Rituximab to Treat Severe Hemophilia A (RICH)

Hemophilia A is a serious blood clotting disorder caused by a lack of factor VIII, a specialized protein needed for normal blood clotting to occur. Individuals with this disease may experience spontaneous bleeding, pain and swelling in their joints due to excess bleeding, and bruising. A common treatment for severe hemophilia A is to intravenously replace the deficient blood clotting factor; however, some individuals may develop antibodies to this replacement factor. This study will evaluate the effectiveness of rituximab at reducing the antibodies that develop in response to the replacement factor in individuals with severe hemophilia A.

Hemophilia A is a hereditary blood clotting disorder. It is caused by a deficiency or abnormality of the blood clotting protein factor VIII. Individuals with hemophilia A are unable to form blood clots to stop bleeding and are at risk for experiencing serious and life-threatening bleeding episodes. The most common treatment for this disease is intravenous replacement of factor VIII. However, between 30 to 40% of individuals eventually develop inhibitors, or antibodies, to the replacement factor. In these individuals, the immune system recognizes the replacement factor as foreign and attacks it, thereby countering any potential benefits of the treatment. Some individuals with severe hemophilia A may undergo immune tolerance therapy (ITT), in which they receive replacement factor on a regular basis as a way for the body to adjust to the factor and stop inhibitor production. This treatment, however, is not always effective for everyone. Preliminary research has shown that rituximab, a medication used to treat non-Hodgkin's lymphoma, may be successful in suppressing or eliminating the inhibitors that develop. The purpose of this study is to evaluate the effectiveness of rituximab at lowering the levels of factor VIII inhibitors in individuals with severe hemophilia A. This study will enroll individuals with severe hemophilia A. At study entry, participants will receive one intravenous dose of factor VIII. Inhibitor levels will be measured with a blood test 5 to 7 days following this procedure. If peak inhibitor level is above 5 Bethesda units (BU)/mL, 5 to 9 days later participants will begin receiving rituximab intravenously once a week for 4 weeks. Blood will be collected at each visit for laboratory testing. Two weeks following the last rituximab treatment, participants will have blood drawn for inhibitor testing; this testing will occur every 4 weeks through Week 22. If the participant's inhibitor level falls below 5 BU/mL, participants will receive a repeat dose of factor VIII, and blood will be drawn 5 to 7 days later for inhibitor testing. Follow-up visits will occur at Weeks 36, 52, and 100, and will include a physical examination, blood collection, and monitoring of bleeding events and infections. Telephone interviews will be conduced at Weeks 64, 76, and 88 to monitor bleeding events and infections.

Rituximab by slow intravenous infusion; for participants greater than or equal to 10 kg, 375 mg per m^2 BSA weekly for 4 weeks; for participants less than 10 kg, 12.5 mg/kg weekly for 4 weeks

Proportion of Subjects With Major Response, i.e. Inhibitor Level Falls to Less Than 5 BU/mL Between Weeks 6 to 22 and Remains Below 5 BU/mL at 5-7 Days Following Re-challenge With FVIII

Presence or absence of a major response in each participant. Major response is defined as occurring when inhibitor level falls to less than 5 BU/mL between Weeks 6 to 22 and remains below 5 BU/mL at 5-7 days following re-challenge with FVIII

Proportion of Subjects With at Least Minor Response, i.e. Inhibitor Level Falls to <5 BU/mL Between Weeks 6-22 and Either Remains <5 BU/mL 5-7 Days Following FVIII Rechallenge or Titer Following FVIII Rechallenge is 5-10 BU/mL & <50% of Original Peak

Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge

percent change=100%*(A-B)/B where A=inhibitor titer measured within 5-7 days following FVIII rechallenge and B=inhibitor titer measured within 5-14 days following baseline FVIII challenge. A FVIII rechallenge was performed within 10-18 days of the first monthly study visit in which an inhibitor titer result <5 BU/mL was obtained beginning 2 weeks and continuing through 18 weeks following the last rituximab infusion.

Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event

Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event

Inclusion Criteria: Severe congenital hemophilia A Documented historical inhibitor titer to factor VIII of at least 5 BU/mL Inhibitor level greater than or equal to 5 BU/mL 5 to 14 days after initial factor VIII exposure during screening Exclusion Criteria: Known hypersensitivities or allergies to murine and/or humanized antibodies Currently participating in investigational hemophilia studies HIV infected Any immunodeficiency disorder Liver disease and serum ALT or AST is greater than three times the upper limit of normal, albumin is less than 2.5g/dl, and/or INR is greater than 1.7 Received interferon or other immunomodulatory drugs, such as steroids or cytotoxic therapy in the 30 days prior to study entry History of cardiac arrhythmias, any active febrile illness, kidney insufficiency, or pulmonary infiltrates Has previously received rituximab treatment Currently undergoing immune tolerance therapy Evidence of Hepatitis B (HBV) infection, defined as one of the following: HBsAg positive HBsAg negative, HBsAb negative, HBcAb positive, and HBV DNA positive Participants with a high responding inhibitor (at least 5 BU/mL) first detected fewer than 12 months prior to study entry, unless the participant has failed immune tolerance therapy, defined as one of the following: Failure to fulfill the criteria for full or partial success within 33 months, as defined by a factor VIII recovery greater than or equal to 66% of expected and half-life greater than or equal to 6 hours measured after a 72-hour treatment-free washout period Failure to achieve greater than 20% reduction in inhibitor titer during each interim non-overlapping 6-month period of ITT in the absence of documented infection, with 9 months as the minimum treatment period and 33 months as the maximum possible duration of unsuccessful ITT Withdrawal from ITT for any other reason Routinely receive factor VIII concentrate for the treatment of both major and minor bleeding events Has received factor VIII concentrate in the 7 days prior to study entry