Relation of Inflammation and Insulin Resistance to Peripheral Arterial Disease - Full Text View

Sponsor:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00225940

Purpose

This study will test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in patients with intermittent claudication (IC) by impairing vascular reactivity and skeletal muscle metabolic function.

Condition	Intervention	Phase
Cardiovascular Diseases Peripheral Artery Disease Inflammation Insulin Resistance	Drug: Atorvastatin Drug: Pioglitazone Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Inflammation and Insulin Resistance in PAD

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines Peripheral Arterial Disease

Drug Information available for: Insulin Pioglitazone Pioglitazone hydrochloride Atorvastatin Atorvastatin calcium

U.S. FDA Resources

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:

Pain free and maximal treadmill walking time [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Insulin resistance [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
Skeletal muscle glucose utilization [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
Systemic inflammatory markers [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
Circulating and local adipocyte markers of PPAR activation [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
In vivo vascular function by ultrasonography [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
Change in ankle/brachial index (ABI) [ Time Frame: Measured pre/post treadmill exercise and at 3 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	240
Study Start Date:	September 2003
Estimated Study Completion Date:	December 2010
Estimated Primary Completion Date:	August 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 Atorvastatin and pioglitazone	Drug: Atorvastatin Atorvastatin 80 mg, taken once daily for 3 months Other Name: Lipitor Drug: Pioglitazone Pioglitazone, 45 mg taken once daily for 3 months Other Name: Actos
Active Comparator: 2 Atorvastatin and placebo	Drug: Atorvastatin Atorvastatin 80 mg, taken once daily for 3 months Other Name: Lipitor Drug: Placebo Placebo, taken daily in the morning and evening
Active Comparator: 3 Pioglitazone and placebo	Drug: Pioglitazone Pioglitazone, 45 mg taken once daily for 3 months Other Name: Actos Drug: Placebo Placebo, taken daily in the morning and evening
Placebo Comparator: 4 Placebo and placebo	Drug: Placebo Placebo, taken daily in the morning and evening

Detailed Description:

BACKGROUND:

Patients with peripheral artery disease (PAD) frequently have functional limitations and symptoms of claudication that impact adversely on their quality of life. Some patients progress to critical limb ischemia and require revascularization. Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Moreover, both inflammation and insulin resistance cause abnormalities in vascular function, and insulin resistance interferes with skeletal muscle metabolism. Therefore, inflammation and insulin resistance provide attractive targets for therapy that could potentially ameliorate the development of symptomatic PAD or improve the function and clinical outcomes of patients with PAD. This study will determine whether inflammation and insulin resistance contribute to the functional and clinical consequences of PAD.

DESIGN NARRATIVE:

This study will test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in patients with IC by impairing vascular reactivity and skeletal muscle metabolic function. Pain-free and maximum treadmill walking time will be measured before and after 12 weeks of treatment with pioglitazone, atorvastatin, or placebo in a 2 times 2 factorial design protocol. Endothelium-dependent and independent vasodilation (assessed by vascular ultrasonography), and plasma markers of inflammation and insulin resistance will also be measured before and after drug intervention. A sub-set of patients may opt to participate in a sub-study of skeletal muscle glucose utilization, assessed (by [18F] fluorodeoxyglucose [FDG] positron emission tomography[PET]).

A separate group of patients with PAD scheduled to undergo elective percutaneous revascularization will be enrolled, and will undergo pre- and post-intervention FDG/PET scanning, to ascertain whether skeletal muscle glucose utilization changes with anticipated improvements in blood flow following intervention.

Patients will be recruited from the vascular medicine, surgery, and cardiology clinics at Brigham and Women's Hospital. All study visits take place in the Vascular Medicine Research Center. After two preliminary visits, patients are randomized to one of four drug interventions. Outcome measurements of the study will include insulin resistance, skeletal muscle glucose utilization by PET, systemic inflammatory markers, circulating and local adipocyte markers of peroxisome proliferator-activated receptor (PPAR) activation, in vivo vascular function by ultrasonography, ankle/brachial index (ABI), and treadmill walking time.

Eligibility

Ages Eligible for Study:	40 Years to 85 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

IC group inclusion criteria are as follows:
1. Lower extremity PAD and IC
2. Stable IC (as defined by the San Diego Claudication Questionnaire) for at least 6 months prior to study entry
3. Resting ABI of less than or equal to 0.90
4. Maximal walking time (MWT) between 1 and 20 minutes and post-exercise ABI drop by greater than or equal to 20% (as measured by an exercise treadmill test at the baseline visit, with assessment of pain free walking time [PFWT], MWT, and measurement of the ABI in the index [most symptomatic] leg within 1 minute of concluding exercise)
Revascularization group inclusion criteria are as follows:
1. PAD
2. Scheduled to undergo lower extremity percutaneous revascularization
Control group participants will have no known medical problems and a normal cardiovascular exam

Exclusion Criteria:

Myocardial infarction or coronary artery bypass surgery within 6 months prior to study entry
Transient ischemic attack or ischemic stroke 6 months prior to study entry
Pregnancy
Uncontrolled hypertension, defined as a systolic pressure greater than 180 mm Hg and/or diastolic pressure greater than 100 mm Hg
Serum creatinine greater than 2.5
Hepatic transaminases greater than 3 times upper limit of normal
Creatine kinase greater than 5 times upper limit of normal
IC group exclusion criteria are as follows:
1. Must discontinue treadmill exercise for reasons other than muscular leg pain (e.g., shortness of breath, chest pain, back pain)
2. Type 1 or insulin-dependent Type 2 diabetes
3. Lower extremity revascularization (surgical or percutaneous intervention) within 6 months prior to study entry
4. Fasting glucose greater than 110 mg/dL
5. Hypersensitivity to HMG-CoA reductase inhibitors
6. Low-density lipoprotein levels greater than 190 mg/dL, after HMG-CoA reductase inhibitors discontinuation (patients treated with HMG-CoA reductase inhibitors [statins] must discontinue therapy for 4 weeks prior to the baseline screening visit, and remain off treatment throughout the study [maximum of 15 weeks])
Revascularization group will exclude patients with an active infection

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00225940

Locations

United States, Massachusetts
Brigham and Women's Hospital	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Jeanne Doyle, RN 617-525-7055 jdoyle7@partners.org
Contact: Nicole Navarrete 617 525-7055 nnavarrete@partners.org
Principal Investigator: Mark A. Creager, M.D.

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:

Mark A. Creager

Brigham and Women's Hospital

More Information

No publications provided

Responsible Party:	Mark A. Creager, MD, Attending Physician, Vascular Medicine, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:	NCT00225940 History of Changes
Other Study ID Numbers:	267, NIH Grant # HL 075771
Study First Received:	September 12, 2005
Last Updated:	July 28, 2009
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Cardiovascular Diseases
Inflammation
Insulin Resistance
Peripheral Arterial Disease
Peripheral Vascular Diseases
Pathologic Processes
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular 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