Efficacy Study of Pioglitazone and Atorvastatin Combination Therapy in Treating Subjects With Elevated Risk for Cardiovascular Disease - Full Text View

Sponsor:	Takeda Pharma GmbH
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00770575

Purpose

The purpose of this study is to determine the effect of pioglitazone, once daily (QD), and atorvastatin combination therapy compared to atorvastatin monotherapy in patients at risk for cardiovascular disease.

Condition	Intervention	Phase
Cardiovascular Diseases	Drug: Pioglitazone and atorvastatin Drug: Atorvastatin	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Double Blinded Study of the Effects of Pioglitazone in Combination With Atorvastatin in Comparison to Atorvastatin Treatment Alone on Intima-Media Thickness in Patients at Risk for Vascular Complications

Resource links provided by NLM:

Genetics Home Reference related topics: 6q24-related transient neonatal diabetes mellitus

MedlinePlus related topics: Diabetes Medicines

Drug Information available for: Pioglitazone Pioglitazone hydrochloride Atorvastatin Atorvastatin calcium

U.S. FDA Resources

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:

Change in the intima-media thickness of the common carotid artery. [ Time Frame: Week 24. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change in the intima-media thickness of the internal carotid artery. [ Time Frame: Week 24. ] [ Designated as safety issue: No ]
Change in the intima-media thickness of the carotid bulbus. [ Time Frame: Week 24. ] [ Designated as safety issue: No ]
Change from Baseline in Efficacy Laboratory findings (Interleukin-6, high sensitive C reactive peptide and monocyte chemotactic protein-1) [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Efficacy Laboratory findings (matrix metalloproteinase-9, soluble CD40 Ligand, P-Selectin, soluble intracellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1). [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Efficacy Laboratory findings (adiponectin, tissue plasminogen activator, Plasma glucose, Insulin and Intact proinsulin). [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Efficacy Laboratory findings (blood lipids (total cholesterol, high density lipoprotein, triglycerides) and low density lipoprotein-subfractions). [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Glycosylated Hemoglobin. [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Beta cell function (Homeostatic Model Assessment - beta cell response Score). [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Insulin sensitivity using the Homeostatic Model Assessment - Sensitivity Score). [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Microcirculation assessment. [ Time Frame: Week: 24. ] [ Designated as safety issue: No ]
Change from Baseline in Pulse wave velocity. [ Time Frame: Weeks: 12 and 24. ] [ Designated as safety issue: No ]

Enrollment:	148
Study Start Date:	June 2005
Study Completion Date:	October 2006
Primary Completion Date:	October 2006 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Pioglitazone 30mg to 45 mg QD + Atorvastatin 20 mg to 40 mg QD	Drug: Pioglitazone and atorvastatin Pioglitazone 30 mg, capsules, orally, once daily and atorvastatin 20 mg, tablets, orally, once daily for 4 weeks; increase to: Pioglitazone 45 mg, capsules, orally, once daily and atorvastatin 40 mg, tablets, orally, once daily for up to 20 weeks. Other Names: ACTOS® AD4833
Active Comparator: Atorvastatin 20mg to 40 mg QD	Drug: Atorvastatin Pioglitazone placebo-matching capsules, orally, once daily and atorvastatin 20 mg, tablets, orally, once daily for 4 weeks; increased to Pioglitazone placebo-matching capsules, orally, once daily and atorvastatin 40 mg, tablets, orally, once daily for up to 20 weeks.

Detailed Description:

Carotid intima-media thickness is a well described surrogate marker for cardiovascular risk. A thickened carotid intima media layer correlates not only with the presence of cardiovascular risk factors but also the risk of future macrovascular events such as myocardial infarction and stroke. The interventional approach of cardiovascular risk factors with angiotensin converting enzyme system blockers, calcium antagonists or beta blockers can result in reduction of progression or even net regression of carotid intima-media thickness. The most potent agents, however, are statins which have consistently shown effects on carotid intima-media thickness in patients with hypercholesterolemia and/or atherosclerotic disease.

Peroxisome proliferator activator receptor-gamma activation by thiazolidinediones is a promising new approach which reduces insulin resistance and improves lipid profile. In addition to their metabolic activities, peroxisome proliferator activator receptor-gamma activators were shown to exert anti-inflammatory effects, to improve endothelial function and to inhibit atherogenesis in diabetic and in non-diabetic atherosclerosis-prone animal models. Treatment with peroxisome proliferator activator receptor-gamma agonists have shown to reduce arterial pressure and carotid intima-media thickness in diabetic and non-diabetic patients at risk for cardiovascular disease.

The aim of this study is to evaluate the effect of Pioglitazone in addition to Atorvastatin compared to Atorvastatin alone on vascular risk markers and intima-media thickness in patients with elevated risk for cardiovascular disease.

Eligibility

Ages Eligible for Study:	30 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Intima-media thickness of Common Carotid Artery greater than or equal to 0.8 mm (at least on one side).
Increased cardiovascular risk defined as one or more of the following:
- medical history of infarction
- coronary angiography with proven cardiovascular disease
- instable Angina pectoris
- duplex-sonography of cervical or leg vessels with proven atherosclerotic vascular alterations
- electrocardiogram with ischemia
- stroke
- transient ischemic attack
- peripheral arterial occlusion
- vessel surgery
- hypertension (RR greater than 140/90)
- antihypertensives
- high density lipoprotein less than 40 mg/dl.
Body mass index greater than or equal to 25 kg/m2.
Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

Exclusion Criteria:

History of overt type-2-diabetes according to the World Health Organization criteria.
History of type-1-diabetes.
History of more than one unexplained hypoglycemic episode within the last 6 months.
Statin therapy within the last 4 weeks.
Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures.
History of severe or multiple allergies.
Treatment with any other investigational drug within 3 months before trial entry.
Progressive fatal disease.
Myopathy.
Drug or alcohol abuse within the last 5 years.
Smoker defined as patient with evidence or history of tobacco or nicotine use within the last 6 months before the screening visit.
A history of heart failure (New York Heart Association stage II - IV) or significant respiratory, gastrointestinal, hepatic (glutamate-pyruvate-transaminase time greater than 2.5 times the normal reference range), renal (creatinine greater than 2.0 mg/dl) or hematological disease.
Blood donation within the last 30 days.
Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:
- ciclosporin
- erythromycin
- clarithromycin
- itraconazole
- ketoconazole
- nefazodone
- niacin
- gemfibrozil and other fibrates
- HIV-Protease-Inhibitors
Pre-treatment with thiazolidinediones within 3 months before trial entry.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00770575

Sponsors and Collaborators

Takeda Pharma GmbH

Investigators

Study Director:

Head of Clinical Research/Licensing/New Products

Takeda Pharma GmbH

More Information

Additional Information:

ACTOS® Package Insert This link exits the ClinicalTrials.gov site

FDA Safety Alerts and Recalls This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Medical Director, Takeda Pharma GmbH, Aachen (Germany)
ClinicalTrials.gov Identifier:	NCT00770575 History of Changes
Other Study ID Numbers:	ATS K015, 2004-004463-30, D-PIO-106, U1111-1115-9124
Study First Received:	October 9, 2008
Last Updated:	July 1, 2010
Health Authority:	European Union: European Medicines Agency

Keywords provided by Takeda Global Research & Development Center, Inc.:

Biological Markers
Biochemical Markers
Carotid Artery, Internal
Carotid Artery, Common

Marker, Surrogate
Vascular Diseases
Diabetes Mellitus
Drug Therapy

Additional relevant MeSH terms:

Cardiovascular Diseases
Pioglitazone
Atorvastatin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Hydroxymethylglutaryl-CoA Reductase Inhibitors

Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 09, 2012