A Study to Evaluate Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Participants With Inhibitors Undergoing the First ITI Treatment (verITI-8 Study)

Study Overview
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Brief Summary
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The primary purpose of this study was to describe the time to tolerization (i.e., ITI success) with rFVIIIFc in participants within a maximum of 48 weeks (12 months) of ITI treatment.

Official Title
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A Non-controlled, Open-Label, Multicenter, Study of Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Subjects With Inhibitors Undergoing the First ITI Treatment

Conditions
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Hemophilia A With Inhibitors

Intervention / Treatment
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* Biological: rFVIIIFc


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability of the participant or his legally authorized representative (e.g., parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local participant privacy regulations Male participants of any age diagnosed with severe hemophilia A (as confirmed from the medical record) Currently diagnosed with high titer inhibitors (historical peak greater than or equal to (>=) 5 Bethesda units per milliliter (BU/mL), according to medical records) Previously treated with any plasma-derived or recombinant conventional or Extended Half-Life FVIII Exclusion Criteria: Other coagulation disorder(s) in addition to hemophilia A Previous immune tolerance induction (ITI) History of hypersensitivity or anaphylaxis associated with any factor VIII (FVIII) administration Planned major surgery scheduled during the study unless deferred until after study completion (minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed) Abnormal renal function (serum creatinine >1.5 milligram per deciliter (mg/dL) or 2 × upper limit of normal (ULN) for participant age based on local laboratory range) as assessed by local laboratory Serum alanine aminotransferase or aspartate aminotransferase > 5 × upper limit of normal (ULN) as assessed by local laboratory
Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant coagulation factor VIII Fc (rFVIIIFc)<br>Participants were to receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the Investigator, starting at baseline visit up to maximum of 48 Weeks in ITI Period. Participants who met the criteria for immune tolerance induction (ITI) success entered the tapering period and received rFVIIIFc at a dose adjusted according to Investigator judgment based on the FVIII activity levels and with the aim of tapering the rFVIIIFc dose to reach a prophylactic dosing regimen within 16 weeks (4 months). Follow-Up was for 32 weeks under an adjusted prophylactic regimen according to Investigator judgment. | Biological: rFVIIIFc<br>* rFVIIIFc 200 IU/kg/day in ITI Period, 50 or 100 IU/kg (adjusted according to Investigator judgement) in tapering Period, and prophylactic regimen in Follow-Up period as powder for injection administered intravenously.<br>* Other names: Fc fusion protein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tolerization With rFVIIIFc | Time required for participants to achieve immune tolerance induction (ITI) success where ITI success is defined as achieving all 3 of the following criteria: confirmed negative titers consisting of 2 consecutive negative inhibitor assessments within 2 weeks (less than [<] 0.6 Bethesda units/milliliter [mL] by the Nijmegen-modified Bethesda assay); incremental recovery (IR) greater than or equal to (>=) 66 percent (%) of the expected IR in 2 consecutive assessments; half-life (t½) >= 7 hours. | Up to 48 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Immune Tolerance Induction (ITI) Success | Number of participants who achieve ITI success where ITI success is defined as achieving all 3 of the following criteria: confirmed negative titers consisting of 2 consecutive negative inhibitor assessments within 2 weeks (<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay); incremental recovery (IR) >= 66% of the expected IR at 2 consecutive assessments; half-life (t½) >=7 hours. | Up to 48 Weeks | 
| Number of Participants Who Experienced Relapse | Number of Participants with ITI success who reaches the criteria for relapse (defined as confirmed positive inhibitor titer >= 0.6 BU/mL or abnormal recovery after tolerance is achieved, and t½ less than [<] 7 hours) evaluated during the Tapering or Follow-Up Periods | Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period) | 
| Annualized Bleeding Rates During ITI Period | A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Annualized bleeding rate for a patient during the ITI period is defined as the number of bleeding episodes divided by the length of the ITI period in days* 365.25. | Up to 48 weeks | 
| Annualized Bleeding Rates After ITI Period | A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Annualized bleeding rate for a patient after the ITT period (for tapering and follow-up period) is defined as the number of bleeding episodes divided by the length of the period after the ITI period in days* 365.25. | Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs) as a Measure of Safety and Tolerability | An AE is any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition. | Up to 2 Years | 
| Average Number of Days Missed From Work or School Per Month During ITI Period | Average number of days missed from school or work per month for a period (counting in non-missing diary days) is defined as number of the missing school/work days in the period divided by number of days with data entry in the period. Number of days per month missed from school or work is reported for those who attend school or have a job. | Up to 48 weeks | 
| Average Number of Days Missed From Work or School Per Month After ITI Period | Average number of days missed from school or work per month for a period (counting in non-missing diary days) is defined as number of the missing school/work days in the period divided by number of days with data entry in the period. Number of days per month missed from school or work is reported for those who attend school or have a job. | Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period) | 
| Annualized Number of Hospitalization Days During ITI Period | Annualized number of hospitalization days during a period for a patient is defined as the number of hospitalization days divided by the length of the period in days * 365.25. | Up to 48 weeks | 
| Annualized Number of Hospitalization Days After ITI Period | Annualized number of hospitalization days during a period for a patient is defined as the number of hospitalization days divided by the length of the period in days * 365.25. | Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period) | 
| Adherence to Treatment Regimen Overall Study Period | Adherence to treatment is based on prescribed daily dose for the overall study period which is defined as the percentage of administered doses versus the prescribed doses to a patient for the entire study duration. | Up to 2 Years | 
| Annualized rFVIIIFc Consumption for Overall Study Period | Annualized rFVIIIFc consumption for a treatment period is the total nominal rFVIIIFc (IU/kg) / length of period in days * 365.25. | Up to 2 Years |