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

Institute of Hospitalization and Scientific Care (IRCCS)

Status and phase: Unknown; Phase 4

Conditions: Hemophilia A

Treatments: Drug: Plasma-derived FVIII/VWF concentrate

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02479087

FCG-CNS-001

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 20 estimated patients

Sex: Male

Ages: Under 12 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Subjects (his/her parent/legal representative), must have given a written informed consent.
2. Male children: age <12 years.
3. Severe or moderate Haemophilia A (FVIII <2%).
4. 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.
5. Any level of inhibitor at study enrollment.
6. Willingness and ability to participate in the study.
7. No other experimental treatments (involving or not FVIII concentrates).

Exclusion criteria

1. 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.
2. Intolerance to active substances or to any of the excipients of FVIII / VWF concentrates.
3. Concomitant systemic treatment with immunosuppressive drugs.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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20 participants in 1 patient group

Plasma-derived FVIII/VWF concentrate

Experimental group

Description:

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.

Treatment:

Drug: Plasma-derived FVIII/VWF concentrate