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

This study has been completed.
Sponsor:
Collaborator:
Tehran University of Medical Sciences
Information provided by:
Royan Institute
ClinicalTrials.gov Identifier:
NCT00677404
First received: May 12, 2008
Last updated: July 27, 2011
Last verified: April 2010
  Purpose

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.


Condition Intervention Phase
Peripheral Vascular Diseases
Ischemia
Biological: BM-MNC injection
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Royan Institute:

Primary Outcome Measures:
  • Major amputation [ Time Frame: six months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Minor amputation [ Time Frame: six months ] [ Designated as safety issue: Yes ]
  • Number and extent of leg ulcers [ Time Frame: six months ] [ Designated as safety issue: No ]
  • Resolvement of rest pain [ Time Frame: six months ] [ Designated as safety issue: No ]
  • Improvement of ankle-brachial index (ABI) [ Time Frame: six months ] [ Designated as safety issue: No ]
  • Improvement of pain free walking distances ( PFWD) [ Time Frame: six months ] [ Designated as safety issue: No ]

Enrollment: 20
Study Start Date: January 2008
Study Completion Date: January 2010
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: stem cell recipient
the patients with peripheral vascular disease who receive bone marrow derived mono nuclear cells
Biological: BM-MNC injection
Bone marrow aspiration A total volume of 400 ml bone marrow will be aspirated from the iliac crest under epidural anaesthesia

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00677404

Locations
Iran, Islamic Republic of
Royan Institute
Tehran, Iran, Islamic Republic of, 1665659911
Tehran University of medical sciences, Vascular Surgery department, Sina Hospital
Tehran, Iran, Islamic Republic of
Sponsors and Collaborators
Royan Institute
Tehran University of Medical Sciences
Investigators
Study Chair: Hamid Gorabi, PhD Royan institute, Tehran, Iran
Study Chair: Mohammad reza Zafarghandi, MD Sina Hospital, Tehran, Iran
Study Director: Nasser Aghdami, MD., PhD Royan institute, Tehran, Iran
Principal Investigator: Hossein Baharvand, PhD Royan institute, Tehran, Iran
Principal Investigator: Hassan Ravari, MD Sina Hospital, Tehran, Iran
  More Information

Additional Information:
Publications:
Responsible Party: Hamid Gourabi, Chief, Royan Institute
ClinicalTrials.gov Identifier: NCT00677404     History of Changes
Other Study ID Numbers: Royan-PVD-001
Study First Received: May 12, 2008
Last Updated: July 27, 2011
Health Authority: Iran: Ministry of Health

Keywords provided by Royan Institute:
Peripheral vascular diseases
chronic lower limb ischemia

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

ClinicalTrials.gov processed this record on August 18, 2014