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)

• ClinicalTrials.gov Identifier: NCT03205163
• Recruitment Status: Completed
• First Posted: July 2, 2017
• Results First Posted: December 2, 2019
• Last Update Posted: April 19, 2022
• Sponsor: Bioverativ, a Sanofi company
• Information provided by (Responsible Party): Sanofi ( Bioverativ, a Sanofi company )

Tracking Information

• First Submitted Date: June 29, 2017
• First Posted Date: July 2, 2017
• Results First Submitted Date: November 11, 2019
• Results First Posted Date: December 2, 2019
• Last Update Posted Date: April 19, 2022
• Actual Study Start Date: August 28, 2017
• Actual Primary Completion Date: November 12, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 11, 2019)

• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period [ Time Frame: Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg ]
  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.
• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period [ Time Frame: Up to 28 days after BIVV001 administration ]
  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.
• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period [ Time Frame: 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 (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period [ Time Frame: Up to 28 days after BIVV001 administration ]
  Number of participants with clinically significant abnormalities (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
• Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay [ Time Frame: Up to 28 days after BIVV001 administration ]
  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.

Original Primary Outcome Measures (submitted: June 29, 2017)

• Number of Participants With Adverse Events [ Time Frame: Approximately 60 days ]
  An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
• Percentage of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Approximately 60 days ]
  Clinically significant laboratory abnormalities including hematology, clinical chemistry, urinalysis, coagulation, thrombosis markers, and development of inhibitors (neutralizing antibodies directed against FVIII) as determined via the Nijmegen-modified Bethesda Assay (an inhibitor test result greater than or equal to (>=) 0.6 Bethesda units (BU)/milliliter (mL), confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive).

Current Secondary Outcome Measures (submitted: November 11, 2019)

• Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  Cmax of Advate and BIVV001 at low dose was assessed and compared based on One-stage activated partial thromboplastin time (aPTT)-based clotting assay.
• PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  Cmax of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Half-Life for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  AUCinfinity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  AUCinfinity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) [ Time Frame: 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 ]
  Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison) [ Time Frame: 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 ]
  Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.

Original Secondary Outcome Measures (submitted: June 29, 2017)

• Maximum Observed Plasma Concentration (Cmax) of Recombinant FVIII (rFVIII) [ Time Frame: up to 72 hours post dose ]
  The Cmax is the maximum observed plasma concentration.
• Half life (t1/2) of rFVIII [ Time Frame: up to 72 hours post dose ]
  Time required for the concentration of the drug to reach half of its original value.
• Clearance (CL) of rFVIII [ Time Frame: up to 72 hours post dose ]
  The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
• Apparent Volume of Distribution at Steady State (Vss) of rFVIII [ Time Frame: up to 72 hours post dose ]
  The apparent volume of distribution at steady state. Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
• Area Under the Plasma Concentration Time Curve From Time Zero to Infinity Time (AUC [0-Infinity]) of rFVIII [ Time Frame: up to 72 hours post dose ]
  Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-infinity).
• Mean Residence Time (MRT) of rFVIII [ Time Frame: up to 72 hours post dose ]
  The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
• Incremental Recovery (IR) of rFVIII [ Time Frame: up to 72 hours post dose ]
  Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight.
• Time to 1 Percent (%) Above Baseline for FVIII Activity of rFVIII [ Time Frame: up to 72 hours post dose ]
  Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels.
• Maximum Observed Plasma Concentration (Cmax) of BIVV001 [ Time Frame: up to 336 hours postdose ]
  The Cmax is the maximum observed plasma concentration.
• Half life (t1/2) of BIVV001 [ Time Frame: up to 336 hours postdose ]
  Time required for the concentration of the drug to reach half of its original value.
• Clearance (CL) of BIVV001 [ Time Frame: up to 336 hours postdose ]
  The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
• Apparent Volume of Distribution at Steady State (Vss) of BIVV001 [ Time Frame: up to 336 hours postdose ]
  The apparent volume of distribution at steady state. Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
• Area Under the Plasma Concentration Time Curve From Time Zero to Infinity Time (AUC [0-Infinity]) of BIVV001 [ Time Frame: up to 336 hours postdose ]
  Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-infinity).
• Mean Residence Time (MRT) of BIVV001 [ Time Frame: up to 336 hours postdose ]
  The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
• Incremental Recovery (IR) of BIVV001 [ Time Frame: up to 336 hours postdose ]
  Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight.
• Time to 1 Percent Above Baseline for FVIII Activity of BIVV001 [ Time Frame: up to 336 hours postdose ]
  Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Hemophilia A

Intervention

• Biological: Advate (Low Dose)
  Participants received a single IV low dose of Advate 25 IU/kg.
• Biological: Advate (High Dose)
  Participants received a single IV high dose of Advate 65 IU/kg.
• Biological: BIVV001 (Low Dose)
  Participants received single IV low dose of BIVV001 25 IU/kg.
• Biological: BIVV001 (High Dose)
  Participants received single IV high dose of BIVV001 65 IU/kg.

Study Arms

• Experimental: Low Dose Cohort: Advate 25 IU/kg Then BIVV001 25 IU/kg
  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.
  Interventions:

  • Biological: Advate (Low Dose)
  • Biological: BIVV001 (Low Dose)
• Experimental: High Dose Cohort: Advate 65 IU/kg Then BIVV001 65 IU/kg
  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.
  Interventions:

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

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 11, 2019): 16
• Original Estimated Enrollment (submitted: June 29, 2017): 18
• Actual Study Completion Date: November 12, 2018
• Actual Primary Completion Date: November 12, 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, United States

Administrative Information

• NCT Number: NCT03205163
• Other Study ID Numbers: TDU16220; 242HA101 ( Other Identifier: Bioverativ, a Sanofi company )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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

• Current Responsible Party: Sanofi ( Bioverativ, a Sanofi company )
• Original Responsible Party: Bioverativ Therapeutics Inc.
• Current Study Sponsor: Bioverativ, a Sanofi company
• Original Study Sponsor: Bioverativ Therapeutics Inc.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Sanofi
• Verification Date: March 2022