Long-term Safety and Efficacy of Efanesoctocog Alfa (BIVV001) in Previously Treated Patients With Hemophilia A

Study Overview
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Brief Summary
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Primary Objective: - To evaluate the long-term safety of BIVV001 in previously treated subjects with hemophilia A Secondary Objectives: To evaluate the efficacy of BIVV001 as a prophylaxis treatment. To evaluate the efficacy of BIVV001 in the treatment of bleeding episodes. To evaluate BIVV001 consumption for prevention and treatment of bleeding episodes. To evaluate the effect of BIVV001 prophylaxis on joint health outcomes. To evaluate the effect of BIVV001 prophylaxis on Quality of Life (QoL) outcomes. To evaluate the safety and tolerability of BIVV001 treatment. To assess the PK of BIVV001 based on the one stage activated partial thromboplastin time (aPTT) and two-stage chromogenic FVIII activity assays (only applicable to Arm B). To evaluate the efficacy of BIVV001 for perioperative management

Detailed Description
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Participants will receive BIVV001 once weekly for a total of at least 100 exposure days to BIVV001 (including exposure during a BIVV001 parent study, if applicable). Participants will have the opportunity to continue in this study for up to 4 years, unless BIVV001 is commercially available in their applicable participating country.

Official Title
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A Phase 3 Open-label, Multicenter Study of the Long-term Safety and Efficacy of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Patients With Severe Hemophilia A

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: efanesoctocog alfa (BIVV001)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : For participants rolling over into Arm A Participants who have completed the studies EFC16923, EFC16925, Arm B or Arm C of the current study, or any other potential BIVV001 study. Male or Female For participants new to BIVV001 (Arm B and C) Participants who have severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII activity as documented either by central laboratory testing at screening or in historical medical records from a clinical laboratory demonstrating <1% FVIII coagulant activity (FVIII:C) or a documented genotype known to produce severe hemophilia A. Previous treatment for hemophilia A (prophylaxis or on-demand) with any recombinant and/or plasma-derived FVIII, or cryoprecipitate for at least 150 EDs or 50 EDs for participants aged <6 years. Platelet count ≥100 000 cells/μL at screening. A participant known to be human immunodeficiency virus (HIV) antibody positive, either previously documented or identified from screening assessments, must have the following results prior to enrollment: CD4 lymphocyte count >200 cells/mm³ and viral load of <400 000 copies/mL Male Only for Arm B: Chinese participants Only for Arm C: planned major surgery within 6 months after Day 1. Exclusion criteria: For participants rolling over into Arm A Positive inhibitor result, defined as ≥0.6 Bethesda units (BU)/mL. Participation in another study. For participants new to BIVV001 (Arm B and Arm C) Any concurrent clinically significant liver disease that, in the opinion of the Investigator, would make the participant unsuitable for enrollment. This may include, but is not limited to cirrhosis, portal hypertension, and acute hepatitis. Serious active bacterial, fungal, or viral infection (other than chronic hepatitis or HIV) present within 30 days of screening. Other known coagulation disorder(s) in addition to hemophilia A. History of hypersensitivity or anaphylaxis associated with any FVIII product. History of a positive inhibitor (to FVIII) test defined as ≥0.6 BU/mL, or any value greater than or equal to the lower sensitivity cut-off for laboratories with cut-offs for inhibitor detection between 0.7 and 1.0 BU/mL, or clinical signs or symptoms of decreased response to FVIII administrations. Family history of inhibitors will not exclude the participant. Positive inhibitor test (FVIII) result, defined as ≥0.6 BU/mL at screening. Treatment with acetylsalicylic acid (ASA) or antiplatelet agents that are not nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to screening. Treatment with NSAIDs greater than the maximum dose specified in the regional prescribing information within 2 weeks prior to screening. Systemic treatment within 12 weeks prior to Screening with chemotherapy and/or other immunosuppressive drugs (except for the treatment of hepatitis C virus [HCV] or HIV). Emicizumab use within the 20 weeks prior to screening. Major surgery within 8 weeks prior to screening. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: It is a 3-arm study with single intervention
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Previously treated in BIVV001 study<br>This arm includes all participants who have completed the previous phase 3 studies on BIVV001, as well as participants who have completed Arm B or Arm C of this study rolling over in Arm A, and participants who will have completed any future BIVV001 study who will be proposed to continue BIVV001 treatment. Participants in this arm will continue receiving BIVV001 prophylaxis treatment once-weekly (QW) for a total of 100 exposure days (EDs) cumulative from the parent study and this study. Participants will have the opportunity to continue in this study for up to 4 years, unless BIVV001 is commercially available in their applicable participating country. | Drug: efanesoctocog alfa (BIVV001)<br>* Pharmaceutical form:Solution for Injection Route of administration: Intravenous<br>|
| Experimental: Arm B: Newly initiated (China Only) in BIVV001<br>This arm includes Chinese participants of any age who will be newly initiated on BIVV001 prophylaxis treatment once-weekly (QW) for 52 weeks. After 52 weeks of treatment in this arm B, participants will be able to roll into arm A. | Drug: efanesoctocog alfa (BIVV001)<br>* Pharmaceutical form:Solution for Injection Route of administration: Intravenous<br>|
| Experimental: Arm C: Newly initiated in BIVV001 with planned major surgery<br>This arm includes participants of any age who will be newly initiated on BIVV001 prophylaxis treatment once-weekly (QW) and will undergo planned major surgery after at least 6 initial EDs with BIVV001, and within 26 weeks from Day 1. After 52 weeks of treatment in arm C, participants will be able to roll into arm A. | Drug: efanesoctocog alfa (BIVV001)<br>* Pharmaceutical form:Solution for Injection Route of administration: Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with the occurrence of inhibitor development (neutralizing antibodies detected against factor VIII [FVIII]) | The number of participants with the occurrence of inhibitor development (neuatralizing antibodies detected against factor VIII [FVIII]) as determined via the Nijmegen modified Bethesda assay. | Baseline to month 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual bleeding rate (ABR) | Annualized bleeding rate (ABR) for treated bleeding episodes and all bleeding episodes (including untreated bleeds). | Baseline to month 48 | 
| Annualized bleeding rate (ABR) by type of bleed | Annualized bleeding rate (ABR) by type during prophylaxis treatment per study arm and parent study. | Baseline to month 48 | 
| Annualized bleeding rate (ABR) by location | Annualized bleeding rate (ABR) by location during prophylaxis treatment per study arm and parent study. | Baseline to month 48 | 
| Percentage of patients who maintain factor VIII (FVIII) above prespecified activity levels | Percentage of participants who maintain factor VIII (FVIII) activity levels over 7 days post dose during prophylaxis treatment per study arm and per parent study or arm. | Baseline to month 48 | 
| Number of injections and dose of BIVV0001 to treat a bleeding episode |  | Month 48 | 
| Percentage of bleeding episode treated with a single injection of BIVV001 |  | Month 48 | 
| Assessment of response to BIVV001 treatment of individual bleeding episodes | Assessment of response to BIVV001 treatment of individual bleeding episodes based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point response scale | Baseline to month 48 | 
| Physician's global assessment (PGA) of participants response to BIVV001 | Physician's global assessment (PGA) of participant's response to BIVV001 treatment based on a 4-point response scale . | Baseline to month 48 | 
| Total annualized BIVV001 consumption | Total annualized BIVV001 consumption per participant during prophylaxis treatment | Baseline to month 48 | 
| Annualized joint bleeding rate (AJBR) |  | Baseline to month 48 | 
| Target joint resolution | Target joint development, resolution and maintenance of target joint resolution based on ISTH criteria. | Month 48 | 
| Change from baseline in Hemophilia Joint Health Score (HJHS) | Change from Baseline to the end of study visit in total score and domain scores (eg, swelling and strength) assessed by the Hemophilia Joint Health Score (HJHS) | Baseline to month 48 | 
| Change from baseline in PROMIS-SF Physical Function | Change in Quality of Life (QoL) measures from baseline to end of study visit per study arm and per parent study arm: PROMIS-SF Physical Function (participants aged ≥18 years old).) | Baseline to month 48 | 
| Change from baseline in Haem-A-QoL total score and physical health score | Change from baseline in Haemophilia QoL Questionnaire for Adults (Haem-A-QoL) total and physical health domain score on participants aged ≥17 years old. | Baseline to month 48 | 
| Change from baselin in Haemo-QoL total score and physical health score | Change from baseline in Haemophilia QoL Questionnaire for Children (Haemo-QoL) total and physical health domain score on participants aged ≥4 to 16 years old and parent proxy for participants aged ≥4 to to <12 years old. | Baseline to month 48 | 
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) | Participants with occurrences of treatment emergent adverse events (AEs) and serious adverse events (SAEs). | Baseline to month 48 | 
| Number of participants with the occurrence of embolic and thrombotic events | Participants with the occurrence of embolic and thrombotic events. | Baseline to month 48 | 
| PK parameter: Maximum activity (Cmax) |  | Baseline to week 52 | 
| PK parameter: Elimination half-life (t1/2) |  | Baseline to week 26 | 
| PK parameter: Total clearance (CL) |  | Baseline to week 26 | 
| PK parameter: Total clearance at steady state (CLss) |  | Baseline to week 26 | 
| PK parameter: Accumulation index (AI) |  | Baseline to week 26 | 
| PK parameter: Area under the activity time curve (AUC) |  | Baseline to week 26 | 
| PK parameter: Volume of distribution at steady state (Vss) |  | Baseline to week 26 | 
| PK parameter: Mean residence time (MRT) |  | Baseline to week 26 | 
| PK parameter: Incremental recovery (IR) |  | Baseline to week 52 | 
| PK parameter: Trough activity (Ctrough) |  | Baseline to week 52 | 
| PK parameter: Time above FVIII activity levels |  | Baseline to week 26 | 
| Investigators' or Surgeons' assessment of participant's hemostatic response to BIVV001 treatment | Investigators' or Surgeons' assessment of participant's hemostatic response to BIVV001 treatment on the ISTH 4 point response for surgical procedures scale. | Baseline to month 48 | 
| Number of injections and dose to maintain hemostasis during perioperative period for major surgery |  | Baseline to month 48 | 
| Total BIVV001 consumption during perioperative period for major surgery |  | Baseline to month 48 | 
| Number and type of blood component transfusions used during perioperative period for major surgery |  | Baseline to month 48 | 
| Estimated blood loss during perioperative period for major surgery |  | Baseline to month 48 |