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

Brief Title

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

Official Title

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

Brief Summary

      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.

Detailed 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.

Study Phase

Phase 4

Study Type

Interventional

Primary Outcome

Efficacy: evaluation of the success of IT induction

Secondary Outcome

 Safety (adverse events)

Condition

Hemophilia A

Intervention

Plasma-derived FVIII/VWF concentrate

Study Arms / Comparison Groups

 Plasma-derived FVIII/VWF concentrate

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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Drug

Estimated Enrollment

Start Date

January 2015

Completion Date

January 2020

Primary Completion Date

January 2019

Eligibility Criteria

        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.

Gender

Male

Ages

N/A - 12 Years

Accepts Healthy Volunteers

No

Contacts

Pier Mannuccio Mannucci, MD, +39 0255038377, [email protected]

Location Countries

Egypt

Location Countries

Egypt

Administrative Informations

NCT ID

NCT02479087

Organization ID

FCG-CNS-001

Responsible Party

Sponsor

Study Sponsor

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Collaborators

 Sintesi Research Srl

Study Sponsor

Pier Mannuccio Mannucci, MD, Study Chair, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico

Verification Date

June 2015