Design of the INHIBIT trial: preventing inhibitors by avoiding 'danger', prolonging half-life and promoting tolerance

Expert Rev Hematol. 2014 Dec;7(6):747-55. doi: 10.1586/17474086.2014.963550. Epub 2014 Nov 5.

Abstract

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.

Keywords: Tregs; coagulation factor VIII; hemophilia A; inhibitor formation; long-lasting factor VIII; tolerance.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Child, Preschool
  • Factor VIII / administration & dosage
  • Factor VIII / immunology
  • Factor VIII / therapeutic use*
  • Half-Life
  • Hemophilia A / drug therapy*
  • Humans
  • Immune Tolerance / drug effects
  • Immunity, Cellular / drug effects
  • Immunoglobulin Fc Fragments / administration & dosage
  • Immunoglobulin Fc Fragments / immunology
  • Immunoglobulin Fc Fragments / therapeutic use*
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / therapeutic use*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology

Substances

  • Immunoglobulin Fc Fragments
  • Recombinant Fusion Proteins
  • factor VIII-Fc fusion protein
  • Factor VIII