Clinical trial NCT02790957: Plerixafor in Diabetic Wound Healing
Official title: Effect of a Single Plerixafor Injection on Diabetic Wound Healing. A Pilot, Double-blind, Placebo-controlled, Randomized Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Diabetes
Wounds
Critical Limb Ischemia
Lead sponsor: University of Padova
Sponsor class: OTHER
Collaborators: name: University Hospital Padova
First posted: 2016-06-06
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Wound healing rate
timeFrame: 6 months
Secondary outcomes:
measure: Wound size
timeFrame: 6 months
measure: Oxygen tension
timeFrame: 6 months
measure: Perfusion
timeFrame: 6 months
measure: Surgical intervention
timeFrame: 6 months
measure: Stem cell mobilization
timeFrame: 6 months
measure: Incidence of adverse events and reactions
timeFrame: 6 months
Other outcomes:
Locations:
city: Padova
country: Italy
facility: University Hospital of Padova
Study officials:
affiliation: University of Padova
name: Gian Paolo Fadini, MD PhD
role: STUDY_CHAIR
References:
citation: Albiero M, D'Anna M, Bonora BM, Zuccolotto G, Rosato A, Giorgio M, Iori E, Avogaro A, Fadini GP. Hematopoietic and Nonhematopoietic p66Shc Differentially Regulates Stem Cell Traffic and Vascular Response to Ischemia in Diabetes. Antioxid Redox Signal. 2022 Apr;36(10-12):593-607. doi: 10.1089/ars.2021.0097. Epub 2022 Jan 4.