Leg Thermotherapy for Intermittent Claudication

Study Overview
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Brief Summary
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This study proposes to evaluate the potential of leg thermotherapy as a non-pharmacological intervention that could improve the mobility and exercise tolerance of patients with intermittent claudication. Thermotherapy is a simple, easily applicable therapy that enhances exercise tolerance in patients with chronic heart failure by improving peripheral vascular endothelial function.

Detailed Description
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Peripheral arterial disease is characterized by atherosclerotic obstruction of the arteries in the lower extremities and affects approximately 10% of individuals older than 65 years. The most common clinical presentation of peripheral arterial disease is intermittent claudication, defined as leg pain caused by insufficient blood flow during walking. Individuals with intermittent claudication have severe exercise intolerance and markedly reduced levels of daily ambulatory activity. It is estimated that up to 40 million people worldwide suffer from intermittent claudication. Despite the increasing prevalence of this condition, few medical therapies improve mobility and exercise tolerance in these patients. An urgent need remains for the development of novel, non-invasive strategies that are more widely accessible and eliminate the need for supervision and frequent traveling to a clinical facility. The study proposes to evaluate the potential of leg thermotherapy as a non-pharmacological intervention that could improve the mobility and exercise tolerance of patients with intermittent claudication. Subjects will complete baseline assessments for eligibility and ability to do study, including medical history, quality of life assessment, ankle-brachial measurement, leg MRI, venous blood draw, assessment of vascular function, and 6-minute walk test. Treatment consists of 3 treatment sessions per week for six consecutive weeks. Subjects will be randomized to low-heat therapy or high-heat therapy. Subjects will wear water-circulating pants through which the heat therapy will be administered during the treatment sessions. Outcome measurements (same as baseline assessments) will be repeated after 9 treatment sessions and after 18 treatment sessions (at the end of the treatment period).

Official Title
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Leg Thermotherapy for Intermittent Claudication

Conditions
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Peripheral Artery Disease

Intervention / Treatment
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* Device: Low Heat Thermotherapy
* Device: High Heat Thermotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women with a stable symptomatic claudication for ≥6 months Ankle brachial index <0.9 Exclusion Criteria: Uncontrolled Diabetes (HbA1C > 8.5 measured within 3 months prior to date of consent) Heart Failure Chronic Obstructive Pulmonary Disease Critical limb ischemia (ischemic rest pain or ischemia-related non healing wounds or tissue loss Prior amputation Exercise-limiting comorbidity (i.e., angina, chronic lung disease, or arthritis) Recent (<3 months) infrainguinal revascularization (surgery or endovascular revascularization) or revascularization planned during study period. Plans to change medical therapy during the duration of the study Active cancer Chronic kidney disease (eGFR <30 by Modification of Diet in Renal Disease or Mayo or Cockcroft-Gault formula). HIV positive, active hepatitis B virus (HBV) or hepatitis C virus (HCV) disease. Presence of any clinical condition that in the opinion of the principal investigator makes the patient not suitable to participate in the trial. Peripheral neuropathy, numbness, or paresthesia in the legs. Morbid obesity BMI > 35. Open wounds or ulcers on the extremity. MRI Exclusions: Cardiac pacemaker Implanted cardiac defibrillator Aneurysm clips Carotid artery vascular clamp Neurostimulator Insulin or infusion pump Implanted drug infusion device Bone growth/fusion stimulator Cochlear, otologic, or ear implant History of claustrophobia or who are unable to lie flat or who do not fit inside the bore of the scanner

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Heat Thermotherapy<br>Low heat thermotherapy will be applied to subject's leg. Subject will wear a garment through which heated water is circulated which in turn supplies low heat to the subject's leg. | Device: Low Heat Thermotherapy<br>* Subject will wear a High Density LCG (Liquid Circulating Garment). Water will be heated and circulated through the garment, which in turn supplies low heat to the subject's leg.<br>|
| Experimental: High Heat Thermotherapy<br>High heat thermotherapy will be applied to subject's leg. Subject will wear a garment through which heated water is circulated which in turn supplies high heat to the subject's leg. | Device: High Heat Thermotherapy<br>* Subject will wear a High Density LCG (Liquid Circulating Garment). Water will be heated and circulated through the garment, which in turn supplies high heat to the subject's leg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise Tolerance Assessed by Measuring Distance (m) Walked in 6-minutes | 6-minutes walk test | Maximal walking distances on a 6mwt were obtained at weeks 3/6 and 6/6 of the study and compared to baseline values. | 
| Blood Pressure | Participants have systolic, diastolic and mean blood pressure recording 14 times during baseline, week 3 and week 6 experimental sessions. | Average blood pressure taken every 5 minutes for 70 minutes was obtained at weeks 3/6 and 6/6 of the study and compared to baseline values. | 
| Circulating Levels of Endothelin-1 (pg/mL) | Blood draw | Serum endothelin-1 levels were obtained at weeks 3/6 and 6/6 of the study and compared to baseline values. | 
| Circulating Total Nitrate Levels (mmol) | Blood Draw | Serum total nitrate levels were obtained at weeks 3/6 and 6/6 of the study and compared to baseline values. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vascular Function Assessed by Leg MRI to Measure Peak Blood Flow in Popliteal Artery (ml/s) | Phase contrast magnetic resonance imaging was performed on the leg that the patient indicated to have the most severe claudication. An inflation cuff was placed around the thigh and inflated to 75 mmHg above resting brachial systolic pressure for 5 minutes. After 5 minutes of inflation, the cuff was release and an additional 10 minutes of imaging took place. | Peak flows after post-occlusive reactive hyperemia were obtained at weeks 3/6 and 6/6 of the study and compared to baseline values. | 
| Vascular Function Measured by Ankle-brachial Index - Calculated by Dividing Higher of Posterior Tibial or Dorsalis Pedis Blood Pressure (mmHg) by Higher of Right or Left Arm Systolic Blood Pressure (mmHg) | Ankle-brachial Index | Ankle-brachial index measures were obtained at weeks 3/6 and 6/6 of the study and compared to baseline values. | 
| Vascular Function Measuring Leg Cutaneous Vascular Conductance - Measured by Laser-doppler Flowmetry of the Skin | Laser-Doppler flowmetry of skin included placement of two heating probes on the anterior portion of the lower leg. The participant sat in a semi-recumbent position for 70 minutes while the temperature of the probe progressed from 33C to 39C at minute 10 and then to 43C at minute 50. Cutaneous vascular conductance was calculated at the average red blood cell flux during the final 2 minutes of the 39C heating portion divided by the mean arterial pressure taken at that time. | Maximal cutaneous vascular conductance values after 40 minutes of localized heating were obtained at weeks 3/6 and 6/6 of the study and compared to baseline values. | 
| Patient Reported Functional Health and Well-being Using 36-item Short Form Health Survey | 36-item Short Form Health Survey. All scales are scored 1-100, with 1 being the poorest rating and 100 being the most optimal. | SF-36 questionnaires were administered at weeks 3/6 and 6/6 of the study and compared to baseline values. |