Use of Autologous Concentrated Bone Marrow Aspirate in Preventing Wound Complications in Below Knee Amputation (BKA)

Study Overview
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Brief Summary
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Patients scheduled for major extremity lower amputation to receive bone marrow cells (cBMA) injected IM in the leg proximal to the amputation in the index limb to prevent ischemic wound complications after surgery.

Detailed Description
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Patients scheduled for amputation will receive bone marrow cells concentrated via the MarrowStim device (cBMA) injected IM at 25 sites in the leg proximal to the amputation in the index limb to prevent ischemic wound complications after surgery. cBMA will be injected into the anterior tibialis muscle below the point of amputation in an area approximately 3cm^2 x 2cm^2 for analytical purposes. Patients will be scheduled for amputation at Days 7, 14, or 21 post injection. Safety will be evaluated by review of treatment related adverse events (AE) during the 52-week follow-up period. The investigator will compare rates of wound complications and amputation revisions to historical controls at the institution to assess trends in therapeutic efficacy. Patients will undergo amputation and injection sites will be harvested at that time. Immunohistochemical staining (IHC) will determine capillary density and local host immune responses. Angiogenic and inflammatory cytokines will be quantified using a multiplex array system and quantitative polymerase chain reaction (PCR).

Official Title
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Safety and Efficacy of Concentrated Autologous Concentrated Bone Marrow Aspirate (cBMA) in Preventing Wound Complications in Below Knee Amputation (BKA) (The MarrowCHAMP Study)

Conditions
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Peripheral Artery Disease, Vascular Disease, Critical Limb Ischemia

Intervention / Treatment
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* Biological: Injection of cBMA aspirate into the index leg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥ 40 and ≤90 years of age. Patients requiring below knee amputation, as determined by an independent vascular specialist. If ulceration or gangrene present, it is distal to malleoli (to allow adequate length of ATM for 4 injections 4 cm. apart) BKA can safely be performed up to 30 days after screening, as determined by an independent vascular or orthopedic surgeon. This information will be documented in subjects' case report forms (CRFs). 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. Significant hepatic dysfunction (ALT or AST greater than 2 times normal). CHF hospitalization within the last 1 month prior to enrollment.* Acute coronary syndrome (ACS) in the last 1 month prior to enrollment.* HIV positive, or active, untreated HCV. History of cancer within the last 5 years, except basal cell skin carcinoma Any bleeding diathesis defined as an INR ≥ 2.0 (off anticoagulation therapy) or history of platelet count less than 70,000 or hemophilia. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted). Concurrent enrollment in another clinical investigative 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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Female

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: Parallel Assignment
Interventional Model Description: Autologous bone marrow derived mesenchymal stromal cells will be delivered intramuscularly in the lower extremity of participants undergoing lower extremity major amputation to assess incidence of wound healing and infection prevention.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Day 7<br>BKA performed at 7 days post autologous cBMA injection. Injection of cBMA aspirate into the index leg | Biological: Injection of cBMA aspirate into the index leg<br>* Injection of cBMA into the anterior tibialis muscle and upper index leg of subjects scheduled for semi-elective BKA 7-21 days before surgery<br>* Other names: cBMA;|
| Experimental: Day 14<br>BKA performed at 14 days post autologous cBMA injection. Injection of cBMA aspirate into the index leg | Biological: Injection of cBMA aspirate into the index leg<br>* Injection of cBMA into the anterior tibialis muscle and upper index leg of subjects scheduled for semi-elective BKA 7-21 days before surgery<br>* Other names: cBMA;|
| Experimental: Day 21<br>BKA performed at 21 days post autologous cBMA injection. Injection of cBMA aspirate into the index leg | Biological: Injection of cBMA aspirate into the index leg<br>* Injection of cBMA into the anterior tibialis muscle and upper index leg of subjects scheduled for semi-elective BKA 7-21 days before surgery<br>* Other names: cBMA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events occurring during the enrollment period as assessed by the Investigator using the CTCAE 4.0 scale. | Safety will be evaluated by review of treatment related AEs during the 12-month follow-up period. The study will be terminated in the event of a Grade 4-5 unexpected event based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Treatment-related AEs will be categorized overlapping systems and severities. Three categories of systems are cardiovascular, respiratory, or infectious. Two categories of severity will be serious adverse (SAE) and major adverse cardiac events (MACE). Binomial confidence Intervals at the 95% confidence level and p-values for these 3 groups will be calculated. Since previous trials have not reported AEs with cBMA treatment, confidence intervals will be generated by the method of the Wilson Score Interval. | Primary follow up in a 12 month period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time period of retention of allogeneic MSCs in harvested human skeletal muscle tissue post-MSC implantation as measured by immunohistochemical staining and number of MSCs per section of skeletal muscle at each time point . | Sections of skeletal muscle collected from each injection site will be stained with specific antibodies for MSC specific markers and the number of MSCs will be counted in each field under a microscope. | Primary follow up in a 12 month period | 
| The role of MSCs injected in human skeletal muscle at the time of below knee amputation as evidenced by recruitment of proangiogenic hematopoietic cells into sites of ischemia. | Continuous confidence intervals at the 95% level will be constructed to explore differences among the time-tiered administration of MSC for the quantity of capillary density in muscle fibers, examine changes in morphology, and the recruitment of HIF-1a/SDF-1/CXCR4 to ischemic muscle. | Primary follow up in a 12 month period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BKA, amputation, MarrowStim, below knee amputation, wound complication, vascular disease, critical limb ischemia, peripheral artery disease, AKA, stem cells, bone marrow