Safety and clinical efficacy of the secretome of stressed peripheral blood mononuclear cells in patients with diabetic foot ulcer-study protocol of the randomized, placebo-controlled, double-blind, multicenter, international phase II clinical trial MARSYAS II

Alfred Gugerell, Ghazaleh Gouya-Lechner, Helmut Hofbauer, Maria Laggner, Franz Trautinger, Gabriele Almer, Anja Peterbauer-Scherb, Marcus Seibold, Wolfram Hoetzenecker, Christiane Dreschl, Michael Mildner, Hendrik Jan Ankersmit, Alfred Gugerell, Ghazaleh Gouya-Lechner, Helmut Hofbauer, Maria Laggner, Franz Trautinger, Gabriele Almer, Anja Peterbauer-Scherb, Marcus Seibold, Wolfram Hoetzenecker, Christiane Dreschl, Michael Mildner, Hendrik Jan Ankersmit

Abstract

Background: Diabetes and its sequelae such as diabetic foot ulcer are rising health hazards not only in western countries but all over the world. Effective, yet safe treatments are desperately sought for by physicians, healthcare providers, and of course patients.

Methods/design: APOSEC, a novel, innovative drug, is tested in the phase I/II study MARSYAS II, where its efficacy to promote healing of diabetic foot ulcers will be determined. To this end, the cell-free secretome of peripheral blood mononuclear cells (APOSEC) blended with a hydrogel will be applied topically three times weekly for 4 weeks. APOSEC is predominantly effective in hypoxia-induced tissue damages by modulating the immune system and enhancing angiogenesis, whereby its anti-microbial ability and neuro-regenerative capacity will exert further positive effects. In total, 132 patients will be enrolled in the multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-ranging phase I/II study and treated with APOSEC at three dose levels or placebo for 4 weeks, followed by an 8-week follow-up period to evaluate safety and efficacy of the drug. Wound area reduction after 4 weeks of treatment will serve as the primary endpoint.

Conclusion: We consider our study protocol to be suitable to test topically administered APOSEC in patients suffering from diabetic foot ulcers in a clinical phase I/II trial.

Trial registration: EudraCT 2018-001653-27 . Registered on 30 July 2019. ClinicalTrials.gov NCT04277598 . Registered on 20 February 2020.

Title: "A randomized, placebo-controlled, double-blind study to evaluate safety and dose-dependent clinical efficacy of APO-2 at three different doses in patients with diabetic foot ulcer (MARSYAS II)".

Keywords: (Impaired) wound healing; Biological; Clinical trial protocol; Diabetic foot ulcer; Hydrogel; Inflammation; Peripheral blood mononuclear cells; Randomized controlled trial; Secretome-based therapy; Skin.

Conflict of interest statement

The study is approved by the ethics committees of Upper Austria (approval number 1139/2018) and Carinthia (approval number MZ 37/18). Written informed consent will be obtained from all study participants. There are no financial and other competing interests for principal investigators.

HJA and HH are minor shareholders of APOSCIENCE AG which developed and produces the investigated secretome and is the sponsor of this study. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study design of the MARSYAS II study

References

    1. Sarwar N, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–2222. doi: 10.1016/S0140-6736(10)60484-9.
    1. Lavery LA, et al. Reevaluating the way we classify the diabetic foot: restructuring the diabetic foot risk classification system of the International Working Group on the Diabetic Foot. Diabetes Care. 2008;31:154–156. doi: 10.2337/dc07-1302.
    1. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366:1736–1743. doi: 10.1016/S0140-6736(05)67700-8.
    1. Bakker K, Apelqvist J, Schaper NC, B. International Working group on diabetic foot editorial Practical guidelines on the management and prevention of the diabetic foot 2011. Diabetes Metab Res Rev. 2012;28(Suppl 1):225–231. doi: 10.1002/dmrr.2253.
    1. McNeely MJ, et al. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks? Diabetes Care. 1995;18:216–219. doi: 10.2337/diacare.18.2.216.
    1. Ghanassia E, et al. Long-term outcome and disability of diabetic patients hospitalized for diabetic foot ulcers: a 6.5-year follow-up study. Diabetes Care. 2008;31:1288–1292. doi: 10.2337/dc07-2145.
    1. Morbach S, et al. Diabetic foot syndrome. Exp Clin Endocrinol Diabetes. 2014;122:416–424. doi: 10.1055/s-0034-1366455.
    1. Toplak H, et al. Austrian Lipid Consensus on the management of metabolic lipid disorders to prevent vascular complications: a joint position statement issued by eight medical societies. 2016 update. Wien Klin Wochenschr. 2016;128 Suppl 2:S216–S228. doi: 10.1007/s00508-016-0993-x.
    1. Kocher AA, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7:430–436. doi: 10.1038/86498.
    1. Martens TP, et al. Mesenchymal lineage precursor cells induce vascular network formation in ischemic myocardium. Nat Clin Pract Cardiovasc Med. 2006;3(Suppl 1):S18–S22. doi: 10.1038/ncpcardio0404.
    1. Gyongyosi M, et al. Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ Res. 2015;116:1346–1360. doi: 10.1161/CIRCRESAHA.116.304346.
    1. Korf-Klingebiel M, et al. Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction. Eur Heart J. 2008;29:2851–2858. doi: 10.1093/eurheartj/ehn456.
    1. Gnecchi M, Danieli P, Cervio E. Mesenchymal stem cell therapy for heart disease. Vasc Pharmacol. 2012;57:48–55. doi: 10.1016/j.vph.2012.04.002.
    1. Petrenko Y, et al. A comparative analysis of multipotent mesenchymal stromal cells derived from different sources, with a focus on neuroregenerative potential. Sci Rep. 2020;10:4290. doi: 10.1038/s41598-020-61167-z.
    1. Jayaraman P, Nathan P, Vasanthan P, Musa S, Govindasamy V. Stem cells conditioned medium: a new approach to skin wound healing management. Cell Biol Int. 2013;37:1122–1128. doi: 10.1002/cbin.10138.
    1. Holzinger C, et al. Treatment of non-healing skin ulcers with autologous activated mononuclear cells. Eur J Vasc Surg. 1994;8:351–356. doi: 10.1016/S0950-821X(05)80155-0.
    1. Ankersmit HJ, et al. Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardium. Eur J Clin Investig. 2009;39:445–456. doi: 10.1111/j.1365-2362.2009.02111.x.
    1. Lichtenauer M, et al. Secretome of apoptotic peripheral blood cells (APOSEC) confers cytoprotection to cardiomyocytes and inhibits tissue remodelling after acute myocardial infarction: a preclinical study. Basic Res Cardiol. 2011;106:1283–1297. doi: 10.1007/s00395-011-0224-6.
    1. Gugerell A, et al. Viral safety of APOSECTM: a novel peripheral blood mononuclear cell derived-biological for regenerative medicine. Blood Transfus. 2020;18(1):30-9. 10.2450/2019.0249-18.
    1. Lichtenauer M, et al. Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction. Basic Res Cardiol. 2011;106:645–655. doi: 10.1007/s00395-011-0173-0.
    1. Pavo N, et al. Long-acting beneficial effect of percutaneously intramyocardially delivered secretome of apoptotic peripheral blood cells on porcine chronic ischemic left ventricular dysfunction. Biomaterials. 2014;35:3541–3550. doi: 10.1016/j.biomaterials.2013.12.071.
    1. Altmann P, et al. Secretomes of apoptotic mononuclear cells ameliorate neurological damage in rats with focal ischemia. F1000Res. 2014;3:131. doi: 10.12688/f1000research.4219.2.
    1. Haider T, et al. The secretome of apoptotic human peripheral blood mononuclear cells attenuates secondary damage following spinal cord injury in rats. Exp Neurol. 2015;267:230–242. doi: 10.1016/j.expneurol.2015.03.013.
    1. Hacker S, et al. Paracrine factors from irradiated peripheral blood mononuclear cells improve skin regeneration and angiogenesis in a porcine burn model. Sci Rep. 2016;6:25168. doi: 10.1038/srep25168.
    1. Wagner T, et al. Different pro-angiogenic potential of gamma-irradiated PBMC-derived secretome and its subfractions. Sci Rep. 2018;8:18016. doi: 10.1038/s41598-018-36928-6.
    1. Hoetzenecker K, et al. Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation. Basic Res Cardiol. 2012;107:292. doi: 10.1007/s00395-012-0292-2.
    1. Beer L, et al. Analysis of the secretome of apoptotic peripheral blood mononuclear cells: impact of released proteins and exosomes for tissue regeneration. Sci Rep. 2015;5:16662. doi: 10.1038/srep16662.
    1. Kasiri MM, et al. Dying blood mononuclear cell secretome exerts antimicrobial activity. Eur J Clin Investig. 2016;46:853–863. doi: 10.1111/eci.12667.
    1. Simader E, et al. Tissue-regenerative potential of the secretome of gamma-irradiated peripheral blood mononuclear cells is mediated via TNFRSF1B-induced necroptosis. Cell Death Dis. 2019;10:729. doi: 10.1038/s41419-019-1974-6.
    1. O’Brien RG, Muller KE. In: Edwards LK, editor. Applied analysis of variance in behavioral science, vol. 8. United Kingdom: Chapman and Hall/CRC; 1993. p. 297–344.
    1. Simader E, et al. Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized phase 1 trial (MARSYAS I) Sci Rep. 2017;7:6216. doi: 10.1038/s41598-017-06223-x.
    1. Sheehan P, Jones P, Giurini JM, Caselli A, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Plast Reconstr Surg. 2006;117:239S–244S. doi: 10.1097/01.prs.0000222891.74489.33.
    1. Cardinal M, Eisenbud DE, Phillips T, Harding K. Early healing rates and wound area measurements are reliable predictors of later complete wound closure. Wound Repair Regen. 2008;16:19–22. doi: 10.1111/j.1524-475X.2007.00328.x.
    1. Gottrup F, Apelqvist J, Price P, European G. Wound Management Association Patient Outcome, Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care. 2010;19:237–268. doi: 10.12968/jowc.2010.19.6.48471.
    1. U.S. Department of Health and Human Services Food and Drug Administration, Guidance for industry chronic cutaneous ulcer and burn wounds — developing products for treatment. 2006. .
    1. Wuschko S, et al. Toxicological testing of allogeneic secretome derived from peripheral mononuclear cells (APOSEC): a novel cell-free therapeutic agent in skin disease. Sci Rep. 2019;9:5598. doi: 10.1038/s41598-019-42057-5.

Source: PubMed

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