Rescue Immunotolerance Study in Induction of Immune Tolerance (ITI)-Experienced Patients (RES.I.S.T. Experienced)

The presence of Factor VIII (FVIII) inhibitor prevents FVIII infusions from working properly
and makes treatment of bleeding episodes very difficult. Having an inhibitor is a serious and
life-threatening complication in patients with Hemophilia. The usual treatment of patients
with FVIII inhibitors involves what is called "immune tolerance induction" (ITI). Immune
Tolerance means that the body can accept infused FVIII and that FVIII is again effective in
controlling bleeds. ITI involves giving high doses of FVIII regularly until the inhibitor
disappears. This treatment is not always effective. The inhibitor persists in about 1 in 5
patients who undergo ITI.

There are 2 types of FVIII concentrates: FVIII concentrates derived from human plasma, which
contain VWF, and concentrates of FVIII without VWF. Both types of concentrates are commonly
used to induce immune tolerance in patients with Hemophilia A. Retrospective studies on
subjects who were treated with VWF containing Factor VIII concentrates after failing ITI with
pure factor VIII concentrates, have shown that tolerance can be achieved in a large
percentage of patients. This study will access prospectively whether treatment with a FVIII
concentrate containing VWF given at a high dose (200 units per kilogram) daily for up to 33
months is able to induce immune tolerance after previous attempts with concentrates
containing only FVIII have failed.

Inclusion Criteria:

1. severe hemophilia A (FVIII<1%) with high responding inhibitors (peak levels >5 BU)

2. male, any age;

3. any inhibitor level at study enrollment;

4. ability and willingness to participate to the study;

5. previous ITI course of at least 9 months with a VWF-free FVIII concentrate at any
dosage, such as recombinant FVIII and/or monoclonally purified FVIII.

Exclusion Criteria:

1. concomitant systemic treatment with immunosuppressive drugs;

2. concomitant experimental treatment;

3. previous history of myocardial infarction and/or cerebral stroke