We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
ClinicalTrials.gov Menu

Mechanisms That Produce the Leg Dysfunction of Claudication (Leg Pain and Limping During Walking) and Treatment Strategies for the Care of Patients With Claudication

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01970332
Recruitment Status : Completed
First Posted : October 28, 2013
Last Update Posted : September 26, 2017
National Institute on Aging (NIA)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Iraklis I Pipinos, MD, University of Nebraska

Brief Summary:
Intermittent claudication afflicts 5% of the US population older than 55 years of age and develops along with hardening of the arteries of the legs. Claudicating patients limp and can only walk very short distances because their legs hurt. This protocol evaluates the mechanisms that may produce the leg dysfunction of claudication and its successful completion can ultimately produce significant new diagnostic and treatment strategies for the care of claudicating patients.

Condition or disease Intervention/treatment Phase
Peripheral Arterial Disease Procedure: Revascularization Surgery Other: Supervised exercise therapy Not Applicable

Detailed Description:
Claudication, defined as walking-induced leg discomfort and gait dysfunction relieved by rest, affects 5% of Americans over 55 years of age. Claudicating patients adopt sedentary lifestyles and cluster at the extreme low end of the physical activity spectrum, escalating risk for adverse health effects. The primary therapeutic goals for claudicating patients are restoration of leg function and prevention of disease progression. Current, rehabilitative interventions focus on inadequate blood flow as the only cause of claudication. Operative revascularization and/or exercise therapy are the principal conventional therapeutic modalities, providing only modest rehabilitative benefit. Applying biomechanical analysis to gait of claudicating patients, the investigators team has developed preliminary data indicating that blood flow is not the only mechanism producing the limb dysfunction of claudication. Several laboratories including the investigators own have demonstrated a myopathy, characterized by mitochondrial dysfunction, oxidative damage and inflammation, in leg skeletal muscle of claudicating patients. These conditions have not been quantified, comprehensively, in relation to claudication, and their association with severity of claudication is not known. The investigators hypothesis is that blood flow restriction is not a good predictor of limb dysfunction in claudication, whereas muscle mitochondrial dysfunction, oxidative damage and inflammation are strong predictors of limb dysfunction both at baseline and after conventional therapy with revascularization or supervised exercise. Under Aim #1, the investigators will acquire precise measurements of gastrocnemius mitochondrial function, oxidative damage and inflammation in claudicating patients, at the time of their initial presentation, and evaluate these measurements as predictors of objective measures of limb function and subjective measures of quality of life. Under Aims #2 and #3, the investigators will evaluate the effects of revascularization (Aim#2) and supervised exercise therapy (Aim#3) on mitochondrial dysfunction, oxidative damage and inflammation in claudicating gastrocnemius and on objective measures of limb function and subjective measures of quality of life. If the investigators hypothesis is correct, the work in Aim #2 will for the first time definitively demonstrate that blood flow restriction due to blockages in the arterial tree is not the only cause of claudication. The work under Aims #2 and #3 will determine whether revascularization or exercise therapy has a beneficial effect on the myopathy of claudicating muscle with associated improvement in limb function and quality of life. Finally, the proposed studies under Aims #1, #2 and #3 will provide quantitative modeling of a panel of mechanistic (bioenergetics, oxidative stress and inflammation) parameters as predictors of objective measurements of claudicating limb function and subjective measures of quality of life commonly used for clinical assessment. Measurements of gastrocnemius mitochondrial function, oxidative damage and inflammation may be useful tools that permit staging of disease for optimum intervention and evaluation of therapeutic interventions that specifically target these conditions, improving rehabilitative outcomes.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 220 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: Mitochondrial Dysfunction, Oxidative Damage and Inflammation in Claudication
Study Start Date : September 2010
Actual Primary Completion Date : May 30, 2016
Actual Study Completion Date : May 30, 2016

Arm Intervention/treatment
No Intervention: No Exercise Therapy or Revascularization operation
The patient is evaluated but no intervention
Experimental: Revascularization Surgery
The patient undergoes surgery to revascularize the ischemic, symptomatic limb(s)
Other: Supervised exercise therapy
Experimental: Exercise Therapy
The patient undergoes supervised exercise therapy for 6 months
Procedure: Revascularization Surgery

Primary Outcome Measures :
  1. Walking distances [ Time Frame: six months ]
    Initial Claudication Distance, Absolute Claudication Distance, 6-Minute Walking Distance

  2. Quality of life [ Time Frame: six months ]
    Walking Impairment Questionnaire and the Medical Outcomes Study Short Form 36 Healthy Survey

  3. Leg biomechanics [ Time Frame: six months ]
    Propulsion Impulse, Ankle plantarflexor torque, Ankle plantarflexor power and maximum isometric plantarflexion force

  4. Leg hemodynamics [ Time Frame: 6 months ]
    Ankle Brachial Index

Secondary Outcome Measures :
  1. Myofiber Mitochondrial Function [ Time Frame: 6 months ]
    Mitochondrial Respiration measured via polarography

  2. Myofiber Oxidative Damage [ Time Frame: 6 months ]
    Myofiber content of HNE adducts and protein carbonyls. Muscle Manganese Superoxide Dismutase activity

  3. Muscle inflammation [ Time Frame: 6 months ]
    Expression of pro- and anti-inflammatory cytokines and monocyte/macrophage cell counts.

  4. Myofiber Morphology [ Time Frame: 6 months ]
    Cross-sectional area of the myofibers

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • a positive history of chronic claudication
  • exercise-limiting claudication established by history and direct observation during a screening walking test administered by the evaluating vascular surgeon
  • an ankle/brachial index < 0.90 at rest

Exclusion Criteria:

  • absence of Peripheral Arterial Disease (PAD)
  • acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma
  • exercise capacity limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01970332

Layout table for location information
United States, Nebraska
Omaha VA Medical Center
Omaha, Nebraska, United States, 68105
Sponsors and Collaborators
University of Nebraska
National Institute on Aging (NIA)
National Heart, Lung, and Blood Institute (NHLBI)
Layout table for additonal information
Responsible Party: Iraklis I Pipinos, MD, Principal Investigator, University of Nebraska
ClinicalTrials.gov Identifier: NCT01970332    
Other Study ID Numbers: 510-10
5R01AG034995 ( U.S. NIH Grant/Contract )
First Posted: October 28, 2013    Key Record Dates
Last Update Posted: September 26, 2017
Last Verified: September 2017
Keywords provided by Iraklis I Pipinos, MD, University of Nebraska:
Peripheral Arterial Disease
Peripheral Vascular Disease
Oxidative stress
Mitochondrial dysfunction
Additional relevant MeSH terms:
Layout table for MeSH terms
Peripheral Arterial Disease
Peripheral Vascular Diseases
Intermittent Claudication
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases