Design of the INHIBIT trial: preventing inhibitors by avoiding 'danger', prolonging half-life and promoting tolerance.
Inhibitor formation is among the most serious complications of hemophilia treatment. With the US FDA licensure of the novel long-lasting recombinant factor VIII (FVIII) Fc fusion protein, Eloctate, which prolongs FVIII half-life, we propose an innovative approach to prevent inhibitor formation. In this paper, we describe a multicenter, Phase II, single-arm, 48-week trial, the INHIBIT trial, to determine if Eloctate, begun before a bleed and continued as once weekly prophylaxis, will reduce inhibitor formation in children with hemophilia A. We hypothesize that avoiding 'danger,' that is, immune activation by a bleed at first factor exposure and prolonging FVIII half-life will prevent inhibitors and promote FVIII-specific T-cell tolerance. If successful, this approach will suggest a new paradigm in clinical practice.
Department of Medicine, Division Hematology/Oncology, University of Pittsburgh, 3636 Boulevard of the Allies, Pittsburgh, 15213-4306, PA, USA.
Margaret V
MV
Ragni
Lynn M
LM
Malec
D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C587014:factor VIII-Fc fusion protein; D005169:Factor VIII
Tregs; coagulation factor VIII; hemophilia A; inhibitor formation; long-lasting factor VIII; tolerance