CSL Behring Sclero XIII

NCT02551042 | Unknown Phase 2 DMC

• 2 other identifiers: 13/04172014-001101-40
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Systemic Sclerosis

Keywords

Digital Ulcers; Raynauds Phenomenon; Factor XIII

Outcome Measures

Primary Outcomes (2)

• Primary outcome assessed by skin involvement measured with modified Rodnan skin score

  24 weeks

• Primary outcome assessed by skin involvement measured with Raynaud condition score

  24 weeks

Secondary Outcomes (16)

• Pulmonary function measured by pulmonary function test

  24 weeks

• Hand function measured with Cochin hand function

  24 weeks

• Quality of life measured with Short Form-36 (SF-36) quality of life questionnaire

  24 weeks

• Number of new digital ulcers (DU)

  24 weeks

• Complete healing of digital ulcers (DU)

  24 weeks

Other Outcomes (8)

• Safety endpoints: Physical examination (including height, weight, BMI, digital ulcer characterization)

  24 weeks

• Safety endpoints: Adverse events

  24 weeks

• Safety endpoints: Serious adverse events

  24 weeks

Study Arms (2)

Active treatment arm

EXPERIMENTAL

Fibrogammin®P, coagulation factor XIII concentrate (Human) IV infusion

Drug: Fibrogammin®P, coagulation factor XIII concentrate (Human)

Placebo arm

PLACEBO COMPARATOR

Placebo will be 0.9 % Sodium chloride solution IV infusion

Drug: 0.9% sodium chloride

Interventions

Fibrogammin®P, coagulation factor XIII concentrate (Human) DRUG

IV infusion

Also known as: Factor XIII

Active treatment arm

0.9% sodium chloride DRUG

IV infusion

Also known as: Normal saline

Placebo arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female adults.
• Subjects with a diagnosis of systemic sclerosis (scleroderma, SSc) according to the 2013 American College of Rheumatology European League Against Rheumatism (ACR EULAR) classification criteria. They will be classified according to LeRoy criteria as limited or diffuse subset.
• Females of childbearing potential must be willing to use a reliable form of medically acceptable contraception and have a negative pregnancy test.
• Subjects will have serological status for hepatitis A and B assessed at screening.
• Patients who have given their free and informed consent. -≥ 18 years.

You may not qualify if:

• Participants must:
• Be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 6 weeks after treatment discontinuation (females of childbearing potential and males)
• Have a negative pregnancy test within 7 days prior to being registered for trial treatment (females of childbearing potential). NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
• Not be breastfeeding (females).
• Participants must not:
• Have allergies to excipients of the investigational medicinal product (IMP) and placebo
• Have uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure ≥ 160 mmHg or sitting diastolic blood pressure ≥ 100 mmHg.
• Have portal hypertension or chronic liver disease defined as mild to severe hepatic impairment (Child-Pugh Class A-C). Subjects positive for Hepatitis C with evidence of active viral replication on sensitive polymerase chain reaction (PCR) testing are also excluded.
• Have hepatic dysfunction, defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of the normal range (× ULN) at the Screening Visit.
• Have chronic renal insufficiency as defined by a serum creatinine ≥ 2.5 mg/dL (≤ 221 micromol/L) or requires dialysis.
• Have a haemoglobin concentration ≤ 10 g/dL (≤ 100 g/L) at the Screening Visit.
• Have a history of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: aortic or mitral valve disease (stenosis or regurgitation) defined as more than minimum aortic insufficiency and more than moderate mitral regurgitation (stenosis or regurgitation≥ grade 1); pericardial constriction; restrictive or congestive cardiomyopathy; left ventricular ejection fraction ≤ 40 % by multiple gated acquisition scan (MUGA), angiography, or echocardiography; left ventricular shortening fraction ≤ 22 % by echocardiography; or symptomatic coronary disease with demonstrable ischemia.
• Have a history of malignancies within 5 years of Screening Visit with the exception of localized skin or cervical carcinomas.
• Have psychiatric, addictive, or other disorder that compromises the ability to give informed consent for participating in this study. This includes subjects with a recent history of abusing alcohol or illicit drugs.
• Be receiving ongoing treatment with hyperbaric oxygen

Sponsors & Collaborators

• University College, London: lead
• CSL Behring: collaborator

Study Sites (1)

Royal Free London NHS Foundation Trust

London, NW3 2QG, United Kingdom

RECRUITING

Related Publications (33)

• 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.

  PMID: 3361530 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.

  PMID: 17660220 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.

  PMID: 22928875 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.

  PMID: 7913750 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.

  PMID: 16616323 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.

  PMID: 17549292 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.

  PMID: 10753838 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.

  PMID: 12031826 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.

  PMID: 12805075 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.

  PMID: 16525585 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.

  PMID: 16540546 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.

  PMID: 15576156 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.

  PMID: 18855619 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.

  PMID: 10859480 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.

  PMID: 10880440 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.

  PMID: 15618543 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.

  PMID: 16129024 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.

  PMID: 19420368 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.

  PMID: 12465153 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.

  PMID: 15855645 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.

  PMID: 21454305 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.

  PMID: 20112379 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.

  PMID: 2777140 BACKGROUND

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  PMID: 12707256 BACKGROUND

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• 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.

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Related Links

• NovoThirteen® Summary of Product Characteristics

MeSH Terms

Conditions

Scleroderma, Systemic; digital ulcers; Raynaud Disease

Interventions

Factor VIII; Factor XIII; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases; Livedoid Vasculopathy; Thrombosis; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases; Skin Diseases, Vascular

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors; Enzyme Precursors; Enzymes and Coenzymes; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Christopher Denton, PhD

  Royal Free London NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christopher Denton, PhD

CONTACT

02073177544; c.denton@ucl.ac.uk

Rachel Ochiel

CONTACT

02073177544; rachel.ochiel@nhs.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2014
• First Posted: September 16, 2015
• Study Start: September 1, 2015
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2018
• Last Updated: May 30, 2016

Record last verified: 2016-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)