CSL Behring Sclero XIII

A Phase II, Double-blind, Randomized, Placebo-controlled Study to Investigate Pharmacokinetics (PK), Safety and Efficacy of Intravenous Factor XIII Treatment in Patients With Systemic Sclerosis

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.

Study Overview

• Status: Unknown
• Conditions: Systemic Sclerosis
• Intervention / Treatment: Drug: Fibrogammin®P, coagulation factor XIII concentrate (Human); Drug: 0.9% sodium chloride

Detailed Description

This is a phase II, double-blind, randomized, placebo-controlled study to investigate pharmacokinetics (PK), safety and efficacy of intravenous factor XIII treatment in patients with systemic sclerosis.

Scleroderma (Systemic sclerosis) is a multisystem rheumatic disease that is characterised by progressive vascular damage e.g Raynaud's phenomenon and digital ulcers and organ fibrosis e.g. skin thickening and pulmonary fibrosis.The disease is associated with significant morbidity and mortality and current therapeutic options are only partially effective, including Cyclophosphamide for skin or lung fibrosis and Bosentan which reduces but does not heal digital ulcers.

There is no cure available and there is therefore a high need for new therapeutic options.Administration of human Factor XIII (FXIII) concentrate in patients with scleroderma demonstrated promising results in the 1980s and 1990s . However these studies were not performed according to current Good Clinical Practice (GCP) guidelines and involved relatively small sample sizes.

This is a single site study, therefore all study participants will be seen at the Royal Free London National Health Service (NHS) Foundation Trust.Total study duration is 36 months and will involve 2 phases: an initial single dose, pharmacokinetic (PK) phase in 8 subjects over 6 weeks and a multiple dose, active treatment phase in 18 subjects over 24 weeks. During the treatment phase subjects will be randomized at 2:1 ratio to either FXIII or Placebo and will receive biweekly injection of either factor XIII Concentrate or placebo.

• Study Type: Interventional
• Enrollment (Anticipated): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Recruiting
    • Royal Free London NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

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
• Have pulmonary artery hypertension (PAH)
• Have received IV Iloprost within the last 2 months
• Have been treated with sympathectomy or toxin botulinum A within the last 3 months
• Have had thrombosis, stroke, pulmonary embolism or myocardial infarction in the last 6 months
• Have a diagnosis of diabetes mellitus requiring dietary restriction of carbohydrate.
• Be on a low sodium diet on medical advice.
• Be participating in another clinical trial involving an investigational medicinal product.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active treatment arm; Fibrogammin®P, coagulation factor XIII concentrate (Human) IV infusion	Drug: Fibrogammin®P, coagulation factor XIII concentrate (Human); IV infusion; Other Names: Factor XIII
Placebo Comparator: Placebo arm; Placebo will be 0.9 % Sodium chloride solution IV infusion	Drug: 0.9% sodium chloride; IV infusion; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary function measured by pulmonary function test	Pulmonary function measured by pulmonary function test	24 weeks
Hand function measured with Cochin hand function	Hand function measured with Cochin hand function	24 weeks
Quality of life measured with Short Form-36 (SF-36) quality of life questionnaire	Quality of life measured with SF36 quality of life questionnaire	24 weeks
Number of new digital ulcers (DU)	Prevention of new DU: Number of new DU developed during a 24-week period of treatment	24 weeks
Complete healing of digital ulcers (DU)	Healing of DU: Complete healing of DUs present at baseline; each DU is considered as an entity	24 weeks
Digital ulcer pain assessment	DU Pain assessment at 4, 8, 12, 16, 24 weeks of treatment: Pain will be assessed by analogue scale for pain (Visual Analogue Scale, VAS)	24 weeks
Digital ulcer pain assessment	DU Pain assessment at 4, 8, 12, 16, 24 weeks of treatment: Pain will be assessed by Raynaud's severity (Raynaud's condition score)	24 weeks
Digital ulcer worsening: hospitalisation required	Number of overnight hospitalisations for digital ulcers	24 weeks
Digital ulcer worsening: surgical intervention required	Number of additional surgical treatments for digital ulcer in outpatient clinic	24 weeks
Digital ulcer worsening: Digital ulcer infection	Number of digital ulcers with infections	24 weeks
Digital ulcer worsening: Gangrene	Number of episodes of gangrene	24 weeks
Digital ulcer worsening: Amputation	Number of amputations	24 weeks
Digital ulcer worsening: Need of local sympathectomy	Number of local sympathectomies	24 weeks
Digital ulcer worsening: Need of toxin Botulinum A	Number of treatments with Botulinum toxin A	24 weeks
Digital ulcer worsening: Need of oral or parenteral antibiotic	Number of treatments needed with oral or parenteral antibiotic	24 weeks
Digital ulcer worsening: Need of intravenous (IV) Iloprost : this is considered treatment failure	Number of treatments needed with intravenous (IV) Iloprost : this is considered treatment failure	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety endpoints: Physical examination (including height, weight, BMI, digital ulcer characterization)	Physical examination (including height, weight, BMI, digital ulcer characterization)	24 weeks
Safety endpoints: Adverse events	Adverse events	24 weeks
Safety endpoints: Serious adverse events	Serious adverse events	24 weeks
Safety endpoints: ECG	ECG	24 weeks
Safety endpoints: Vital signs	Vital signs	24 weeks
Safety endpoints: Clinical laboratory parameters	Clinical laboratory parameters	24 weeks
Safety endpoints: Pregnancy	Serum or urine pregnancy tests will be performed at each visit and will be reported positive or negative	24 weeks
Safety endpoints -Adverse events of special interest: thromboembolic events	Adverse events of special interest: thromboembolic events	24 weeks

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: CSL Behring
• Investigators: Principal Investigator: Christopher Denton, PhD, Royal Free London NHS Foundation Trust

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• NovoThirteen® Summary of Product Characteristics

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Anticipated): September 1, 2016
• Study Completion (Anticipated): September 1, 2018

Study Registration Dates

• First Submitted: December 17, 2014
• First Submitted That Met QC Criteria: September 15, 2015
• First Posted (Estimate): September 16, 2015

Study Record Updates

• Last Update Posted (Estimate): May 30, 2016
• Last Update Submitted That Met QC Criteria: May 27, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Factor XIII; Digital Ulcers; Raynauds Phenomenon
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse; Coagulants; Factor VIII
• Other Study ID Numbers: 13/0417; 2014-001101-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No