Safety and Efficacy of Autologous Bone Marrow Mononuclear Cells in Patients With Severe Critical Limb Ischemia

To Study and Demonstrate the Safety and Efficacy of RES-Q Prepared Bone Marrow Mononuclear Cells Injected Into Ischemic Tissue of Patients With Non-Reconstructable Critical Limb Ischemia (CLI).

The purpose of this study is to evaluate the safety and efficacy of the concentrated autologous bone marrow derived stem cells for the treatment of Critical Limb Ischemia patients.

A total of 15 patients suffering from end stage IV and V Rutherford /CLI in whom all previous therapeutic strategies failed (e.g. surgical revascularization) will be selected and undergo local transplantation of autologous BMMNCs. Conventional treatments include angioplasty and /or bypass to remove blood vessel blockage for restoring blood supply, along with prescribed medicines that aid in ulcer recovery and wound healing and debridement of damaged/infected tissue. Amputation is inevitable in many cases because some blood capillaries cannot be corrected and restenosis of vessels is very common. Cell therapies with mononuclear cells from patients own bone marrow is promising because these stem cells are capable of stimulating and regenerating capillaries and blood vessels (neovascularization).

This is a Phase Ib (feasibility study), prospective, non randomized and open labeled study aimed to find out the safety and efficacy of intramuscular autologous bone marrow mononuclear cells implantation in patients with chronic critical limb ischemia.

The efficacy/safety of this therapy will be assessed by using several endpoints such as (a) prevention of amputation, (b) wound healing and (c) degree of angiogenesis. In order to assess the limb ischemia, the measurements will be performed at pre- and post transplantation at a variety of time intervals. The measurements include: ABI-ankle brachial index, Transcutaneous partial pressure of Oxygen (TcPO2), 6 min walk test, Rest pain and intermittent Claudication assessment, Healing of ulcers/ wounds and angiography of the affected limb.

Inclusion Criteria:

• Atherosclerotic ischemic peripheral vascular disease (PVD) or Thromboangiitis Obliterans with severe Critical Limb Ischemia (Rutherford Category 4 and 5: ischemic pain at rest and minor tissue loss and Fontaine Class 4: Ischemic ulcers or gangrene, whivh may be dry or humid).
• A non-surgical candidate for revascularization e.g. prior vascular reconstruction, inability to locate a suitable vein for grafting, diffuse multi- segment disease, or extensive infra-popliteal disease not amenable to a vascular graft.
• Major amputation recommended patients due to severe life threatening PAD.
• Subjects must be on maximal tolerated medical therapy for peripheral vascular disease including A) Cessation of smoking B) Referral to endocrinologist for control of HgA1c to < 8% mg/dl, C) control of hyperlipidemia with statins or other anti-hyperlipidemic drugs as indicated, D) control of hypertension as indicated E) Antiplatelet therapy with aspirin and / or cilostazol (unless medically contraindicated, e.g. bleeding or allergy).
• Ankle Brachial Pressure Index (ABI) ≤ 0.6 or ankle systolic pressure ≤ 60 mm Hg or TcPO2 ≤ 35 mmHg in the foot.
• Subjects who are able to understand the requirements of the study, and willing to provide voluntary written informed consent, which abide by the study requirements, and agree to return for required follow-up visits.

Exclusion Criteria:

• Subjects with CLI suitable for surgical or percutaneous revascularization and Subjects with acute and chronic inflammatory condition.
• CLI patient requiring amputation proximal to trans-metatarsal level
• Subjects with spreading (wet) gangrene
• Subjects with gait disturbance for reasons other than CLI.
• Subjects with poorly controlled diabetes mellitus.
• Subjects diagnosed with Thromboangiitis Obliterans (Buerger's Disease) who are smokers and are unwilling or unable to quit smoking or the physician feels the smoking cessation is doubtful.
• Subjects having moderate to severe COPD with GOLD Classification IIb or III.
• Uncontrolled congestive heart failure or Subjects with left ventricular ejection fraction < 25% or AHA Stage C or D heart failure or NYHA Class IV CHF
• Stroke or myocardial infarction within last 3 months.
• Subjects who are contraindicated for CT Angiogram.
• Illnesses or conditions that are uncontrolled or whose control, in the opinion of the Principal Investigator, may be jeopardized by participation in this study or by the complications of this therapy.
• Documented terminal illness or cancer or any concomitant disease process with a life expectancy of less than 1 year.
• Subjects already enrolled in another investigational drug trial or completed within 3 months.
• History of severe alcohol or drug abuse within 3 months of screening.
• Hb% < 10 gm%; Serum creatinine ≥ 2.0mg%; Serum total bilirubin ≥2.0mg%; HbA1c > 8.0%.
• Women of child bearing potential; pregnant and lactating women.
• Subjects with a) myocardial infarction within the last 30 days or left ventricular ejection fraction < 35%, B) Subjects with a cerebrovascular accident within the last 6 months.
• INR > 1.5 at the time of Bone Marrow harvest.