search
Back to results

A Clinical and Histological Analysis of Mesenchymal Stem Cells in Amputation (CHAMP)

Primary Purpose

Ischemia, Peripheral Arterial Disease, Peripheral Vascular Disease

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Allogeneic bone marrow derived mesenchymal stem cells
Sponsored by
Indiana University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Ischemia focused on measuring Stem cells, MSCs, Mesenchymal, Amputation, BKA, below knee amputation, CHAMP, AKA, Above Knee Amputation, Stromal cells, bone marrow stem cell injection, Allogeneic

Eligibility Criteria

40 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

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.

Sites / Locations

  • Indiana University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

No Intervention

No Intervention

No Intervention

No Intervention

Arm Label

Active/Treatment Group

Observation Group 1

Observation Group 2

Observation Group 3

Control Group 4

Arm Description

Amputation performed at 7 days post allogeneic bone marrow derived mesenchymal stem cell injections.

Amputation performed with no MSC administration. Subjects will be followed for incidence of infection and wound healing status to week 24 as a comparator to the Active/Treatment group.

Tissue Collection Group: Amputation performed with no MSC administration. Subjects will not be followed after amputation is performed. Tissue collection will occur at time of amputation.

Patients undergoing lower extremity bypass grafting procedure. Skeletal muscle samples of the sartorius and anterior tibial muscle will be collected for comparison to treatment group. No study testing, nor follow up visits will occur.

Patients undergoing a standard of care surgical procedure under anesthesia. Core needle biopsies will be collected from the anterior tibial muscle at the time of surgical procedure. No study testing, nor follow up visits will occur.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.

Full Information

First Posted
February 2, 2016
Last Updated
September 29, 2023
Sponsor
Indiana University
search

1. Study Identification

Unique Protocol Identification Number
NCT02685098
Brief Title
A Clinical and Histological Analysis of Mesenchymal Stem Cells in Amputation
Acronym
CHAMP
Official Title
A Clinical and Histological Analysis of Mesenchymal Stem Cells in Amputation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 23, 2017 (Actual)
Primary Completion Date
October 3, 2023 (Anticipated)
Study Completion Date
October 3, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Indiana University

4. Oversight

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

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemia, Peripheral Arterial Disease, Peripheral Vascular Disease, Vascular Disease, Arterial Occlusive Disease, Arteriosclerosis, Atherosclerosis, Cardiovascular Disease, Pathologic Processes, Orthopedic Procedures, Amputation
Keywords
Stem cells, MSCs, Mesenchymal, Amputation, BKA, below knee amputation, CHAMP, AKA, Above Knee Amputation, Stromal cells, bone marrow stem cell injection, Allogeneic

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
81 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active/Treatment Group
Arm Type
Experimental
Arm Description
Amputation performed at 7 days post allogeneic bone marrow derived mesenchymal stem cell injections.
Arm Title
Observation Group 1
Arm Type
No Intervention
Arm Description
Amputation performed with no MSC administration. Subjects will be followed for incidence of infection and wound healing status to week 24 as a comparator to the Active/Treatment group.
Arm Title
Observation Group 2
Arm Type
No Intervention
Arm Description
Tissue Collection Group: Amputation performed with no MSC administration. Subjects will not be followed after amputation is performed. Tissue collection will occur at time of amputation.
Arm Title
Observation Group 3
Arm Type
No Intervention
Arm Description
Patients undergoing lower extremity bypass grafting procedure. Skeletal muscle samples of the sartorius and anterior tibial muscle will be collected for comparison to treatment group. No study testing, nor follow up visits will occur.
Arm Title
Control Group 4
Arm Type
No Intervention
Arm Description
Patients undergoing a standard of care surgical procedure under anesthesia. Core needle biopsies will be collected from the anterior tibial muscle at the time of surgical procedure. No study testing, nor follow up visits will occur.
Intervention Type
Biological
Intervention Name(s)
Allogeneic bone marrow derived mesenchymal stem cells
Other Intervention Name(s)
cBMA, MSCs
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of participants with treatment-related adverse events occurring during the enrollment period as assessed by the Investigator using the MeDRA scale.
Description
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
Secondary Outcome Measure Information:
Title
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.
Description
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
Title
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.
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Be ≥ 40 and ≤90 years of age. Patients requiring lower extremity major amputation, as determined by an independent vascular specialist. 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) Amputation can safely be performed up to 30 days after screening, as determined by an independent vascular or orthopedic surgeon. 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. Exclusion Criteria: Patients who are pregnant, planning to become pregnant in the next 12 months, or lactating. CHF hospitalization within the last 1 month prior to enrollment.* Acute coronary syndrome in the last 1 month prior to enrollment.* HIV positive, or active, untreated HCV as determined by review of medical records. History of cancer within the last 5 years, except basal cell skin carcinoma Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted). Concurrent enrollment in another clinical investigative trial that may alter the outcomes of enrollment in this trial. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata). 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael P Murphy, MD
Organizational Affiliation
Indiana University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
21514773
Citation
Murphy MP, Lawson JH, Rapp BM, Dalsing MC, Klein J, Wilson MG, Hutchins GD, March KL. Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia. J Vasc Surg. 2011 Jun;53(6):1565-74.e1. doi: 10.1016/j.jvs.2011.01.074. Epub 2011 Apr 22.
Results Reference
background
PubMed Identifier
29395424
Citation
Wang SK, Green LA, Drucker NA, Motaganahalli RL, Fajardo A, Murphy MP. Rationale and design of the Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial investigating the therapeutic mechanism of mesenchymal stromal cells in the treatment of critical limb ischemia. J Vasc Surg. 2018 Jul;68(1):176-181.e1. doi: 10.1016/j.jvs.2017.09.057. Epub 2018 Feb 1.
Results Reference
derived

Learn more about this trial

A Clinical and Histological Analysis of Mesenchymal Stem Cells in Amputation

We'll reach out to this number within 24 hrs