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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Hemophilia A
• Intervention / Treatment: Drug: efanesoctocog alfa (BIVV001)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 261
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1015ABO
    • Investigational Site Number : 0320003
  • Ciudad De Buenos Aires
    • Caba, Ciudad De Buenos Aires, Argentina, C1425BWE
      • Investigational Site Number : 0320001
  • Mendoza
    • Godoy Cruz, Mendoza, Argentina, M5504FKD
      • Investigational Site Number : 0320002
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Investigational Site Number : 0360004
    • Westmead, New South Wales, Australia, 2145
      • Investigational Site Number : 0360001
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Investigational Site Number : 0360002
  • Western Australia
    • Murdoch, Western Australia, Australia, 6961
      • Investigational Site Number : 0360003
• Belgium
  • Sint-Lambrechts-Woluwe, Belgium, 1200
    • Investigational Site Number : 0560003
• Brazil
  • São Paulo
    • Campinas, São Paulo, Brazil, 13083-970
      • Hemocentro Campinas - UNICAMP Site Number : 0760001
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Investigational Site Number : 1000171
  • Sofia, Bulgaria, 1756
    • Investigational Site Number : 1000172
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 8E7
      • Investigational Site Number : 1240005
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Investigational Site Number : 1240004
    • Ottawa, Ontario, Canada, K1H 8L1
      • Investigational Site Number : 1240002
    • Toronto, Ontario, Canada, M5G 1X8
      • Investigational Site Number : 1240001
• China
  • Beijing, China, 100045
    • Investigational Site Number : 1560002
  • Beijing, China, 100730
    • Investigational Site Number : 1560006
  • Guangzhou, China, 510515
    • Investigational Site Number : 1560001
  • Hangzhou, China, 310003
    • Investigational Site Number : 1560003
  • Hangzhou, China, 310003
    • Investigational Site Number : 1560004
  • Jinan, China, 250013
    • Investigational Site Number : 1560005
  • Kunming, China, 650032
    • Investigational Site Number : 1560009
  • Kunming, China, 650101
    • Investigational Site Number : 1560010
  • Lanzhou, China, 730000
    • Investigational Site Number : 1560013
  • Suzhou, China, 215006
    • Investigational Site Number : 1560007
• France
  • Brest, France, 29200
    • Investigational Site Number : 2500005
  • Bron, France, 69500
    • Investigational Site Number : 2500004
  • Kremlin Bicetre, France, 94275
    • Investigational Site Number : 2500001
  • Lille, France, 59037
    • Investigational Site Number : 2500003
  • Marseille, France, 13385
    • Investigational Site Number : 2500006
• Germany
  • Berlin, Germany, 10249
    • Investigational Site Number : 2760304
  • Bonn, Germany, 53127
    • Investigational Site Number : 2760302
  • Frankfurt am Main, Germany, 60590
    • Investigational Site Number : 2760001
  • München, Germany, 80337
    • Investigational Site Number : 2760002
• Greece
  • Athens, Greece, 11527
    • Investigational Site Number : 3000001
• Hungary
  • Budapest, Hungary, 1134
    • Investigational Site Number : 3480002
  • Debrecen, Hungary, 4093
    • Investigational Site Number : 3480004
  • Pécs, Hungary, 7623
    • Investigational Site Number : 3480005
• Ireland
  • Dublin, Ireland, D12 N512
    • Investigational Site Number : 3720001
• Italy
  • Milano, Italy, 20121
    • Investigational Site Number : 3800001
  • Vicenza, Italy, 36100
    • Investigational Site Number : 3800003
  • Campania
    • Napoli, Campania, Italy, 80123
      • Investigational Site Number : 3800002
• Japan
  • Aichi
    • Nagoya-shi, Aichi, Japan, 466-0065
      • Investigational Site Number : 3920425
  • Fukuoka
    • Kitakyushu-shi, Fukuoka, Japan, 807-8556
      • Investigational Site Number : 3920423
  • Kanagawa
    • Kawasaki-shi, Kanagawa, Japan, 216-8511
      • Investigational Site Number : 3920426
  • Niigata
    • Kashihara-Shi, Niigata, Japan, 634-8521
      • Investigational Site Number : 3920422
  • Tokyo
    • Shinjuku-ku, Tokyo, Japan, 160-0023
      • Investigational Site Number : 3920421
    • Suginami-ku, Tokyo, Japan, 167-0035
      • Investigational Site Number : 3920424
• Korea, Republic of
  • Daegu-gwangyeoksi
    • Daegu, Daegu-gwangyeoksi, Korea, Republic of, 41404
      • Investigational Site Number : 4100603
  • Seoul-teukbyeolsi
    • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03722
      • Investigational Site Number : 4100601
    • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 05278
      • Investigational Site Number : 4100600
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Investigational Site Number : 5280002
  • Utrecht, Netherlands, 3584 CX
    • Investigational Site Number : 5280001
• Spain
  • Catalunya [Cataluña]
    • Esplugues de Llobregat, Catalunya [Cataluña], Spain, 08950
      • Investigational Site Number : 7240002
  • Madrid, Comunidad De
    • Madrid, Madrid, Comunidad De, Spain, 28046
      • Investigational Site Number : 7240001
• Sweden
  • Malmo, Sweden, 20502
    • Investigational Site Number : 7520001
• Switzerland
  • Zürich, Switzerland, 8032
    • Investigational Site Number : 7560001
• Taiwan
  • Changhua County, Taiwan, 500
    • Investigational Site Number : 1580005
  • Taichung, Taiwan, 40201
    • Investigational Site Number : 1580001
  • Taichung, Taiwan, 407
    • Investigational Site Number : 1580003
  • Taipei, Taiwan, 10002
    • Investigational Site Number : 1580002
  • Taipei, Taiwan, 11031
    • Investigational Site Number : 1580004
• Turkey
  • Antalya, Turkey, 07059
    • Investigational Site Number : 7920004
  • Istanbul, Turkey, 34390
    • Investigational Site Number : 7920001
  • Izmir, Turkey, TR-35100
    • Investigational Site Number : 7920003
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Investigational Site Number : 8260003
  • Hampshire, United Kingdom, RG24 9NA
    • Investigational Site Number : 8260004
  • London, City Of
    • London, London, City Of, United Kingdom, NW3 2QG
      • Investigational Site Number : 8260005
    • London, London, City Of, United Kingdom, WC1N 3JH
      • Investigational Site Number : 8260001
• United States
  • California
    • Los Angeles, California, United States, 90007
      • Orthopaedic Institute for Children Site Number : 8400003
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles Site Number : 8400009
    • San Diego, California, United States, 92121
      • University of California San Diego Site Number : 8400007
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida Health Site Number : 8400008
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta Site Number : 8400016
  • Illinois
    • Chicago, Illinois, United States, 60612-3833
      • Rush University Medical Center Site Number : 8400010
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Children's Hospital Of Iowa Site Number : 8400011
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center Site Number : 8400006
    • East Lansing, Michigan, United States, 48824
      • Michigan State University School Of Med Site Number : 8400002
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • Hemostasis and Thrombosis Center of Nevada Site Number : 8400001
  • New York
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital/Weill Cornell Medical Center Site Number : 8400017
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University -2390 Hemby Ln Site Number : 8400015
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center Site Number : 8400012
    • Columbus, Ohio, United States, 43205-2696
      • Children's Research Institute Site Number : 8400013
  • Washington
    • Seattle, Washington, United States, 98104
      • Bloodworks Northwest Site Number : 8400005
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-0509
      • Children's Hospital of Wisconsin Site Number : 8400014

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Previously treated in BIVV001 study; 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); Pharmaceutical form:Solution for Injection Route of administration: Intravenous
Experimental: Arm B: Newly initiated (China Only) in BIVV001; 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); Pharmaceutical form:Solution for Injection Route of administration: Intravenous
Experimental: Arm C: Newly initiated in BIVV001 with planned major surgery; 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); Pharmaceutical form:Solution for Injection Route of administration: Intravenous

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bioverativ, a Sanofi company
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2021
• Primary Completion (Estimated): January 15, 2027
• Study Completion (Estimated): January 15, 2027

Study Registration Dates

• First Submitted: November 23, 2020
• First Submitted That Met QC Criteria: November 23, 2020
• First Posted (Actual): November 25, 2020

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: LTS16294; 2020-002215-22 (EudraCT Number); U1111-1244-0517 (Registry Identifier: ICTRP); 2023-508929-27 (Registry Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No