Monocentric Trial: Stem Cell Emergency Life Threatening Limbs Arteriopathy (SCELTA)

Study Overview
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Brief Summary
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The investigators designed a randomized clinical trial (stem cell emergency life threatening arteriopathy or SCELTA) to compare the therapeutic efficacy of the auto-transplant of enriched circulating EPCs (ECEPCs) with auto-transplant of BM-MNCs. ECEPCs, obtained by immunoselection of CD14+ and CD34+ cells, or BM-MNCs, were injected intramuscularly in the affected limb of patients with critical limb ischemia (CLI).

Detailed Description
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Peripheral arterial disease comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia (CLI), which is a very invalidating condition characterized by rest pain, march inability, trophic lesions and unavoidable progression to major amputations, which are burdened by a high mortality in the first year. The pathophysiology of CLI often associates with a defect in the development of collateral vessels and angiogenesis, a process which refers to the formation of new blood vessels into tissue, due to circulating endothelial progenitor cells (EPCs) and vascular progenitor cells. In the last few years, significant improvement of this condition has been reported following bone marrow (BM) autotransplant or autotransplant of peripheral EPCs mobilized from BM through the injection of granulocyte-colony stimulatory factor (G-CSF). In a previous study, the investigators found that individually variable proportions of circulating CD14+ cells expressed low levels of CD34 (CD14+CD34low) and revealed the functional phenotype of EPCs. The investigators therefore designed a monocentric randomized clinical trial to compare the therapeutic efficacy of BM autotransplant with the autotransplant of a population of circulating CD34+ and CD14+CD34low enriched by a closed sterile immunomagnetic system (enriched circulating EPCs or ECEPCs), without a previous EPC mobilization from BM. Patients will be evaluated for clinical parameters and ABI, TBI, TCp02 before autotransplant and at three follow-up times after the autotransplant (4, 24 and 52 weeks); also angio-TAC of legs, capillaroscopy, and photoplethysmography will be evaluated at 4, and even at 52 weeks.

Official Title
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Monocentric Randomized Study for the Therapy of Critic Limb Ischemia With Bone Marrow- or Peripheral Blood-derived Stem Cells

Conditions
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Critical Limb Ischemia

Intervention / Treatment
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* Biological: Transplantation of circulating CD14+CD34+cells
* Biological: Transplantation of BM MNC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible patients were men and women aged more than 40 years with a diagnosis of CLI due to atherosclerosis of the lower extremities, as defined by the presence of persistent rest pain requiring systemic and continued analgesic treatment in the last 15 days and/or the presence of trophic lesions imputable to the occluding arteriopathy, an ankle-brachial Index (ABI) < 0.40 (with systolic ankle pressure < 50-70 Hg mm), a toe/brachial index (TBI) < 0.40 (with big toe systolic pressure < 30-50 Hg mm), and a transcutaneous oxygen pressure (TC pO2) < 30 Hg mm. The patient was considered as eligible for the treatment and enrolled only after the demonstration that intravascular or surgical re-vascularization was not possible, as revealed by ecography and angio-CAT, or when the patient refused to undergo surgical treatments and after having obtained his/her written informed consensus. Exclusion Criteria: Exclusion criteria were: age < 40; not atherosclerotic CLI, myocardial infarction occurrence in the 6 months; cardiac failure of III-IV class NYHA; ejection fraction lower than 40%; arterial hypertension (>160/100 Hg mm) uncontrolled despite the usage of two anti-hypertensive drugs; presence of current or chronic severe infectious diseases; osteomyelitis; diabetes with glycate hemoglobin > 7.5; proliferative diabetic retinopathy; hemorrhagic disorders; non-atherosclerotic arteriopathy; chronic airway insufficiency (p02 <65 Hg mm, pCO2 > 0.50 Hg mm); renal failure (creatinine > 2mg/dl); contraindications or intolerance to contrast media for radiologic imaging

Ages Eligible for Study
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Minimum Age: 40 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: peripheral blood EPC injection<br> | Biological: Transplantation of circulating CD14+CD34+cells<br>* intramuscular injection of circulating EPC at leg level<br>|
| Active Comparator: bone marrow MNC injection<br> | Biological: Transplantation of BM MNC<br>* intramuscular injection of BM MNC at leg level<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by evaluation of any adverse event temporary correlated with the treatment | Evaluation of any adverse event temporary correlated with the treatment | 52 weeks of follow-up | 
| Changes in ischemic leg perfusion from baseline | Improvement of leg perfusion as assessed by values of Time to Pick (TTP) evaluated by ultrasound tools | 4, 22, 52 weeks of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of Mean values of the transcutaneous partial oxygen pressure (TCP02) | Improvement of mean values of the transcutaneous partial oxygen pressure of at least 20% | 4, 22, 52 weeks of follow-up | 
| Improvement of mean values of ankle brachial pressure index (ABI) | improvement (at least 25% increase) of Mean values of ankle brachial pressure index | 4, 22, 52 weeks of follow-up | 
| Improvement of vessel anatomical status | Improvement of leg vascularization as assessed by color Doppler ultrasound | 4, 22, 52 weeks of follow-up | 
| Improvement of leg perfusion | Improvement of leg perfusion as assessed by plethysmography characterization | 4, 22, 52 weeks of follow-up | 
| Improvement of vessel anatomical status | Improvement of leg vascularization as assessed by Angio-CT, defined as presence of new vessels | 4, 22, 52 weeks of follow-up | 
| Quality of life Improvement | Quality of life, as assessed by the disease-specific ST22 and SF36 questionaries | -28, 0, 28 weeks of follow-up | 
| improvement of rest pain | Rest pain as evaluated by visual analogue pain scale (VAS) | 4, 22, 52 weeks of follow-up | 
| Improvement of trophic limb lesions | Mean score of trophic limb lesions, as evaluated according to Wagner international grade | 4, 22, 52 weeks of follow-up | 
| Reduction of numbers of major amputation (amputation free survival ) | Reduction of numbers of major amputation compared with untreated patients | 4, 22, 52 weeks of follow-up | 
| improvement of microvascular anatomy | evaluation of microvascular anatomy as assessed by capillaroscopy | 4, 22, 52 weeks of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EPC, CD34+, CD14+CD34low