Cell Therapy in Chronic Limb Ischemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00533104
Recruitment Status : Completed
First Posted : September 21, 2007
Last Update Posted : February 6, 2009
Information provided by:
CHU de Reims

Brief Summary:
The primary focus of the trial is safety and efficacy of the intra-muscular implantation of either bone-marrow, or peripheral blood mononuclear cells, in critical limb ischemia, as judged by the proportion of patients which are alive without major amputation 6 months after inclusion.

Condition or disease Intervention/treatment Phase
Peripheral Vascular Diseases Procedure: BM-MNC preparation Procedure: PB-MNC preparation Phase 1 Phase 2

Detailed Description:

Critical limb ischemia is a frequent situation whose incidence can be evaluated to 500 to 1,000 per million per year. Limb salvage is the main goal of therapy and is usually attempted by surgical or percutaneous vascularization procedures. However approximately 25 % of patients are not suitable for such procedures and it was estimated that less than half of these patients were alive without any major amputation after 6 months. In this setting cell therapy has been proposed to stimulate angiogenesis. The first significant experience in humans was reported by TATEISHI-YUYAMA et al who showed that autologous implantation of bone marrow mononuclear cells (BM-MNC) was safe and increased blood flow in ischemic limbs resulting in clinical improvement. The same authors did not observe any efficacy of peripheral blood mononuclear cells (PB-MNC). Subsequently other publications reported positive effects of PB-MNC which were harvested after previous treatment with haematopoietic growth factor to induce a mobilization of stem cells. However such a treatment could have deleterious effects in patients presenting with advanced arterial disease. In this context we propose a prospective bi-centric trial to evaluate the safety and efficacy of autologous implantation of either BM-MNC or PB-MNC without previous mobilization with hematopoïetic factor, in patients with critical limb ischemia.

The trial is designed in two steps : a first series of eight patients are treated with BM-MNC and the following eight will receive PB-MNC. An interim analysis is planned after these first sixteen cases. Based on this analysis, it will be decided to include 12 further patients with each type of cells.Patients are consecutively included as soon as they present with appropriate criteria and are not selected to receive one or another type of cells.

Before implantation, MNC counts, differential and viability are determined. CD34+, CD34+/CD133+ and CD34+/CD133+/flk-1+ cells are counted by flow-cytometry.

Clinical symptoms and TcPO2 are monitored 1, 2, 7 and 14 days, 1, 3, and 6 months after cell implantation. Blood cell count, C-reactive protein, Interleukin-6, tumor necrosis factor-α, myoglobin, and creatinin-kinase are determined at day 0, 1, 3 and 7 ; blood vascular-endothelial-growth-factor (VEGF) level and CD34+, CD34+/CD133+ blood cells are measured before and 72 hours after implantation

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Critical Limb Ischemia Treatment by Local Intra-Muscular Injection of Autologous Mononuclear Cells
Study Start Date : October 2004
Actual Primary Completion Date : February 2009
Actual Study Completion Date : February 2009

Arm Intervention/treatment
Experimental: BM-MNC
Patients are implanted with bone marrow - mononuclear cells
Procedure: BM-MNC preparation

For autologous bone marrow - mononuclear cells preparation, 500ml of bone marrow are collected under general anaesthesia; mononuclear cells are separated using a blood-cells separator (COBE SPECTRA, GAMBRO BCT) and concentrated to produce a final volume of 40ml.

Cells are implanted 1 to 3 hours after preparation by multiple intramuscular injections into the gastrocnemius of the ischemic leg.(30 injection sites, 1 to 1.5 cm deep, spaced 1 cm apart,1 ml per injection).

Experimental: PB-MNC
Patients are implanted with peripheral blood - mononuclear cells
Procedure: PB-MNC preparation

Peripheral blood - mononuclear cells are collected through cytapheresis with the same blood-cells separator which is adjusted to obtain a 40 mL cell product. No previous mobilization with hematopoïetic growth-factor is administered.

Cells are implanted 1 to 3 hours after preparation by multiple intramuscular injections into the gastrocnemius of the ischemic leg.(30 injection sites, 1 to 1.5 cm deep, spaced 1 cm apart,1 ml per injection).

Primary Outcome Measures :
  1. Survival without major amputation [ Time Frame: 6 months after implantation ]

Secondary Outcome Measures :
  1. clinical symptoms and haemodynamic parameters [ Time Frame: Within 6 months after implantation ]

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients with unilateral critical chronic limb ischemia but not suitable candidates for non-surgical or surgical revascularization
  • Before being included, the patient must be screened for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, treponema pallidum

Exclusion Criteria:

  • Buerger disease
  • Ischemic ulcers with infectious symptoms
  • Diabetes mellitus with HbA1c > 7,5% or with proliferative retinopathy
  • Past or current malignancy
  • Contra-indication to general anaesthesia
  • Chronic haemodialysis
  • Prothrombin Time < 60%,
  • Recent onset (within 3 months) of myocardial infarction or brain infarction
  • Coronary angioplasty within 1 year
  • Atrial fibrillation, mechanical mitral prosthetic valve
  • Unexplained hematological abnormality.
  • Expected life span less than six months
  • Patient not competent to give informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00533104

Nantes, France, 44000
Sponsors and Collaborators
CHU de Reims
Study Director: Bernard PIGNON, MD University Hospital REIMS FRANCE
Principal Investigator: Marie-Antoinette SEVESTRE, MD University Hospital AMIENS FRANCE

Publications of Results:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: PIGNON / MD, Centre Hospitalier Universitaire de REIMS - FRANCE Identifier: NCT00533104     History of Changes
Other Study ID Numbers: PHRC Région 2003 / R11-05 / 95
First Posted: September 21, 2007    Key Record Dates
Last Update Posted: February 6, 2009
Last Verified: February 2009

Keywords provided by CHU de Reims:
Limb ischemia
Cell Therapy

Additional relevant MeSH terms:
Vascular Diseases
Peripheral Vascular Diseases
Peripheral Arterial Disease
Pathologic Processes
Cardiovascular Diseases
Arterial Occlusive Diseases