A prospective, multicentre, open-label, single-arm clinical trial for treatment of chronic complex diabetic foot wounds with exposed tendon and/or bone: positive clinical outcomes of viable cryopreserved human placental membrane

Robert G Frykberg, Gary W Gibbons, Jodi L Walters, Dane K Wukich, Farrell C Milstein, Robert G Frykberg, Gary W Gibbons, Jodi L Walters, Dane K Wukich, Farrell C Milstein

Abstract

Complex diabetic foot ulcers (DFUs) with exposed tendon or bone remain a challenge. They are more susceptible to complications such as infection and amputation and require treatments that promote rapid development of granulation tissue and, ultimately, reepithelialisation. The clinical effectiveness of viable cryopreserved human placental membrane (vCHPM) for DFUs has been established in a level 1 trial. However, complex wounds with exposed deeper structures are typically excluded from randomised controlled clinical trials despite being common in clinical practice. We report the results of a prospective, multicentre, open-label, single-arm clinical trial to establish clinical outcomes when vCHPM is applied weekly to complex DFUs with exposed deep structures. Patients with type 1 or type 2 diabetes and a complex DFU extending through the dermis with evidence of exposed muscle, tendon, fascia, bone and/or joint capsule were eligible for inclusion. Of the 31 patients enrolled, 27 completed the study. The mean wound area was 14·6 cm2 , and mean duration was 7·5 months. For patients completing the protocol, the primary endpoint, 100% wound granulation by week 16, was met by 96·3% of patients in a mean of 6·8 weeks. Complete wound closure occurred in 59·3% (mean 9·1 weeks). The 4-week percent area reduction was 54·3%. There were no product-related adverse events. Four patients (13%) withdrew, two (6·5%) for non-compliance and two (6·5%) for surgical intervention.

Keywords: Chronic; Complex wound; Cryopreserved placental membrane; Diabetes; Ulcer.

© 2016 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Incidence of granulation and closure versus time, per protocol and intent to treat populations.
Figure 2
Figure 2
Cumulative probability of 100% granulation versus time: 96·0% at 16 weeks.
Figure 3
Figure 3
Cumulative probability of complete wound closure versus time: 58·5% at 16 weeks.
Figure 4
Figure 4
Baseline image of a chronic complex wound with an area of 70·00 cm2.
Figure 5
Figure 5
The patient's wound at 16 Weeks with a 98·9% area reduction compared to Baseline. Additionally, this wound met the primary endpoint of 100% granulation after only 5 Weeks.
Figure 6
Figure 6
Baseline image of deep left heel ulcer after debridement for necrotising infection in a type 2 diabetic man with right below‐knee amputation. Plantar fascia is exposed.
Figure 7
Figure 7
The patient's wound was fully closed at 12 weeks.

References

    1. Centers for Disease Control and Prevention . National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta, 2014.
    1. Hingorani A, LaMuraglia GM, Henke P, Meissner MH, Loretz L, Zinszer KM, Driver VR, Frykberg R, Carman TL, Marston W, Mills JL Sr, Murad MH. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg 2016;63:3S–21.
    1. Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, Landsman AS, Lavery LA, Moore JC, Schuberth JM, Wukich DK, Andersen C, Vanore JV, American College of Foot and Ankle Surgeons . Diabetic foot disorders. A clinical practice guideline. J Foot Ankle Surg, 2006 2006;45(5 Suppl):S1–66.
    1. Yamaguchi Y, Yoshida S, Sumikawa Y, Kubo T, Hosokawa K, Ozawa K, Hearing VJ, Yoshikawa K, Itami S. Rapid healing of intractable diabetic foot ulcers with exposed bones following a novel therapy of exposing bone marrow cells and then grafting epidermal sheets. Br J Dermatol 2004;151:1019–28.
    1. Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle) 2015;4:560–82.
    1. Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, Kashefsky H, Owings TM, Nadarajah J, The Grafix Diabetic Foot Ulcer Study . The efficacy and safety of Grafix(®) for the treatment of chronic diabetic foot ulcers: results of a multi‐centre, controlled, randomised, blinded, clinical trial. Int Wound J 2014;11:554–60.
    1. Margolis DJ, Malay DS, Hoffstad OJ, Leonard CE, MaCurdy T, Lopez de Nava K, Tan Y, Molina T, Siegel KL. Incidence of diabetic foot ulcer and lower extremity amputation among Medicare beneficiaries, 2006 to 2008: data points #2, Data Points Publication Series. 2011: Rockville. Agency for Healthcare Research and Quality (US). URL
    1. Armstrong DG, Kanda VA, Lavery LA, Marston W, Mills JL Sr, Boulton AJ. Mind the gap: disparity between research funding and costs of care for diabetic foot ulcers. Diabetes Care 2013;36:1815–7.
    1. American Diabetes Association . Economic costs of diabetes in the U.S. in 2012. Diabetes Care 2013;36:1033–46.
    1. Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: the economic case for the limb salvage team. J Am Podiatr Med Assoc 2010;100:335–41.
    1. Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB. Burden of diabetic foot ulcers for medicare and private insurers. Diabetes Care 2014;37:651–8.
    1. Harrington C, Zagari MJ, Corea J, Klitenic J. A cost analysis of diabetic lower‐extremity ulcers. Diabetes Care 2000;23:1333–8.
    1. Hicks CW, Selvarajah S, Mathioudakis N, Sherman RE, Hines KF, Black JH 3rd, Abularrage CJ. Burden of infected diabetic foot ulcers on hospital admissions and costs. Ann Vasc Surg 2016;33:149–58.
    1. Lavery LA, Armstrong DG, Harkless LB. Classification of diabetic foot wounds. J Foot Ankle Surg 1996;35:528–31.
    1. Jones G, Nahai F. Management of complex wounds. Curr Probl Surg 1998;35:179–270.
    1. Park H, Copeland C, Henry S, Barbul A. Complex wounds and their management. Surg Clin North Am 2010;90:1181–94.
    1. Gibbons GW, Orgill DP, Serena TE, Novoung A, O'Connell JB, Li WW, Driver VR. A prospective, randomized, controlled trial comparing the effects of noncontact, low‐frequency ultrasound to standard care in healing venous leg ulcers. Ostomy Wound Manage 2015;61:16–29.
    1. Gibbons GW. Grafix®, a cryopreserved placental membrane, for the treatment of chronic/stalled wounds. Adv Wound Care (New Rochelle) 2015;4:534–44.
    1. Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998;21:855–9.
    1. Aragon‐Sanchez J. Seminar review: a review of the basis of surgical treatment of diabetic foot infections. Int J Low Extrem Wounds 2011;10:33–65.
    1. Clerici G, Faglia E. Saving the limb in diabetic patients with ischemic foot lesions complicated by acute infection. Int J Low Extrem Wounds 2014;13:273–93.
    1. Faglia E, Clerici G, Caminiti M, Curci V, Somalvico F. Prognostic difference between soft tissue abscess and osteomyelitis of the foot in patients with diabetes: data from a consecutive series of 452 hospitalized patients. J Foot Ankle Surg 2012;51:34–8.
    1. Pickwell K, Siersma V, Kars M, Apelqvist J, Bakker K, Edmonds M, Holstein P, Jirkovska A, Jude E, Mauricio D, Piaggesi A, Ragnarson Tennvall G, Reike H, Spraul M, Uccioli L, Urbancic V, van Acker K, van Baal J, Schaper N. Predictors of lower‐extremity amputation in patients with an infected diabetic foot ulcer. Diabetes Care 2015;38:852–7.
    1. Snyder RJ, Cardinal M, Dauphinee DM, Stavosky J. A post‐hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks. Ostomy Wound Manage 2010;56:44–50.
    1. Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta‐analysis. Diabetes Care 1999;22:692–5.
    1. Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian AM. Properties of the amniotic membrane for potential use in tissue engineering. Eur Cell Mater 2008;15:88–99.
    1. Talmi YP, Sigler L, Inge E, Finkelstein Y, Zohar Y. Antibacterial properties of human amniotic membranes. Placenta 1991;12:285–8.
    1. Maxson S, Lopez EA, Yoo D, Danilkovitch‐Miagkova A, Leroux MA. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med 2012;1:142–9.
    1. Duan‐Arnold Y, Gyurdieva A, Johnson A, Uveges TE, Jacobstein DA, Danilkovitch A. Retention of endogenous viable cells enhances the anti‐inflammatory activity of cryopreserved amnion. Adv Wound Care (New Rochelle) 2015;4:523–33.
    1. Duan‐Arnold Y, Gyurdieva A, Johnson A, Jacobstein DA, Danilkovitch A. Soluble factors released by endogenous viable cells enhance the antioxidant and chemoattractive activities of cryopreserved amniotic membrane. Adv Wound Care (New Rochelle) 2015;4:329–38.
    1. Duan‐Arnold Y, Uveges TE, Gyurdieva A, Johnson A, Danilkovitch A. Angiogenic potential of cryopreserved amniotic membrane is enhanced through retention of all tissue components in their native state. Adv Wound Care (New Rochelle) 2015;4:513–22.
    1. Regulski M, Jacobstein DA, Petranto RD, Migliori VJ, Nair G, Pfeiffer D. A retrospective analysis of a human cellular repair matrix for the treatment of chronic wounds. Ostomy Wound Manage 2013;59:38–43.
    1. Suess JJ, Kim PJ, Steinberg JS. Negative pressure wound therapy: evidence‐based treatment for complex diabetic foot wounds. Curr Diab Rep 2006;6:446–50.
    1. Andros G, Armstrong DG, Attinger CE, Boulton AJ, Frykberg RG, Joseph WS, Lavery LA, Morbach S, Niezgoda JA, Toursarkissian B, Tucson Expert Consensus Conference . Consensus statement on negative pressure wound therapy (V.A.C. Therapy) for the management of diabetic foot wounds. Ostomy Wound Manage 2006;Suppl:1–32.
    1. Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum‐assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008;31:631–6.
    1. Orgill DP, Manders EK, Sumpio BE, Lee RC, Attinger CE, Gurtner GC, Ehrlich HP. The mechanisms of action of vacuum assisted closure: more to learn. Surgery 2009;146:40–51.
    1. Argenta LC, Morykwas MJ. Vacuum‐assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg 1997;38:563–76; discussion 577.
    1. DeFranzo AJ, Argenta LC, Marks MW, Molnar JA, David LR, Webb LX, Ward WG, Teasdall RG. The use of vacuum‐assisted closure therapy for the treatment of lower‐extremity wounds with exposed bone. Plast Reconstr Surg 2001;108:1184–91.
    1. Armstrong DG, Lavery LA, Diabetic Foot Study Consortium . Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet 2005;366:1704–10.
    1. Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study Group . The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 2003;26:1701–5.
    1. Warriner RA 3rd, Cardinal M, TIDE Investigators . Human fibroblast‐derived dermal substitute: results from a treatment investigational device exemption (TIDE) study in diabetic foot ulcers. Adv Skin Wound Care 2011;24:306–11.
    1. Edmonds M, European and Australian Apligraf Diabetic Foot Ulcer Study Group . Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds 2009;8:11–8.
    1. DiDomenico L, Landsman AR, Emch KJ, Landsman A. A prospective comparison of diabetic foot ulcers treated with either a cryopreserved skin allograft or a bioengineered skin substitute. Wounds 2011;23:184–9.
    1. Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J 2013;10:502–7.
    1. Frykberg RG, Marston WA, Cardinal M. The incidence of lower‐extremity amputation and bone resection in diabetic foot ulcer patients treated with a human fibroblast‐derived dermal substitute. Adv Skin Wound Care 2015;28:17–20.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren