Intra-arterial Stem Cell Therapy for Patients With Chronic Limb Ischemia (CLI)

Study Overview
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Brief Summary
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The purposes of this study are to determine whether intra-arterial injection of autologous stem cells is effective in the treatment of chronic limb ischemia (CLI), to characterize stem cell dysfunction in patients with CLI, and to relate the stem cell function with clinical outcome.

Detailed Description
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Despite advances in surgical and radiological vascular techniques, a significant number of patients with chronic critical limb ischaemia (CLI) are not eligible for revascularization procedures, often leaving amputation as the only option. Consequently, exploring new strategies for revascularization of ischemic limbs is of major importance. Preclinical studies and pioneering clinical trials suggest that administration of bone marrow (BM) mononuclear cells (MNC) into ischemic limbs enhances neovascularization, improves tissue perfusion and prevents amputation. However, no definite proof is available as the clinical studies thus far have been small and lacked double-blinded controls. JUVENTAS is a randomized, double-blinded placebo-controlled trial in 109 - 160 patients with CLI to investigate the potential clinical effects of repeated intra-arterial infusion of BM-MNC in these patients (the exact number of patients to be included cannot be specified in advance because of the planned group sequential interim analyses). In addition, it will study the functional characteristics of the BM-MNC obtained from CLI patients and relate BM-MNC dysfunction to clinical outcome.

Official Title
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Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Cells in Patients With Chronic Critical Limb Ischemia: a Randomized, Placebo-controlled Clinical Trial

Conditions
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Peripheral Vascular Diseases, Arterial Occlusive Diseases, Leg Ulcer, Gangrene, Ischemia

Intervention / Treatment
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* Procedure: Bone marrow punction
* Procedure: BM-MNC infusion
* Procedure: Placebo infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Severe infra-popliteal peripheral arterial occlusive disease [PAOD] (Fontaine class IIb, III or IV) Invalidating intermittent claudication, persistent, recurring rest pain requiring analgesia and/or non-healing ulcers present for > 4 weeks without evidence of improvement in response to conventional therapies Ankle brachial index < 0.6 or unreliable Not eligible for surgical or radiological revascularization Written informed consent Exclusion Criteria: History of neoplasm or malignancy in the past 10 years Serious known concomitant disease with life expectancy of less than one year Anticipated inability to obtain 100 ml of bone marrow aspirate Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus Follow-up impossible

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: BM-MNC<br>autologous bone marrow-derived mononuclear cells | Procedure: Bone marrow punction<br>* A total volume of 100 ml bone marrow will be aspirated from the iliac crest under local anaesthesia (lidocaine) according to local routine. To maximise the patients comfort, 5-10 mg midazolam and 50 ug fentanyl will be administered intravenously.<br>Procedure: BM-MNC infusion<br>* Repeated intra-arterial infusion of autologous BM-MNC into the common femoral artery<br>|
| Placebo Comparator: Placebo<br>Placebo | Procedure: Bone marrow punction<br>* A total volume of 100 ml bone marrow will be aspirated from the iliac crest under local anaesthesia (lidocaine) according to local routine. To maximise the patients comfort, 5-10 mg midazolam and 50 ug fentanyl will be administered intravenously.<br>Procedure: Placebo infusion<br>* Repeated intra-arterial infusion of placebo (PBS/4% HAS/heparin, coloured with autologous erythrocytes to match the colour of BM-MNC suspension) into the common femoral artery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| major amputation |  | six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| minor amputation |  | six months | 
| number and extent of leg ulcers |  | six months | 
| resolvement of rest pain |  | six months | 
| improvement of ankle-brachial index (ABI) |  | six months | 
| improvement transcutaneous oxygen pressure (TcpO2) |  | six months | 
| changes in quality of life |  | suix months | 
| changes in clinical status (Rutherford classification) |  | six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leg pain, cell therapy, clinical trial, chronic critical limb ischemia, bone marrow, mononuclear, progenitor cell, stem cell, critical limb ischemia, nonhealing leg ulcer