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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Dose: 1 x 10\^7 cells/1 mL/vial (1,000 clusters of adipose-derived mesenchymal stem cells)
Dose: 1 x 10\^8 cells/1 mL/vial (10,000 clusters of adipose-derived mesenchymal stem cells)
Samsung Medical Center
Seoul, Seoul, South Korea
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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: The degrees of changes in Ulcer size on week 4, week 12, week 24, compared to the baseline.
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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.
Time frame: 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
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.)