RANDOMISED STUDY OF FIRST CHOICE IMMUNOTOLERANCE INDUCTION IN PATIENTS WITH SEVERE TYPE A HAEMOPHILIA WITH INHIBITOR AT HIGH RISK OF FAILURE: COMPARISON OF INDUCTION OF IMMUNE TOLERANCE WITH FVIII CONCENTRATES WITH OR WITHOUT VON WILLEBRAND FACTOR

INTERVENTION: Product Name: Fanhdi Pharmaceutical Form: Powder and solvent for solution for infusion INN or Proposed INN: Coagulation factor VIII Concentration unit: IU international unit(s) Concentration type: equal Concentration number: 200‐ Product Name: Fanhdi Pharmaceutical Form: Powder and solvent for solution for infusion INN or Proposed INN: Coagulation factor VIII Concentration unit: IU international unit(s) Concentration type: equal Concentration number: 200‐ Product Name: Fanhdi Pharmaceutical Form: Powder and solvent for solution for infusion INN or Proposed INN: Coagulation factor VIII Concentration unit: IU international unit(s) Concentration type: equal Concentration number: 200‐ Product Name: alphanate Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Coagulation factor VIII Concentration unit: IU/kg international unit(s)/kilogram Concentration type: equal Concentration number: 200‐ Pharmaceutical Form: Powder and solvent for solution for infusion INN or Proposed INN: FATTORE VIII UMANO DI COAGULAZIONE/FATTORE DI VON WILLEBRAND Concentration unit: IU/kg international unit(s)/kilogram Concentration type: equal Concentration number: 200‐ Pharmaceutical Form: Powder and solvent for solution for injection INN or Proposed INN: Coagulation factor VIII Concentration unit: IU/kg international unit(s)/kilogram Concentration type: equal Concentration number: 200‐ Product Name: alphanate Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Coagulation factor VIII Concentration unit: IU/kg international unit(s)/kilogram Concentration type: equal Concentration number: 200‐ Product Name: alphanate Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Coagulation factor VIII Concentration unit: IU/kg international unit(s)/kilogram Concentration type: equal Concentration number: 200‐ Product Name: alphanate Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Coa CONDITION: SEVERE TYPE A HAEMOPHILIA ; MedDRA version: 9.1 Level: LLT Classification code 10010432 Term: Congenital deficiency of other clotting factors PRIMARY OUTCOME: Main Objective: The study is aimed at evaluating whether FVIII/VWF concentrates can induce more frequently or more rapidly immune tolerance to FVIII in haemophilia A patients with high‐responding inhibitors at high risk to fail in comparison with VWF‐free FVIII concentrates. Primary end point(s): The study is aimed to evaluate whether FVIII/VWF concentrates can induce more frequently or more rapidly immune tolerance to FVIII in haemophilia A patients with high‐responding inhibitors at high risk to fail in comparison with VWF‐free FVIII concentrates. Secondary Objective: I.Maintenance of immune tolerance II.Time to achieve success III.Safety ‐ compliance to treatment IV.Cost of care INCLUSION CRITERIA: a. severe hemophilia A (FVIII<1%) b. male patients, any age; c. high responders (peak inhibitor levels > 5 BU); d. any inhibitor level at study enrolment; e. ability and willingness to participate in to the study; f. no concomitant systemic treatment with drugs with immunosuppressive side effects (eg. Corticosteroids, if used more than 5 days every iii months and/or at a dose of > 2mg/kg or 60 mg/day), azathioprine, cyclophosphamide, high?dose immunoglobulin as well as the use of a protein A column or plasmapheresis, interferons); g. no concomitant experimental treatment; h. at least one of the following risk factors for ITI failure: i. peak inhibitor titer > 200 BU ii. titer at ITI start > 10 BU iii. age > 7 years iv. time between inhibitor occurrence and ITI > 2 years i. no previous ITI attempt. Are the trial subjects under 18? yes Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range