ARREST PAD (Peripheral Arterial Disease)

September 22, 2014 updated by: Mark Alan Creager, MD, Brigham and Women's Hospital

The Contribution of Inflammation and Insulin Resistance to Intermittent Claudication

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

76

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Brigham & Women's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lower Extremity Skeletal Muscle Glucose Uptake
Time Frame: 60 minutes
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
Time Frame: every 5 minutes for 20 minutes
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Brigham and Women's Hospital

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Mark Creager, M.D., Brigham and Women's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2004

Primary Completion (Actual)

November 1, 2010

Study Completion (Actual)

December 1, 2011

Study Registration Dates

First Submitted

September 8, 2005

First Submitted That Met QC Criteria

September 8, 2005

First Posted (Estimate)

September 12, 2005

Study Record Updates

Last Update Posted (Estimate)

September 30, 2014

Last Update Submitted That Met QC Criteria

September 22, 2014

Last Verified

September 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2003P-001501
  • R01HL075771 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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