HIPS-Hemophilia Inhibitor PUP Study

Confidential Human Clinical Trial Title: Hemophilia Inhibitor PUP Study (HIPS) Rationale: Hemophilia A is a congenital bleeding disorder caused by deficiency of factor VIII (FVlll} and is treated by replacement therapy with FVlll concentrate. The prevention and treatment of bleeding symptoms is confounded by the development of FVlll neutralizing antibodies, or inhibitors, in approximately 30% of patients with severe hemophilia after exposure to FVlll concentrate (Wight 2003). Patients with inhibitors have substantially increased morbidity (Morfini 2007) and increased cost of care (Nerich 2008). Individual and environmental risk factors for inhibitor formation have been identified,· but more information is required before prediction models and prevention strategies can be developed. Furthermore, mechanisms of inhibitor formation and conversely, tolerance to FVlll among patients with hemophilia who do not develop inhibitors, are poorly understood, limiting the ability to develop rational therapies to overcome inhibitors. The purpose of the HIPS study is to prospectively evaluate changes in immunity upon exposure to FVlll in patients with severe hemophilia A, and identify immunologic predictors of FVlll inhibitor development or tolerance. The underlying premise of this study is that the type of FVI 11- specific T-cell that is activated during the first days of exposure to FVlll determines whether the immune system will develop tolerance to FVlll or develop FVlll inhibitors. Study Design: This is a multinational, multicenter, observational study to evaluate the changes in immunity upon exposure to FVlll in patients with severe hemophilia A previously untreated with factor concentrates. A single source of recombinant FVlll will be used (Advate) and treatment is at the discretion of the investigator. Subjects will be evaluated for 50 days of exposure to FVlll treatment, or three years, whichever comes first. An exposure day is defined as a calendar day during which one or more infusions of FVlll are given. Study Objectives: Primary Objectives: • Evaluate changes in the immune system upon exposure to FVlll in patients with severe hemophilia A • Identify immunologic predictors of FVlll inhibitor development or tolerance Primary Endpoints: An inhibitor is defined by a Nijmegen test_::: 0.6 Bethesda units (BU) on two consecutive tests conducted in the central laboratory. During the first 50 days of exposure to a single FVll I product: • Analyze and quantify subclasses of anti-FVlll antibodies • Characterize FVlll-specific T-cells and changes which occur • Quantify total FOXP3-positive regulatory T-cells (Treg) • Assess RNA expression, transcript profile, and exon usage in relevant pathways • Identify FB gene mutation and other known genomic predictors of inhibitor development • Record in