Thrombin Generation Assay (TGA) as Predictive Test for Haemostatic. Effectiveness of FVIII Concentrates in Haemophiliac A With Inhibitors
NCT ID: NCT01505946
Last Updated: 2013-06-17
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
25 participants
OBSERVATIONAL
2012-03-31
2016-06-30
Brief Summary
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Detailed Description
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Hemophilia A is a serious and common hereditary bleeding disorder caused by deficiency of coagulation factor VIII (FVIII). Patients with this disease are treated with recombinant factor VIII or factor VIII concentrates derived from plasma.
Administration of exogenous FVIII in 15-35% of cases, cause the formation of antibodies to FVIII (inhibitors) that neutralize the activity of factor VIII, making the treatment ineffective.The development of inhibitors of factor VIII (FVIII) is the most serious and challenging complication of the treatment of hemophilia A and represents the highest economic burden for a chronic disease. Therefore, research is making great efforts to optimize the best therapeutic approach for the disease.
It has been observed that FVIII inhibitors display a wide range of immunoreactivity when tested against different classes of FVIII concentrates (with/without von Willebrand factor -VWF). It has been demonstrated that the different inhibitors reactivity may correlate with different ability of inhibitors to impair thrombin generation, as tested by Thrombin Generation Assay (TGA). In these patients TGA assay might be a tool to predict which FVIII concentrate has the greater haemostatic effectiveness.
It is also uncertain if the different classes of FVIII used in ITI protocols may have a different effectiveness in reducing the occurrence of BT bleedings and if this may correlate to lower reactivity, epitope specificity, VWF content and may be predicted by TGA. It would be very helpful to be able to give an evidence based diagnostic and prognostic instrument, the TGA, to aid physician to optimize the therapy for all inhibitors patients.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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LOW RESPONDERS
Documented low anamnestic response after FVIII exposure (FVIII inhibitors titre \>0.6 and \< 5 BU/ml tested by Bethesda assay, Nijmegen modification). Patients who have never been submitted to ITI and also those patients who have completed ITI with partial success (defined as inhibitors titre \>0.6 and \< 5 BU/ml and no increase in the INH titer \> 5 BU over treatment with FVIII)
TGA (Thrombin generation Assay)
TGA will be performed on plasma in order to evaluate differences in the ability to stimulate the thrombin generation among the different class of FVIII concentrates and possibly identify the "most effective". The TGA will be quarterly repeated in order to verify if it is also adequate to check the therapy effectiveness during the study period
HIGH RESPONDERS
Patients who documented high response after FVIII exposure (FVIII inhibitors titre \> 5 BU/ml tested by Bethesda assay, Nijmegen modification) and who are potential candidates to a first or rescue ITI
TGA (Thrombin generation Assay)
TGA will be performed on plasma in order to evaluate differences in the ability to stimulate the thrombin generation among the different class of FVIII concentrates and possibly identify the "most effective". The TGA will be quarterly repeated in order to verify if it is also adequate to check the therapy effectiveness during the study period
Interventions
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TGA (Thrombin generation Assay)
TGA will be performed on plasma in order to evaluate differences in the ability to stimulate the thrombin generation among the different class of FVIII concentrates and possibly identify the "most effective". The TGA will be quarterly repeated in order to verify if it is also adequate to check the therapy effectiveness during the study period
Eligibility Criteria
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Inclusion Criteria
* Any age
* Ability to comply with study methods and willingness to participate to the study
* Written informed consent.
FOR THE LOW RESPONDERS COHORT
\- Documented low anamnestic response after FVIII exposure (FVIII inhibitors titre \>0.6 and \< 5 BU/ml tested by Bethesda assay, Nijmegen modification). It will be included in this study those patients who have never been submitted to ITI and also those patients who have completed ITI with partial success (defined as inhibitors titre \>0.6 and \< 5 BU/ml and no increase in the INH titer \> 5 BU over treatment with FVIII)
* Documented high response after FVIII exposure (FVIII inhibitors titre \> 5 BU/ml tested by Bethesda assay, Nijmegen modification). It will be included in this study those patients who are potential candidates to a first or rescue ITI.
* Any historical peak ≥ 5 BU
Exclusion Criteria
* Diagnosis of inherited mild haemophilia A (FVIII \> 2%)
* Life expectancy lower than 1 year
* Psychiatric illness and any other conditions may impair ability to comply with study methods
MALE
No
Sponsors
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Thrombinoscope
UNKNOWN
Grifols Italia S.p.A
INDUSTRY
Responsible Party
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Principal Investigators
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Elena Santagostino, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Angelo Bianchi Bonomi" Haemophilia Thrombosis Centre I.R.C.S.S. Maggiore Hospital and University of Milan Via Pace 9, 20122 Milan - Italy
Locations
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Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
Bari, Apulia, Italy
Ospedale Civile dell' Annunziata
Cosenza, Calabria, Italy
Az. Universitaria Policlinico "Federico II" Dip. Assist. di Clinica Medica
Napoli, Campania, Italy
UO Angiologia e Malattie della Coagulazione "Marino Golinelli" Az Osp. Policlinico S. Orsola Malpighi
Bologna, Emilia-Romagna, Italy
Azienda Ospedaliera "Santa Maria della Misericordia"
Udine, Friuli Venezia Giulia, Italy
Ematologia Dipartimento di Biotecnologie Cellulari Università La Sapienza - Policlinico Umberto I
Rome, Lazio, Italy
Ospedale Pediatrico Bambino Gesù di Roma
Rome, Lazio, Italy
Università Cattolica - Policlinico A. Gemelli
Rome, Lazio, Italy
Centro di Riferimento Emostasi e Trombosi in età pediatrica Ospedale dei bambini G. Di Cristina
Palermo, Palermo, Italy
Azienda Ospedialiera Ospedale Infantile Regina Margherita - S.Anna
Turin, Piedmont, Italy
Ospedale Le Molinette "S. G. Battista"
Turin, Piedmont, Italy
Agenzia per l'Emofilia Azienda Ospedaliera Universitaria Careggi
Florence, Tuscany, Italy
Az. Ospedaliera di Padova, Clinica Medica IIa
Padua, Veneto, Italy
Azienda Ospedaliera Univesitaria Integrata di Verona - Borgo Roma
Verona, Veneto, Italy
Dipartimento di Terapie Cellulari ed Ematologia Ospedale San Bortolo
Vicenza, Veneto, Italy
Countries
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Central Contacts
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Facility Contacts
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Giancarlo Castaman, MD
Role: primary
References
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Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003 Jul;9(4):418-35. doi: 10.1046/j.1365-2516.2003.00780.x.
Salvagno GL, Astermark J, Ekman M, Franchini M, Guidi GC, Lippi G, Poli G, Berntorp E. Impact of different inhibitor reactivities with commercial factor VIII concentrates on thrombin generation. Haemophilia. 2007 Jan;13(1):51-6. doi: 10.1111/j.1365-2516.2006.01400.x.
Iorio A, Halimeh S, Holzhauer S, Goldenberg N, Marchesini E, Marcucci M, Young G, Bidlingmaier C, Brandao LR, Ettingshausen CE, Gringeri A, Kenet G, Knofler R, Kreuz W, Kurnik K, Manner D, Santagostino E, Mannucci PM, Nowak-Gottl U. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost. 2010 Jun;8(6):1256-65. doi: 10.1111/j.1538-7836.2010.03823.x. Epub 2010 Mar 17.
Astermark J, Santagostino E, Keith Hoots W. Clinical issues in inhibitors. Haemophilia. 2010 Jul;16 Suppl 5:54-60. doi: 10.1111/j.1365-2516.2010.02294.x.
Gringeri A, Mantovani LG, Scalone L, Mannucci PM; COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood. 2003 Oct 1;102(7):2358-63. doi: 10.1182/blood-2003-03-0941. Epub 2003 Jun 19.
Kopecky EM, Greinstetter S, Pabinger I, Buchacher A, Romisch J, Jungbauer A. Mapping of FVIII inhibitor epitopes using cellulose-bound synthetic peptide arrays. J Immunol Methods. 2006 Jan 20;308(1-2):90-100. doi: 10.1016/j.jim.2005.10.016. Epub 2005 Dec 5.
Chambost H. Assessing risk factors: prevention of inhibitors in haemophilia. Haemophilia. 2010 Mar;16 Suppl 2:10-5. doi: 10.1111/j.1365-2516.2009.02197.x.
Boekhorst J, Lari GR, D'Oiron R, Costa JM, Novakova IR, Ala FA, Lavergne JM, VAN Heerde WL. Factor VIII genotype and inhibitor development in patients with haemophilia A: highest risk in patients with splice site mutations. Haemophilia. 2008 Jul;14(4):729-35. doi: 10.1111/j.1365-2516.2008.01694.x. Epub 2008 May 12.
Coppola A, Margaglione M, Santagostino E, Rocino A, Grandone E, Mannucci PM, Di Minno G; AICE PROFIT Study Group. Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost. 2009 Nov;7(11):1809-15. doi: 10.1111/j.1538-7836.2009.03615.x. Epub 2009 Sep 9.
Kallas A, Talpsep T. von Willebrand factor in factor VIII concentrates protects against neutralization by factor VIII antibodies of haemophilia A patients. Haemophilia. 2001 Jul;7(4):375-80. doi: 10.1046/j.1365-2516.2001.00530.x.
Astermark J, Voorberg J, Lenk H, DiMichele D, Shapiro A, Tjonnfjord G, Berntorp E. Impact of inhibitor epitope profile on the neutralizing effect against plasma-derived and recombinant factor VIII concentrates in vitro. Haemophilia. 2003 Sep;9(5):567-72. doi: 10.1046/j.1365-2516.2003.00802.x.
Berntorp E. Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations: is it of clinical importance? Haematologica. 2003 Jun;88(6):EREP03.
Gringeri A. VWF/FVIII concentrates in high-risk immunotolerance: the RESIST study. Haemophilia. 2007 Dec;13 Suppl 5:73-7. doi: 10.1111/j.1365-2516.2007.01579.x.
Goudemand J, Rothschild C, Demiguel V, Vinciguerrat C, Lambert T, Chambost H, Borel-Derlon A, Claeyssens S, Laurian Y, Calvez T; FVIII-LFB and Recombinant FVIII study groups. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood. 2006 Jan 1;107(1):46-51. doi: 10.1182/blood-2005-04-1371. Epub 2005 Sep 15.
Gringeri A, Monzini M, Tagariello G, Scaraggi FA, Mannucci PM; Emoclot15 Study Members. Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate. Haemophilia. 2006 Mar;12(2):128-32. doi: 10.1111/j.1365-2516.2006.01201.x.
Kurth MA, Dimichele D, Sexauer C, Sanders JM, Torres M, Zappa SC, Ragni M, Leonard N. Immune tolerance therapy utilizing factor VIII/von Willebrand factor concentrate in haemophilia A patients with high titre factor VIII inhibitors. Haemophilia. 2008 Jan;14(1):50-5. doi: 10.1111/j.1365-2516.2007.01560.x. Epub 2007 Oct 18.
Orsini F, Rotschild C, Beurrier P, Faradji A, Goudemand J, Polack B. Immune tolerance induction with highly purified plasma-derived factor VIII containing von Willebrand factor in hemophilia A patients with high-responding inhibitors. Haematologica. 2005 Sep;90(9):1288-90.
Gringeri A, Musso R, Mazzucconi MG, Piseddu G, Schiavoni M, Pignoloni P, Mannucci PM; RITS-FITNHES Study Group. Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response. Haemophilia. 2007 Jul;13(4):373-9. doi: 10.1111/j.1365-2516.2007.01484.x.
Other Identifiers
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373
Identifier Type: OTHER
Identifier Source: secondary_id
PredicTGA
Identifier Type: -
Identifier Source: org_study_id
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