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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Severe Hemophilia A With Inhibitor

Intervention / Treatment
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* Other: TGA (Thrombin generation Assay)


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| LOW RESPONDERS<br>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)<br>* 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<br>|
| HIGH RESPONDERS<br>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)<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epitope mapping results | epitope mapping test on the plasma patient during the therapy for a follow-up period of 12 month | 12 months | 
| Incidence of all breakthrough (BT) bleedings | events/month | 12 months | 
| Total FVIII dose required to treat the patients | (IU/year) | 12 months | 
| the inhibitor titre course |  | 12 months | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thrombin, Hemophilia, Inhibitors, Immunotolerance, Haemostatic, FVIII, Epitopes, Moderately severe Hemophilia A with inhibitor