Clinical trial NCT02479087: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hemophilia A
Keywords: von Willebrand Factor
Factor VIII
Hemorrhage
Immune Tolerance
Hemophilia A
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sponsor class: OTHER
Collaborators: name: Sintesi Research Srl
First posted: 2015-06-23
Enrollment: 20
Sex: MALE
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Efficacy: evaluation of the success of IT induction
timeFrame: Up to33 months
Secondary outcomes:
measure: Safety (adverse events)
timeFrame: Up to 33 months
measure: Analysis of treatment compliance
timeFrame: Up to 33 months
measure: Efficacy evaluation - Time to achieve ITI
timeFrame: Up to 33 months
measure: Evaluation of the cost of therapy
timeFrame: Up to 33 months
measure: Efficacy evaluation - IT persistence
timeFrame: Up to 33 months+ 12 months FU
measure: Efficacy evaluation - FVIII genetic defect role in IT achievement
timeFrame: Up to 33 months
measure: Efficacy evaluation - Role of an immediate IT to delayed IT in IT induction.
timeFrame: Up to 33 months
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Ain Shams Pediatric hospital, Ain Shams University
city: Cairo
country: Egypt
facility: Almoneera Pediatric Cairo University Hospital (Abu El- Reesh)
city: Bangalore
country: India
facility: St. John's Medical College Hospital
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
Study officials:
affiliation: IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico
name: Pier Mannuccio Mannucci, MD
role: STUDY_CHAIR
affiliation: Università di Milano, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico
name: Flora Peyvandi, MD
role: STUDY_DIRECTOR
affiliation: Centro Emofilia e Trombosi Angela Bianchi Bonomi, IRCCS Fondazione Ospedale Maggiore Policlinico
name: Elena Santagostino, MD
role: STUDY_DIRECTOR
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