or Final Visit
measure: Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 1.81 mmol/L (70 mg/dL)
timeFrame: Week 24 or Final Visit
measure: Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 2.59 mmol/L (100 mg/dL)
timeFrame: Week 24 or Final Visit
measure: Percentage of subjects who achieve Low Density Lipoprotein cholesterol concentrations less than 3.37 mmol/L (130 mg/dL)
timeFrame: Week 24 or Final Visit
measure: Best corrected visual acuity
timeFrame: Week 24 or Final Visit
measure: Adverse Events
timeFrame: Weeks 2, 4, 8, 12, 16, 20, and 24 or Final Visit
measure: Clinical Laboratory Tests
timeFrame: Weeks 2, 4, 8, 12, 16, 20, and 24 or Final Visit
measure: Vital Signs
timeFrame: Weeks 2, 4, 8, 12, 16, 20, and 24 or Final Visit
measure: 12-lead Electrocardiogram
timeFrame: Weeks 12 and 24 or Final Visit
measure: Physical Examination
timeFrame: Week 24 or Final Visit
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Artesia
country: United States
state: California
city: Jacksonville
country: United States
state: Florida
city: Dunwoody
country: United States
state: Georgia
city: Idaho Falls
country: United States
state: Idaho
city: Aurora
country: United States
state: Illinois
city: Chicago
country: United States
state: Illinois
city: Melrose Park
country: United States
state: Illinois
city: Naperville
country: United States
state: Illinois
city: Overland Park
country: United States
state: Kansas
city: Livonia
country: United States
state: Michigan
city: Chesterfield
country: United States
state: Missouri
city: Margate
country: United States
state: New Jersey
city: Trenton
country: United States
state: New Jersey
city: Cincinnati
country: United States
state: Ohio
city: Bristol
country: United States
state: Tennessee
city: San Antonio
country: United States
state: Texas
city: Richmond
country: United States
state: Virginia
city: Benesov
country: Czech Republic
city: Holice v Cechach
country: Czech Republic
city: Kladno
country: Czech Republic
city: Mlada Boleslav
country: Czech Republic
city: Olomouc
country: Czech Republic
city: Praha
country: Czech Republic
city: Trutnov
country: Czech Republic
city: Usti nad Orlici
country: Czech Republic
city: Zlin
country: Czech Republic
city: Parnu
country: Estonia
city: Tallinn
country: Estonia
city: Tartu
country: Estonia
city: Helsinki
country: Finland
city: Hyvinkaa
country: Finland
city: Tampere
country: Finland
city: Turku
country: Finland
city: Berlin
country: Germany
city: Bochum
country: Germany
city: Chemnitz
country: Germany
city: Dresden
country: Germany
city: Frankfurt
country: Germany
city: Goerlitz
country: Germany
city: Leipzig
country: Germany
city: Nurnberg
country: Germany
city: Krakow
country: Poland
city: Leszno
country: Poland
city: Lublin
country: Poland
city: Niemodlin
country: Poland
city: Ostrowiec Swietokrzyski
country: Poland
city: Skierniewice
country: Poland
city: Sroda Wlkp
country: Poland
city: Starachowice
country: Poland
city: Warszawa
country: Poland
city: Zakopane
country: Poland
city: Banska Bystrica
country: Slovakia
city: Bojnice
country: Slovakia
city: Bratislava
country: Slovakia
city: Lucenec
country: Slovakia
city: Presov
country: Slovakia
city: Samorin
country: Slovakia
city: Zilina
country: Slovakia
city: Bloemfontein
country: South Africa
city: Cape Town
country: South Africa
city: Durban
country: South Africa
city: Lyttleton
country: South Africa
city: Pretoria
country: South Africa
city: Randburg
country: South Africa
city: Bath
country: United Kingdom
city: Birmingham
country: United Kingdom
city: Blackpool
country: United Kingdom
city: Blantyre
country: United Kingdom
city: Chippenham
country: United Kingdom
city: Edinburgh
country: United Kingdom
city: Glasgow
country: United Kingdom
city: Harrow
country: United Kingdom
city: Hinckley
country: United Kingdom
city: Newport
country: United Kingdom
city: NOttingham
country: United Kingdom
city: Woolpit
country: United Kingdom
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
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.