Mechanisms That Produce the Leg Dysfunction of Claudication & Treatment Strategies

NCT ID: NCT01970332

Last Updated: 2023-09-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 220 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-09-01
• Study Completion Date: 2016-05-30

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.

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.

Conditions

Peripheral Arterial Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: NONE

Study Groups

No Exercise Therapy or Revascularization operation

The patient is evaluated but no intervention

Group Type: NO_INTERVENTION

No interventions assigned to this group

Revascularization Surgery

The patient undergoes surgery to revascularize the ischemic, symptomatic limb(s)

Group Type: EXPERIMENTAL

Supervised exercise therapy

Intervention Type: OTHER

Exercise Therapy

The patient undergoes supervised exercise therapy for 6 months

Group Type: EXPERIMENTAL

Revascularization Surgery

Intervention Type: PROCEDURE

Interventions

Revascularization Surgery

Intervention Type: PROCEDURE

Supervised exercise therapy

Intervention Type: OTHER

Eligibility Criteria

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

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

American Heart Association

OTHER

Sponsor Role: collaborator

University of Nebraska

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Iraklis I Pipinos, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Nebraska

Locations

Veterans Affairs Medical Center, Omaha

Omaha, Nebraska, United States

Countries

United States

References

Rahman H, Leutzinger T, Hassan M, Schieber M, Koutakis P, Fuglestad MA, DeSpiegelaere H, Longo GM, Malcolm P, Johanning JM, Casale GP, Pipinos II, Myers SA. Peripheral artery disease causes consistent gait irregularities regardless of the location of leg claudication pain. Ann Phys Rehabil Med. 2024 Apr;67(3):101793. doi: 10.1016/j.rehab.2023.101793. Epub 2023 Dec 20.

Reference Type: DERIVED

PMID: 38118246 (View on PubMed)

Other Identifiers

5R01AG034995

Identifier Type: NIH

Identifier Source: secondary_id

View Link

15POST25520004

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

0510-10-ET

Identifier Type: -

Identifier Source: org_study_id