Evaluation of Carbothera in the Treatment of Foot Ulcers

Study Overview
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Brief Summary
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Foot ulceration usually precedes more serious foot complications such as infection, gangrene or amputation. The risk of developing foot ulcers has been estimated to be higher in individuals with kidney disease. Patients with kidney disease receiving dialysis have an increased prevalence of critical limb ischemia. Carbon dioxide (CO2) foot bathing has been reported to improve subcutaneous microcirculation. The proposed clinical study will evaluate the therapeutic potential of CO2 enriched water (produced by the Carbothera device) on treating foot ulcers in patients with critical limb ischemia and undergoing hemodialysis. Forty individuals how have a distal extremity ulcer who are currently undergoing hemodialysis will participate in this study.

Detailed Description
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This is a multi-centered, placebo controlled and randomized clinical study designed to evaluate the therapeutic potential of CO2 enriched water on the treatment of distal extremity (foot) ulcers in patients with critical limb ischemia undergoing hemodialysis. Study participants will be patients receiving dialysis at two local hospitals in Winnipeg and will have been diagnosed with CLI and foot ulceration. Patients will be randomized to receive either treatment with CO2-enriched tap water, 1,000-1200 ppm CO2 (TREATMENT GROUP), or non-enriched tap water (CONTROL GROUP), bath therapy at 37ºC on the same day as dialysis (typically 3 times/wk), for 15 min for 4 months,. Blood (approximately 20 ml) will also be collected at baseline and at the end of every month of the treatment period (for a total of 5 collections) for the measurement of the different biomarkers.

Official Title
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Evaluation of the Clinical Utility, Efficacy and Safety of a Novel Medical Device (Carbothera) in the Treatment of Foot Ulcers

Conditions
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Critical Lower Limb Ischemia, Critical Limb Ischemia, Foot Ulcer, Skin Ulceration

Intervention / Treatment
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* Procedure: CO2-Enriched Tap Water (Carbothera)
* Procedure: Non-CO2-Enriched Tap Water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants ≥ 18 years of age with at least one distal extremity ulcer (arterial ischemic ulcer). No acute medical illness and on conventional medical management prior to Carbothera. Willingness and ability to provide written informed consent Exclusion Criteria: DVT or PE within 12 months. Subjects with known active cancer, HIV, hepatitis B virus, hepatitis C virus, human transmissible spongiform encephalopathy, Treponema pallidum. Subjects who are deemed to have an infection of the distal extremity ulcer. Women who are pregnant Unstable angina. Acute MI within 1 month. Stroke within 1 month. Patient scheduled for revascularization during the 4-month intervention period.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CO2-Enriched Tap Water (Carbothera)<br>CO2-enriched tap water (CO2 concentration, 1000-1200 ppm) maintained at a temperature of 37˚C. Tap water will be enriched with CO2 by the investigational Carbothera device. | Procedure: CO2-Enriched Tap Water (Carbothera)<br>* Participants will undergo foot bathing with CO2-enriched tap water (CO2 concentration, 1000-1200 ppm) maintained at a temperature of 37˚C with an immersion time of 15 mins, 3 times per week for 4 consecutive months. Participants will be rested on a chair for 15 min before foot bathing. If participant is undergoing hemodialysis, foot bathing will occur prior to their routine hemodialysis procedure.<br>|
| Placebo Comparator: Non-CO2-Enriched Tap Water<br>Non-CO2-enriched tap water (i.e. normal tap water) maintained at a temperature of 37˚C. | Procedure: Non-CO2-Enriched Tap Water<br>* Participants will undergo foot bathing with non-CO2-enriched tap water maintained at a temperature of 37˚C with an immersion time of 15 mins, 3 times per week for 4 consecutive months. Participants will be rested on a chair for 15 min before foot bathing. If participant is undergoing hemodialysis, foot bathing will occur prior to their routine hemodialysis procedure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Ulceration Area, Volume, Depth and Rate | Measurement of ulceration area, volume, depth and rate will be completed at Baseline (Day 1), Week 4, Week 8, Week 12 and Week 16 using an approved (Health Canada) portable hand-held 3D digital wound imaging camera (SilhouetteStar from Aranz Medical, New Zealand). | 4 months | 
| Changes in Ankle Brachial Index (ABI)/Blood Flow | A continuous wave, hand held Doppler machine will be used with a blood pressure cuff and a conventional sphygmomanometer to measure the systolic pressure in both the posterior tibial (PT) and dorsalis pedis (DP) arteries. If no PT or DP arterial signals are found, the anterior tibial and/or peroneal artery pressure will be recorded. The ankle systolic pressure and brachial systolic blood pressure will be calculated as ankle systolic pressure/bronchial systolic pressure (ABI). The subject will be asked to rest supine for 10 minutes before ABI measurements. Brachial systolic and diastolic pressures as well as heart rate will be measured. Measurement of ABI will be conducted at Baseline (Day 1), and at weeks 4, 8, 12 and 16. | 4 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Degree of Rest Pain | Changes in the degree of rest pain will be measured using the McGill Pain Questionnaire which will be administered at Baseline (Day 1), Weeks 8 and 16. | 4 Months | 
| Changes Limb Oxygenation | Changes in limb blood volume and oxygenation will be recorded using noninvasive near infra-red spectroscopy (NIRS). NIRS measures the percentage of hemoglobin oxygen saturation in the microcirculation of tissue up to 3 cm below the skin. | 4 Months | 
| Changes in Angiogenesis Marker: vascular endothelial growth factor (VEGF) | A fasting blood sample will be obtained from the participant at the Baseline Visit (Day 1), and Weeks 4, 8, 12 and 16 visits for the purpose of measurement of the angiogenesis marker: vascular endothelial growth factor (VEGF). | 4 Months | 
| Changes in Inflammatory Markers: TNFα, IL-6 and C - reactive protein | A fasting blood sample will be obtained from the participant at the Baseline Visit (Day 1), and Weeks 4, 8, 12 and 16 visits for the purpose of measurement of inflammatory markers: TNFα, IL-6 and C - reactive protein. | 4 Months | 
| Changes in Markers of Glucose Handling: HbA1c and Fasting Blood Glucose | A fasting blood sample will be obtained from the participant at the Baseline Visit (Day 1), and Weeks 4, 8, 12 and 16 visits for the purpose of measurement of blood glucose and glycated hemoglobin (hemoglobin A1c). | 4 Months | 
| Changes in Lipid Profile | A fasting blood sample will be obtained from the participant at the Baseline Visit (Day 1), and Weeks 4, 8, 12 and 16 visits for the purpose of measurement of the participant's lipid profile, specifically, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides. | 4 Months | 
| Changes in Use of Bespoke Footwear and/or ability to Walk Barefoot | A patient self-report on the use of bespoke footwear or insoles and the ability to walk barefoot at home will be obtained at the Baseline Visit (Day 1) and at Weeks 8 and 16. | 4 Months | 
| Incidence of Amputation | Incidence of amputation of the distal extremity under study will be monitored during participation in the study. | 4 Months | 
| Use of Antibiotics Indicated for the Ulcer Treatment | Use of antibiotics indicated for the ulcer treatment during the period of the trial will also be recorded in a questionnaire. | 4 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Critical Limb Ischemia, Limb Ischemia, Wound Care, Hemodialysis, Dialysis, Skin Ulceration