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ARREST PAD (Peripheral Arterial Disease)

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ClinicalTrials.gov Identifier: NCT00153166
Recruitment Status : Completed
First Posted : September 12, 2005
Results First Posted : September 30, 2014
Last Update Posted : September 30, 2014
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Mark Alan Creager, MD, Brigham and Women's Hospital

Tracking Information
First Submitted Date  ICMJE September 8, 2005
First Posted Date  ICMJE September 12, 2005
Results First Submitted Date  ICMJE April 24, 2013
Results First Posted Date  ICMJE September 30, 2014
Last Update Posted Date September 30, 2014
Study Start Date  ICMJE January 2004
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 22, 2014)
Lower Extremity Skeletal Muscle Glucose Uptake [ Time Frame: 60 minutes ]
Net calf skeletal muscle glucose uptake determined by Patlak modeling.
Original Primary Outcome Measures  ICMJE
 (submitted: September 8, 2005)
Pain-free and maximal treadmill walking time
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2014)
'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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 8, 2005)
  • Endothelium-dependent vasodilation
  • Insulin-mediated skeletal muscle glucose utilization
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ARREST PAD (Peripheral Arterial Disease)
Official Title  ICMJE The Contribution of Inflammation and Insulin Resistance to Intermittent Claudication
Brief Summary 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

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Arterial Occlusive Disease
  • Intermittent Claudication
  • Insulin Resistance
Intervention  ICMJE
  • 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 Name: atorvastatin: lipitor
  • Drug: pioglitazone/placebo
    pioglitazone 30 mg orally once daily and matching placebo orally once daily
    Other Name: pioglitazone: actos
  • Drug: placebo/placebo
    placebo orally three times daily
Study Arms  ICMJE
  • Experimental: Patients with PAD (Including diabetics)
    Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
    Interventions:
    • Drug: atorvastatin and pioglitazone
    • Drug: atorvastatin/placebo
    • Drug: pioglitazone/placebo
    • Drug: placebo/placebo
  • Active Comparator: PAD (Excluding Diabetics)
    Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
    Interventions:
    • Drug: atorvastatin and pioglitazone
    • Drug: atorvastatin/placebo
    • Drug: pioglitazone/placebo
    • Drug: placebo/placebo
  • Active Comparator: Healthy Controls
    Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
    Interventions:
    • Drug: atorvastatin and pioglitazone
    • Drug: atorvastatin/placebo
    • Drug: pioglitazone/placebo
    • Drug: placebo/placebo
Publications * Pande RL, Brown J, Buck S, Redline W, Doyle J, Plutzky J, Creager MA. Association of monocyte tumor necrosis factor α expression and serum inflammatory biomarkers with walking impairment in peripheral artery disease. J Vasc Surg. 2015 Jan;61(1):155-61. doi: 10.1016/j.jvs.2014.06.116. Epub 2014 Aug 2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 22, 2014)
76
Original Enrollment  ICMJE
 (submitted: September 8, 2005)
200
Actual Study Completion Date  ICMJE December 2011
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00153166
Other Study ID Numbers  ICMJE 2003P-001501
R01HL075771 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mark Alan Creager, MD, Brigham and Women's Hospital
Study Sponsor  ICMJE Brigham and Women's Hospital
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Mark Creager, M.D. Brigham and Women's Hospital
PRS Account Brigham and Women's Hospital
Verification Date September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP