Clinical trial NCT04161495: A Phase 3 Open-label Interventional Study of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein, Efanesoctocog Alfa (BIVV001), in Patients With Severe Hemophilia A
Official title: 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: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Factor VIII Deficiency
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2019-11-13
Enrollment: 159
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 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 coagulation factor VIII (FVIII) activity assays.

Detailed description: Participants in prophylaxis arm received a weekly prophylactic dose of BIVV001 for 52 weeks. Participants in on-demand arm received BIVV001 on demand for 26 weeks followed by a switch to weekly prophylaxis for another 26 weeks.

The Sponsor planned to perform a long-term safety trial. Enrollment in this open-label extension study would be offered to participants completing the treatment period based on eligibility criteria.

Eligibility criteria: 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 less than (\<) 1 international units per deciliter (IU/dL) (\<1 percent \[%\]) 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 exposure days.
* Current regimen included 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 was accepted 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 greater than or equal to \[\>=\] 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 Bethesda unit per milliliter (BU/mL) at screening. History of a positive inhibitor test defined as \>=0.6 BU/mL. Family history of inhibitors would 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 was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Estimated Annualized Bleeding Rate (ABR) in Arm A: Prophylaxis
timeFrame: Baseline to Week 52
measure: Observed Annualized Bleeding Rate in Arm A: Prophylaxis
timeFrame: Baseline to Week 52
Secondary outcomes:
measure: Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Non-inferiority Analysis
timeFrame: Historical prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 prophylaxis: Baseline up to Week 52 of current study EFC16293
measure: Observed Annualized Bleeding Rate During the Efficacy Period in Prophylaxis - Non-inferiority Analysis
timeFrame: Historical prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293
measure: Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis
timeFrame: Historical Prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293
measure: Observed Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis
timeFrame: Historical Prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293
measure: Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Week 52 in Arm A: Prophylaxis
timeFrame: Baseline, Week 52
measure: Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pain Intensity 3a Score at Week 52 in Arm A: Prophylaxis
timeFrame: Baseline, Week 52
measure: Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52 in Arm A: Prophylaxis
timeFrame: Baseline, Week 52
measure: Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Annualized Bleeding Rate for All Bleeding Episodes
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Annualized Bleeding Rate: Intra-participant Comparison of Arm B Participants
timeFrame: Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis
timeFrame: Baseline to Week 52
measure: Number of Injections of BIVV001 Required to Treat a Bleeding Episode
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Total Dose of BIVV001 Required to Treat Bleeding Episode
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Physicians' Global Assessment of Participant's Response to BIVV001 Treatment
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Total Annualized BIVV001 Consumption Per Participant
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis
timeFrame: Baseline, Week 52
measure: Estimated Annualized Joint Bleeding Rate (AJBR)
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Observed Annualized Joint Bleeding Rate (AJBR)
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Total Number of Target Joint Resolved in Participants at Week 52 in Arm A: Prophylaxis
timeFrame: Week 52
measure: Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults Total Score at Week 52 in Arm A: Prophylaxis
timeFrame: Baseline, Week 52
measure: Change From Baseline in Patient Reported Outcomes Measurements Information Systems Short Form (PROMIS-SF) Physical Function (PF) 6b at Week 52 in Arm A: Prophylaxis
timeFrame: Baseline, Week 52
measure: Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment
timeFrame: Baseline to Week 52
measure: Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery
timeFrame: During the perioperative period (any time during Baseline up to Week 52)
measure: Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery
timeFrame: Day -1 to Day 0 (day of surgery)
measure: Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery
timeFrame: Day -1 to Day 14
measure: Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery
timeFrame: During the perioperative period (any time during Baseline up to Week 52)
measure: Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery
timeFrame: During the perioperative period (any time during Baseline up to Week 52)
measure: Estimated Blood Loss During Major Surgery
timeFrame: Day 0 (i.e., day of surgery)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)
timeFrame: Arm A: From Baseline (Day 1) up to 3 weeks post last dose of BIVV001 (i.e., up to Week 55); Arm B: On-demand: Baseline to Week 26 and Arm B: Prophylaxis: From Week 26 up to 3 weeks post last dose of BIVV001 in Week 52 (i.e., up to Week 55)
measure: Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Number of Participants With Occurrence of Embolic and Thrombotic Events
timeFrame: Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52
measure: Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)
timeFrame: Baseline (15 minutes post-dose on Day 1) and 15 minutes post-dose on Week 52
measure: Pharmacokinetics: Elimination Half-life (t1/2z)
timeFrame: pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26
measure: Pharmacokinetics: Clearance (CL)
timeFrame: Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline)
measure: Pharmacokinetics: Total Clearance at Steady State (CLss)
timeFrame: Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26
measure: Pharmacokinetics: Accumulation Index (AI)
timeFrame: Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26
measure: Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)
timeFrame: Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183)
measure: Pharmacokinetics: Volume of Distribution at Steady State (Vss)
timeFrame: Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183)
measure: Pharmacokinetics: Mean Residence Time (MRT)
timeFrame: Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183)
measure: Pharmacokinetics: Incremental Recovery (IR)
timeFrame: Pre-dose, 0.25 hours post-dose on Day 1 (Baseline); pre-dose, 0.25 hours post-dose on Week 26 (Day 183)
measure: Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)
timeFrame: Pre-dose at Baseline (Day 1) and Week 52
measure: Pharmacokinetics: Time Above Predefined (10 and 40%) FVIII Activity Levels
timeFrame: Pre-dose and 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Investigational Site Number 920
state: California
city: Los Angeles
country: United States
facility: Investigational Site Number 921
state: California
city: San Diego
country: United States
facility: Investigational Site Number 911
state: California
city: Gainesville
country: United States
facility: Investigational Site Number 917
state: Florida
city: Ann Arbor
country: United States
facility: Investigational Site Number 919
state: Michigan
city: Lansing
country: United States
facility: Investigational Site Number 908
state: Michigan
city: Las Vegas
country: United States
facility: Investigational Site Number 906
state: Nevada
city: Seattle
country: United States
facility: Investigational Site Number 902
state: Washington
city: Buenos Aires
country: Argentina
facility: Investigational Site Number 136
city: Buenos Aires
country: Argentina
facility: Investigational Site Number 137
city: Mendoza
country: Argentina
facility: Investigational Site Number 139
city: Perth
country: Australia
facility: Investigational Site Number 121
city: Sydney
country: Australia
facility: Investigational Site Number 122
city: Brussels
country: Belgium
facility: Investigational Site Number 161
city: Campinas
country: Brazil
facility: Investigational Site Number 181
city: Plovdiv
country: Bulgaria
facility: Investigational Site Number 171
city: Sofia
country: Bulgaria
facility: Investigational Site Number 172
city: Hamilton
country: Canada
facility: Investigational Site Number 202
city: Hamilton
country: Canada
facility: Investigational Site Number 205
city: Brest
country: France
facility: Investigational Site Number 281
city: Lille
country: France
facility: Investigational Site Number 283
city: Lyon
country: France
facility: Investigational Site Number 282
city: Marseille
country: France
facility: Investigational Site Number 284
city: Berlin
country: Germany
facility: Investigational Site Number 304
city: Bonn
country: Germany
facility: Investigational Site Number 302
city: Frankfurt
country: Germany
facility: Investigational Site Number 303
city: Athens
country: Greece
facility: Investigational Site Number 321
city: Budapest
country: Hungary
facility: Investigational Site Number 312
city: Debrecen
country: Hungary
facility: Investigational Site Number 314
city: Milan
country: Italy
facility: Investigational Site Number 402
city: Vicenza
country: Italy
facility: Investigational Site Number 401
city: Kawasaki
country: Japan
facility: Investigational Site Number 426
city: Kitakyushu
country: Japan
facility: Investigational Site Number 423
city: Nagoya
country: Japan
facility: Investigational Site Number 425
city: Nara
country: Japan
facility: Investigational Site Number 422
city: Tokyo
country: Japan
facility: Investigational Site Number 421
city: Tokyo
country: Japan
facility: Investigational Site Number 424
city: Daegu
country: Korea, Republic of
facility: Investigational Site Number 603
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 600
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 601
city: Durango
country: Mexico
facility: Investigational Site Number 435
city: Utrecht
country: Netherlands
facility: Investigational Site Number 641
city: Madrid
country: Spain
facility: Investigational Site Number 521
city: Chang Hua
country: Taiwan
facility: Investigational Site Number 531
city: Taipei
country: Taiwan
facility: Investigational Site Number 532
city: Basingstoke
country: United Kingdom
facility: Investigational Site Number 581
city: London
country: United Kingdom
facility: Investigational Site Number 581
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: