Intraarterial Infusion of Autologous Bone Marrow in Diabetic Patients With Chronic Ischemia of Lower Limbs (CLI) no Revascularization

Study Overview
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Brief Summary
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The aim of the study is to evaluate the safety and feasibility of autologous bone marrow mononuclear cells autologous administered intra-arterially in the affected limb of diabetic patients with chronic critical ischemia of the lower limbs (CLI) without possibility of revascularization or other therapeutic alternatives. The trial hypothesis we propose consists of mononuclear cells of bone marrow providing progenitor cells with regenerative capacity and secrete also several angiogenic factors, and their implantation into ischemic tissues with both elements should contribute to angiogenesis and tissue regeneration with recovery of the circulation in the affected limb

Detailed Description
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Phase II Clinical Trial, a prospective, multicenter, open, randomized, parallel-group controlled with three dose levels. The study population will consist of a total of 60 diabetic patients with chronic critical ischemia of one leg (CLI) and no possibility of revascularization. In the experimental group will include a total of 45 patients divided into three dose levels, 15 patients in each level (increasing doses of mononuclear cells of bone marrow evenly) and 15 patients in control group (no cell therapy). Patients will be randomly assigned to either the control group or to any of the three experimental groups in which the dose of mononuclear cells of bone marrowo will be: Group 1(15 patients): no cell therapy. Group 2(15 patients): 1x108 mononuclear cells of bone marrow Gropu 3(15 patients): 5x108 mononuclear cells of bone marrow Group 4(15 patients): 1x109 mononuclear cells of bone marrow The cell therapy medicinal product shall be administered in all cases intraarterially. Patients were evaluated by clinical, radiological and angiologist methods. This is a randomized controlled trial in which the safety and feasibility of cell therapy medicinal product shall be measured by comparing the response variables after treatment compared to baseline prior to implementation. Secondarily the results obtained are compared with each of the dose groups. Patients will receive in a concomitant way the drug treatment established by the good practice, so it would certainly be possible that some improvement occurs due to drug treatment. The primary variable is the improvement in the vascularización of the treated limb determined by clinical, angiologic and angiographic parameters. It is estimated that the inclusion period lasts between twelve and eighteen months with twelve months follow-up. Therefore the total study duration range between twenty-four and thirty months from the inclusion of the first patient to the end of the follow-up of the last patient included. Objectives of the study: - Main objective: To evaluate the safety and feasibility of mononuclear cells of autologous bone marrow administered intra-arterially in the affected limb of diabetic patients with chronic critical ischemia of the lower limbs without possibility of revascularization or other therapeutic alternatives. Secondary objectives:

Official Title
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Phase II Clinical Trial of Therapeutic Angiogenesis With Mononuclear Cells Autologous Bone Marrow in Patients With Chronic Ischemia Diabetics Critical Limb (CLI) no Revascularization.

Conditions
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Critical Limb Ischemia (CLI), Diabetic Foot

Intervention / Treatment
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* Other: Intraarterial infusion of autologous bone marrow cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 or 2 diabetes mellitus Grade II-III Rutherford-Becker peripheral vascular disease affecting at least one limb Arterial obstruction(s) located at infrapopliteal level No options of endoarterial or surgical revascularization Life expectancy more than 2 years Unlikelihood of major amputation of the leg during the next 12 months Normal analytical parameters in blood: leucocytes>3000/micoL, neutrophils>1500 microL, Hb>10mg/dl, platelets>100000 microL,AST and ALT<2.5 standard value, creatinin<2.5 mg/dl Written informed consent Negative pregnancy test when applicable Exclusion Criteria: History of neoplasm or hematological disease Uncontrolled high blood pressure (>180/110) Severe cardiac insufficiency (NYHA IV) or ejection fraction<30% Malignant ventricular arrythmia Deep venous thrombosis during the last 3 months Active bacterial infection Treatment with hyperbaric oxygen, vasoactive drugs, Cox-II inhibitors or antiangiogenic agents Body mass index > 40 Alcoholism Proliferative retinopathy HIV, HBV or HCV viral infection Stroke or myocardial infarction during the last 3 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Low dose (1x10 E8)<br>Dose of 1x10 E8 autologous bone marrow-derived mononuclear cells | Other: Intraarterial infusion of autologous bone marrow cells<br>* Autologous bone marrow-derived mononuclear cells will be infused by an intraarterial catheter into de ischemic limb. The number of infused cells will be 1x10 E8, 5x10E8 and 1x10 E9 in the low,intermediate and high dose arms respectively<br>|
| Experimental: Intermediate dose (5x10 E8)<br>Dose of 5x10 E8 autologous bone marrow-derived mononuclear cells | Other: Intraarterial infusion of autologous bone marrow cells<br>* Autologous bone marrow-derived mononuclear cells will be infused by an intraarterial catheter into de ischemic limb. The number of infused cells will be 1x10 E8, 5x10E8 and 1x10 E9 in the low,intermediate and high dose arms respectively<br>|
| Experimental: High dose (1x10 E9)<br>Dose of 1x10 E9 autologous bone marrow-derived mononuclear cells | Other: Intraarterial infusion of autologous bone marrow cells<br>* Autologous bone marrow-derived mononuclear cells will be infused by an intraarterial catheter into de ischemic limb. The number of infused cells will be 1x10 E8, 5x10E8 and 1x10 E9 in the low,intermediate and high dose arms respectively<br>|
| No Intervention: Control<br>Conventional treatment established by the good clinical practice | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events |  | 24 h, 1,3 ,6 ,9 and 12 months | 
| AngioRNM and/or AngioTC changes |  | baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically objective improvement in the ischemic limb | (Ankle/brachial index, transcutaneous oxygen pressure, degree of Rutherford-Becker, greater ulcer size and perimeter calf muscle) | 1, 3, 6, 9 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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critical limb ischemia (CLI), diabetic foot, bone marrow derived mononuclear cells, cell therapy