Cell Therapy With Mesenchymal Stem Cell in Ischemic Limb Disease

Study Overview
=================
Brief Summary
-----------------
Bone marrow MSCs will be isolated from allogenic donors, expanded under hypoxic conditions using medium containing no serum or animal-derived reagents, and applies for Phase Ⅰ/Ⅱ study in treating 18 recipients with ischemic limb diseases.

Detailed Description
-----------------
Ischemic limb disease remains one of the major causes of morbidity and mortality in the industrialized world despite the development of several new therapeutic modalities. Based on experimental data demonstrating that infusion or injection of stem/progenitor cells enhances blood flow in models of cardiovascular diseases, clinical trials were initiated in 2001 to treat patients with critical limb ischemia or cardiac ischemia with circulating blood or bone marrow-derived cells. Despite all promises, pending uncertainties and practical limitations attenuate the therapeutic use of stem/progenitor cells for ischemic limb disease. The main theme and method in the current program project, based on expertise, track record, and preliminary results of PI's laboratory, is to focus on clinical studies of using allogenic mesenchymal stem cells (MSCs), expanded under hypoxic conditions (1% O2), in treating ischemic limbs. This project is an integrated and coordinated effort aimed to overcome the regulation of cell product, and the barriers of preclinical and clinical studies. For the purposes, we have specially set up the core laboratory for stem/progenitor cells production and quality control in Cell Therapy Clean Room on the 9th floor of Medical Science Technology Building in Taipei Veterans General Hospital. We have also completed the preclinical studies in using allogenic hypoxic mouse MSCs in treating limb ischemia. In the current project, bone marrow MSCs will be isolated from allogenic donors, expanded under hypoxic conditions using medium containing no serum or animal-derived reagents, and applies for Phase Ⅰ/Ⅱ study in treating 18 recipients with ischemic limb diseases in three years.

Official Title
-----------------
Cell Therapy With Mesenchymal Stem Cell in Ischemic Limb Disease

Conditions
-----------------
Critical Limb Ischemia

Intervention / Treatment
-----------------
* Drug: Allogenic MSC
* Drug: Normal saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Fontaine stage > II, total walking distance < 100 m, stair < 1 floor, or ulcer / necrosis Established critical limb ischemia, clinically and hemodynamically confirmed as per Rutherford- Ⅱ-4, Ⅲ-5, or Ⅲ-6; Patients having Infra-inguinal arterial occlusive disease with rest pain or ischemic ulcer/necrosis, who are not eligible for or have failed traditional revascularization treatment Ankle Brachial Pressure Index (ABPI) ≤ 0.8，ankle pressure ≤ 70 mm Hg, or TcPO2 ≤ 70 mmHg in the foot No response to medication (aspirin and cilostazol) Normal liver and renal function On regular medication for hypertension if any Exclusion Criteria: The above mentioned patients combined with infection or systemic septicemia. (ps, patients with poor control of diabetes, hypertension and hyperlipidemia will also be excluded Patient with Immunocompromised or immunosuppressed Type I Diabetes Patients having stroke or myocardial infarction within last 3 months Hb% < 10 gm%, Serum Creatinine ≥ 2mg%, Serum Total Bilirubin ≥2mg%, HbA1c > 8%

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Allogenic MSC<br>Low dose allogenic mesenchymal stem cells with IM injection | Drug: Allogenic MSC<br>* Hypoxia-cultured human bone marrow derived mesenchymal stem cells<br>* Other names: Biochymal;|
| Experimental: High Dose Allogenic MSC<br>High dose allogenic mesenchymal stem cells with IM injection | Drug: Allogenic MSC<br>* Hypoxia-cultured human bone marrow derived mesenchymal stem cells<br>* Other names: Biochymal;|
| Placebo Comparator: Placebo<br>normal saline with Intramuscular injection | Drug: Normal saline<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Number of adverse events reported | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy-The Wong Baker FACES® pain rating scale | The Wong Baker FACES® pain rating scale, for evaluation of ischemic pain in the diseased lower limb of subjects receiving cell injection compared to placebo | 6 months | 
| Efficacy-Transcutaneous oxygen pressure(TcPO2) | The Transcutaneous oxygen pressure (TcPO2) on foot of subjects receiving cell injection compared to placebo | 6 months | 
| Efficacy-walking distance (TWD) | Total walking distance (TWD) on a standardized treadmill test compared to placebo | 6 months | 
| Efficacy-Ankle Brachial Pressure Index (ABPI) | The Ankle Brachial Pressure Index (ABPI) in the lower limb of subjects receiving cell injection compared to placebo | 6 months |