Pharmacokinetics of rFVIIIFc at Two Vial Strengths

A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of 2 Vial Strengths of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in Previously Treated Subjects With Severe Hemophilia A

The primary objective of the study is to characterize the pharmacokinetics (PK) of rFVIIIFc administered at vial strengths of 1000 and 3000 IU in subjects with severe hemophilia A. The secondary objective of the study is to evaluate the safety of rFVIIIFc beyond the PK assessment for up to 6 months for a continued treatment period.

Study Overview

• Status: Completed
• Conditions: Severe Hemophilia A
• Intervention / Treatment: Biological: rFVIIIFc

Detailed Description

This is a randomized, open-label, crossover study during which each participant receives a single injection of rFVIIIFc from 2 different vial concentrations (PK assessment). After the PK assessment, participants are provided with rFVIIIFc for either prophylactic or episodic (on-demand) treatment for up to 6 months.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Herston, Australia
    • Research Site
  • Perth, Australia
    • Research Site
• United Kingdom
  • Basingstoke, United Kingdom
    • Research Site
  • Cambridge, United Kingdom
    • Research Site
  • London, United Kingdom
    • Research Site
• United States
  • California
    • Los Angeles, California, United States
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84101
      • Research Site
  • Washington
    • Seattle, Washington, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Key Inclusion Criteria:

• Have severe hemophilia A
• Previously treated subject, defined as having at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products (other than any use of rFVIIIFc- study drug or commercial product) at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days.
• No history of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors will not exclude subjects.
• No measurable inhibitor activity using the Nijmegen-modified Bethesda assay at Screening.
• Platelet count ≥100,000 platelets/μL at screening
• CD4 lymphocytes >200 mm3 if known as HIV antibody positive at screening.
• Viral load of <400 copies/mL if known HIV antibody positive at screening.

Key Exclusion Criteria:

• Subject is at high risk of bleeding during the 5-day period between the first and second injections for PK analyses, as per Investigator discretion.
• Previous treatment with rFVIIIFc as study drug or commercial product.
• Other coagulation disorder(s) in addition to hemophilia A.
• History of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration.
• Currently taking (or likely to require during the study) acetylsalicylic acid (ASA), except for low-dose ASA as prophylaxis (other nonsteroidal anti-inflammatory drugs are permitted).
• Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to Day 1. Exceptions to this include: ribavirin for treatment of hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days at a dose of ≤1 mg/kg within 12 weeks prior to Day 1) and/or inhaled steroids.

NOTE: Other protocol-defined inclusion/exclusion Criteria May Apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rFVIIIFc 1000 / 3000 PK Assessment; A single intravenous (IV) injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial followed by a single IV injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial. Following the PK assessment, participants will receive either an episodic (on-demand) regimen with doses between 20 and 50 IU/kg based on the severity of the bleeding episode, or 1 of 2 prophylactic regimens: 50 IU/kg every 3 to 5 days or 65 IU/kg weekly. Participants will be allowed to switch from one regimen to another if approved by the Investigator.	Biological: rFVIIIFc; Administered as specified in the treatment arm.; Other Names: Eloctate; recombinant coagulation factor VIII Fc fusion protein; BIIB031; efmoroctocog alfa; Elocta; antihemophilic factor [recombinant] FC fusion protein
Experimental: rFVIIIFc 3000 / 1000 PK Assessment; A single IV injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial followed by a single IV injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial. Following the PK assessment, participants will receive either an episodic (on-demand) regimen with doses between 20 and 50 IU/kg based on the severity of the bleeding episode, or 1 of 2 prophylactic regimens: 50 IU/kg every 3 to 5 days or 65 IU/kg weekly. Participants will be allowed to switch from one regimen to another if approved by the Investigator.	Biological: rFVIIIFc; Administered as specified in the treatment arm.; Other Names: Eloctate; recombinant coagulation factor VIII Fc fusion protein; BIIB031; efmoroctocog alfa; Elocta; antihemophilic factor [recombinant] FC fusion protein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay	Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay	The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay	Maximum measured concentration of rFVIIIFc.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Half-life (t½) as Measured by aPTT Clotting Assay	Time required for the concentration of the drug to reach half of its original value.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Clearance (CL) as Measured by the aPTT Clotting Assay	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.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay	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.)	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay	The average time at which the number of absorbed molecules reside in the body, after single-dose administration.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Time of Cmax (Tmax) as Measured by aPTT Clotting Assay	Time at which maximum activity (Cmax) is observed.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay	Area under the plasma concentration time-curve from zero to the last measured concentration.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay	First order rate constant associated with the terminal portion of the curve (lambda z) .	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay	Percentage of AUCinf extrapolated from the last data point to infinity.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay	Dose normalized area under the FVIII activity-time curve.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT	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.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay	Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay	The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Cmax as Measured by Two-Stage Chromogenic Clotting Assay	Maximum measured concentration of rFVIIIFc.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
t½ as Measured by Two-Stage Chromogenic Clotting Assay	Time required for the concentration of the drug to reach half of its original value.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
CL as Measured by Two-Stage Chromogenic Clotting Assay	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.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Vss as Measured by Two-Stage Chromogenic Clotting Assay	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.)	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
MRT as Measured by Two-Stage Chromogenic Clotting Assay	The average time at which the number of absorbed molecules reside in the body, after single-dose administration.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Tmax as Measured by Two-Stage Chromogenic Clotting Assay	Time at which maximum activity (Cmax) is observed.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
AUClast as Measured by Two-Stage Chromogenic Clotting Assay	Area under the plasma concentration time-curve from zero to the last measured concentration.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay	First order rate constant associated with the terminal portion of the curve (lambda z).	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
AUCext as Measured by Two-Stage Chromogenic Clotting Assay	Percentage of AUCinf extrapolated from the last data point to infinity.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
DNAUC as Measured by Two-Stage Chromogenic Clotting Assay	Dose normalized area under the FVIII activity-time curve.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Vz as Measured by Two-Stage Chromogenic Clotting Assay	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.	Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay	An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of participants with confirmed inhibitor development was summarized overall.	Predose, Month 3, Month 6/early withdrawal. Additionally: If inhibitor suspected; at 10-15 EDs; 2-4 weeks prior to scheduled surgery; preoperatively on day of surgery; 1-2 weeks post-surgery; at last postoperative visit (last 2 for major surgery only)

Collaborators and Investigators

• Sponsor: Bioverativ Therapeutics Inc.
• Investigators: Study Director: Medical Director, Bioverativ Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: March 7, 2014
• First Submitted That Met QC Criteria: March 7, 2014
• First Posted (Estimate): March 11, 2014

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: May 1, 2017

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; Coagulants; Factor VIII
• Other Study ID Numbers: 997HA307; 2013-003013-18 (EudraCT Number)