Plerixafor in Diabetic Wound Healing

Study Overview
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Brief Summary
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Chronic non-healing wounds represent a major source of morbidity, disability, and mortality in diabetic patients. Diabetes is the leading cause of non-traumatic limb amputations worldwide. Many patients with ischemic or neuroischemic wounds are not candidate to surgical/endovascular revascularization, owing to anatomical vascular reasons or for the underlying conditions and co-morbidities. Therefore, identification of novel medical treatment strategies to improve wound healing in diabetic patients is a major challenge for clinicians, researchers, and health care systems. Defects in bone marrow (BM)-derive stem and progenitor cells, including EPCs (endothelial progenitor cells), contribute to diabetic complications. Stem cell mobilizing agents have been previously studied as an adjunctive therapy for critical limb ischemia and chronic non-healing wounds in diabetic and non-diabetic patients, as well as for the treatment of diabetic wound infections . Meta-analyses of such studies indicate that stem cell mobilization in these clinical conditions is safe and potentially effective in improving surrogate outcome measures and hard endpoints (such as rates of wound healing and amputation). This study plans to evaluate whether a single injection of Plerixafor improves wound healing in diabetic patients with stage III-IV (neuro)ischemic wounds.

Detailed Description
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Chronic non-healing wounds represent a major source of morbidity, disability, and mortality in diabetic patients. Diabetes is the leading cause of non-traumatic limb amputations worldwide. Many patients with ischemic or neuroischemic wounds are not candidate to surgical/endovascular revascularization, owing to anatomical vascular reasons or for the underlying conditions and co-morbidities. Therefore, identification of novel medical treatment strategies to improve wound healing in diabetic patients is a major challenge for clinicians, researchers, and health care systems. Defects in bone marrow (BM)-derive stem and progenitor cells, including EPCs, contribute to diabetic complications. Stem cell mobilizing agents have been previously studied as an adjunctive therapy for critical limb ischemia and chronic non-healing wounds in diabetic and non-diabetic patients, as well as for the treatment of diabetic wound infections . Meta-analyses of such studies indicate that stem cell mobilization in these clinical conditions is safe and potentially effective in improving surrogate outcome measures and hard endpoints (such as rates of wound healing and amputation). However, diabetes impairs the response to the most commonly agent used to mobilize stem cells, namely human recombinant granulocyte colony stimulating factor (hrG-CSF). This notion comes from extensive data in animal models, a retrospective case series in patients with hematological disorders, a meta-analysis of studies conducted in patients with cardiovascular disease, and our proof-of-concept prospective study in otherwise healthy outpatients. Vice versa, our data strongly indicate that diabetic patients adequately mobilize stem/progenitor cells (including vascular progenitors, like EPCs) in response to the CXCR4 antagonist Plerixafor. Plerixafor (Mozobil, Sanofi) is clinically available in Europe (including Italy) as a second-line regimen for stem cell mobilization in patients with myeloma or lymphoma scheduled for autotransplantation, only in combination with hrG-CSF, after failure of hrG-CSF alone, to mobilize a sufficient amount of CD34+ stem cells to start apheresis. Preclinical studies in animal models of delayed and diabetic wound healing support the idea that Plerixafor can be effective as an adjunct therapy to accelerate diabetic wound healing. This study plans to evaluate whether a single injection of Plerixafor improves wound healing in diabetic patients with stage III-IV (neuro)ischemic wounds.

Official Title
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Effect of a Single Plerixafor Injection on Diabetic Wound Healing. A Pilot, Double-blind, Placebo-controlled, Randomized Trial

Conditions
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Wounds, Diabetes, Critical Limb Ischemia

Intervention / Treatment
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* Drug: Plerixafor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 or type 2 diabetes Men of 18-85 years or post-menopausal women <85 years of age Presence of neuroischemic or ischemic diabetic wound(s) of the leg(s) / foot(s) Texas grade 3 or 4, with or without infection. Ability to provide informed consent. Exclusion Criteria: Sepsis Dialysis or severe chronic kidney disease (eGFR <20ml/min/1.73 mq) Advanced liver disease (defined as cirrhosis or transaminases >3 times ULN) Clinically relevant abnormalities in white blood cell counts at baseline. Hematologic disorders (lymphoma, myeloma, acute or chronic leukemia, chronic myeloproliferative disorders) Known or highly suspected solid cancer Women with childbearing potential Known hypersensitivity to Mozobil (Plerixafor or its components) Inability to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plerixafor<br>Single subcutaneous injection of Plerixafor (0.24 mg/kg) | Drug: Plerixafor<br>* Single injection of 0.24 mg/kg Plerixafor<br>* Other names: Mozobil;|
| Placebo Comparator: Placebo<br>Single injection of an equal volume of NaCl solution | Drug: Placebo<br>* Single injection of an equal volume of NaCl solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wound healing rate | Comparison of wound healing rates in the 2 groups, defined as the complete healing of wounds after 6 months from randomization | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wound size | Comparison of changes in wound size over time (up to 6 months) in the 2 groups. | 6 months | 
| Oxygen tension | Comparison of changes in TcO2 (transcutaneous oxygen tension) over time (up to 6 months) in the 2 groups. | 6 months | 
| Perfusion | Comparison of changes in ankle/brachial index over time (up to 6 months) in the 2 groups. | 6 months | 
| Surgical intervention | Comparison of the rates of surgical intervention (including debridement and amputations) at 6 months in the 2 groups. | 6 months | 
| Stem cell mobilization | Comparison of CD34+ cell mobilization (ratio of cell level at 6 hour post-Plerixafor administration and baseline) in patients with good versus poor outcomes | 6 months | 
| Incidence of adverse events and reactions | Comparison in the incidence of adverse events and reactions in the 2 groups | 6 months |