Intramuscular Mononuclear Cells and Mesenchymal Stem Cells Transplantation to Treat Chronic Critical Limb Ischemia

Study Overview
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Brief Summary
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This is a randomized and single blinded study aimed to compare the efficacy between intramuscular autologous bone marrow mononuclear cells plus mesenchymal stem cell implantation and intramuscular autologous bone marrow mononuclear cells implantation only in patients with chronic critical limb ischemia. Patients will be randomized into two groups of equal number; patients in one group will be implanted with mononuclear cells and mesenchymal stem cells, and the other implanted with mononuclear cells only in the area of affected limb.

Detailed Description
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When the long blood vessels supplying blood to the arms and legs become blocked (ischemic), patient will experience painful sensations in their calves when they walked which slowly become excruciating painful at rest. When the condition worsens, the patients will not be able to feel any pain from their legs and they will not know if there are any small ulcers or cuts on their legs. As a result, a small ulcer which goes unnoticed becomes bigger and can sometimes become infected. In the worst situations, infection might lead towards gangrene and septicaemia. Severe rest pain and/or ulcerations of ischemic limbs are defined as the state of chronic critical limb ischemia and at this point, amputation of the affected limb is suggested. Conventional treatments include angioplasty/bypass operation to remove blood vessel blockage to restore blood supply, the use of prescribed medicines to aid in ulcer recovery and clear infection and debridement of damaged/infected tissue. Some procedures have to be performed multiple times. Amputation is inevitable in many cases because some blood capillaries cannot be corrected and restenosis of vessels is very common. Cell therapy with mononuclear cells and mesenchymal stem cells from bone marrow is promising because these stem cells are capable of stimulating and regenerating capillaries and blood vessels.

Official Title
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Phase II Efficacy Study of Intramuscular Autologous Bone Marrow Mononuclear Cells Plus Mesenchymal Stem Cell Implantation Versus Autologous Bone Marrow Mononuclear Cells Implantation Only in Patients With Chronic Critical Limb Ischemia

Conditions
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Critical Limb Ischemia

Intervention / Treatment
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* Biological: Mononuclear and mesenchymal stem cells
* Biological: Mononuclear cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of critical limb ischemia leading to ischemic ulcers in which amputation is indicated Not suitable for, or remain symptomatic despite angioplasty, bypass operation or collateralization Exclusion Criteria: Contraindication to epidural anesthesia and bone marrow aspiration Contraindication to contrast angiography Evidence of neoplasia and bone marrow diseases Any acute or chronic communicable diseases including Hepatitis B, Hepatitis C and HIV Patients with a limited life expectancy (< 1 year) Patients with myocardial infarction or stroke within 6 months Patients with coronary intervention within 6 months Renal impairment indicated by serum creatinine greater than two times upper limit of the normal range Liver impairment indicated by serum aspartate transaminase and alanine transaminase greater than two times upper limit of normal Any other co-morbidity which the physician deems as a contraindication to stem cell transplantation

Ages Eligible for Study
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Minimum Age: 20 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mononuclear and mesenchymal stem cells<br>Autologous bone marrow-derived mononuclear cells and mesenchymal stem cells | Biological: Mononuclear and mesenchymal stem cells<br>* Intramuscular administration into the ischemic limb<br>* Other names: BM-MNC and BM-MSC;|
| Active Comparator: Mononuclear cells only<br>Autologous bone marrow-derived mononuclear cells | Biological: Mononuclear cells<br>* Intramuscular administration into the ischemic limb<br>* Other names: BM-MNC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in angiogenesis | Measurement of angiogenesis by presence of peripheral pulses, capillary refill and transcutaneous oxygen saturation (TCOS). | 1 month, 3 months, 6 months, 9 months, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ulcer size | Measurement of ulcer size by clinical assessment and grid maps. | 1 month, 3 months, 6 months, 9 months, 12 months | 
| Visual Analog Score |  | 1 month, 3 months, 6 months, 9 months, 12 months | 
| Exercise Treadmill Test |  | 1 month, 3 months, 6 months, 9 months, 12 months | 
| Improvement in vascularity and blood supply | Measured by digital subtraction angiography (DSA) and ankle brachial systemic pressure index (ABI). | 1 month, 3 months, 6 months, 9 months and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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autologous, bone marrow, critical limb ischemia, efficacy, mesenchymal stem cells, mononuclear cells