Efficacy and Safety of Mesenchymal Stem Cell Clusters in Patients With Critical Limb Ischemia

Study Overview
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Brief Summary
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This clinical trial is designed as a Phase 1/2a clinical trial targeting patients with critical limb ischemia. The trial is composed of Phase 1 to assess the tolerability and safety and Phase 2a to assess the safety and efficacy of the investigational product(A cluster of adipose-derived mesenchymal stem cells (3D-A) (cluster of adipose- derived mesenchymal stem cells)) and proceeds in that order.

Detailed Description
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This clinical trial is designed as a Phase 1/2a clinical trial targeting patients with critical limb ischemia. The trial is composed of Phase 1 to assess the tolerability and safety and Phase 2a to assess the safety and efficacy of the investigational product. Phase 1: Open-label, 3 + 3 design, single-center This phase is conducted in a 3 + 3 design by dose level to evaluate the tolerability of the investigational product. If the subject voluntarily agrees signs the informed consent formin writing to participate in this clinical trial, the subjects who had necessary check-ups and tests and meet the inclusion criteria after subject conformity assessment are registered in the clinical trial.The subjects receive the investigational product once and are checked for adverse events through day 1 and then discharged. The safety and efficacy assessments are conducted through visits at week 4, week 12, and week 24 after administration. Subjects are evaluated for adverse events up to week 4 after the administration of the investigational product by registering 3 subjects each at the dosing phase. This evaluation is conducted according to the number of persons subjects who developed Grade 3 or higher adverse drug reactions (ADRs) according to CTCAE Version_5.0 in which a causal relation with the investigational product cannot be ruled out. If the maximum tolerated dose (MTD) is determined with the test group 2 (high dose) in the Phase 1 clinical trial, the Phase 2a clinical trial will be conducted with the two groups, test group 2 and test group 1. However, if adverse events occur in 1 of 6 subjects, the test group 2 will be decided considered as the maximum tolerated dose (MTD), or but only the test group 1 will proceed to Phase 2a. If adverse events occur in 2 or more subjects out of 6 subjects, a dose smaller than test group 1 (low dose) is determined to be the maximum tolerated dose. The Phase 2a clinical trial will not proceed and the clinical trial will end. Phase 2a: Open-label, sequential assignment, single-center If tolerability and safety are secured 4 weeks after administration of the investigational product of Phase 1, Phase 2a is conducted. Only those subjects meeting the final inclusion criteria are sequentially assigned, admitted by the same procedure, and administered the investigational product once. Subjects are checked for adverse events through day 1 and discharged. Safety and efficacy assessments are performed at week 4, week 12, and week 24 after administration. All subjects are tested with the same schedule, excluding their doses. The subjects enrolled in Phase 1 are analyzed for efficacy through visits at week 12 and week 24 so that all subjects (Phase 1 and Phase 2a) are assessed and analyzed for efficacy.

Official Title
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A Phase 1/2a Clinical Trial to Evaluate the Efficacy and Safety of Allogenic Adipose Tissue-derived Mesenchymal Stem Cell Clusters in Patients With Critical Limb Ischemia

Conditions
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Critical Limb Ischemia

Intervention / Treatment
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* Biological: Clusters of adipose-derived mesenchymal stem cells (Dose: 1 x 10^7 cells/1 mL/vial)
* Biological: Clusters of adipose-derived mesenchymal stem cells (Dose: 1 x 10^8 cells/1 mL/vial)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged 19 or older A person diagnosed with critical limb ischemia due to peripheral artery stenosis or obstructive occlusive disease (Rutherford category 4, 5, 6) Patients with critical limb ischemia where symptoms do not improve even after medication treatment for more than 3 months[1] Persons who voluntarily agreed to participate in this clinical trial Exclusion Criteria: Persons whose life expectancy is less than 6 months Patients who underwent surgery and interventional procedures (percutaneous vascular intervention, vascular reconstruction, etc.) in the same disease within 3 months of screening Patients in need of interventional procedure or surgery Patients with a history of administration of other cell therapy products Persons who have received systemic immunosuppression treatment within 3 months of screening Persons with a history of a malignant tumor within 5 years of screening (However, non-metastatic basal cell skin carcinoma, squamous cell carcinoma of the skin or carcinoma in situ of the cervix that does not recur for at least 1 year before the registration are excluded) Persons with a hematologic disease with major bleeding or bleeding predisposition within 3 months of screening Women who are pregnant, breastfeeding or planning to become pregnant during the clinical trial period or women of childbearing potential who do not use medically acceptable birth control *Medically acceptable contraception: Medicine: Oral contraceptives, skin patches or progestin medications (Transplant or injection) Diaphragm: Condoms, diaphragms, intrauterine devices (IUDs), vaginal suppositories Abstinence: Absolute abstinence (However, periodic abstinence (e.g., calendar method, ovulation method, sympto-thermal method) and control are not considered acceptable contraceptive methods.) Persons who participated in other clinical trials within 3 months of screening Persons who were administered prohibited concomitant medications related to this clinical trial Persons with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels more than twice the normal upper limit at the time of screening Persons identified with estimated glomerular filtration rate (eGFR) levels < 30 mL/min/1.73 m2 at the time of screening Persons with a history of allergies or hypersensitivity to the investigational product or its components Persons who are judged to be inadequate to participate in clinical trials by other investigators

Ages Eligible for Study
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Minimum Age: 19 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 is conducted to evaluate the tolerability of the IP Subjects receive the IP once and are checked for adverse events. Subjects are evaluated for adverse events after the administration of the IP by registering 3 subjects each at the dosing phase. If the maximum tolerated dose (MTD) is determined with the test group 2 (high dose) in the Phase 1, the Phase 2a clinical trial will be conducted. However, if 1 adverse events occur, the test group 2 will be considered as the maximum tolerated dose (MTD), or but only the test group 1 will proceed to Phase 2a. If 2 adverse events occur, a dose smaller than test group 1 (low dose) is determined to be the maximum tolerated dose. The Phase 2a clinical trial will not proceed and the clinical trial will end. If tolerability and safety are secured, subjects meeting the final inclusion criteria are assigned to Phase 2a, admitted by the same procedure, and administered the IP once. Safety and efficacy assessments are performed.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test Group 1 (Low Dose)<br>- Administration Method: 1 mL is withdrawn from 1 vial of clusters of adipose-derived mesenchymal stem cells, composed of adipose-derived mesenchymal stem cells and diluted with 20 mL of saline, which is divided into 1 cc pre-filled syringes and administered in 20 divided doses to 15-20 parts of the muscle in divided doses along the working areacourse of the tibial artery and peroneal artery below the knee joint (above the lower ischemic area) of the subject (above the lower ischemic area) of the subjects under general anesthesia or spinal anesthesia so that the entire diluted solution is administered. | Biological: Clusters of adipose-derived mesenchymal stem cells (Dose: 1 x 10^7 cells/1 mL/vial)<br>* Dose: 1 x 10^7 cells/1 mL/vial (1,000 clusters of adipose-derived mesenchymal stem cells)<br>|
| Experimental: Test Group 2 (High Dose)<br>- Administration Method: 1 mL is withdrawn from 1 vial of clusters of adipose-derived mesenchymal stem cells, composed of adipose-derived mesenchymal stem cells and diluted with 20 mL of saline, then administered to 15-20 parts of the muscle along the working areacourse of the tibial artery and peroneal artery below the knee joint (above the lower ischemic area) of the subject (above the lower ischemic area) of the subjects under general anesthesia or spinal anesthesia. | Biological: Clusters of adipose-derived mesenchymal stem cells (Dose: 1 x 10^8 cells/1 mL/vial)<br>* Dose: 1 x 10^8 cells/1 mL/vial (10,000 clusters of adipose-derived mesenchymal stem cells)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in ischemic pain | Changes in 10 cm VAS (Visual analog score) measurement shall be recorded, and statistically analyzed (mean, median, max, min, STD, average). The degree of change shall be compared between the test groups using two sample t-test or Wilcoxon's rank sum test) | The degrees of changes in VAS measurement on week 4, week 12, week 24, compared to the baseline. | 
| Changes in pain-free walking distance | Changes in maximum walking distance on a treadmill shall be measured, and statistically analyzed(mean, median, max, min, STD, average). The degree of change shall be compared between the test groups using two sample t-test or Wilcoxon's rank sum test) | The degrees of changes in pain-free walking distance on week 4, week 12, week 24, compared to the baseline. | 
| Changes in TBI (Toe Brachial Index) | Changes in TBI (Toe Brachial Index) shall be recorded, and statistically analyzed (mean, median, max, min, STD, average). The degree of change shall be compared between the test groups using two sample t-test or Wilcoxon's rank sum test) | The degrees of changes in TBI on week 4, week 12, week 24, compared to the baseline. | 
| Changes in ABI (Ankle Brachial Index) | Changes in ABI (Ankle Brachial Index) shall be recorded, and statistically analyzed (mean, median, max, min, STD, average). The degree of change shall be compared between the test groups using two sample t-test or Wilcoxon's rank sum test) | The degrees of changes in ABI on week 4, week 12, week 24, compared to the baseline. | 
| Change in size of the Ulcer | The size of the largest ulcer shall be measured and statistically analyzed (mean, median, max, min, STD, average). The degree of change shall be compared between the test groups using two sample t-test or Wilcoxon's rank sum test) | The degrees of changes in Ulcer size on week 4, week 12, week 24, compared to the baseline. | 
| Determination of maximum tolerable dose according to DLT occurrence | Occurrence of adverse drug reactions that are definitely related to the administrated drug are monitored. Maximum tolerable dose is determined when ADR with grade 3 or higher with accordance to CTCAE version 5.0 has occurred to at least one of the three subjects. | Occurrence of ADR is monitored throughout the baseline to week 4 during phase 1. | 
| Incidence of abnormal laboratory tests results | The following laboratory tests are conducted. In case the results are abnormal, it shall be recorded as a adverse event or excluded from study (screening). Hematologic Test: WBC, RBC, Hemoglobin, Hematocrit, Platelets count, Blast, Promyelocyte, Metamyelocyte, Neutrophil (Seg, Band), Eosinophil, Basophil, Lymphocyte, Monocyte, Atypical Lymphocyte, Immature cell, Plasma cell, Nucleated RBC, Abnormal lymphoid cell Blood Chemistry Test: Total protein, Albumin, Globulin, Total Bilirubin, AST, ALT, ALP, BUN, Creatinine, Glucose, Uric Acid, Estimated GFR, Ca, P, CRP, CPK Urine Test: Specific gravity, pH, Glucose, Albumin, Bilirubin, Urobilinogen, Ketone, Blood, Nitrite, Leukocyte Esterase | Laboratory tests are performed on screening(-4 -2 week), baseline, 1 day after the baseline, and on week 4, week 12, week 24, compared to the baseline. | 
| Incidence of abnormal blood pressure | Systolic/Diastolic blood pressure is measured after relaxing in sitted position for 5 minutes. In case the results are clinically abnormal, it shall be recorded as an adverse event or excluded from study (screening). | Blood pressure is measured throughout the study (on screening visit(4 2 week before the baseline), base line, a day after the baseline, week 4, 12, 24 compared to the baseline.) | 
| Incidence of abnormal temperature | Temperature is measured via eardrum after relaxing in sitted position for 5 minutes. In case the results are clinically abnormal, it shall be recorded as an adverse event. | Temperature is measured throughout the study (on screening visit(4 2 week before the baseline), base line, a day after the baseline, week 4, 12, 24 compared to the baseline.) | 
| Incidence of abnormal physical condition | Appearance, skin, head, neck, heart, stomach, urology system, reproductive system, limbs, musculoskeletal system, nervous system, lymphatic glands and etc are examined. In case any clinically abnormal condition has been monitored, it shall be recorded as an adverse event. | Examined on every visits, throughout the study (on screening visit(4 2 week before the baseline), base line, a day after the baseline, week 4, 12, 24 compared to the baseline.) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adipose-derived mesenchymal stem cells, Critical limb ischemia, Stem cells, Ischemia, S.Biomedics