ARREST PAD (Peripheral Arterial Disease)

Study Overview
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Brief Summary
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This trial will test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in subjects with intermittent claudication by impairing vascular reactivity and skeletal muscle metabolic function.

Detailed Description
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People with peripheral arterial disease (PAD), an important clinical manifestation of atherosclerosis, often suffer symptoms of intermittent claudication that impair their walking ability and adversely affect their quality of life. People with PAD are also at increased risk for adverse cardiovascular events, including myocardial infarction, stroke and death. Unfortunately, medical therapies directed to the functional and limb-threatening manifestations are limited. Little attention has been paid to the biologic processes that cause PAD, and to atherogenic mechanisms that may preferentially affect the peripheral circulation. Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Subjects in this trial (160 adults with stable intermittent claudication who are not taking insulin or insulin-sensitizing medications, such as thiazolidinediones) will be randomized in a placebo-controlled, parallel design manner, to atorvastatin 80 mg orally daily (to reduce inflammation) and pioglitazone 45 mg orally once daily (to improve insulin sensitivity). Forty healthy adult subjects, age and gender-matched to a subset of the study group, will be enrolled to serve as a control population. Primary and secondary study endpoints include: treadmill walking time, endothelium-dependent vasodilation, and insulin-mediated skeletal muscle glucose uptake.

Official Title
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The Contribution of Inflammation and Insulin Resistance to Intermittent Claudication

Conditions
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Arterial Occlusive Disease, Intermittent Claudication, Insulin Resistance

Intervention / Treatment
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* Drug: atorvastatin and pioglitazone
* Drug: atorvastatin/placebo
* Drug: pioglitazone/placebo
* Drug: placebo/placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: symptomatic intermittent claudication for >= 6 months resting ankle/brachial index (ABI) <=0.90 maximal treadmill walking time between 1-20 minutes >= 20% decrease in ABI post treadmill exercise 4 week statin wash-out prior to initial study testing (if applicable) Exclusion Criteria: myocardial infarction or coronary artery bypass surgery within past 6 months lower extremity revascularization (surgical or percutaneous) within past 6 months transient ischemic attack or ischemic stroke within past 6 months pregnancy uncontrolled hypertension (systolic pressure > 180mmHg and/or diastolic pressure > 100mmHg serum creatinine >2.5 hepatic transaminases (AST, ALT) > 3x upper limit of normal (ULN) creatine kinase > 5x ULN known hypersensitivity to HMG-CoA reductase inhibitors insulin dependent Type 2 diabetes current treatment with thiazolidinedione

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with PAD (Including diabetics)<br>Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo. | Drug: atorvastatin and pioglitazone<br>* atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity)<br>* Other names: pioglitazone: actos;Drug: atorvastatin/placebo<br>* atorvastatin 80 mg orally once daily and matching placebo orally twice daily<br>* Other names: atorvastatin: lipitor;Drug: pioglitazone/placebo<br>* pioglitazone 30 mg orally once daily and matching placebo orally once daily<br>* Other names: pioglitazone: actos;Drug: placebo/placebo<br>* placebo orally three times daily<br>|
| Active Comparator: PAD (Excluding Diabetics)<br>Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo. | Drug: atorvastatin and pioglitazone<br>* atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity)<br>* Other names: pioglitazone: actos;Drug: atorvastatin/placebo<br>* atorvastatin 80 mg orally once daily and matching placebo orally twice daily<br>* Other names: atorvastatin: lipitor;Drug: pioglitazone/placebo<br>* pioglitazone 30 mg orally once daily and matching placebo orally once daily<br>* Other names: pioglitazone: actos;Drug: placebo/placebo<br>* placebo orally three times daily<br>|
| Active Comparator: Healthy Controls<br>Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo. | Drug: atorvastatin and pioglitazone<br>* atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity)<br>* Other names: pioglitazone: actos;Drug: atorvastatin/placebo<br>* atorvastatin 80 mg orally once daily and matching placebo orally twice daily<br>* Other names: atorvastatin: lipitor;Drug: pioglitazone/placebo<br>* pioglitazone 30 mg orally once daily and matching placebo orally once daily<br>* Other names: pioglitazone: actos;Drug: placebo/placebo<br>* placebo orally three times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lower Extremity Skeletal Muscle Glucose Uptake | Net calf skeletal muscle glucose uptake determined by Patlak modeling. | 60 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 'M' = Whole Body Insulin Sensitivity | A hyperinsulinemic-euglycemic clamp was performed prior to and during FDG-PET imaging to measure insulin sensitivity and to standardize metabolic conditions. Subjects were required to fast for 8 hours prior to the study. Patients were given a primed insulin infusion of 2 mU/kg/min. Serum glucose measurements were made at five-minute intervals from an arterialized venous sample achieved by placing the hand in a warming box at 50°C. Blood glucose levels are checked every 5 minutes and 20% dextrose infusion is adjusted to maintain a serum glucose level of approximately 80 mg/dL. Subjects were considered to have achieved steady state when the dextrose infusion rate required to maintain a serum glucose level of 80 mg/dL varied by no greater than 5%. To compute the steady-state glucose disposal rate, we averaged the glucose infusion rates over the last 20 minutes of the clamp and applied a space correction to account for small changes in serum glucose levels over that time period. | every 5 minutes for 20 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peripheral arterial disease, intermittent claudication