A Survey on the Success of Inhibitor Elimination Using Individualized Concentrate Selection and Controlled ITI

This research program is initiated to evaluate and document data on the success of ITI in 300 haemophilia A patients with newly developed or already existing FVIII-inhibitors (also patients who might potentially have failed in earlier ITIs), which will be treated with ITI - preferably high-dose based on individualized product selection, in order to improve management of this potentially devastating complication of haemophilia treatment. In order to investigate the role of in vitro tests on individual ITI success rate in patients undergoing ITI, the inhibitor plasma samples can be assayed against different FVIII concentrates using the following in vitro tests: Batch selection, Thrombin generation assay (TGA), Thrombin Generation Test (TGT) to monitor FVIII efficacy, Epitope mapping,IgG Subclasses specific for FVIII, Immunogenotyping.

As a result of many technological advances in the last two decades, current factor VIII (FVIII) concentrates (both plasma-derived and recombinant products) are considered very safe in terms of pathogen safety. The development of inhibitors against FVIII or factor IX (FIX) is considered as a major complication during replacement therapy of haemophiliacs. Prospective studies of previously untreated patients (PUPs) have suggested that inhibitors develop in up to 33% of patients with moderate to severe haemophilia A. Several strategies are used to control bleedings in such patients, e.g. high-dose treatment with FVIII concentrates, treatment with activated prothrombin complex concentrate (aPCC) or treatment with activated factor VII (FVIIa). Immune tolerance induction (ITI) in order to eradicate inhibitors in patients suffering from an inhibitor to FVIII with high dose treatment of FVIII was first reported in 1977 by Brackmann \& Gormsen in the so-called "Bonn Protocol" and was investigated from then on in a series of clinical studies applying the same or a modified version of the "Bonn Protocol". During these investigations high dose FVIII treatment has been proven efficacious in inducing immune tolerance and was shown to exert a long lasting effect in more than 80 % of the patients treated. The observational immune tolerance induction research program (ObsITI) will allow a systematic prospective and retrospective data documentation and analysis on the success rate of ITI by using individualized concentrate selection. Pre-ITI-phase: Aim of this evaluation is to assess current pre-ITI treatment strategies in inhibitor patients from detection of inhibitor until start of ITI (early start vs. delayed start) and the effect of pre-ITI treatment (prophylaxis and on-demand treatment in case of bleeds/surgery) with bypassing agents (rFVIIa, NovoSeven®, aPCC, FEIBA®, emicizumab, Hemlibra®) and / or FVIII on the titre at start of ITI, on the success rate of ITI, the number of break-through bleeds and life-threatening bleeds. ObsITI-Rescue ITI Study: Patients who fail FVIII-stand-alone ITI or who are no candidates for FVIII-stand-alone ITI and who are treated with ITI regimens including immunosuppressive agents can be included in this sub-study. Aim of this study is to document ITI regimens including immunosuppressive therapy (Rituximab, steroids, mycophenolate mofetil/MMF, sirolimus or other immunosuppressive agents) combined with regular FVIII administration, potential drug related side effects, outcome and duration of immune tolerance (relapse and recurrence of inhibitors). Optional sub-studies: In order to investigate the role of in vitro tests on individual ITI success rate in patients undergoing ITI, the inhibitor plasma samples can be assayed against different FVIII concentrates using the following in vitro tests: 1. Batch selection: The potential variation in inhibitor reactivity with different FVIII concentrates/batches of the same concentra trial.show_full_description

Inclusion Criteria: * Based on the decision of the treating physicians in the participating centres, male patients at any age suffering from severe (FVIII activity \< 1%), moderate (FVIII activity \>1% - 5%), or mild (FVIII activity \> 5%) haemophilia A will be included into this post marketing observation if relevant inhibitor levels (\> 0.6 BU) have been detected, or - in case of an inhibitor level \<0.6 BU - with reduced recovery or half-life of FVIII. * The observation is also open for patients who failed an earlier ITI attempt. Exclusion Criteria: * Female