A Clinical and Histological Analysis of Mesenchymal Stem Cells in Amputation

Phase 1

Active, not recruiting

• Conditions: Arteriosclerosis; Atherosclerosis; Arterial Occlusive Disease; Peripheral Arterial Disease; Ischemia; Peripheral Vascular Disease; Pathologic Processes; Amputation; Vascular Disease; Cardiovascular Disease
• Interventions: Biological: Allogeneic bone marrow derived mesenchymal stem cells

• Registration Number: NCT02685098
• Lead Sponsor: Indiana University

Brief Summary

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.

Detailed Description

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2016-02-02
• Study First Submitted QC: 2016-02-12
• Study First Posted: 2016-02-18
• Study Start: 2017-01-23
• Primary Completion: 2023-10-03
• Status Verified: 2024-04
• Last Update Submitted: 2024-12-05
• Last Update Posted: 2024-12-10
• Study Completion: 2025-05-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 81

Inclusion Criteria

1. Be ≥ 40 and ≤90 years of age.
2. Patients requiring lower extremity major amputation, as determined by an independent vascular specialist.
3. If ulceration or gangrene present, it is distal to malleoli (to allow adequate length of ATM area of approximately 3cm x 10cm x 3 cm)
4. Amputation can safely be performed up to 30 days after screening, as determined by an independent vascular or orthopedic surgeon.
5. Females of childbearing potential must be willing to use one form of birth control for the duration of the study. Female participants must undergo a blood or urine pregnancy test at screening.

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Exclusion Criteria

1. Patients who are pregnant, planning to become pregnant in the next 12 months, or lactating.

2. CHF hospitalization within the last 1 month prior to enrollment.*

3. Acute coronary syndrome in the last 1 month prior to enrollment.*

4. HIV positive, or active, untreated HCV as determined by review of medical records.

5. History of cancer within the last 5 years, except basal cell skin carcinoma

6. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted).

7. Concurrent enrollment in another clinical investigative trial that may alter the outcomes of enrollment in this trial.

8. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata).

9. Presence of any clinical condition that in the opinion of the PI or the sponsor makes the patient not suitable to participate in the trial.

   • As defined by the standard definitions of CHF and ACS by the American Heart Association.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active/Treatment Group	Allogeneic bone marrow derived mesenchymal stem cells	Amputation performed at 7 days post allogeneic bone marrow derived mesenchymal stem cell injections.

Primary Outcome Measures

Name	Time	Method
Number of participants with treatment-related adverse events occurring during the enrollment period as assessed by the Investigator using the MeDRA scale.	Primary follow up in a 6 month period	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.

Secondary Outcome Measures

Name	Time	Method
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.	Primary follow up in a 6 month period	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.
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.	Primary follow up in a 6 month period	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.

Trial Locations

Locations (1)

Indiana University; 🇺🇸 Indianapolis, Indiana, United States