A Safety and Efficacy Study of Autologous Bone Marrow Derived Mesenchymal Stem Cells in Critical Limb Ischemia

Study Overview
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Brief Summary
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This clinical trial to study the Safety and Efficacy of Autologous Mesenchymal stem cells in critical limb ischemia.

Detailed Description
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If the participant voluntarily agrees to participate in the clinical trial before registration, the investigator conducts a screening test to evaluate the participant's suitability. A participant that satisfies all inclusion and exclusion criteria is assigned a test group(2-time injection group). Participants conduct cell therapy within 30 days after bone marrow aspiration, and will re-inject autologous mesenchymal stem cells within 30 days after first injection. Participants will make a total of 5 hospital visits after registration, and Safety and Efficacy will be evaluated based on a fixed procedure on every visit.

Official Title
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An Open Labeled, Single-center, Phase I Study Assessing the Safety and Efficacy of Autologous Bone Marrow Derived Mesenchymal Stem Cells in Critical Limb Ischemia

Conditions
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Critical Limb Ischemia

Intervention / Treatment
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* Drug: Cellgram-CLI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from 20 to 80 years Patients with resting pain or ulceration of limb (Rutherford's class: II-4, III-5 or III-6) Ankle Brachial Pressure Index (ABPI) ≤ 0.6 or TCPO2 ≤ 60mmHg in the foot Patients who were unsuitability for percutaneous transluminal angioplasty or a bypass operation Patients who are not expected other treatments for at least 6 months Patients who can agree to participate in the clinical trial by oneself or by one's legal representative Patients who can conduct the clinical trial according to the protocol Exclusion Criteria: Buerger's disease History of hematologic disease Patients who are at risk of embolism due to atrial fibrillation Primary hematologic disease, including hypercoagulable states Entrapment syndrome Patients with osteomyelitis Patients whose blood serum AST(Aspartate transaminase)/ALT(Alanine Transaminase) rates are more than three times the normal maximum rate, or whose creatinine rates are more than 1.5 times the normal maximum rate Patients with history of anaphylaxis to gentamicin Patients with hypersensitivity of bovine-derived ingredients Patients with chronic heart failure, Glomerular disease and Obstructive pulmonary disease Patients with Stroke or transient ischemic attack within 6 months prior to registration Patients tested positive for HIV(Human Immunodeficiency Virus), HCV(Hepatitis C Virus), HBV(Hepatitis B Virus) and Syphilis Patients with history of aorta and artery bypass operation, or angioplasty within 2 months recently Patients in need of a immediate amputation and have a potentially life-threatening complications of critical ischemia Patients with history of cell therapy Type I diabetes Uncontrolled diabetes mellitus (HgbA1C>8%) Uncontrolled hypertension Has a medical record of solid cancer, or diagnosed with solid cancer and currently receiving cancer treatment Positive of tumor markers test(AFP((Alpha fetoprotein), CEA(Carcinoembryonic antigen), CA15-3(Cancer antigen 15-3 for breast cancer) and PSA(Prostate-specific antigen), or have received a diagnosis of cancer based on National cancer screening program Pregnancy, possible candidate for pregnancy or lactating women Infectious disease Administrating of immunosuppressive agents, corticosteroid formulation and cell toxicity formulation, or requiring administration of the test period Patients already enrolled in another clinical trials or completed within 3 months Patients who cannot adapt to the protocol and follow-up observation Patients who has experienced drug abuse for the past 1 year Patients with any disease or condition which the investigator fell would interfere with trial or the safety of the subject

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2-time injection group : Cellgram-CLI<br>Within 30 days after extracting bone marrow, autologous bone marrow-derived mesenchymal stem cells is directly injected into the lesion. Then the second cell is injected within 30 days after the first cell injection. | Drug: Cellgram-CLI<br>* Appearance: White cell suspension is filled in a clear plastic syringe, and fixed with an occlude on the prefilled syringe tip Main ingredient: Autologous bone marrow-derived mesenchymal stem cells Dosage: 50,000,000 cells/10ml, 2-time injection Storage: An airtight container, 20 25℃ Injection Method: Intramuscular<br>* Other names: Autologous bone marrow derived Mesenchymal Stem Cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ankle Brachial Pressure Index, ABPI | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference of between the two visits(Screening and 6 month post treatment) before and after treatment. | 6 months after BM-MSC therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Collateral vessel formation on digital subtraction angiography (DSA) | Analyze the difference of pre and post treatment using McNemar test for homogeneity test. | 6 months after BM-MSC therapy | 
| Difference of Wound size | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference of pre and post treatment Healing of ulcerations (change in size of ulcers) or reduction of ulcer area in the target limb. | 6 months after BM-MSC therapy | 
| Improved transcutaneous oxygen pressure (TCPO2) | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference of pre and post treatment transcutaneous oxygen pressure (TCPO2). | 6 months after BM-MSC therapy | 
| Pain on the Visual Analogue Scale(VAS) | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference of pre and post Visual Analogue Scale(VAS). Visual Analogue Scale(VAS): Using a ruler, the score is determined by mea-suring the distance (mm) on the 10-cm line between the no pain anchor and the patient's mark, providing a range of scores from 0-100. A higher score indicates greater pain intensity. the following cut points on the pain VAS have been recommended: no pain (0-4 mm), mild pain(5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm) | 6 months after BM-MSC therapy | 
| Reduced limb amputation | Described and define as minor amputation is below midtarsal level, major amputation is more than midtarsal level. | 6 months after BM-MSC therapy | 
| Temperature change on thermography | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference of pre and post thermography. | 6 months after BM-MSC therapy | 
| Dose about using analgesic medicine | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference between pre and post dose of the using analgesic medicine. | 6 months after BM-MSC therapy | 
| Change in Rutherford classification | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference of pre and post Rutherford classification. Rutherford classification: commonly used clinical staging system for describing peripheral arterial disease. Stage 0 - Asymptomatic Stage 1 - Mild claudication Stage 2 - Moderate claudication - The distance that delineates mild, moderate and severe claudication is not specified in the Rutherford classification, but is mentioned in the Fontaine classification as 200 meters. Stage 3 - Severe claudication Stage 4 - Rest pain Stage 5 - Ischemic ulceration not exceeding ulcer of the digits of the foot Stage 6 - Severe ischemic ulcers or frank gangrene | 6 months after BM-MSC therapy | 
| Frequency about using analgesic medicine | Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference between pre and post frequency of the using analgesic medicine. | 6 months after BM-MSC therapy |