Hemophilia A is an X-linked bleeding disorder resulting from deficiency of factor VIII, and characterized by bleeding into joints, muscles, and body cavities. Among the most serious complications of hemophilia treatment is inhibitor formation, that is, the development of antibodies directed against infused factor VIII Inhibitor antibodies occur in 25-35% of patients and result in uncontrolled bleeding and significant morbidity. Inhibitor risk is associated with intensive treatment, such as given for major bleeds or surgeries, in which tissue damage and inflammation activate the immune system. Increasing evidence suggests if so-called "danger" signals could be avoided, inhibitor formation could be prevented. The purpose of this U34 Exploratory Clinical Research Grant is to establish the feasibility of conducting a Phase III trial of recombinant factor VIII (rF.VIII) begun preemptively weekly before the first bleed versus standard three-times weekly rF.VIII begun after the first bleed in children with severe hemophilia A. The original concept for this study was developed as one of four clinical trial concepts by six hemophilia treatment center (HTC) physicians, members of the NHBLI State of the Science (SoS) Hemophilia Subcommittee, who are members of the Steering Committee for this study. We hypothesize that recombinant F.VIII (rF.VIII) prophylaxis given preemptively before the first bleed, in the absence of "danger", will prevent inhibitor formation, as compared with standard three times weekly prophylaxis begun after the first bleed. This is an innovative concept as it challenges current treatment, and, if successful, will be practice-changing. It is also innovative in evaluating F.VIII-specific T cell responses by ELISPOT assay to determine the mechanism of inhibitor formation and tolerance. The ultimate goal of this project is to identify and resolve barriers to the conduct of a future phase III randomized, controlled clinical trial, the specific aims of which are:
Aim 1. To establish an HTC infrastructur of 60+ HTC physicians to jointly build consensus on trial design, subject recruitment and participation to assure a sufficient number of eligible subjects to conduct a future R01 48-week randomized trial to compare preemptive weekly vs. standard three times weekly rF.VIII prophylaxis in the prevention of inhibitor formation in children with severe hemophilia A. The HTC network will be operationalized by 1) conducting facilitated structured interviews with HTC physicians and with parents to determine acceptability of trial design and participation potential; 2) collaborating with a Steering Committee and the U24 Clinical Resource to optimize trial design, recruitment strategy, and to prepare case report forms and a manual of operations;3) developing and pilot-testing a web-based data entry system;4) conducting exploratory meetings with foreign HTC physicians to determine potential for trial participation and subject recruitment;and 5) hiring two dedicated nurse coordinators to prepare IRB submissions and contracts for HTCs.
Aim 2. To determine the feasibility of a phase III 48-week, open-label, randomized clinical trial comparing preemptive weekly rF.VIII prophylaxis begun before the first bleed versus standard three times weekly rF.VIII prophylaxis begun after the first bleed in children with severe hemophilia A, F.VIII<0.01 U/ml, enrolled at local HTCs. This will be accomplished by 1) validating and optimizing the anti-F.VIII inhibitor antibody, the primary endpoint, for pediatric volumes, low- and high-titer antibodies, and shipping;2) validating the F.VIII-specific T cell ELISPOT assay, a secondary endpoint to assess inhibitor mechanism, in adult inhibitor samples and optimizing it for pediatric volumes and shipping;3) establishing safety stopping guidelines to assure safety of the intervention, to minimize bleeding events and central line infections;4) setting up a repository of blood samples linked to study subject data via web-based data entry;and 5) seeking advice of a community advisory board to provide feedback and promote communication regarding the future phase III trial.
The purpose of this U34 proposal is to determine the feasibility of a randomized trial to compare prophylaxis (factor VIII to prevent bleeds) given preemptively, once weekly, before the first bleed vs. standard three times weekly prophylaxis beginning after the first bleed to prevent inhibitor formation in children with severe hemophilia A If successful, our approach could reduce morbidity and cost, and change clinical practice. We will recruit hemophilia center investigators, conduct structured interviews with HTC physicians and parents, groups, and finalize protocol design, set up an infrastructure to accomplish IRB and contract approval for 60+ HTCs, and explore foreign HTC participation, to assure the feasibility of a future Phase III randomized trial.