Clinical trial NCT02502149: Pharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale
Official title: A Randomized, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) Manufactured at 15K Scale and at Different Vial Strengths in Previously Treated Subjects With Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Hemophilia A
Keywords: rFVIIIFc
Eloctate
Hemophilia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Swedish Orphan Biovitrum
First posted: 2015-07-20
Enrollment: 24
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The primary objective of the study is to compare the pharmacokinetic (PK) of recombinant coagulation factor VIII Fc fusion protein (rFVIIIFc) manufactured at the current scale of 2000 L (2K) to the PK of rFVIIIFc manufactured at the 15,000 L (15K) scale in previously treated participants with severe hemophilia A. The secondary objectives are: to characterize the PK of rFVIIIFc manufactured at the 15K scale at the 15K baseline and after 13 weeks of treatment; to characterize the PK of rFVIIIFc manufactured at the 15K scale at 1000 IU/vial and 6000 IU/vial strengths; and to evaluate the safety of rFVIIIFc manufactured at the 15K scale.

Detailed description: PK assessments are in 3 phases: Pharmacokinetic Assessment 1(PK1): PK assessments following single injection of rFVIIIFc manufactured at the 2K scale. Pharmacokinetic Assessment 2 (PK2): PK assessments are made following a single injection of rFVIIIFc manufactured at the 15K scale where participants are randomized to the 1000 IU vial or 6000 IU/vial strengths. Pharmacokinetic Assessment 3 (PK3): PK assessments are made following 13 weeks of rFVIIIFc treatment manufactured at the 15K scale where participants are randomized to the 1000 IU vial or 6000 IU/vial strengths. After study completion, in countries where rFVIIIFc is not commercially available, eligible participants will be offered enrollment into a long-term safety and efficacy extension study (8HA01EXT \[NCT01454739\]).

Eligibility criteria: Key Inclusion Criteria:

* Have severe hemophilia A, defined as \<1 IU/dL (\<1%) endogenous FVIII as determined by one-stage clotting assay from the central laboratory at Screening.
* Previously treated subject, defined as having at least 150 documented prior exposure days (EDs) 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.
* No history of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors will not exclude the subject.
* No measurable inhibitor activity using the Nijmegen-modified Bethesda assay (\>=0.6 Bethesda Unit per milliliter \[BU/mL\] is considered positive) at Screening.

Key Exclusion Criteria:

* Current enrollment in any interventional clinical study in which an investigational drug or approved therapy for investigational use is administered within 30 days prior to the Baseline Visit OR prior participation in any of the following Biogen studies: 998HA101 (NCT01027377), 997HA301 (NCT01181128), 8HA02PED (NCT01458106), 997HA307 (NCT02083965), and 8HA01EXT (NCT01454739).
* Previous participation in this study.
* Any concurrent clinically significant major disease that, in the opinion of the Investigator or Biogen, makes the subject unsuitable for participation in the study.
* Other coagulation disorder(s) in addition to hemophilia A.
* History of hypersensitivity or anaphylaxis associated with FVIII or intravenous (IV) immunoglobulin administration.

NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage Activated Partial Thromboplastin Time (aPTT) Clotting Assay for Pharmacokinetic Assessment 1 (PK1) and Pharmacokinetic Assessment 2 (PK2)
timeFrame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Secondary outcomes:
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured the Two-stage Chromogenic Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
timeFrame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
measure: Development of Inhibitors as Measured by the Nijmegen-modified Bethesda Assay
timeFrame: At screening and predose on Day 1, 13 and 26 weeks after PK2 injection or at Early Termination (Approximately 43 weeks)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) at 15K Manufacturing Scale
timeFrame: Approximately 43 weeks
measure: Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) at 15K Manufacturing Scale
timeFrame: Approximately 43 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: East Lansing
country: United States
facility: Research Site
state: Michigan
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Camperdown
country: Australia
facility: Research Site
state: New South Wales
city: Melbourne
country: Australia
facility: Research Site
state: Victoria
city: Murdoch
country: Australia
facility: Research Site
state: Western Australia
city: Grafton
country: New Zealand
facility: Research Site
state: Auckland
city: Newtown
country: New Zealand
facility: Research Site
state: Wellington
city: Christchurch
country: New Zealand
facility: Research Site
city: Hamilton
country: New Zealand
facility: Research Site
Study officials:
affiliation: Bioverativ Therapeutics Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: