Endogenous Progenitors Cell Therapy for Diabetic Foot Ulcers

Study Overview
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Brief Summary
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Diabetic foot ulcers, a complication of diabetes leading to 80.000 lower limb amputations annually in the US, are a significant burden to our health system, costing more than a billion dollars annually. Here, we propose a novel combination of two drugs (Mozobil® and Regranex®Gel) to mobilize a specific sub-type of stem cells (endothelial progenitor cells) from the bone marrow and traffic them toward the wound, increasing the blood supply that subsequently improves wound healing. Because we are using the human body's own resources to regenerate itself by targeting and correcting the underlying pathophysiology, we believe that this novel therapy yields great promise in the treatment of diabetic foot ulcers.

Detailed Description
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Because diabetes impairs wound healing by altering fibroblast function, promotes chronic infection and diminishes blood supply to the skin, the lifetime risk of a person with diabetes developing a diabetic foot ulcer (DFU) is as high as 25%. Current strategies focus independently on the fibroblast dysfunction (growth factors such as PDGF/Regranex® Gel), on the chronic infection (debridement, antibacterial dressings) or on the blood supply (VAC®). This project is different from the other projects because we propose to combine two drugs in a dual approach to first improve the fibroblast function using PDGF/Regranex® Gel and second to induce neovascularization in DFU by recruiting progenitor cells into the wound through a combination therapy of subcutaneous AMD3100 (Plerixafor/Mozobil®) with topical PDGF/Regranex® Gel. By contrast to novel stem cell therapies where cells are extracted, processed ex vivo and engrafted into the wound (exogenous stem cell therapy), here we propose to keep the stem cells in vivo (endogenous stem cell therapy). Specifically, the first aim of the study will be to launch a prospective evaluator-blind pilot phase I/II safety and efficacy study to evaluate the clinical effect of AMD3100 (Plerixafor/Mozobil®) treatment with topical PDGF/Regranex® Gel compared to historical controls (standard of care and PDGF). AMD3100 (240 µg/kg SC) will be administered daily for 2 weeks. Our primary endpoint will be the measure of the percentage of change in area of the wound at 4 weeks (surrogate endpoint). In a second aim, we will measure the effect of AMD3100 treatment with PDGF using a quality-of-life index dedicated to DFU (DFS-SF). Because we are addressing the underlying physiopathology in a dual approach, because we are avoiding the need for ex vivo processing and because both drugs are FDA approved, we believe that this novel therapy yields great promise in the treatment of DFUs.

Official Title
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Endogenous Progenitors Cell Therapy for Diabetic Foot Ulcers

Conditions
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Diabetic Ulcer

Intervention / Treatment
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* Drug: AMD3100 injection + rhPDGF-BB topical


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Insulin-dependant type 2 diabetic patients Age between 35 and 60 years-old HbA1C between 6 and 12% Full-thickness diabetic neuropathic foot ulcers ≥ 2 weeks duration Following standard of care débridement, ulcer size must be between 1 and 6 cm2 Adequate perfusion, defined as either transcutaneous oxygen measurements on the dorsum of the foot >30 mmHg or ankle brachial indexes 0.7<ABI<1.2, as well as toe pressure >30 mmHg. Exclusion Criteria: Clinical infection at the studied ulcer site (bacterial and fungal) Clinically significant lower-extremity ischemia (as defined by an ankle/brachial index of <0.65) Active Charcot's foot as determined by clinical and radiographic examination Ulcer of a non-diabetic pathophysiology (e.g., rheumatoid, radiation-related, and vasculitis-related ulcers, and especially venous stasis ulcer) Significant medical conditions that would impair wound healing will also be excluded from the study. These conditions include liver disease, aplastic anemia, scleroderma and malignancy, treatment with immunosuppressive agents or steroids, myocardial infarcts, stroke, major surgery within 6 months of the study, usage of tobacco Subjects with cancerous or pre-cancerous lesions in the area to be treated Body weight > 160 kg (because of Plerixafor's pharmacokinetic limitation) Severe renal dysfunction (creatinine clearance < 50 ml/min) Severe non-proliferative or proliferative diabetic retinopathy Capillary blood glucose >350

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 60 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of Care<br>All patients will be receiving the Standard of Care treatments regardless of whether or not they are receiving study drug. | |
| Active Comparator: Novel Combination Therapy<br>AMD3100 (Plerixafor) injection with Regranex Gel topical application | Drug: AMD3100 injection + rhPDGF-BB topical<br>* drug therapy to be given for the first 2 week duration given on a daily basis initiated during the first visit (Day 0).<br>* Other names: Regranex Gel;|
| Active Comparator: Becaplermin (Regranex Gel)<br>Topical application | Drug: AMD3100 injection + rhPDGF-BB topical<br>* drug therapy to be given for the first 2 week duration given on a daily basis initiated during the first visit (Day 0).<br>* Other names: Regranex Gel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Wound Closure | The safety and efficacy of AMD3100 (Plerixafor) with rhPDGF-BB (Becaplermin) compared to two historical treatments group (Beclapermin versus standard of care (SOC) treatment) for the treatment of DFUs.[21] The central hypothesis to be tested is that a novel combination therapy will significantly increase the rate of closure of DFUs as compared to historical treatments groups, while presenting no major side effect. | 1 year | 
| Quality of Life | Test whether patients treated with the novel combination therapy will have an improvement in their quality of life, with higher scores on the DFS-SF than those of the historical control groups. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycosylated hemoglobin (HbA1C) | long-term measure of diabetes control | 4 weeks | 
| capillary blood glucose (ACCUCHEK Finger Stick) | short-term measure of diabetes control | 4 weeks | 
| Transcutaneous oxygen tension measurements on wound and 1 cm-radius periphery (Radiometer adult sensor) | non-invasive measure of skin circulation | 4 weeks | 
| Ankle-brachial index (ABI, Prestige sphygmomanometer and Summit doppler probe) | measure of peripheral vascular disease | 4 weeks | 
| pain (Visual-Analog Scale) | measure of the subjective symptom of pain | 4 weeks | 
| temperature of surrounding skin in a 1 cm-radius around the DFU (TempTouch Dermal Thermometer) | to identify increased skin temperatures, intended as an early warning of inflammation, impending infection, and possible foot ulceration. | 4 weeks | 
| sensation (Nk Pressure-Specified Sensory Device) | Quantification of sensory nerve function in patients with symptoms of, or the potential for, neurologic damage or disease | 4 weeks | 
| photogrammetry (Photoshop CS3, Adobe Systems) | used to document wound appearance | 4 weeks | 
| glomerular filtration rate (GFR, estimated by 24 hr. urine creatinine measurement) | to estimate renal function | 4 weeks | 
| diabetic retinopathy (digital ophthalmologic examination) | to evaluate for development of nonproliferative and proliferative retinopathy | 4 weeks | 
| cEPCs by FACS analysis | to measure the extent of BM EPC mobilization into the circulation and correlate the number cEPCs to other primary and secondary endpoints | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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wound healing