A Safety, Tolerability, and Pharmacokinetics Study of a Single Intravenous Injection of Recombinant Coagulation Factor VIII Fc - Von Willebrand Factor - XTEN Fusion Protein (rFVIIIFc-VWF-XTEN) (BIVV001) in Previously Treated Adults With Severe Hemophilia A (EXTEN-A)

NCT03205163 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: TDU16220242HA101
• Study Type: interventional
• Target: 16
• Locations: 2 countries
• Sites: 10

Brief Summary

The primary purpose was to assess the safety and tolerability of a single intravenous (IV) administration of BIVV001 in adult previously treated patients (PTPs) with severe hemophilia A.

Conditions

Hemophilia A

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period

  AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the single dose of Advate but before the single dose of BIVV001. Serious AE (SAE) was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.

  Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg

• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period

  AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the study treatment (BIVV001) and within 28 days after BIVV001 administration. SAE was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.

  Up to 28 days after BIVV001 administration

• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period

  Number of Participants with Clinically Significant Abnormalities in Laboratory tests (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.

  Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg

• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period

  Number of participants with clinically significant abnormalities (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.

  Up to 28 days after BIVV001 administration

• Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay

  Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (\>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample, collected within 2 to 4 weeks of the first positive sample, with both tests performed by the central laboratory using Nijmegen-modified Bethesda assay.

  Up to 28 days after BIVV001 administration

Secondary Outcomes (16)

• Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison)

  For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours

• PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison)

  For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours

• PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison)

  For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours

• PK: Half-Life for Advate and BIVV001 (High Dose Comparison)

  For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours

• PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison)

  For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours

Study Arms (2)

Low Dose Cohort: Advate 25 IU/kg Then BIVV001 25 IU/kg

EXPERIMENTAL

Participants received a single intravenous (IV) dose of Advate 25 international units per kilogram (IU/kg) on Day 1 of Advate treatment period (3 days) followed by a single IV dose of BIVV001 25 IU/kg in BIVV001 treatment period (BTP) (28 days). Advate treatment period (ATP) consisted of a washout of at least 72 hours which was started from the time of Advate dosing.

Biological: Advate (Low Dose); Biological: BIVV001 (Low Dose)

High Dose Cohort: Advate 65 IU/kg Then BIVV001 65 IU/kg

EXPERIMENTAL

Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days) followed by a single IV dose of BIVV001 65 IU/kg in BTP (28 days). ATP consisted of a washout of at least 96 hours which was started from the time of Advate dosing.

Biological: Advate (High Dose); Biological: BIVV001 (High Dose)

Interventions

Advate (Low Dose) BIOLOGICAL

Participants received a single IV low dose of Advate 25 IU/kg.

Low Dose Cohort: Advate 25 IU/kg Then BIVV001 25 IU/kg

Advate (High Dose) BIOLOGICAL

Participants received a single IV high dose of Advate 65 IU/kg.

High Dose Cohort: Advate 65 IU/kg Then BIVV001 65 IU/kg

BIVV001 (Low Dose) BIOLOGICAL

Participants received single IV low dose of BIVV001 25 IU/kg.

Low Dose Cohort: Advate 25 IU/kg Then BIVV001 25 IU/kg

BIVV001 (High Dose) BIOLOGICAL

Participants received single IV high dose of BIVV001 65 IU/kg.

High Dose Cohort: Advate 65 IU/kg Then BIVV001 65 IU/kg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability of the participant, or his legally authorized representative (e.g., parent or legal guardian) if applicable in accordance with local regulations, to understand the purpose and risks of the study and provide signed and dated informed consent/assent and authorization to use confidential health information in accordance with national and local participant privacy regulations.
• Previous treatment for hemophilia A, defined as at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days.
• Platelet count \>=100,000 cells/ microliter (mcL) at screening (test performed by the central laboratory and reviewed prior to the Day 1 Advate dose).
• 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 Day 1 Advate dose: cluster of differentiation 4 (CD4) lymphocyte count greater than (\>) 200 cells/millimeter (mm)\^3; viral load of \<400 copies/mL.

You may not qualify if:

• Medical History:
• Any concurrent clinically significant major disease that, in the opinion of the Investigator, made the participant unsuitable for enrollment.
• 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.
• Known or suspected allergy to mice, hamsters, or any ingredient in Advate.
• History of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors not excluded the participant.
• Medications and Procedures:
• \- Current enrollment or participation within 30 days prior to screening in any other investigational study.
• Other:
• Inability to comply with study requirements as assessed by the Investigator.
• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, made the participant unsuitable for enrollment.

Sponsors & Collaborators

• Bioverativ, a Sanofi company: lead

Study Sites (10)

University of California Los Angeles Medical Center

Los Angeles, California, 90007, United States

Location

Indiana Hemophilia and Thrombosis Center

Indianapolis, Indiana, 46260, United States

Location

University of Iowa Hospitals & Clinics

Iowa City, Iowa, 52242, United States

Location

Michigan State University

East Lansing, Michigan, 48823, United States

Location

Mississippi Center for Advanced Medicine

Madison, Mississippi, 39110, United States

Location

Hemophilia Center of Western PA

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Washington

Seattle, Washington, 98104, United States

Location

Nara Medical University Hospital

Kashihara-shi, Nara, 634-8521, Japan

Location

Tokyo Medical University Hospital

Shinjuku-Ku, Tokyo-To, 160-0023, Japan

Location

Ogikubo Hospital

Tokyo, Tokyo-To, 167-8515, Japan

Location

Related Publications (1)

• Konkle BA, Shapiro AD, Quon DV, Staber JM, Kulkarni R, Ragni MV, Chhabra ES, Poloskey S, Rice K, Katragadda S, Fruebis J, Benson CC. BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. N Engl J Med. 2020 Sep 10;383(11):1018-1027. doi: 10.1056/NEJMoa2002699.

  PMID: 32905674 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

Factor VIII; BIVV001

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Bioverativ, a Sanofi company

Contact-US@sanofi.com

800-633-1610

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 29, 2017
• First Posted: July 2, 2017
• Study Start: August 28, 2017
• Primary Completion: November 12, 2018
• Study Completion: November 12, 2018
• Last Updated: April 19, 2022
• Results First Posted: December 2, 2019

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

JP (3); US (7)