Clinical trial NCT03205163: 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)
Official title: A Phase 1/2a, Open-Label, Dose-Escalation Study to Determine the Safety, Tolerability, and Pharmacokinetics of a Single Intravenous Injection of rFVIIIFc-VWF-XTEN (BIVV001) in Previously Treated Adults With Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hemophilia A
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2017-07-02
Enrollment: 16
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.


Eligibility criteria: Inclusion Criteria:

* 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.
* Severe hemophilia A, defined as less than (\<) 1 international units per deciliter (IU/dL) (\<1 percent \[%\]) endogenous FVIII at screening as determined by the one-stage clotting assay from the central laboratory. If the initial screening result was greater than or equal to (\>=) 1%, then a repeat endogenous FVIII activity level was performed using the one stage clotting assay from the central laboratory. If the repeated result was \< 1 IU/dL (\<1%), then the participant met this inclusion requirement.
* 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.

Exclusion Criteria:

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.

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period
timeFrame: Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period
timeFrame: Up to 28 days after BIVV001 administration
measure: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period
timeFrame: Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg
measure: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period
timeFrame: Up to 28 days after BIVV001 administration
measure: Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay
timeFrame: Up to 28 days after BIVV001 administration
Secondary outcomes:
measure: Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
measure: PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Half-Life for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
measure: PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
measure: PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
measure: PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
measure: PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
measure: PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
measure: PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison)
timeFrame: 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
measure: PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison)
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center
state: California
city: Indianapolis
country: United States
facility: Indiana Hemophilia and Thrombosis Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Madison
country: United States
facility: Mississippi Center for Advanced Medicine
state: Mississippi
city: Pittsburgh
country: United States
facility: Hemophilia Center of Western PA
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Kashihara-Shi
country: Japan
facility: Nara Medical University Hospital
state: Nara-Ken
city: Shinjuku-Ku
country: Japan
facility: Tokyo Medical University Hospital
state: Tokyo-To
city: Tokyo
country: Japan
facility: Ogikubo Hospital
state: Tokyo-To
Study officials:
References:
citation: 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.