Dynamics of the Anti-factor VIII Antibody Signature During Treatment With Emicizumab

Study Overview
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Brief Summary
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The goal of this observational study is to learn about the changes of antibodies and inhibitors against the coagulation factor VIII in patients with severe hemophilia A receiving emicizumab therapy. No additional visits or procedures are planned. Patients in this study will continue to receive their routine care and analysis will be done from left over samples from routine visits.

Official Title
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Dynamics of the Anti-factor VIII Antibody Signature During Treatment With Emicizumab

Conditions
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Severe Hemophilia A, Severe Hemophilia A With Inhibitor, Severe Hemophilia A Without Inhibitor

Intervention / Treatment
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* Other: no interventions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe congenital hemophilia A (CHA) Treatment with emicizumab irrespective of any other treatment Informed consent Exclusion Criteria: No therapy with emicizumab Immunosuppressive therapy HIV-infection with CD4 (cluster of differentiation 4) cells <200/µl
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Inhibitor negative, FVIII on demand or regularly<br>Patients with severe hemophilia A receiving emicizumab therapy which are negative for factor VIII Inhibitor (including patients post ITI) and are receiving factor VIII therapy either on demand or regularly, | Other: no interventions<br>* no intervention, only 3 different patients groups<br>|
| Inhibitor positive, FVIII therapy regularly (ITI)<br>Patients with severe hemophilia A receiving emicizumab therapy which are positive for factor VIII Inhibitor and are receiving regularly factor VIII therapy (ITI) | Other: no interventions<br>* no intervention, only 3 different patients groups<br>|
| Inhibitor positive, no FVIII therapy<br>Patients with severe hemophilia A receiving emicizumab therapy which are positive for factor VIII Inhibitor and are receiving no factor VIII therapy | Other: no interventions<br>* no intervention, only 3 different patients groups<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FVIII inhibitor development in inhibitor negative subjects | Rate of FVIII inhibitor development during three years of emicizumab prophylaxis in inhibitor negative subjects. Assessed with Bethesda Assay (BU/ml). Number of patients who develop an FVIII inhibitor within the study period, but were FVIII inhibitor negative at start of the study. | 3 years | 
| FVIII antibody development in inhibitor negative subjects | Rate of FVIII antibody development during three years of emicizumab prophylaxis in inhibitor negative subjects. FVIII anti drug antibody (ADA) is assessed by FVIII specific ELISA (OD=Optical Density). Number of patients who develop an FVIII antibody (ADA) within the study period, but were FVIII inhibitor negative at start of the study. | 3 years | 
| FVIII inhibitor disappearance in inhibitor positive subjects | Rate of FVIII inhibitor disappearance during three years of emicizumab prophylaxis in inhibitor positive subjects. Assessed with Bethesda Assay (BU/ml). Number of patients who loose an FVIII inhibitor within the study period, but were FVIII inhibitor positive at start of the study. | 3 years | 
| FVIII antibody disappearance in inhibitor positive subjects | Rate of FVIII antibody disappearance during three years of emicizumab prophylaxis in inhibitor positive subjects. FVIII anti drug antibody (ADA) is assessed by FVIII specific ELISA (OD=Optical Density). Number of patients who develop an FVIII antibody within the study period, but were FVIII inhibitor positive at start of the study. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-FVIII inhibitor development | Anti-FVIII inhibitor development (median BU/ml) over time. Assessed with Bethesda Assay (BU/ml). Description of inhibitor development in the different patient groups within the study period. Cut off is 0,6 BU/ml. | 3 years | 
| Anti-FVIII antibody development | Anti-FVIII antibody development (median arbitrary units, OD) over time. Description of antibody development in the different patient groups within the study period. | 3 years | 
| Time to negative inhibitor titers | Time to negative inhibitor titers. Assessed with Bethesda Assay (BU/ml). Description of the Time (days) observed for FVIII inhibitor disappearance within the study period in the patient groups. Cut off for inhibitor titer is 0,6 BU/ml. | 3 years | 
| Treatment of bleeds | Description of the use of FVIII and/or Bypassing agents treatment in addition to Emicizumab treatment in case of bleeds. | 3 years | 
| Response to treatment | Classification of bleeds as Effective, Partially Effective, Ineffective. Defined as: Effective: Bleeding episode responded to the usual number of injections or dose of FVIII as expected by the treating physician; Partially Effective: The bleeding episode responded with a higher number of injections and/or dose as expected by the treating physician; Ineffective: Routine failure to control hemostasis or hemostatic control required additional agents | 3 years | 
| Quality of the antibody response (FVIII epitopes) | Description of the location of FVIII epitopes over time, assessed by epitope mapping technique (ELISA) | 3 years | 
| Quality of the antibody response (IgG subclasses) | Description of a potential immune response over time, assessed by IgG subclass determination (ELISA). | 3 years |