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

Primary Purpose

Critical Limb Ischemia

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Cellgram-CLI
Sponsored by
Pharmicell Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Critical Limb Ischemia

Eligibility Criteria

20 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    2-time injection group : Cellgram-CLI

    Arm Description

    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.

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    Collateral vessel formation on digital subtraction angiography (DSA)
    Analyze the difference of pre and post treatment using McNemar test for homogeneity test.
    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.
    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).
    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)
    Reduced limb amputation
    Described and define as minor amputation is below midtarsal level, major amputation is more than midtarsal level.
    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.
    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.
    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
    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.

    Full Information

    First Posted
    June 10, 2015
    Last Updated
    March 21, 2019
    Sponsor
    Pharmicell Co., Ltd.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02477540
    Brief Title
    A Safety and Efficacy Study of Autologous Bone Marrow Derived Mesenchymal Stem Cells in Critical Limb Ischemia
    Official Title
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2019
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Study was stopped by sponsers internal reason.
    Study Start Date
    December 2019 (Anticipated)
    Primary Completion Date
    June 2020 (Anticipated)
    Study Completion Date
    June 2020 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Pharmicell Co., Ltd.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Critical Limb Ischemia

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    2-time injection group : Cellgram-CLI
    Arm Type
    Experimental
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Cellgram-CLI
    Other Intervention Name(s)
    Autologous bone marrow derived Mesenchymal Stem Cells
    Intervention Description
    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
    Primary Outcome Measure Information:
    Title
    Ankle Brachial Pressure Index, ABPI
    Description
    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.
    Time Frame
    6 months after BM-MSC therapy
    Secondary Outcome Measure Information:
    Title
    Collateral vessel formation on digital subtraction angiography (DSA)
    Description
    Analyze the difference of pre and post treatment using McNemar test for homogeneity test.
    Time Frame
    6 months after BM-MSC therapy
    Title
    Difference of Wound size
    Description
    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.
    Time Frame
    6 months after BM-MSC therapy
    Title
    Improved transcutaneous oxygen pressure (TCPO2)
    Description
    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).
    Time Frame
    6 months after BM-MSC therapy
    Title
    Pain on the Visual Analogue Scale(VAS)
    Description
    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)
    Time Frame
    6 months after BM-MSC therapy
    Title
    Reduced limb amputation
    Description
    Described and define as minor amputation is below midtarsal level, major amputation is more than midtarsal level.
    Time Frame
    6 months after BM-MSC therapy
    Title
    Temperature change on thermography
    Description
    Use Student's paired t-test or Wilcoxon's signed rank test to compare the difference of pre and post thermography.
    Time Frame
    6 months after BM-MSC therapy
    Title
    Dose about using analgesic medicine
    Description
    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.
    Time Frame
    6 months after BM-MSC therapy
    Title
    Change in Rutherford classification
    Description
    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
    Time Frame
    6 months after BM-MSC therapy
    Title
    Frequency about using analgesic medicine
    Description
    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.
    Time Frame
    6 months after BM-MSC therapy
    Other Pre-specified Outcome Measures:
    Title
    For safety analysis we will observed clinical laboratory tests, physical examinations, tumor marker tests
    Description
    Analyze using McNemar's test by making a table of changes that occurred in the test. clinical laboratory tests(Follow the unit of each institution): <Blood> WBC, RBC, Hb, Hct, Platelets count, WBC Differential count, BUN, ALT, AST, Glucose, Total bilirubin, Total Cholesterol <Urine> Protein, Glucose, Blood, Ketone, Billrubin, Urobillnogen physical examinations: -Allergy, Cardiovascular, Respiratory, Gastrointestinal /Liver biliary, Metabolic / endocrine, Kidney / urinary system, Reproductive, Musculoskeletal, Skin and connective, Nervous, Psyatric, Others tumor marker tests(Follow the unit of each institution): AFP CEA CA15-3(female) PSA(male)
    Time Frame
    12 months after BM-MSC therapy
    Title
    occurrence and severity of adverse events
    Description
    Analyze the adverse events by using seriousness, severity and relevance of IP.
    Time Frame
    12 months after BM-MSC therapy

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    20 Years
    Maximum Age & Unit of Time
    80 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    WoongChol Kang, MD, Ph.D
    Organizational Affiliation
    Gachon University Gil Medical Center
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

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

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