Autologous CD133(+) Cells as an Adjuvant to Below the Knee Percutaneous Transluminal Angioplasty

Study Overview
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Brief Summary
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The main aim of the present study was to evaluate the therapeutic potential and safety of transarterial infusion of granulocyte colony stimulating factor (G-CSF) mobilized cluster of differentiation (CD) 133(+) cells when combined with percutaneous transluminal angioplasty (PTA) in treatment of below the knee (BTK) peripheral arterial disease (PAD) in diabetic patients.

Detailed Description
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CD133+ cell, a bone marrow derived subpopulation of adult hematopoietic progenitor cells, confers high proliferative, vasculogenic and regenerative capacity in vitro and in vivo. thereby suggesting that CD133+ cells may induce vasculogenesis, improve limb perfusion, prevent tissue loss and restore ambulatory function in patients with critical limb ischemia. Although several small, randomized trials have been conducted so far demonstrating safety of autologous cells of bone marrow origin for the treatment, the reported benefits were found to be variable. A meta-analysis of autologous bone marrow derived cell therapy for critical limb ischemia trials suggested that application of autologous stem cell transplantation in curing limb ischemic patients does not have obviously effectiveness in the improvement of ankle brachial pressure (ABI) of the limb ischemic patients. But it can dramatically reduce the rate of amputation. Therefore, in the present study, the investigators aim to evaluate the therapeutic potential and safety of transarterial infusion of g-csf-mobilized CD 133(+) cells when combined with PTA in treatment of below the knee PAD in diabetic patients.

Official Title
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Autologous CD133(+) Cells as an Adjuvant to Below the Knee Percutaneous Transluminal Angioplasty: A Randomized Controlled Clinical Trial in Diabetic Patients With Below the Knee Critical Limb Ischemia

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Biological: G-CSF + CD133(+) cells
* Biological: G-CSF
* Procedure: percutaneous transluminal angioplasty (PTA)
* Biological: Placebo infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range: 18-75 years , Gender: Both Patients with below the knee limb ischemia with diabetes. Rutherford class 2-6. Target lesions with a diameter reduction of at least 50% and have an occlusion of longer than 4 cm on angiography. Have no previous history of any stem cell therapy [infusion of CD133 endothelial progenitor cell (EPC)]. Written informed consent signed by the patients or representatives. - Exclusion Criteria: Previous bypass surgery or stent placement at the ipsilateral lower limb History of intolerance to antiplatelet therapy, heparin, or contrast media. Presence of any of the following conditions: severe liver disease (such as ascites, esophageal varices, liver transplantation); hemodynamic instability; Severely impaired renal function (serum creatinine level > 2.5 mg/dL). Receiving immunosuppressive therapy; History of decompensated heart failure (New York Heart Association class III or IV and level) or myocardial infarction, or heart bypass surgery; Bleeding diathesis; Active systemic bacterial infection; Acute thrombophlebitis or deep vein thrombosis of the target limb; 4) Pregnant or lactating women, or women of child bearing age unable or unwilling to use effective contraception during the study period; 5) Expected survival time of less than 24 months -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: G-CSF + CD133(+) cells + PTA<br>Intramuscular injection of G-CSF along with transarterial infusion of CD133 (+) cells combined with percutaneous transluminal angioplasty | Biological: G-CSF + CD133(+) cells<br>* Patients in the G-CSF + CD133(+) cells + PTA group, received 150 unit of recombinant human G-CSF intramuscular injection to mobilize CD 133 cells from bone marrow to peripheral blood. After 72-120 hrs, 100 ml suspension of peripheral arterial blood were collected and send to Good Products Manufacturing (GPM) certified laboratory (Shanghai Chen Chuan Biological Material Co. Ltd.) within 24 hrs of obtaining sample to isolate CD 133(+) endothelial progenitor cells (EPC) using magnetic cell separator. Subjects in this group, after vascular PTA treatment, received transarterial infusion of 50 ml suspension of isolated autologous CD 133(+) cells over 30 min via catheter opened into popliteal artery. The infusion of CD 133 cells was repeated after 24 hours.<br>Procedure: percutaneous transluminal angioplasty (PTA)<br>* Subjects in this group only underwent below the knee percutaneous transluminal angioplasty .<br>|
| Active Comparator: PTA + G-CSF<br>Percutaneous transluminal angioplasty along with intramuscular injection of G-CSF | Biological: G-CSF<br>* Subjects in this group, after vascular PTA treatment, received 150 unit of recombinant human G-CSF intramuscular injection to mobilize EPCs from bone marrow to peripheral blood. But the C133 (+) cells were not isolated from the peripheral blood to infuse transarterially as in G-CSF + CD133(+) + PTA.<br>Procedure: percutaneous transluminal angioplasty (PTA)<br>* Subjects in this group only underwent below the knee percutaneous transluminal angioplasty .<br>|
| Placebo Comparator: Only PTA<br>Only Percutaneous transluminal angioplasty along with placebo infusion of sodium chloride injection | Procedure: percutaneous transluminal angioplasty (PTA)<br>* Subjects in this group only underwent below the knee percutaneous transluminal angioplasty .<br>Biological: Placebo infusion<br>* Neither G-CSF was injected nor CD133(+) cells. Instead, subjects received placebo infusion (50 ml of 0.9% sodium chloride injection ) over 30 min.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Restenosis rate | Occurrence of > 50% of restenosis in the treated vessel after 12 months as assessed by digital substraction angiography (DSA) (Efficacy endpoints). | 12 months | 
| Peak systolic velocity ratio | Peak systolic velocity ratio ≥ 2.4 by Doppler's ultrasonography for patients who did not undergo angiography after 12 months (Efficacy endpoints). | 12 months | 
| Severe adverse effects (SAEs) | Number of SAEs per subject across actual treatment cohorts (Safety Endpoint). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ABI value | Improvement in ABI value by ≥ 0.1 after the procedure and lack of deterioration > 0.15 in relation to the maximal value recorded before the procedure. | 6 and 12 months | 
| Rutherford classification | improvement in Rutherford scale of at least one category after the procedure. | 6 and 12 months | 
| Transcutaneous oxygen pressures (TcPO2) | .Changes in TcPO2 was assessed at each follow up interval and compared to baseline. | 6 and 12 months | 
| Amputation-free survival (AFS) | Time to below the knee amputation of the ipsilateral leg. | 6 and 12 months | 
| Rest pain | Rest pain was measured using Wong-Baker FACES pain rating scale at baseline and each follow-up visit. | 6 and 12 months | 
| Six Minute Walk test | Walking distance, time to onset of leg cramping/pain were recorded. | 6 and 12 months | 
| Ulcer healing rate | Ulcer status was assessed at each follow up interval and compared to baseline. | 6 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelial progenitor cell, Percutaneous transluminal angioplasty