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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
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).
Ain Shams Pediatric hospital, Ain Shams University
Cairo, Egypt
NOT_YET_RECRUITINGAlmoneera Pediatric Cairo University Hospital (Abu El- Reesh)
Cairo, Egypt
NOT_YET_RECRUITINGSt. John's Medical College Hospital
Bangalore, India
RECRUITINGEfficacy: evaluation of the success of IT induction
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.
Time frame: Up to33 months
Safety (adverse events)
Description and incidence of adverse events during the course of prophylactic treatment, with severity, correlation with the investigational product and final outcome.
Time frame: Up to 33 months
Analysis of treatment compliance
Description of the patient's adherence to the optimal prolonged treatment.
Time frame: Up to 33 months
Efficacy evaluation - Time to achieve ITI
Time to achieve the complete or partial response (as defined in the primary outcome measure).
Time frame: Up to 33 months
Evaluation of the cost of therapy
Recording of overall amount of direct costs of therapy.
Time frame: Up to 33 months
Efficacy evaluation - IT persistence
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All India Institute of Medical Sciences
New Delhi, India
RECRUITINGAbsence of relapse, assessed at 12 months from IT achievement
Time frame: Up to 33 months+ 12 months FU
Efficacy evaluation - FVIII genetic defect role in IT achievement
Role of FVIII mutations in influencing IT achievement
Time frame: Up to 33 months
Efficacy evaluation - Role of an immediate IT to delayed IT in IT induction.
Time elapsing between the onset of the inhibitor and the beginning of treatment and its importance for induction of IT in achieving primary endpoints.
Time frame: Up to 33 months