Clinical trial NCT01505946: Thrombin Generation Assay (TGA) as Predictive Test for Haemostatic. Effectiveness of FVIII Concentrates in Haemophiliac A With Inhibitors
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.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Severe Hemophilia A With Inhibitor
Keywords: Thrombin
Hemophilia
Inhibitors
Immunotolerance
Haemostatic
FVIII
Epitopes
Moderately severe Hemophilia A with inhibitor
Lead sponsor: Grifols Italia S.p.A
Sponsor class: INDUSTRY
Collaborators: name: Thrombinoscope
First posted: 2012-01-09
Enrollment: 25
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Thrombin generation result
timeFrame: 12 months
Secondary outcomes:
measure: Epitope mapping results
timeFrame: 12 months
measure: Incidence of all breakthrough (BT) bleedings
timeFrame: 12 months
measure: Total FVIII dose required to treat the patients
timeFrame: 12 months
measure: the inhibitor titre course
timeFrame: 12 months
measure: Use of bypassing agents
timeFrame: 12 months
measure: ITI outcome only for patient under this kind of treatment
timeFrame: 3 years
Other outcomes:
Locations:
city: Cosenza
country: Italy
facility: Ospedale Civile dell' Annunziata
state: Calabria
city: Napoli
country: Italy
facility: Az. Universitaria Policlinico "Federico II" Dip. Assist. di Clinica Medica
state: Campania
city: Bologna
country: Italy
facility: UO Angiologia e Malattie della Coagulazione "Marino Golinelli" Az Osp. Policlinico S. Orsola Malpighi
state: Emilia Romagna
city: Udine
country: Italy
facility: Azienda Ospedaliera "Santa Maria della Misericordia"
state: Friuli Venezia Giulia
city: Rome
country: Italy
facility: Ematologia Dipartimento di Biotecnologie Cellulari Università La Sapienza - Policlinico Umberto I
state: Lazio
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù di Roma
state: Lazio
city: Rome
country: Italy
facility: Università Cattolica - Policlinico A. Gemelli
state: Lazio
city: Turin
country: Italy
facility: Azienda Ospedialiera Ospedale Infantile Regina Margherita - S.Anna
state: Piemonte
city: Turin
country: Italy
facility: Ospedale Le Molinette "S. G. Battista"
state: Piemonte
city: BAri
country: Italy
facility: Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
state: Puglia
city: Florence
country: Italy
facility: Agenzia per l'Emofilia Azienda Ospedaliera Universitaria Careggi
state: Tuscany
city: Padua
country: Italy
facility: Az. Ospedaliera di Padova, Clinica Medica IIa
state: Veneto
city: Verona
country: Italy
facility: Azienda Ospedaliera Univesitaria Integrata di Verona - Borgo Roma
state: Veneto
city: Vicenza
country: Italy
facility: Dipartimento di Terapie Cellulari ed Ematologia Ospedale San Bortolo
state: Veneto
city: Palermo
country: Italy
facility: Centro di Riferimento Emostasi e Trombosi in età pediatrica Ospedale dei bambini G. Di Cristina
Study officials:
affiliation: Angelo Bianchi Bonomi" Haemophilia Thrombosis Centre I.R.C.S.S. Maggiore Hospital and University of Milan Via Pace 9, 20122 Milan - Italy
name: Elena Santagostino, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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