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

Peripheral Artery Disease Clinical Trial

— MarrowCHAMP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02863926
• Other study ID #: 1511774456
• Status: Completed
• Phase: Phase 1
• Start date: January 6, 2017
• Est. completion date: July 27, 2018

Study information

• Verified date: September 2023
• Source: Indiana University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: July 27, 2018
• Est. primary completion date: July 27, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 40 Years to 90 Years

Eligibility

Inclusion Criteria:

1. Be = 40 and =90 years of age.

2. Patients requiring below knee 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 for 4 injections 4 cm. apart)

4. 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).

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. Significant hepatic dysfunction (ALT or AST greater than 2 times normal).

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

4. Acute coronary syndrome (ACS) in the last 1 month prior to enrollment.*

5. HIV positive, or active, untreated HCV.

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

7. Any bleeding diathesis defined as an INR = 2.0 (off anticoagulation therapy) or history of platelet count less than 70,000 or hemophilia.

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

9. Concurrent enrollment in another clinical investigative trial.

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

11. 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.

Related Conditions & MeSH terms

• Chronic Limb-Threatening Ischemia
• Critical Limb Ischemia
• Ischemia
• Peripheral Arterial Disease
• Peripheral Artery Disease
• Vascular Disease
• Vascular Diseases

Intervention

Biological:
• Injection of cBMA aspirate into the index leg
Injection of cBMA into the anterior tibialis muscle and upper index leg of subjects scheduled for semi-elective BKA 7-21 days before surgery

Locations

Country	Name	City	State
United States	Indiana University School of Medicine	Indianapolis	Indiana

Sponsors (2)

Lead Sponsor	Collaborator
Michael Murphy	Zimmer Biomet

Country where clinical trial is conducted

United States, 

References & Publications (17)

Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005 Dec 3;366(9501):1925-34. doi: 10.1016/S0140-6736(05)67704-5. — View Citation

Albers M, Fratezi AC, De Luccia N. Assessment of quality of life of patients with severe ischemia as a result of infrainguinal arterial occlusive disease. J Vasc Surg. 1992 Jul;16(1):54-9. — View Citation

Castronuovo JJ Jr, Deane LM, Deterling RA Jr, O'Donnell TF Jr, O'Toole DM, Callow AD. Below-knee amputation: is the effort to preserve the knee joint justified? Arch Surg. 1980 Oct;115(10):1184-7. doi: 10.1001/archsurg.1980.01380100032007. — View Citation

Cruz CP, Eidt JF, Capps C, Kirtley L, Moursi MM. Major lower extremity amputations at a Veterans Affairs hospital. Am J Surg. 2003 Nov;186(5):449-54. doi: 10.1016/j.amjsurg.2003.07.027. — View Citation

Deutsch MA, Sturzu A, Wu SM. At a crossroad: cell therapy for cardiac repair. Circ Res. 2013 Mar 15;112(6):884-90. doi: 10.1161/CIRCRESAHA.112.275974. No abstract available. — View Citation

Dillingham TR, Pezzin LE, MacKenzie EJ. Limb amputation and limb deficiency: epidemiology and recent trends in the United States. South Med J. 2002 Aug;95(8):875-83. doi: 10.1097/00007611-200208000-00018. — View Citation

Dillingham TR, Pezzin LE, Shore AD. Reamputation, mortality, and health care costs among persons with dysvascular lower-limb amputations. Arch Phys Med Rehabil. 2005 Mar;86(3):480-6. doi: 10.1016/j.apmr.2004.06.072. — View Citation

Huang PP, Li SZ, Han MZ, Xiao ZJ, Yang RC, Qiu LG, Han ZC. Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities. Thromb Haemost. 2004 Mar;91(3):606-9. doi: 10.1160/TH03-06-0343. — View Citation

Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004 Mar 30;109(12):1543-9. doi: 10.1161/01.CIR.0000124062.31102.57. Epub 2004 Mar 15. Erratum In: Circulation. 2005 Jul 26;112(4):e73. — View Citation

Lim TS, Finlayson A, Thorpe JM, Sieunarine K, Mwipatayi BP, Brady A, Abbas M, Angel D. Outcomes of a contemporary amputation series. ANZ J Surg. 2006 May;76(5):300-5. doi: 10.1111/j.1445-2197.2006.03715.x. — View Citation

Markel TA, Wang Y, Herrmann JL, Crisostomo PR, Wang M, Novotny NM, Herring CM, Tan J, Lahm T, Meldrum DR. VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function. Am J Physiol Heart Circ Physiol. 2008 Dec;295(6):H2308-14. doi: 10.1152/ajpheart.00565.2008. Epub 2008 Oct 10. — View 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. — View Citation

Nehler MR, Coll JR, Hiatt WR, Regensteiner JG, Schnickel GT, Klenke WA, Strecker PK, Anderson MW, Jones DN, Whitehill TA, Moskowitz S, Krupski WC. Functional outcome in a contemporary series of major lower extremity amputations. J Vasc Surg. 2003 Jul;38(1):7-14. doi: 10.1016/s0741-5214(03)00092-2. — View Citation

Prockop DJ. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol Ther. 2009 Jun;17(6):939-46. doi: 10.1038/mt.2009.62. Epub 2009 Mar 31. — View Citation

Santilli JD, Santilli SM. Chronic critical limb ischemia: diagnosis, treatment and prognosis. Am Fam Physician. 1999 Apr 1;59(7):1899-908. — View Citation

Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, Lopez CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG; Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12. doi: 10.1073/pnas.1222878110. Epub 2013 Feb 11. — View Citation

Wang L, Cao L, Shansky J, Wang Z, Mooney D, Vandenburgh H. Minimally invasive approach to the repair of injured skeletal muscle with a shape-memory scaffold. Mol Ther. 2014 Aug;22(8):1441-1449. doi: 10.1038/mt.2014.78. Epub 2014 Apr 28. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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