Passive Training as a Treatment for Diabetic Foot Ulcers

Study Overview
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Brief Summary
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Overall project design: This PhD project involves a randomized study on diabetic individuals with healing resistant wounds, comparing the effect of passive movement of the lower limb with standard treatment of diabetic wounds. How to effectively improve the condition of peripheral arterial disease is limited. The primary purpose of this study is to uncover whether passive movement of the lower limb will influence muscle oxygen demand and thereby increasing blood flow. An increase in muscle oxygen demand is likely to increase both blood flow rate and the number of capillaries, which would induce the healing of wounds, that were not previously possible. The secondary purpose is to increase understanding of the pathophysiological processes in wound healing through the study of biochemical markers of vascularization, inflammation and stem cell recruitment in blood samples. Further on analyzing the skin and muscle biopsies of the number and quality of endothelial cells and Capillary density and to develop new quantifiable methods to evaluate wound healing in. The project is a randomized trial, consisting of simple passive training to improve blood vessel function, increase the growth of the smallest blood vessels, thereby preventing ulceration and ultimately amputation.

Detailed Description
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Background information Diabetic foot ulcers are one of the most frequent and serious complication in diabetes mellitus. Despite attempts of prophylaxis*, only two-thirds of the diabetic foot ulcers eventually heal, and up to 15-20% will ultimately require a minor or major amputation (Major lower extremity amputation is defined as through or above the ankle joint, and minor amputations is below the ankle joint. The incidence of diabetes is growing, but the multifactorial causes of impaired healing of chronic diabetic ulcers are still not well understood. The diabetic foot ulcers are known to reduce the quality of life for patients both psychically and psychologically and therefore further investigation in new treatment options is plausible. Current knowledge regarding how to improve the condition in the beginning phase of peripheral artery disease (PAD) is limited. Investigators know that high oxygen tension and perfusion of the limb as well as an adequate density of microvessels in the tissue, is essential to wound healing. Therefore, interventions that increase blood flow and promote microcirculatory growth are likely to be beneficial in the treatment of wound healing. *Dressings, debridement, compression, clinical observation, antibiotics and glycemic control It has been reported that passive training consisting of knee flexion/extension in a kinetic machine has a beneficial effect on up regulation of growth factors, remicrovascularization and improved blood flow. Høier et al described that passive movement of the leg induced a two-fold elevation in blood flow, elevation of angiogenic factors and initiates capillarization in skeletal muscle. All three factors are often impaired in the diabetic leg, which results in poor wound healing. Due to the typical localization of the diabetic foot ulcers, this patient group is unable to exercise properly. Therefore will the investigators use a recent innovative model for the improvement of the limb microcirculation, developed at the Department of Nutrition, Exercise and Sports, University of Copenhagen, involving passive movement of the lower leg, for inducing increased blood flow and microcirculatory growth. Rationale for the trial Diabetic patients have impaired wound healing due to multifactorial causes. The investigators know that high oxygen tension, and perfusion is essential to wound healing, and according to Høier et al's study, passive training can increase the perfusion and elevate proangiogenic factors in both young healthy males and peripheral artery disease (PAD) patients. Null hypothesis: Passive training does not lead to enhanced healing of diabetic foot ulcers. Passive training of the lower limb does not affect perfusion of the trained limb. Perspective: This projects aim is to discover that passive training of the lower limb will increase the healing in diabetic foot ulcers. In addition, present a new treatment offer to diabetic patients with ulcers, who are not able to heal properly or perform active exercises. The investigators hope to see that the benefits of training and accelerated healing affect the PROM's. Further on to present new knowledge of the specific molecular and functional changes that occur in the tissue during wound healing. This knowledge will be very important to improve our understanding of why ulcerations occur and why the tissue begins to decompose. This is a prospective, randomized, single-blinded, parallel controlled design trial in subjects with diabetes mellitus investigating passive training as a treatment for the diabetic ulcer. The participants are randomized to either a control group or intervention. The control group receiving standard wound treatment, and an intervention group receiving standard wound treatment, and passive training exercises for 8 weeks. The participants will be followed for 16 weeks or until clinical wound healing. All participants will receive standard wound care consisting of debridement, dressings, compression, offloading footwear and if necessary antibiotics The comparison groups should be as similar as possible as regard to important participant characteristics that might influence the response to the intervention. Therefore, a block randomization to ensure that equal numbers of participants with a characteristic thought to affect prognosis or response to the intervention, will be allocated to each comparison group.

Official Title
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Passive Training as a Treatment for Diabetic Foot Ulcers: A Randomized, Single-blinded Clinical Trial of Wound Healing

Conditions
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Diabetic Foot Ulcers

Intervention / Treatment
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* Device: Passive knee extensor machine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial. Diabetes mellitus according to the World Health Organisation (WHO) criteria (see http://www.who.int/diabetes/publications/en/ ) and a stable treatment treated in a period of 14 days prior to screening with insulin or an oral antidiabetic agent. Stable is defined as stable HBA1c. 4. Foot ulcer: size: diameter > 1cm. Duration of wound > 6 weeks Location: Full thickness skin defect distal to the malleoli. 5. Male or female, age >18 years at the time of signing informed consent. 6. Non-dementia diagnosis. Exclusion Criteria: Major infection; acute cellulitis, osteomyelitis or gangrene anywhere in the affected extremity. Malignant disease Major traumatic tissue damage. Major lower extremity amputation.

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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group<br>A control group receiving standard wound treatment consisting of debridement, dressings, compression, offloading footwear and if necessary antibiotics. | |
| Experimental: Passive training group<br>An Intervention group doing passive exercise for 8 weeks in knee extensor machine, and receiving standard wound treatment consisting of debridement, dressings, compression, offloading footwear and if necessary antibiotics. | Device: Passive knee extensor machine<br>* The passive training machine, moves both legs from flexion to extension and back, 60 times per minute in 1 hour, 3 times per week. ROM is 60 degrees<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wound healing change quantified by digital photo planimetry | The digital photo planimetry measurements are compared to the baseline measurement at week 0 | Photos are taken at week 0 and 8 | 
| The change in Wagner's wound classification. | measurements at baseline are compared to week 8 | week 0 and 8 | 
| The change in Wagner's wound classification. | The measurements at week 3, 5 and 16 are compared to the baseline week 0 and 8 | week 3, 5 and 16 | 
| Wound healing change quantified by digital photo planimetry | The measurements at week 3, 5 and 16 are compared to the baseline week 0 and 8 | week 3, 5 and 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perfusion of the lower extremity. | Quantified by measuring the blood flow in arteria femoralis (doppler) | week 0, 3, 5, 8 and 16. | 
| Distal blood pressure measurement. | Includes skin perfusion test | week 0 and 8. | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Hemoglobin mmol/L | Week 0, 5 and 8 | 
| Histological changes of the muscle tissue. | Analysed from muscle biopsies | Week 0,5 and 8 | 
| Histological changes of the tissue composition in the edge of the wound. | Analysed from wound edge biopsy | Week 0,5 and 8 | 
| Angiogenetic factors analysed from muscle biopsy | • Total RNA isolated from the muscle biopsies, and the mRNA content of VEGF, eNOS, MMP-2, MMP-9, TIMP-1, TIMP-2, Tie-2, ANG-1, ANG-2 determined by PCR | Week 0,5 and 8 | 
| Dexa Scanning of the lower limb. | To measure the tissue composition change | Week 0 and 8 | 
| Dexa Scanning of the lower limb. | To measure the bone mineral density change | Week 0 and 8 | 
| Patient related outcome measurements (PROM's) | Medical Outcome Study Short Form 36 (MOS SF36) | Week 0, 8 and 16 | 
| the change in 30 second chair stand test |  | Week 0 and 8 | 
| the change in maximum leg extension test |  | Week 0 and 8 | 
| Adverse events |  | Week 0, 3, 5, 8 and 16 | 
| Autonomic neuropathy | vagus device measurements at baseline and after 8 weeks | Week 0 and 8 | 
| Distal blood pressure change measurement. | Arm, ankle and toe pressure. The ankle brachial index (ABI) is calculated from measuring the arm and ankle systolic blood pressure. | week 0 and 8 | 
| Autonomic neuropathy | sudoscan measurements at baseline and after 8 weeks | Week 0 and 8 | 
| Patient related outcome measurements (PROM's) | the Euroqol five Dimensions questionnaire (EQ-5D) | Week 0, 8 and 16 | 
| Histological changes of the endothelial cells | analysed from muscle biopsies | 0,5 and 8 | 
| Histological changes of the capillary density | Analysed from muscle biopsies | 0,5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Glycated HbA1c in mmol/mol | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Glucose in mmol/l | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | C-reactive protein in mg/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | leucocytes and differential count, in 10^9/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Thrombocytes in 10^9/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Sodium,mmol/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | potassium in mmol/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | eGlomerular filtration rate, mL/min/1,73 m^2 | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Albumin g/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Creatinine, μmol/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Alanine Transaminase, U/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | Basic Phosphatase, U/L | Week 0, 5 and 8 | 
| The biochemical changes during wound healing, is assessed by biochemical markers in peripheral venous blood samples. | YKL 40, μg/L | Week 0, 5 and 8 |