Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients (ITI)

Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients

IMMUNE TOLERANCE INDUCTION, BY FACTOR VIII CONCENTRATE CONTAINING VON WILLEBRAND FACTOR, IN SEVERE OR MODERATE HAEMOPHILIA A PATIENTS WITH INHIBITORS

The purpose of this study is to assess the role of a FVIII/VWF complex concentrate (Emoclot) in successfully inducing immune tolerance (I.T.I.) in patients with Haemophilia A with inhibitors, including patients at high risk of failure.

The development of factor VIII inhibitors occurs in approximately 30 to 40% of patients with severe Haemophilia A. The main negative clinical and cost consequence is the ineffectiveness of replacement therapy in patients with high-titer antibodies, who have a shorter life and greater morbidity than those who do not develop inhibitors. It is known from immunology that a regular and frequent exposure to the antigen of FVIII can induce tolerance of the immune system of the patient with inhibitors. This effect, called "immune tolerance induction" (ITI) is usually achieved after a prolonged exposure of the patient to FVIII, and is a common way of managing the condition of patients with inhibitors as well as the treatment of bleeding episodes with large amounts of hemostatic agents. In vitro and retrospective clinical studies suggest that FVIII/VWF complex concentrates may have less immunogenicity with respect to those plasma-derived concentrates purified with monoclonal antibodies (MABs), and recombinant DNA factor VIII concentrates (rFVIII), in both which the von Willebrand factor (VWF) is absent. Immune tolerance induction (ITI) showed to be effective in about 70% of Haemophiliacs with inhibitors. Poor prognosis factors have been identified by different registries: age ≥ 6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titer >10 BU at the start of ITI and previously failed ITI. The results of clinical studies suggest that complex concentrates of VWF/FVIII can be effective in ITI, even in patients at high risk of failure. To explain these findings, a role for VWF (i.e. prolonged antigen exposure) has been hypothesized.

The drug will be delivered through intravenous slow infusion/injection. The starting dosage can vary between the minimum dosage of 50 IU/Kg 3 times a week up to a maximum of 200 IU/kg per day. This starting dosage will be decided by the Principal Investigator according to patient's condition and other variables. The initial dosage can be then adjusted on the base of response.

The investigational treatment is with lyophilized plasma-derived Factor VIII. The product belongs to the factor VIII concentrates class, containing also VW Factor in an average ratio VW/VIII of > 1: 4.5. The product is as a powder and a solvent solution for continuous infusion of Factor VIII. The specific activity of Factor VIII is of approximately 80 IU/mg protein. The number of units of FVIII administered is expressed in International Units (IU), which are consistent with current WHO standards for products containing Factor VIII. The activity of Factor VIII in plasma is expressed either as a percentage (compared to normal human plasma) or in International Units (compared to the international standard for FVIII in plasma).

Success:Inhibitor disappearance/reduction to <0.6 BU/ml with FVIII activity recovery of at least ≥ 66% within 33 months of treatment ; Partial Success: inhibitor reduction to <5 BU/ml with clinical response to FVIII treatment, not followed by an inhibitor increase to values >5 BU/ml for a treatment period of 6 months on demand, or for 12 months of prophylactic treatment; No Response (Failure):Failure in relation to the above criteria defining complete response and partial response within 33 months, OR a reduction of the concentration of the inhibitor, less than 20%, compared to the peak of inhibitor in the IT, in every period of 6 months after the first 3 months of treatment. This implies that 9 months represents the minimum period of treatment and 33 months the maximum possible duration of ITI without success, OR patient withdrawal from the study for any reason.

Description and incidence of adverse events during the course of prophylactic treatment, with severity, correlation with the investigational product and final outcome.

Time elapsing between the onset of the inhibitor and the beginning of treatment and its importance for induction of IT in achieving primary endpoints.

Inclusion Criteria: Subjects (his/her parent/legal representative), must have given a written informed consent. Male children: age <12 years. Severe or moderate Haemophilia A (FVIII <2%). High responders (clinical history of inhibitor peak > 5BU) or low-responders (clinical history of inhibitor peak < 5 BU) with potential bleedings, assessed by responsible physicians as not to be treated with high FVIII doses. Any level of inhibitor at study enrollment. Willingness and ability to participate in the study. No other experimental treatments (involving or not FVIII concentrates). Exclusion Criteria: Any clinically relevant abnormality, in hematological, biochemical and urinary routine examinations, or any condition or treatment which in the investigator's opinion, makes the patient not eligible for the study. Intolerance to active substances or to any of the excipients of FVIII / VWF concentrates. Concomitant systemic treatment with immunosuppressive drugs.

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