Thrombin Generation Assay (TGA) as Predictive Test for Haemostatic. Effectiveness of FVIII Concentrates in Haemophiliac A With Inhibitors

Severe Hemophilia A With Inhibitor Clinical Trial

— PredicTGA  

Official title:

Thrombin Generation Assay (TGA) as Predictive Test for Haemostatic Effectiveness of Factor VIII (FVIII) Concentrates in Patients Affected by Inherited Haemophilia A With FVIII Inhibitors High and Low Anamnestic Response.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01505946
• Other study ID #: PredicTGA
• Secondary ID: 373
• Status: Recruiting
• Phase: N/A
• First received: January 5, 2012
• Last updated: June 14, 2013
• Start date: March 2012
• Est. completion date: June 2016

Study information

• Verified date: June 2013
• Source: Grifols Italia S.p.A
• Contact: Elena Santagostino, Scientific Coordinator
• Phone: +39 02 55035273
• Email: hemophilia_ctr[@]policlinico.mi.it
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines AgencyItaly: National Monitoring Centre for Clinical Trials - Ministry of Health
• Study type: Observational

Clinical Trial Summary

This is an observational, prospective, longitudinal, multicenter, cohort study designed with the scope to verify whether or not TGA may predict effectiveness of different FVIII concentrates class (devoid or rich of VWF) in patient affected by severe or moderately severe inherited haemophilia A and inhibitors.

Description:

Rationale:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: June 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Diagnosis of inherited, severe (FVIII:C < 1%) or moderately severe haemophilia A (FVIII = 2%)

• 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)

INCLUSION CRITERIA FOR THE HIGH RESPONDERS COHORT

• 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 acquired haemophilia

• 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

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Hemophilia A
• Severe Hemophilia A With Inhibitor

Intervention

Other:
• 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

Locations

Country	Name	City	State
Italy	Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari	BAri	Puglia
Italy	UO Angiologia e Malattie della Coagulazione "Marino Golinelli" Az Osp. Policlinico S. Orsola Malpighi	Bologna	Emilia Romagna
Italy	Ospedale Civile dell' Annunziata	Cosenza	Calabria
Italy	Agenzia per l'Emofilia Azienda Ospedaliera Universitaria Careggi	Florence	Tuscany
Italy	Az. Universitaria Policlinico "Federico II" Dip. Assist. di Clinica Medica	Napoli	Campania
Italy	Az. Ospedaliera di Padova, Clinica Medica IIa	Padua	Veneto
Italy	Centro di Riferimento Emostasi e Trombosi in età pediatrica Ospedale dei bambini G. Di Cristina	Palermo
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	Azienda Ospedialiera Ospedale Infantile Regina Margherita - S.Anna	Turin	Piemonte
Italy	Ospedale Le Molinette "S. G. Battista"	Turin	Piemonte
Italy	Azienda Ospedaliera "Santa Maria della Misericordia"	Udine	Friuli Venezia Giulia
Italy	Azienda Ospedaliera Univesitaria Integrata di Verona - Borgo Roma	Verona	Veneto
Italy	Dipartimento di Terapie Cellulari ed Ematologia Ospedale San Bortolo	Vicenza	Veneto

Sponsors (2)

Lead Sponsor	Collaborator
Grifols Italia S.p.A	Thrombinoscope

Country where clinical trial is conducted

Italy, 

References & Publications (18)

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. Review. — View Citation

Astermark J, Voorberg J, Lenk H, DiMichele D, Shapiro A, Tjönnfjord 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. — View Citation

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. Review. — View Citation

Boekhorst J, Lari GR, D'Oiron R, Costa JM, Nováková 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. — View Citation

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. Review. — View Citation

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. — View Citation

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. Epub 2005 Sep 15. — View Citation

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. Epub 2003 Jun 19. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Iorio A, Halimeh S, Holzhauer S, Goldenberg N, Marchesini E, Marcucci M, Young G, Bidlingmaier C, Brandao LR, Ettingshausen CE, Gringeri A, Kenet G, Knöfler R, Kreuz W, Kurnik K, Manner D, Santagostino E, Mannucci PM, Nowak-Göttl 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. Review. — View Citation

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. — View Citation

Kopecky EM, Greinstetter S, Pabinger I, Buchacher A, Römisch 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. Epub 2005 Dec 5. — View Citation

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. Epub 2007 Oct 18. Erratum in: Haemophilia. 2008 Jul;14(4):878. Haemophilia. 2008 Mar;14(2):414. — View Citation

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. — View Citation

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. — View Citation

Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003 Jul;9(4):418-35. Review. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Thrombin generation result	Thrombin generation results of the TGA applied on plasma patients whith inhibitor matched with different class of FVIII concentrate	12 months	No
Secondary	Epitope mapping results	epitope mapping test on the plasma patient during the therapy for a follow-up period of 12 month	12 months	No
Secondary	Incidence of all breakthrough (BT) bleedings	events/month	12 months	No
Secondary	Total FVIII dose required to treat the patients	(IU/year)	12 months	No
Secondary	the inhibitor titre course		12 months	No
Secondary	Use of bypassing agents	incidence of BT bleedings who require bypassing agents (events/months) average dose of bypassing agents (or days of treatment) needed to treat BT bleedings total dose of bypassing agent (and days of treatment) required overall (IU/year) and (days of treatment/year)	12 months	No
Secondary	ITI outcome only for patient under this kind of treatment	% of Success (total, partial success or failure will be defined as in ITI study protocol) Time to tolerance (months), defined as the time to ITI success (total/partial)	3 years	No