Patients undergoing semi-elective lower extremity major amputation from complications associated with atherosclerotic limb ischemia will received intra-muscular injections of allogeneic Mesenchymal Stromal Cells in the leg above and below the point of amputation to prevent ischemic wound complications after surgery and decrease the incidence of revision and further amputation. Cohort Groups 1-4 will serve as controls.
This is a phase I single center open label trial study that will enroll twenty-six (26) patients requiring semi-elective lower extremity major amputation within a 30 day period for non-infectious complications related to critical limb ischemia (CLI). After enrollment patients will be scheduled for amputation 7 days after MSC administration. The investigational treatment uses allogeneic bone marrow derived mesenchymal stem cells at the point of care. Allogeneic MSCs will be injected in the gastrocnemius muscle and anterior tibialis muscle of twenty-six (26) patients undergoing major amputation. Through a review of treatment related adverse events over 6 months we will test the hypothesis that allogeneic MSCs do not result in significant cardiovascular, respiratory, or infectious treatment related adverse events. Through an exploratory investigation we will assess the efficacy of MSCs in promoting freedom from gangrene, revision of amputation, and death after major amputation.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
81
Injection of HLA-A2+ and/or gender mismatched allogeneic MSCs above the site of amputation and into the anterior tibialis muscle (ATM) of patients scheduled for semi-elective lower extremity major amputation at 7 days before amputation.
Indiana University
Indianapolis, Indiana, United States
Number of participants with treatment-related adverse events occurring during the enrollment period as assessed by the Investigator using the MeDRA scale.
Treatment-related adverse events will be categorized in overlapping systems of cardiovascular, respiratory, or infectious and severities of serious adverse events (SAE) and major adverse cardiac events (MACE). The sum and difference between routes of delivery will be reported. Confidence intervals will be generated and summarize the data by the method of the Wilson Score Interval. Binomial confidence intervals at the 95% confidence level and p-values for these groups will be calculated. Continuous confidence intervals at the 95% level will be constructed to explore the effect of administration of MSCs on the composite endpoint at 6-months of death, amputation revision and gangrene, and will be compared to historical cohorts. The critical levels for the multiplicity adjustment will be determined by simple Monte Carlo simulation.Unanticipated SAEs and those affecting the rights, safety, or welfare of subjects will be documented and reported immediately upon discovery.
Time frame: Primary follow up in a 6 month period
Gene and protein arrays, IHC staining, and multiparametric flow cytometry will measure the time period of retention of allogeneic MSCs in harvested human skeletal muscle tissue post-MSC implantation.
Quantities over time of MSC will be fit to an exponential decay curve using a residual pseudo-likelihood procedure and cell half-life (λ) will be estimated. Binomial confidence intervals at the 95% confidence level and p-values will be calculated for the presence or absence of MHC expression and SDF-1activation. The correlation between capillary density (CD31 counts) with tissue perfusion (ICA) for each time point will be estimated by Spearman's rank coefficient. The gene and protein expression profiles and histological findings will be used to test the hypotheses that MSCs have limited survival post-injection.
Time frame: Primary follow up in a 6 month period
Recruitment of proangiogenic hematopoietic cells into sites of ischemia will be measured and reported as assessed by the role of MSCs injected in human skeletal muscle at the time of amputation.
Continuous confidence intervals at the 95% level will be constructed to explore differences among the time-tiered administration of MSC for (1) the CD34+CD133+ pro-angiogenic hematopoietic cells recruitment of HIF-1α/SDF-1/CXCR4 to ischemic muscle, (2) the quantify of capillary density in muscle fibers using hematoxylin phloxin saffron and CD31 counts, (3) VEGF-A,C,D, hepatocyte growth factor, angiopoietin-1 to characterize angiogenic cytokine expression, (4) percent coverage, fiber diameter and cross-sectional area to examine changes in morphology. The gene and protein expression profiles and histological findings will be used to test the hypotheses that MSCs act to recruit CD34+CD133+ proangiogenic hematopoietic cells.
Time frame: Primary follow up in a 6 month period
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