ATHN 2: Factor Switching Study

Study Overview
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Brief Summary
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This is a longitudinal, observational study of patients with Hemophilia A or B who are planning to switch to a newly approved coagulation factor replacement product, or who have recently switched factor products. The study will follow each patient for up to 1 year. Patients will be recruited at Hemophilia Treatment Centers (HTC) which are ATHN-affiliates. The primary outcome being studied is the development of inhibitor (i.e., antibodies to factor) at 1 year or 50 exposure days, whichever comes first. The study will be conducted at approximately 30 HTCs, with a planned enrollment of 600 patients.The entire study duration is projected to be approximately 6 years. In addition, optional substudies will be included for some products, as Product-Specific Modules. These will be questionnaires to collect data for subjects receiving selected Factor products. For example, subjects receiving Kovaltry will be approached to participate in the 'Kovaltry Product-Specific Module'; subjects receiving Adynovate will be approached to participate in the 'Adynovate Product-Specific Module'. Questions will be related to product use, perceptions of product use, and other post-marketing consumer data.

Detailed Description
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This non-interventional, minimal risk cohort study will enroll patients with Hemophilia A or B who are planning or have recently switched to a new Factor product. The study will have 2 Arms, prospective and retrospective. The Prospective Arm will enroll patients who plan to switch to a new factor. The Retrospective Arm will enroll patients who have recently switched to a new factor (within the previous 50 weeks). Patient will be seen at baseline and for up to 4 additional visits, and quarterly follow-up by phone. Required study visits will be planned to coincide with routine follow-up visits whenever possible. Please note that Factor Replacement Products are not being provided by the study. The primary objective is to assess and characterize the rate of inhibitor development within one (1) year or fifty (50) exposure days, whichever is first, after switching clotting factor replacement products in previously treated patients (PTPs) with hemophilia A or B. Data collected will include eligibility, demographics, medical history, hemophilia history (clotting history, product history, genotype and family history), inhibitor history, co-morbidities at baseline (i.e., HIV, Hepatitis C.), detailed clotting factor replacement product(s) usage and switching plan, and reasons for switching factor products. Also targeted physical exams will be performed at baseline and during follow-up, and targeted concomitant medication data will be collected. Data collection will also include patient-reported outcome(s) after 1 year, bleeding events, surgeries, laboratory Inhibitor testing and details regarding testing methodology, pharmacokinetic (PK) data (if known), new diagnoses, and co-morbidities (targeted), Safety/Adverse Events using European Union Hemophilia Safety Surveillance (EUHASS) definitions. This study will evolve to include any newly approved (since January 2013) factors as they come to market. Cohorts will be defined by the brand/type of new clotting factor replacement product approved after January 1, 2013. The current list of specific new Factor VIII replacement products include Eloctate® (Bioverativ) and NovoEight® (NovoNordisk); Factor IX replacement products include Alprolix® (Bioverativ), Rixubis® (Baxalta), and IXinity® (Emergent Biosolutions). Others are both now available and imminent and include: Adynovate®, Idelvion®, Afstyla®, Kovaltry® and Jivi®. The over-arching rationale for this protocol is that a pragmatic study which is consistent with real world practices across a wide range of patients that is not principally tied to a particular manufacturer or product may be of great advantage to the entire hemophilia community. Study Duration Subjects on prophylaxis will be followed on study for up to 1 year. Each subject will be seen during a study visit or contacted by telephone at least once every 3 months (i.e., quarterly). Patients may participate for multiple 'cycles', if they switch factor products more than once while the study is actively recruiting. Treatment regimen will be at the discretion of the subject's hemophilia caregivers. No treatment is being provided by the study. Substudies A number of substudies are planned with pharmaceutical sponsors to collect information from patients about their products' use. Participation in these optional substudies (product-specific modules) will be planned to coincide with study visits. These modules will collect information from subjects about their perception and use of factor use/treatment, physical activity levels and other general health questions. These data will be collected via questionnaire, primarily via phone. Concomitant and Excluded Therapies Immune tolerance therapy is excluded on study. This includes immunosuppressive treatments used to eradicate inhibitors. Steroid treatments for allergic disorders and asthma, are allowed. Data Collection System All data collected will be entered into electronic case report forms (eCRFs) within the secure ATHN Study Manager system. Subject Identifiers (IDs) will be generated in Clinical Manager. Reimbursement will be managed by each participating HTC. Most study centers will reimburse study subjects for travel and parking, but this varies by center.

Official Title
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A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Factor Replacement Products

Conditions
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Hemophilia

Intervention / Treatment
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* Biological: Factor VIII Replacement Products for Hemophilia which were FDA approved after January 1, 2013
* Biological: Factor IX Replacement Products for Hemophilia which were FDA approved after January 1, 2013


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Moderate or Severe Congenital Hemophilia A or B (FVIII or FIX clotting activity less than or equal to 5% of normal). Able to give informed consent (by patient or parent/authorized guardian). Previously treated with plasma-derived or recombinant clotting factor replacement products with at least 50 exposure days (as assessed either from direct clinical records in children under age 5, or by clinical history of dosing in older patients). For Arm B being enrolled retrospectively, this previous treatment must be prior to product switch under study. Planning to switch, or recently switched within the previous 50 weeks, to a new brand or type of replacement factor VIII or IX, FDA approved after January 1, 2013. Arm B only: Negative inhibitor screen within the last 6 months prior to switching. Note: History of prior transient inhibitor or inhibitor eradicated by immune tolerance induction (ITI) are eligible. Exclusion Criteria Presence of any known bleeding disorder other than hemophilia A or B (i.e., patients with concurrent hemophilia and a second hemostatic defect are NOT eligible). Low Von Willebrand Factor (VWF) without VWF diagnosis are not excluded. Presence of an active inhibitor >0.6 BU for factor VIII, > 0.4 BU for factor IX at the time of eligibility assessment. Detection of such an inhibitor at the baseline visit prior to dosing with the new product (Arm A), or after dosing with new factor dosing (Arm B), would result in early termination without other study assessments. Currently undergoing ITI. Immunosuppressive therapy (cyclophosphamide, mycophenolate, IVIG) within 90 days and Rituximab within 6 months; topical steroid treatments and short course steroids for asthma or allergy allowed. Previous participation in Phase I, II or III interventional trials of the factor product being switched to.
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 |
| --- | --- |
| Arm A Prospective<br>Patients who are switching to a new Factor VIII and Factor IX Replacement Product for Hemophilia A and B which was FDA approved after January 1, 2013. These patients will be followed prospectively for up to 1 year. | Biological: Factor VIII Replacement Products for Hemophilia which were FDA approved after January 1, 2013<br>* Prophylaxis for prevention of bleeding, various regimens.<br>* Other names: Kovaltry®;Biological: Factor IX Replacement Products for Hemophilia which were FDA approved after January 1, 2013<br>* Prophylaxis for prevention of bleeding, various regimens.<br>* Other names: Rebinyn®;|
| Arm B Retrospective<br>Patients who have recently switched to a new Factor VIII and Factor IX Replacement Product for Hemophilia A and B which was FDA approved after January 1, 2013. Patients must have switched products within the past 50 weeks at the time of enrollment. These patients will be assessed retrospectively and/or followed prospectively for up to 1 year. | Biological: Factor VIII Replacement Products for Hemophilia which were FDA approved after January 1, 2013<br>* Prophylaxis for prevention of bleeding, various regimens.<br>* Other names: Kovaltry®;Biological: Factor IX Replacement Products for Hemophilia which were FDA approved after January 1, 2013<br>* Prophylaxis for prevention of bleeding, various regimens.<br>* Other names: Rebinyn®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibitor Development | Inhibitor development is the primary outcome. Subjects will be followed closely and tested at baseline, after 10 Exposure Days and 50 Exposure Days, and/or at 1 year. Specimens will be submitted to local laboratories and evaluated for inhibitor titers, and inhibitors will be confirmed by local laboratories and CDC. | After 50 Exposure Days or 1 Year, whichever comes first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibitor Development | To determine the prospective incidence of inhibitor development after 10 exposure days to a new, novel recombinant factor following a switch from another clotting factor replacement product. | 10 days | 
| Prevalence of risk factors for inhibitor development | To compare the prevalence of selected risk factors in patients with hemophilia who develop inhibitors following switching to a new product, to those found in subjects who do not develop inhibitors. | 1 year | 
| Targeted post-marketing approval safety and efficacy data | To collect and summarize targeted post-marketing approval safety and efficacy data for events related to clotting factor replacement products, specifically To collect data on bleeding events following switching factor. To summarize replacement factor product dosing regimens prescribed to the study population. | 1 year | 
| Platform for additional substudies | To serve as a platform for product-specific questionnaires in cohorts of patients who switch to a particular product. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Factor, Coagulation, Inhibitor, HTC, Bleeding