A Phase 3, Open-label Interventional Study of an Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein, Efanesoctocog Alfa (BIVV001), in Patients With Severe Hemophilia A

Overview

Primary Objective: – To evaluate the efficacy of BIVV001 as a prophylaxis treatment in prophylaxis treatment arm. 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 the 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 efficacy of BIVV001 for perioperative management – To evaluate the safety and tolerability of BIVV001 treatment – To assess the pharmacokinetics (PK) of BIVV001 based on the 1-stage activated partial thromboplastin time (aPTT) and 2-stage chromogenic FVIII activity assays

Full Title of Study: “A Phase 3 Open-Label, Multicenter Study of the Safety, Efficacy, and Pharmacokinetics of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Patients ≥12 Years of Age With Severe Hemophilia A”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: February 3, 2022

Detailed Description

Participants in prophylaxis arm will receive a weekly prophylactic dose of BIVV001 for 52 weeks. Participants in on-demand arm will receive BIVV001 on demand for 26 weeks followed by a switch to weekly prophylaxis for another 26 weeks. The Sponsor plans to perform a long-term safety trial. Enrollment in this open-label extension study will be offered to patients completing the treatment period based on eligibility criteria.

Interventions

  • Drug: efanesoctocog alfa (BIVV001)
    • Pharmaceutical form:solution for injection Route of administration: intravenous injection

Arms, Groups and Cohorts

  • Experimental: Prophylaxis
    • Participants will receive BIVV001 once-weekly (QW) during a prophylaxis treatment regimen for 52 weeks
  • Experimental: On Demand
    • Participants will receive BIVV001 on demand for 26 weeks, followed by a switch to a prophylaxis treatment regimen with BIVV001 for 26 weeks.

Clinical Trial Outcome Measures

Primary Measures

  • Annualized bleeding rate (ABR) in prophylaxis treatment arm
    • Time Frame: baseline to 52 weeks
    • Annualized bleeding rate (ABR) will be estimated for the weekly (QW) prophylaxis treatment arm.

Secondary Measures

  • Intra-patient comparison of ABR of participants of this study to the ABR of same participants previously participated in an observational study
    • Time Frame: baseline to week 52
    • Intra patient comparison of ABR during the BIVV001 weekly prophylaxis treatment period versus the historical prophylaxis ABR for participants in prophylaxis treatment who participated in Study 242HA201/OBS16221, an observational study
  • Annualized bleeding rate (ABR) by type of bleed
    • Time Frame: baseline to week 52
    • ABR by type of bleed such as spontaneous or traumatic per study arm
  • Annualized bleeding rate (ABR) by location of bleed
    • Time Frame: baseline to week 52
    • ABR by location of bleed such as joint, muscle, internal, or skin/mucosa per study arm
  • Annualized bleeding rate (ABR) for all bleeding episodes including untreated bleeding episodes
    • Time Frame: baseline to week 52
    • ABR for all bleeding episodes (including untreated bleeding episodes) for prophylaxis treatment per study arm
  • Intra-patient comparison of ABR during the weekly once (QW) prophylaxis treatment period versus ABR during the on-demand treatment period
    • Time Frame: baseline to week 52
    • Intra-patient comparison of ABR during the QW prophylaxis treatment period versus the ABR during the on-demand treatment period in the on-demand Arm
  • Percentage of participants who maintain FVIII activity levels
    • Time Frame: 52 weeks
    • Percentage of participants who maintain FVIII activity levels in prophylaxis treatment arm
  • Number of injection and dose of BIVV001 to treat a bleeding episode
    • Time Frame: 52 weeks
    • Number of injections and dose of BIVV001 to treat a bleeding episode per study arm and treatment regimen
  • Percentage of bleeding episodes treated with a single injection of BIVV001
    • Time Frame: 52 weeks
    • Percentage of bleeding episodes treated with a single injection of BIVV001 per study arm and treatment regimen
  • Assessment of response to BIVV001 treatment of individual bleeding episodes
    • Time Frame: baseline to week 52
    • Assessment of response to BIVV001 treatment of individual bleeding episodes based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point response scale per study arm and treatment regimen
  • Physician’s global assessment of the participant’s response based on BIVV001 treatment
    • Time Frame: baseline to week 52
    • Physician’s global assessment (PGA) of participant’s response to BIVV001 treatment based on a 4-point response scale per study arm and treatment regimen
  • Total annualized BIVV001 consumption
    • Time Frame: baseline to week 52
    • Total annualized BIVV001 consumption per participant per study arm and treatment regimen
  • Change in Hemophilia Joint Health Score (HJHS) total score and domain scores
    • Time Frame: baseline to week 52
    • Change from baseline to week 52 in total score and domain scores (eg, swelling and strength) assessed by the HJHS in prophylaxis treatment arm.
  • Annualized Joint Bleeding Rate (AJBR)
    • Time Frame: baseline to week 52
    • Annualized Joint Bleeding Rate (AJBR) per study arm and treatment regimen
  • Target joint resolution
    • Time Frame: baseline to week 52
    • Target joint resolution at week 52, based on ISTH criteria, for the prophylaxis treatment arm
  • Changes in Haem-A-QoL total score and physical health score
    • Time Frame: baseline to week 52
    • Changes in Haem-A-QoL (≥ 17 years old) total score and physical health score measures from baseline to Week 52 in prophylaxis treatment arm
  • Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Pain intensity
    • Time Frame: baseline to week 52
    • Changes in PROMIS Pain Intensity from Baseline to Week 52 in prophylaxis treatment arm
  • Change in Patient-Reported Outcomes Measurement Information System-Short Form (PROMIS-SF) Physical Function
    • Time Frame: baseline to week 52
    • Changes in PROMIS-SF Physical Function (>=18 years old) measures from baseline to week 52 in prophylaxis treatment arm
  • Investigators’ or Surgeons’ assessment of participant’s hemostatic response to BIVV001 treatment
    • Time Frame: baseline to week 52
    • Investigators’ or Surgeons’ assessment of participant’s hemostatic response to BIVV001 treatment on the ISTH 4 point response for surgical procedures scale
  • Number of injections and dose to maintain hemostasis during perioperative period for major surgery
    • Time Frame: baseline to week 52
  • Total BIVV001 consumption during perioperative period for major surgery
    • Time Frame: baseline to week 52
  • Number of blood component transfusions used during perioperative period for major surgery
    • Time Frame: baseline to week 52
  • Type of blood component transfusions used during perioperative period for major surgery
    • Time Frame: baseline to week 52
  • Estimated blood loss during perioperative period for major surgery
    • Time Frame: baseline to week 52
  • Number of participants with occurrences of adverse events (AEs) and serious adverse events (SAEs)
    • Time Frame: baseline to week 52
    • Participants with occurrences of adverse events (AEs) and serious adverse events (SAEs)
  • Number of participants with inhibitor development
    • Time Frame: baseline to week 52
    • Development of inhibitors (neutralizing antibodies directed against VIII [FVIII] as determined via the Nijmegen modified Bethesda assay
  • Number of participants with occurrence of embolic and thrombotic events
    • Time Frame: baseline to week 52
    • Participants with occurrences of embolic and thrombotic events
  • PK parameter: Maximum activity (Cmax)
    • Time Frame: baseline to week 52
  • PK parameter: Elimination half-life (t1/2)
    • Time Frame: baseline to week 26
  • PK parameter: Total clearance (CL)
    • Time Frame: baseline to week 26
  • PK parameter: Total clearance at steady state (CLss)
    • Time Frame: baseline to week 26
  • PK parameter: Accumulation index (AI)
    • Time Frame: baseline to week 26
  • PK parameter: Area under the activity time curve (AUC)
    • Time Frame: baseline to week 26
  • PK parameter: Volume of distribution at steady state (Vss)
    • Time Frame: baseline to week 26
  • PK parameter: Mean residence time (MRT)
    • Time Frame: baseline to week 26
  • PK parameter: Incremental recovery (IR)
    • Time Frame: baseline to week 26
  • PK parameter: Trough activity (Ctrough)
    • Time Frame: baseline to week 52
  • PK parameter: Time above FVIII activity levels
    • Time Frame: baseline to week 52

Participating in This Clinical Trial

Inclusion criteria :

  • Participant, male or female, must be equal to or greater than 12 years of age inclusive, at the time of signing the informed consent. – 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. – Current regimen includes one of the following: – Prophylactic treatment regimen with a FVIII product or prophylactic emicizumab therapy for at least 6 months during the previous 12 months. Appropriate washout time needs to be taken into account. – On-demand regimen with a FVIII product with a history of at least 12 bleeding episodes in the previous 12 months or at least 6 bleeding episodes in the previous 6 months prior to study enrollment. – On-demand participant is accepting to move to a prophylaxis treatment regimen after 26-week on-demand period. – Willingness and ability of the participant or surrogate (a caregiver or a family member ≥18 years of age) to complete training in the use of the study electronic Patient Diary (ePD) and to use the ePD throughout the study. – Ability of the participant or his or her legally authorized representative (eg., parent or legal guardian) to understand the purpose and risks of the study, willing and able to comply with study requirements and provide signed and dated informed consent or assent (as applicable) and authorization to use protected health information in accordance with national and local participant privacy regulations. Exclusion criteria:

  • Clinically significant liver disease. – Serious active bacterial 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 – Positive inhibitor results, defined as ≥0.6 BU/mL at Screening. History of a positive inhibitor test defined as ≥0.6 BU/mL. Family history of inhibitors will not exclude the participant. – Use of Emicizumab 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.

Gender Eligibility: All

Minimum Age: 12 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Bioverativ, a Sanofi company
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Clinical Sciences & Operations, Study Director, Sanofi

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