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Autologous Transplantation of Bone Marrow Mononuclear Cell (BM-MNC) With and Without Granulocyte-Colony Stimulation Factor (G-CSF) for Treatment of Chronic Lower Limb Ischemic Patients

Primary Purpose

Peripheral Vascular Diseases, Ischemia

Status

Completed

Phase

Phase 1

Locations

Iran, Islamic Republic of

Study Type

Interventional

Intervention

BM-MNC injection

About this trial

This is an interventional treatment trial for Peripheral Vascular Diseases focused on measuring Peripheral vascular diseases, chronic lower limb ischemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Presence of Critical Limb ischemia according to the guidelines of the Transatlantic Consensus Group (TASC) Rutherford grade II or III. Perfusion is measured with absolute perfusion pressure and ankle-brachial index (ABI) and transcutaneous oxygen tension (TcpO2); for inclusion, ABI has to be less than or equal to 0.6 or absolute ankle pressure must be less than 60 mmHg. If ABI is technically not feasible, e.g. in patients with media calcification, inclusion criteria are a tcpO2 value (supine, forefoot, 44°C) of less than 20 mmHg if there is no tissue loss, or a tcpO2 of less than 40 mmHg if there is tissue loss.
No sufficient response to best standard care delivered for six weeks.
No surgical or radiological interventional option for revascularisation as confirmed by a vascular surgeon and an interventional radiologist
Signed informed consent
Absence of life-threatening complications from the ischemic limb

Exclusion Criteria:

Expected life span less than six months
Bone marrow diseases which preclude transplantation (eg lymphoma, leukaemia, myelodysplastic syndrome and others)
Patients with poorly controlled diabetes mellitus (HbA1C > 8%)
Patients with renal insufficiency (creatinine > 2.5).
Patients with evidence of infectious disease as determined by e. above or other medical findings.
Pregnant women (women capable of childbearing must have a negative pregnancy test).
Patients with cognitive impairments.
Other comorbid disease that would be expected to result in less than one year life expectancy
Past malignancy or history of chemotherapy or radiation affecting the bone marrow.
History of inflammatory or progressively fibrotic conditions: .e.g., rheumatoid arthritis, systemic lupus erythematosis, vasculitic disorders, idiopathic pulmonary fibrosis, retroperitoneal fibrosis
Infection as evidenced by WBC count of >15,000 and/or temperature more than 38C. Large area of cellulitis in the afflicted limb that in the opinion ofthe investigators would require the institution of antibiotics OR evidence of osteomyelitis corroborated by radiographic or scintigraphic examination
Cardiovascular conditions:
EF<30%
Acute ST elevation myocardial infarction (MI) within 1month;
Transient ischemic attack or stroke within 1 month;
Severe valvular disease
CVA
Patients with any history of organ transplants

Sites / Locations

Royan Institute
Tehran University of medical sciences, Vascular Surgery department, Sina Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

stem cell recipient

Arm Description

the patients with peripheral vascular disease who receive bone marrow derived mono nuclear cells

Outcomes

Primary Outcome Measures

Major amputation

Secondary Outcome Measures

Minor amputation

Number and extent of leg ulcers

Resolvement of rest pain

Improvement of ankle-brachial index (ABI)

Improvement of pain free walking distances ( PFWD)

Full Information

NCT ID

NCT00677404

First Posted

May 12, 2008

Last Updated

July 27, 2011

Sponsor

Royan Institute

Collaborators

Tehran University of Medical Sciences

1. Study Identification

Unique Protocol Identification Number

NCT00677404

Brief Title

Autologous Transplantation of Bone Marrow Mononuclear Cell (BM-MNC) With and Without Granulocyte-Colony Stimulation Factor (G-CSF) for Treatment of Chronic Lower Limb Ischemic Patients

Official Title

Evaluation of Clinical Outcome in Advanced Chronic Lower Limb Ischemia by Stem Cell Transplantation With or Without (Granulocyte-colony Stimulation Factor) G-CSF Injection

Study Type

Interventional

2. Study Status

Record Verification Date

April 2010

Overall Recruitment Status

Completed

Study Start Date

January 2008 (undefined)

Primary Completion Date

October 2009 (Actual)

Study Completion Date

January 2010 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Royan Institute

Collaborators

Tehran University of Medical Sciences

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to investigate the efficacy and safety of autologous transplantation of mononuclear cells with and without G-CSF in patients with chronic lower limb ischemia.

Detailed Description

Critical limb ischemia (CLI) results from severe occlusive disease that impairs distal limb perfusion to the point where oxygen delivery is no longer adequate to meet the metabolic needs of the tissue, even under resting conditions. The limits of peripheral artery disease (PAD) compensatory mechanisms, such as distal vasodilatation and collateral formation, have been exceeded at this point. PAD is a widespread disease, affecting up to 15% of all adults older than 55 years. Formation of true new blood vessels, or angiogenesis, and development of collateral vessels from preexisting blood vessels, or arteriogenesis, is important in the pathophysiology of vascular disease. By stimulating these processes we might be able to provide an alternative treatment strategy for patients with lower limb ischemia. In response to tissue injury and remodeling, neovascularization usually occurs via the proliferation and migration of progenitor endothelial cells (EPC) from preexisting vasculature. The EPCs resident within bone marrow and peripheral blood, so it seems implantation of BM cells can contribute to injury-induced and pathology induced neovascularization. Indeed, recent studies have shown that bone-marrow mononuclear cell (BM-MNC) implantation increases collateral vessel formation in both ischemic limb models and patients with limb ischemia. In addition, granulocyte-colony stimulation factor could mobilize the EPCs to peripheral blood. After BM-MNC implantation, G-CSF can contribute more EPC in PB for effective angiogenesis in PAD patients. In this study, Bone marrow puncture will be performed in a common manner. The iliac crest is punctured under epidural anesthesia and 400 mL of bone marrow will be aspirated. The MNCs are isolated under good manufacturing practice conditions by Ficoll density separation and is intramuscularly injected (40 sites, in 3 × 3 cm distance, 1-1.5 cm deep, into ischemic leg. In some patients G-CSF (10 microgr/day) is administration by subcutaneous injection from day of cell injection for 5 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Peripheral Vascular Diseases, Ischemia

Keywords

Peripheral vascular diseases, chronic lower limb ischemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

stem cell recipient

Arm Type

Experimental

Arm Description

the patients with peripheral vascular disease who receive bone marrow derived mono nuclear cells

Intervention Type

Biological

Intervention Name(s)

BM-MNC injection

Intervention Description

Bone marrow aspiration A total volume of 400 ml bone marrow will be aspirated from the iliac crest under epidural anaesthesia

Primary Outcome Measure Information:

Title

Major amputation

Time Frame

six months

Secondary Outcome Measure Information:

Title

Minor amputation

Time Frame

six months

Title

Number and extent of leg ulcers

Time Frame

six months

Title

Resolvement of rest pain

Time Frame

six months

Title

Improvement of ankle-brachial index (ABI)

Time Frame

six months

Title

Improvement of pain free walking distances ( PFWD)

Time Frame

six months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Presence of Critical Limb ischemia according to the guidelines of the Transatlantic Consensus Group (TASC) Rutherford grade II or III. Perfusion is measured with absolute perfusion pressure and ankle-brachial index (ABI) and transcutaneous oxygen tension (TcpO2); for inclusion, ABI has to be less than or equal to 0.6 or absolute ankle pressure must be less than 60 mmHg. If ABI is technically not feasible, e.g. in patients with media calcification, inclusion criteria are a tcpO2 value (supine, forefoot, 44°C) of less than 20 mmHg if there is no tissue loss, or a tcpO2 of less than 40 mmHg if there is tissue loss. No sufficient response to best standard care delivered for six weeks. No surgical or radiological interventional option for revascularisation as confirmed by a vascular surgeon and an interventional radiologist Signed informed consent Absence of life-threatening complications from the ischemic limb Exclusion Criteria: Expected life span less than six months Bone marrow diseases which preclude transplantation (eg lymphoma, leukaemia, myelodysplastic syndrome and others) Patients with poorly controlled diabetes mellitus (HbA1C > 8%) Patients with renal insufficiency (creatinine > 2.5). Patients with evidence of infectious disease as determined by e. above or other medical findings. Pregnant women (women capable of childbearing must have a negative pregnancy test). Patients with cognitive impairments. Other comorbid disease that would be expected to result in less than one year life expectancy Past malignancy or history of chemotherapy or radiation affecting the bone marrow. History of inflammatory or progressively fibrotic conditions: .e.g., rheumatoid arthritis, systemic lupus erythematosis, vasculitic disorders, idiopathic pulmonary fibrosis, retroperitoneal fibrosis Infection as evidenced by WBC count of >15,000 and/or temperature more than 38C. Large area of cellulitis in the afflicted limb that in the opinion ofthe investigators would require the institution of antibiotics OR evidence of osteomyelitis corroborated by radiographic or scintigraphic examination Cardiovascular conditions: EF<30% Acute ST elevation myocardial infarction (MI) within 1month; Transient ischemic attack or stroke within 1 month; Severe valvular disease CVA Patients with any history of organ transplants

Overall Study Officials: