Hemophilia A

Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (A TMH CTN Study)

NCT00331006

Transfusion Medicine/Hemostasis Clinical Trials Network

National Heart, Lung, and Blood Institute (NHLBI)

21 U.S. medical centers will enroll patients

50 patients

Intervention Model: Single Group Assignment. Masking: None (Open Label). Primary Purpose: Treatment.

One-third of individuals with severe hemophilia A (< 1% of normal factor VIII [FVIII] activity) develop neutralizing anti-FVIII allo-antibodies. Bleeding patients with high-titer FVIII inhibitors require alternative or bypassing factors, such as recombinant factor VIIa and prothrombin complex concentrates. Immune tolerance induction protocols can suppress allo-antibody titers, but durable responses require frequent, prolonged, and expensive FVIII infusion schedules. Recent anecdotal observations suggest that rituximab can reduce anti-FVIII titers. This phase II, non-randomized, multicenter trial is designed to assess the benefits and safety of rituximab in individuals ≥ 18 months old with severe congenital hemophilia A and a past history of anti-FVIII inhibitor ≥ 5 Bethesda units (BU)/mL. Study participants who mount an allo-antibody recall response ≥ 5 BU/mL after FVIII infusion will receive four weekly rituximab doses. If the inhibitor titer falls below 5 BU/mL, another FVIII infusion will be given, and the allo-antibody levels will be further assessed. The primary study outcome is the proportion of patients with inhibitor levels < 5 BU/mL at weeks six through 22 postrituximab and with < 5 BU/mL titer after FVIII rechallenge. Secondary outcomes include the proportions of patients with minor allo-antibody responses to rituximab and the frequency and severity of treatment-related adverse events.

While the scope is purposely limited by the phase II design, this pilot study should provide important preliminary data on the frequency and depth of anti- FVIII allo-antibody responses to rituximab along with an assessment of short-term safety. If the results are positive, a larger randomized clinical trial to compare this approach to immune tolerance induction will be justified. The ultimate goal is to identify the most beneficial, safe, and cost-effective strategy for those challenging patients with severe hemophilia A and high-titer inhibitors.