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

Phase 1

Completed

Conditions: Critical Limb Ischemia

Interventions: Other: Autologous Bone Marrow Mononuclear cells (BMMNCs)

Registration Number: NCT01472289

Lead Sponsor: TotipotentSC Scientific Product Pvt. Ltd.

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BMMNC treated group	Autologous Bone Marrow Mononuclear cells (BMMNCs)	Autologous bone marrow mononuclear cell concentrate (BMMNCs) prepared using the Res-Q 60 technology (a point of care system) to be injected intramuscularly into multiple sites in the ischemic muscle tissue of the affected limb at 0.5 cc/injection for a total of 15-20 cc.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events as a Measure of Safety and Major Limb Amputation Free Survival Post BMMNC Administration	1, 3, 6 and 12 Months	The Primary objective of this study was to determine the safety of intramuscular administration of concentrated autologous BMMNCs harvested, and processed using the Res-Q 60 technology (a point-of-care system). Safety measurements included close vigilance for major limb amputation free survival at 1, 3, 6 and 12 months post BMMNCs administration and stringent reporting of AEs and SAEs.

Secondary Outcome Measures

Name	Time	Method
Degree of Angiogenesis Measured by the Number of Collateral Blood Vessels Formed at 12 Months	Baseline and 12 month	Measurement of blood supply facilitated by the formation of collateral blood vessels assessed by CT angiography after the procedure.
Measurement of Mean Change in Ankle Brachial Index From Baseline to 12 Months	Baseline, 1, 3, 6 and 12 months	ABI was used to provide a measure of blood flow in the lower limbs. It is the ratio of the blood pressure in the lower limbs to the blood pressure in the upper limbs. Compared to the upper limb, lower blood pressure in the lower limb is an indication of blocked arteries (peripheral vascular disease). The ABI was calculated by dividing the systolic blood pressure at the ankle by the systolic blood pressures in the arm. ABI test was performed at baseline, 1 month, 3 months, 6 months, and 12 months.
Clinical Evaluation for the Presence of Ulcer and/or Gangrene in the Affected Limb From Baseline to 12 Months	Baseline, 1, 3, 6 and 12 months	Evaluation of the integument for ulceration, gangrene and other skin changes in the affected limb was performed at baseline and follow-up visits at 1 month, 3 months, 6 months, and 12 months.The ulceration and gangrene in the affected limb of the subjects was evaluated by visual clinical inspection.
Number of Participants Able to Walk From Baseline to 12 Months as Measured by 6-Minute Walk Test	Baseline, 1, 3, 6 and 12 months	Subjects were analyzed to see if they were able to walk any distance and the distance covered by patients in 6 minutes was measured to assess the functional changes from baseline. The American Thoracic Society has issued guidelines for the 6-minute walk test (6 MWT). The 6 MWT is safe, easy to administer, well tolerated, and reflects activities of daily living.
Measurement of Change in Transcutaneous Oxygen Pressure (TcPO2) From Baseline to 12 Months	Baseline, 1, 3, 6 and 12 months	TcPO2 was used to assess the partial pressure (tension) of oxygen in the capillaries of tissues of lower limbs. It was measured by applying a special set of electrodes to the skin. These electrodes contain photoelectric sensors capable of detecting the specific wavelengths of radiation emitted by oxygenated versus reduced hemoglobin.
Change in Rest Pain and Intermittent Claudication Assessment From Baseline to 12 Months	Baseline, 1, 3, 6 and 12 months	Rest pain is a burning sensation felt at rest, usually in the skin of the foot. It is a symptom of critical ischemia due to severe, chronic, and occlusive peripheral arterial disease (PAD). While, Intermittent Claudication is a crampy leg pain that occurs during exercise, especially walking. The pain is due to the insufficient blood flow in the legs (caused by blocked arteries). Intermittent claudication is the most prominent symptom of PAD. Both Rest Pain assessment and Intermittent Claudication assessment was performed through Visual Analog Scale or Visual Analogue Scale (VAS). VAS is a psychometric (self-report) response scale that ranges from 0 to 10, where a mark of zero indicates no pain and a mark of 10 indicates worst possible pain.