Study of First TIME Immunotolerance Induction in Severe Hemophilia A Patients With Inhibitor at High Risk of Failure: Comparison With FVIII Concentrates With or Without Von Willebrand Factor - RES.I.S.T. Naive (RESIST NAIVE)

• Absence of relapse, up to 12 months after achievement of Immune Tolerance [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Time to achieve partial or complete success as defined in the protocol. [ Time Frame: 33 months ] [ Designated as safety issue: Yes ]
• Safety Compliance to treatment [ Time Frame: 33 months ] [ Designated as safety issue: Yes ]
• Cost of Care [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

• Absence of relapse, up to 12 months after achievement of Immune Tolerance [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Time to achieve success Referring to either partial or complete success as defined in the protocol. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Safety Compliance to treatment [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Cost of Care [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

This is a prospective, controlled, randomized, open label study, aimed at comparing FVIII/VWF concentrates with FVIII concentrates at 200 IU/kg daily in their ability to induce immune tolerance in Haemophilia A patients with high responding inhibitors and poor prognosis for success.

The presence of Factor VIII (FVIII) inhibitor prevents FVIII infusions from working properly and makes treatment of bleeding episodes very difficult. Having an inhibitor is a serious and life-threatening complication in patients with Hemophilia. The usual treatment of patients with FVIII inhibitors involves "immune tolerance induction" (ITI). Immune Tolerance means that the body can accept infused FVIII and that FVIII is again effective in controlling bleeds. ITI involves giving high doses of FVIII regularly until the inhibitor disappears. This treatment is not always effective. The inhibitor persists in about 1 in 5 patients who undergo ITI.

There are 2 types of FVIII concentrates: FVIII concentrates derived from human plasma, which contain the von Willebrand factor, and concentrates of FVIII without VWF (recombinant or plasma derived). Both types of concentrates are commonly used to induce immune tolerance in patients with Hemophilia A. Retrospective studies in subjects with hemophilia and inhibitors at risk for failing ITI, have indicated a higher rate of success if patients were treated with von Willebrand containing factor VIII concentrates. It is not known whether the addition of Von Willebrand factor offers an advantage to achieving immune tolerance.

• Drug: FVIII Concentrates
  Patients will be centrally randomized to receive a von Willebrand factor-free FVIII concentrate (recombinant or plasma-derived, monoclonally-purified). The choice of product brand will be based on physician / patients preferences.
  Other Names:

  • Including but not limited to:
  • Advate
  • Beriate P
  • Hemofil M
  • Helixate
  • Kogenate
  • Kogenate SF
  • Monarch M
  • Monoclate
  • Recombinate
  • Refacto
  • Replenate
  • Xyntha
• Drug: FVIII/VWF concentrates
  Patients will be centrally randomized to receive a FVIII/VWF concentrate of 200 IU/Kg by one or two bolus injections daily.The choice of product brand will be based on physician / patients preferences.
  Other Names:

  • Including but not limited to:
  • Koate-DVI
  • 8Y
  • Optivate
  • Alphanate
  • Fahndi
  • Haemate P
  • Humate P
  • Haemoctine SDH
  • Octanate
  • Wilate
  • Emoclot DI
  • Factane

• Active Comparator: von Willebrand factor-free FVIII concentrates
  Patients treated with FVIII concentrates
  Intervention: Drug: FVIII Concentrates
• Active Comparator: FVIII/VWF concentrates
  Patients treated with FVIII/VWF concentrates
  Intervention: Drug: FVIII/VWF concentrates

• Bentorp E, Ekman M, Gunnarson M. Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations Haemophilia 1996; 2: 95-99.
• Kreutz W: Immune tolerance induction (ITI) in Haemophilia A-patients with inhibitors - the choice of concentrate affecting success. Haematologica2001; 86 (S4):16-20
• Gringeri A, Musso R, Mazzucconi MG, Piseddu G, Schiavoni M, Pignoloni P, Mannucci PM; RITS-FITNHES Study Group. Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response. Haemophilia. 2007 Jul;13(4):373-9.

Inclusion Criteria:

1. severe hemophilia A (FVIII<1%);
2. male, any age;
3. high responders (peak inhibitor levels > 5 BU);
4. any inhibitor level at study enrolment;
5. ability and willingness to participate in the study;

6. at least one of the following risk factors for ITI failure:

   • peak inhibitor titer > 200 BU
   • titer at ITI start > 10 BU
   • age > 7 years
   • time between inhibitor occurrence and ITI > 2 years
7. absence of high risk of cardiovascular, cerebrovascular or other thromboembolic events as deemed by the treating clinician.

Exclusion Criteria:

1. concomitant systemic treatment with immunosuppressive drugs;
2. concomitant experimental treatment;
3. previous ITI attempt;
4. previous history of myocardial infarction and/or cerebral stroke.

• Charta Fondazione Grant Provided by
• Grifols Biologicals Inc.
• CSL Behring
• Biotest Pharmaceuticals Corporation
• City of Hope Grant Provided by
• Grifols Therapeutics Inc. (Talecris Biotherapeutics)