Rituximab to Treat Severe Hemophilia A (RICH)

• 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 [ Time Frame: Measured within approximately 22 weeks ] [ Designated as safety issue: No ]
  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 [ Time Frame: Measured within approximately 22 weeks ] [ Designated as safety issue: No ]
  Presence or absence of at least a minor response in each participant
  
  
• Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge [ Time Frame: Measured within approximately 22 weeks ] [ Designated as safety issue: No ]
  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 Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event [ Time Frame: Measured through Week 100 ] [ Designated as safety issue: Yes ]
  Median number of bleeding events per subject meeting the criteria of a serious adverse event
  
  
• Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event [ Time Frame: Measured through Week 100 ] [ Designated as safety issue: Yes ]
  Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
  
  
• Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events [ Time Frame: Measured through Week 100 ] [ Designated as safety issue: Yes ]
  Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
  
  
• Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event [ Time Frame: Measured through Week 100 ] [ Designated as safety issue: Yes ]
  Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event
  
  
• Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported [ Time Frame: Measured at Week 1 through Week 4 ] [ Designated as safety issue: Yes ]
  Proportion of rituximab infusions in which a reaction to the infusion was reported
  
  

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.