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

NCT01505946 | Unknown DMC

• 2 other identifiers: PredicTGA373
• Study Type: observational
• Target: 25
• Locations: 1 country
• Sites: 15

Brief 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.

Conditions

Severe Hemophilia A With Inhibitor

Keywords

Thrombin; Hemophilia; Inhibitors; Immunotolerance; Haemostatic; FVIII; Epitopes; Moderately severe Hemophilia A with inhibitor

Outcome Measures

Primary Outcomes (1)

• Thrombin generation result

  Thrombin generation results of the TGA applied on plasma patients whith inhibitor matched with different class of FVIII concentrate

  12 months

Secondary Outcomes (6)

• Epitope mapping results

  12 months

• Incidence of all breakthrough (BT) bleedings

  12 months

• Total FVIII dose required to treat the patients

  12 months

• the inhibitor titre course

  12 months

• Use of bypassing agents

  12 months

Study Arms (2)

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)

Other: TGA (Thrombin generation Assay)

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

Other: TGA (Thrombin generation Assay)

Interventions

TGA (Thrombin generation Assay) OTHER

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; LOW RESPONDERS

Eligibility Criteria

• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with moderate or severe hemophilia A with inhibitors divided into two groups: 1. Patients with inhibitors to FVIII and low anamnestic response: Low responders cohort 2. Patients with inhibitors to FVIII and high anamnestic response: High responders cohort

You may qualify if:

• 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)
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Grifols Italia S.p.A: lead
• Thrombinoscope: collaborator

Study Sites (15)

Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari

Bari, Apulia, 70124, Italy

ACTIVE NOT RECRUITING

Ospedale Civile dell' Annunziata

Cosenza, Calabria, 87100, Italy

RECRUITING

Az. Universitaria Policlinico "Federico II" Dip. Assist. di Clinica Medica

Napoli, Campania, 80131, Italy

ACTIVE NOT RECRUITING

UO Angiologia e Malattie della Coagulazione "Marino Golinelli" Az Osp. Policlinico S. Orsola Malpighi

Bologna, Emilia-Romagna, 40138, Italy

RECRUITING

Azienda Ospedaliera "Santa Maria della Misericordia"

Udine, Friuli Venezia Giulia, 33100, Italy

RECRUITING

Ematologia Dipartimento di Biotecnologie Cellulari Università La Sapienza - Policlinico Umberto I

Rome, Lazio, 00161, Italy

ACTIVE NOT RECRUITING

Ospedale Pediatrico Bambino Gesù di Roma

Rome, Lazio, 00165, Italy

RECRUITING

Università Cattolica - Policlinico A. Gemelli

Rome, Lazio, 00168, Italy

ACTIVE NOT RECRUITING

Centro di Riferimento Emostasi e Trombosi in età pediatrica Ospedale dei bambini G. Di Cristina

Palermo, Palermo, Italy

RECRUITING

Azienda Ospedialiera Ospedale Infantile Regina Margherita - S.Anna

Turin, Piedmont, 10126, Italy

RECRUITING

Ospedale Le Molinette "S. G. Battista"

Turin, Piedmont, 10126, Italy

RECRUITING

Agenzia per l'Emofilia Azienda Ospedaliera Universitaria Careggi

Florence, Tuscany, 50134, Italy

RECRUITING

Az. Ospedaliera di Padova, Clinica Medica IIa

Padua, Veneto, 35128, Italy

RECRUITING

Azienda Ospedaliera Univesitaria Integrata di Verona - Borgo Roma

Verona, Veneto, 37126, Italy

ACTIVE NOT RECRUITING

Dipartimento di Terapie Cellulari ed Ematologia Ospedale San Bortolo

Vicenza, Veneto, 36100, Italy

RECRUITING

Related Publications (18)

• 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.

  PMID: 12828678 BACKGROUND

• 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.

  PMID: 17212725 BACKGROUND

• 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.

  PMID: 20345722 BACKGROUND

• 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.

  PMID: 20590857 BACKGROUND

• 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.

  PMID: 12816859 BACKGROUND

• 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.

  PMID: 16376372 BACKGROUND

• 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.

  PMID: 20132333 BACKGROUND

• 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.

  PMID: 18503540 BACKGROUND

• 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.

  PMID: 19740093 BACKGROUND

• 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.

  PMID: 11442642 BACKGROUND

• 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.

  PMID: 14511295 BACKGROUND

• 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.

  PMID: 12826529 BACKGROUND

• 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.

  PMID: 18078402 BACKGROUND

• 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.

  PMID: 16166584 BACKGROUND

• 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.

  PMID: 16476086 BACKGROUND

• 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.

  PMID: 17941829 BACKGROUND

• 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.

  PMID: 16154861 BACKGROUND

• 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.

  PMID: 17610550 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

plasma samples

MeSH Terms

Conditions

Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Elena Santagostino, MD, PhD

  Angelo Bianchi Bonomi" Haemophilia Thrombosis Centre I.R.C.S.S. Maggiore Hospital and University of Milan Via Pace 9, 20122 Milan - Italy

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elena Santagostino, Scientific Coordinator

CONTACT

+39 02 55035273; hemophilia_ctr@policlinico.mi.it

Elisa Mancuso

CONTACT

+39 02 55035273; hemophilia_ctr@policlinico.mi.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 5, 2012
• First Posted: January 9, 2012
• Study Start: March 1, 2012
• Primary Completion: December 1, 2015
• Study Completion: June 1, 2016
• Last Updated: June 17, 2013

Record last verified: 2013-06

Locations

IT (15)