Cell Therapy in Chronic Limb Ischemia

Peripheral Vascular Diseases Clinical Trial

Official title:

Critical Limb Ischemia Treatment by Local Intra-Muscular Injection of Autologous Mononuclear Cells

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00533104
• Other study ID #: PHRC Région 2003 / R11-05 / 95
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 19, 2007
• Last updated: February 5, 2009
• Start date: October 2004
• Est. completion date: February 2009

Study information

• Verified date: February 2009
• Source: CHU de Reims
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: February 2009
• Est. primary completion date: February 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Peripheral Arterial Disease
• Peripheral Vascular Diseases
• Vascular Diseases

Intervention

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).
• 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).

Locations

Country	Name	City	State
France	Patricia LEMARCHAND	Nantes

Sponsors (1)

Lead Sponsor	Collaborator
CHU de Reims

Country where clinical trial is conducted

France, 

References & Publications (1)

Pignon B, Sevestre MA, Chatelain D, Albertini JN, Sevestre H. Histological changes after implantation of autologous bone marrow mononuclear cells for chronic critical limb ischemia. Bone Marrow Transplant. 2007 May;39(10):647-8. Epub 2007 Mar 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival without major amputation		6 months after implantation
Secondary	clinical symptoms and haemodynamic parameters		Within 6 months after implantation