CSL Behring Sclero XIII

Summary

Many patients with Scleroderma (Systemic sclerosis) experience damage to blood vessels, mainly to the small arteries. A common manifestation of this is Raynaud's phenomenon (fingers or toes turning white then blue in the cold) and digital ulcers (open sores on the fingertips). The purpose of this study is to see how effective the study drug Human Factor XIII Concentrate is in treating patients who have these and other common manifestation of Scleroderma. It will be given in addition to the accepted treatments used for this disease.

Timeline

Start

2015-09

Primary completion

2016-09

Completion

2018-09

Publications

• Background LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202-5. No abstract available.
• Background Nihtyanova SI, Brough GM, Black CM, Denton CP. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2008 Jan;67(1):120-3. doi: 10.1136/ard.2007.072686. Epub 2007 Jul 27.
• Background Levy JH, Greenberg C. Biology of Factor XIII and clinical manifestations of Factor XIII deficiency. Transfusion. 2013 May;53(5):1120-31. doi: 10.1111/j.1537-2995.2012.03865.x. Epub 2012 Aug 28.
• Background Yee VC, Pedersen LC, Le Trong I, Bishop PD, Stenkamp RE, Teller DC. Three-dimensional structure of a transglutaminase: human blood coagulation factor XIII. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7296-300. doi: 10.1073/pnas.91.15.7296.
• Background Nugent DJ. Prophylaxis in rare coagulation disorders -- factor XIII deficiency. Thromb Res. 2006;118 Suppl 1:S23-8. doi: 10.1016/j.thromres.2006.02.009. Epub 2006 Apr 17.
• Background Ivaskevicius V, Seitz R, Kohler HP, Schroeder V, Muszbek L, Ariens RA, Seifried E, Oldenburg J; Study Group. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost. 2007 Jun;97(6):914-21.
• Background Dallabrida SM, Falls LA, Farrell DH. Factor XIIIa supports microvascular endothelial cell adhesion and inhibits capillary tube formation in fibrin. Blood. 2000 Apr 15;95(8):2586-92.
• Background Dardik R, Shenkman B, Tamarin I, Eskaraev R, Harsfalvi J, Varon D, Inbal A. Factor XIII mediates adhesion of platelets to endothelial cells through alpha(v)beta(3) and glycoprotein IIb/IIIa integrins. Thromb Res. 2002 Feb 15;105(4):317-23. doi: 10.1016/s0049-3848(02)00014-2.
• Background Dardik R, Solomon A, Loscalzo J, Eskaraev R, Bialik A, Goldberg I, Schiby G, Inbal A. Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression. Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1472-7. doi: 10.1161/01.ATV.0000081636.25235.C6. Epub 2003 Jun 12.
• Background Dardik R, Leor J, Skutelsky E, Castel D, Holbova R, Schiby G, Shaish A, Dickneite G, Loscalzo J, Inbal A. Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice. Thromb Haemost. 2006 Mar;95(3):546-50. doi: 10.1160/TH05-06-0409.
• Background Khanna D, Furst DE, Hays RD, Park GS, Wong WK, Seibold JR, Mayes MD, White B, Wigley FF, Weisman M, Barr W, Moreland L, Medsger TA Jr, Steen VD, Martin RW, Collier D, Weinstein A, Lally EV, Varga J, Weiner SR, Andrews B, Abeles M, Clements PJ. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis. 2006 Oct;65(10):1325-9. doi: 10.1136/ard.2005.050187. Epub 2006 Mar 15.
• Background Kilian O, Fuhrmann R, Alt V, Noll T, Coskun S, Dingeldein E, Schnettler R, Franke RP. Plasma transglutaminase factor XIII induces microvessel ingrowth into biodegradable hydroxyapatite implants in rats. Biomaterials. 2005 May;26(14):1819-27. doi: 10.1016/j.biomaterials.2004.06.015.
• Background Mirochnik Y, Kwiatek A, Volpert OV. Thrombospondin and apoptosis: molecular mechanisms and use for design of complementation treatments. Curr Drug Targets. 2008 Oct;9(10):851-62. doi: 10.2174/138945008785909347.
• Background Nor JE, Mitra RS, Sutorik MM, Mooney DJ, Castle VP, Polverini PJ. Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res. 2000 May-Jun;37(3):209-18. doi: 10.1159/000025733.
• Background Streit M, Velasco P, Riccardi L, Spencer L, Brown LF, Janes L, Lange-Asschenfeldt B, Yano K, Hawighorst T, Iruela-Arispe L, Detmar M. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J. 2000 Jul 3;19(13):3272-82. doi: 10.1093/emboj/19.13.3272.
• Background Dardik R, Loscalzo J, Eskaraev R, Inbal A. Molecular mechanisms underlying the proangiogenic effect of factor XIII. Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):526-32. doi: 10.1161/01.ATV.0000154137.21230.80. Epub 2004 Dec 23.
• Background Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and angiogenesis. J Thromb Haemost. 2006 Jan;4(1):19-25. doi: 10.1111/j.1538-7836.2005.01473.x. Epub 2005 Aug 26.
• Background Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009 May 7;360(19):1989-2003. doi: 10.1056/NEJMra0806188. No abstract available.
• Background Macko RF, Gelber AC, Young BA, Lowitt MH, White B, Wigley FM, Goldblum SE. Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation. J Rheumatol. 2002 Dec;29(12):2565-70.
• Background Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K. Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts. Am J Pathol. 2005 May;166(5):1451-63. doi: 10.1016/s0002-9440(10)62362-0.
• Background Avouac J, Clemessy M, Distler JH, Gasc JM, Ruiz B, Vacher-Lavenu MC, Wipff J, Kahan A, Boileau C, Corvol P, Allanore Y. Enhanced expression of ephrins and thrombospondins in the dermis of patients with early diffuse systemic sclerosis: potential contribution to perturbed angiogenesis and fibrosis. Rheumatology (Oxford). 2011 Aug;50(8):1494-504. doi: 10.1093/rheumatology/keq448. Epub 2011 Mar 30.
• Background Farina G, Lafyatis D, Lemaire R, Lafyatis R. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2010 Feb;62(2):580-8. doi: 10.1002/art.27220.
• Background Paye M, Nusgens BV, Lapiere CM. Factor XIII of blood coagulation modulates collagen biosynthesis by fibroblasts in vitro. Haemostasis. 1989;19(5):274-83. doi: 10.1159/000215988.
• Background Denton CP, Zheng B, Evans LA, Shi-wen X, Ong VH, Fisher I, Lazaridis K, Abraham DJ, Black CM, de Crombrugghe B. Fibroblast-specific expression of a kinase-deficient type II transforming growth factor beta (TGFbeta) receptor leads to paradoxical activation of TGFbeta signaling pathways with fibrosis in transgenic mice. J Biol Chem. 2003 Jul 4;278(27):25109-19. doi: 10.1074/jbc.M300636200. Epub 2003 Apr 21.
• Background Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell. 1998 Jun 26;93(7):1159-70. doi: 10.1016/s0092-8674(00)81460-9.
• Background Thivolet J, Perrot H, Meunier F, Bouchet B. [Therapeutic action of coagulation factor XIII in scleroderma. 20 cases]. Nouv Presse Med. 1975 Nov 15;4(39):2779-82. French.
• Background Delbarre F, Godeau P, Thivolet J. Factor XIII treatment for scleroderma. Lancet. 1981 Jul 25;2(8239):204. doi: 10.1016/s0140-6736(81)90385-8. No abstract available.
• Background Guillevin L, Chouvet B, Mery C, Thivolet J, Godeau P, Delbarre F. [Treatment of generalized scleroderma with factor XIII. Study of 25 cases]. Rev Med Interne. 1982;3(3):273-7. doi: 10.1016/s0248-8663(82)80031-3. No abstract available. French.
• Background Guillevin L, Euller-Ziegler L, Chouvet B, De Gery A, Chassoux G, Lafay P, Ziegler G, Godeau P, Amor B, Thivolet J. [Treatment of systemic scleroderma with factor XIII in 86 patients, with long-term follow-up]. Presse Med. 1985 Dec 28;14(46):2327-9. French.
• Background Euller-Ziegler L, Corolleur YR, Marcou J, Commandre F, Grisot C, Ziegler G. [Long-term treatment of systemic scleroderma with coagulation factor XIII. Developmental monitoring, especially of respiratory function]. Rev Rhum Mal Osteoartic. 1984 Oct;51(9):503-5. No abstract available. French.
• Background Maekawa Y, Nogita T, Yamada M. Favorable effects of plasma factor XIII on lower esophageal sphincter pressure of progressive systemic sclerosis. Arch Dermatol. 1987 Nov;123(11):1440-1. No abstract available.
• Background Guillevin L, Chouvet B, Mery C, De Gery A, Thivolet J, Godeau P, Delbarre F. Treatment of progressive systemic sclerosis using factor XIII. Pharmatherapeutica. 1985;4(2):76-80.
• Background Quillinan NP, McIntosh D, Vernes J, Haq S, Denton CP. Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): a phase II double-blind placebo-controlled trial. Ann Rheum Dis. 2014 Jan;73(1):56-61. doi: 10.1136/annrheumdis-2013-203674. Epub 2013 Sep 25.

Drugs

Indications