Autologous Bone Marrow-derived Mononuclear Cells for Therapeutic Arteriogenesis in Patients With Limb Ischemia

Study Overview
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Brief Summary
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The investigators propose confirm and extend the findings of open studies on the apparent efficacy of bone-marrow derived mononuclear cells for the induction of arteriogenesis in patients with severe claudication or critical leg ischemia and pay special attention to the influence of diabetic disease on the outcome of the study and to the possible pro-atherogenic/ pro-inflammatory effects of BM-MNC injections.

Detailed Description
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Although the safety and beneficial effects of intramuscular transplantation of bone marrow derived mononuclear cells procedure appear well documented, a number of critical question regarding application of BM-MNC for peripheral vascular disease remain to be answered. First, although the original study has been partially performed as semi-blinded study (patients with double sided claudication were recruited and blindly treated with BM-MNC in one leg and peripheral blood injections in the other leg), this approach does exclude a placebo effect. Second, although patients with mild diabetes were included in the protocol, the results for diabetic patients were not analyzed separately. Diabetic disease is characterized by monocyte and endothelial progenitor cell dysfunction and it is still unclear whether this approach is also effective in diabetic patients. Third, although six-month results are reported long-term efficacy has not been established yet. To address these issues, the investigators now propose confirm and extend the findings from open studies in a randomized double-blind study in patients with severe claudication or critical leg ischemia and pay special attention to the influence of diabetic disease on the outcome of the study and to the possible pro-atherogenic/ pro-inflammatory effects of BM-MNC injections.

Official Title
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Autologous Bone Marrow-derived Mononuclear Cells for Therapeutic Arteriogenesis in Patients With Limb Ischemia A Double Blind, Placebo Controlled, Study in Diabetic and Non-diabetic Patients

Conditions
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Intermittent Claudication, Peripheral Vascular Diseases

Intervention / Treatment
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* Biological: bone marrow derived mononuclear cells
* Biological: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: persistent (>3 months) disabling claudication (Fontaine's stages IIb or Rutherford's categories 3, viz. pain free walking distance less than 100 meter) despite optimal therapy or critical limb ischemia (Fontaine's stages III/IV or Rutherford's categories 4-6) ineligibility for angioplasty or bypass procedures male of female, >18 years old life expectancy > 1 year written informed consent Exclusion Criteria: candidates for angioplasty or bypass procedures inability to undergo bone marrow harvesting any condition in the affected limb that is anticipated to require surgical intervention in the first weeks after BM-MNC treatment life threatening co-morbidity poorly controlled diabetes (HbA1C > 10%) active malignancy in the 5 years prior to treatment INR >1.5 at the time of bone-marrow harvest bleeding diathesis inability to undergo arterial catheterization inability to follow the protocol and to comply with the follow up requirements any other conditions that, in the opinion of the investigators, could interfere with the therapy or could pose a significant threat to the subject if the investigational therapy was to be initiated

Ages Eligible for Study
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Minimum Age: 16 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>non diabetic patients with Fontaine IIb-IV peripheral artery disease | Biological: bone marrow derived mononuclear cells<br>* 40 IM injections (calf muscle) of 1-8 10E9 mono nuclear cells<br>|
| Placebo Comparator: 2<br>non diabetic patients with Fontaine IIb-IV peripheral artery disease | Biological: placebo<br>* 40 IM injections (calf muscle) of placebo suspension<br>|
| Active Comparator: 3<br>diabetic patients with Fontaine IIb-IV peripheral artery disease | Biological: bone marrow derived mononuclear cells<br>* 40 IM injections (calf muscle) of 1-8 10E9 mono nuclear cells<br>|
| Placebo Comparator: 4<br>diabetic patients with Fontaine IIb-IV peripheral artery disease | Biological: placebo<br>* 40 IM injections (calf muscle) of placebo suspension<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Limb salvage/wound healing at t=6 months; Pain free walking distance |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| quality of life (RAND-36), pain Scores (Brief Pain Inventory), tcO2 (wrist/ankle ratio) ABI Collateral artery scores (angiogram) at t=6 months, Limb salvage/wound healing at t= 3 and 12 months, Pain free walking distance at t=3 and 12 months, |  | 3, 6 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Claudication, Critical limb ischemia, Cell therapy, Bone marrow