International Immune Tolerance Study

An International Randomised Controlled Trial Of Immune Tolerance Induction

The purpose of this study is to see if a low-dose arm or a high dose-arm of immune tolerance is more effective in eliminating inhibitors in patients with hemophilia A.

Subjects will be randomized into a low-dose or high-dose immune tolerance regimen and this study will compare the success rates, the time to achieve tolerance,the complications and the cost of both regimens.It will also aim to identify predictors of successful immune tolerance.

Inclusion Criteria:

• Severe hemophilia A (FVIII level <1%).
• A maximum historical inhibitor titer of between 5 BU and 200 BU that must be confirmed once prior to the beginning of ITI.
• The inhibitor titer should be <10 BU at the start of ITI, confirmed once.
• The inhibitor must be present for <24 months when ITI begins.
• Maximum age of 7 at the start of ITI.
• Willingness to comply with the protocol.

Exclusion Criteria:

• Moderate or mild hemophilia A (FVIII level >1%).
• Spontaneous disappearance of the inhibitor prior to ITI.
• Historical maximum inhibitor titer <5 BU or > 200 BU before starting ITI.
• Inhibitor titer > 10 BU at the start of ITI.
• Inhibitor present for more than 24 months before starting ITI.
• Systemic immunomodulatory drug therapy during immune tolerance e.g. corticosteroids (< 5 days every 2 months maximum dose 2 mg/kg or 60 mg/day), azathioprine, cyclophosphamide, high-dose immunoglobulin or the use of a protein A column or plasmapheresis.
• Age > 7 years at the start of ITI.
• Inability or unwillingness to comply with the protocol.
• Previous attempt at ITI.