Pharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale (Elevate)

• ClinicalTrials.gov Identifier: NCT02502149
• Recruitment Status: Completed
• First Posted: July 20, 2015
• Results First Posted: April 6, 2018
• Last Update Posted: December 19, 2020
• Sponsor: Bioverativ Therapeutics Inc.
• Collaborator: Swedish Orphan Biovitrum
• Information provided by (Responsible Party): Sanofi ( Bioverativ Therapeutics Inc. )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Severe Hemophilia A	Biological: rFVIIIFc	Phase 3

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]).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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 Start Date: August 2015
• Actual Primary Completion Date: April 2017
• Actual Study Completion Date: June 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: rFVIIIFc (15K scale) 1000 IU vial; Single injection of rFVIIIFc (current 2K scale) followed by 2 single injections of rFVIIIFc (15K scale) 1000 IU vial at PK2 and PK3 timepoints. Participants will be on prophylaxis regimen along with treatment for bleeding episodes for 26 weeks of treatment period using the rFVIIIFc (15K scale) 1000 IU vial.	Biological: rFVIIIFc; As per arm description; Other Names: Eloctate; BIIB031; efmoroctocog alfa; recombinant coagulation factor VIII Fc fusion protein; antihemophilic factor [recombinant]; Fc fusion protein
Experimental: rFVIIIFc (15K scale) 6000 IU vial; Single injection of rFVIIIFc (current 2K scale) followed by 2 single injections of rFVIIIFc high strength vial (15K scale) at PK2 and PK3 timepoints. Participants will be on prophylaxis regimen along with treatment for bleeding episodes for 26 weeks of treatment period using the rFVIIIFc (15K scale) 6000 IU vial.	Biological: rFVIIIFc; As per arm description; Other Names: Eloctate; BIIB031; efmoroctocog alfa; recombinant coagulation factor VIII Fc fusion protein; antihemophilic factor [recombinant]; Fc fusion protein

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
2. Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).

Secondary Outcome Measures :

1. Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
2. Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Half-life is time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K 1000 IU/vial and 6000 IU/Vial (PK2).
3. Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
4. Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
5. Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
6. Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
7. Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Incremental Recovery is defined as the increase in the circulating FVIII activity in IU/dL per unit dose administered in IU/kg (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
8. Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
9. Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
   Time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
10. Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
11. Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
12. Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
13. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    AUCinf is area under the concentration-time curve from time zero to infinity.
14. Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
15. Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Cmax is defined as maximum activity of rFVIIIFc.
16. Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Time required for the concentration of the drug to reach half of its original value.
17. Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]).
18. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
19. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
20. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    AUCinf is area under the concentration-time curve from time zero to infinity.
21. Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
22. Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Cmax is defined as maximum activity of rFVIIIFc.
23. Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Time required for the concentration of the drug to reach half of its original value.
24. Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]).
25. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
26. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
27. Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
28. Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Incremental Recovery is defined as the increase in the circulating FVIII activity in IU/dL per unit dose administered in IU/kg (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
29. Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
30. Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
31. Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
32. Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
33. Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
34. Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
35. Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Incremental Recovery is defined as the increase in the circulating FVIII activity in IU/dL per unit dose administered in IU/kg (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
36. Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
37. Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
38. Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
39. Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured the Two-stage Chromogenic Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
40. Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3 [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
41. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    AUCinf is area under the concentration-time curve from time zero to infinity.
42. Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
43. Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Cmax is defined as maximum activity of rFVIIIFc.
44. Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Time required for the concentration of the drug to reach half of its original value.
45. Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]).
46. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
47. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
48. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    AUCinf is area under the concentration-time curve from time zero to infinity.
49. Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
50. Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Cmax is defined as maximum activity of rFVIIIFc.
51. Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Time required for the concentration of the drug to reach half of its original value.
52. Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]).
53. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
54. 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) [ Time Frame: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr ]
    The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
55. Development of Inhibitors as Measured by the Nijmegen-modified Bethesda Assay [ Time Frame: At screening and predose on Day 1, 13 and 26 weeks after PK2 injection or at Early Termination (Approximately 43 weeks) ]
    An inhibitor test result greater than or equal to (>=)0.6 Bethesda units [BU]/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. The test was performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the percentage of participants 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.
56. Number of Participants With Treatment Emergent Adverse Events (TEAEs) at 15K Manufacturing Scale [ Time Frame: Approximately 43 weeks ]
    An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Number of Participants with TEAEs were summarized overall.
57. Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) at 15K Manufacturing Scale [ Time Frame: Approximately 43 weeks ]
    An SAE is any untoward medical occurrence that at any dose: results in death or in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or results in a congenital anomaly/birth defect. All major surgeries will be reported as SAEs. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the SAE definition. Number of participants with TESAEs were summarized overall.

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, California

Research Site

Los Angeles, California, United States, 90007

United States, Illinois

Research Site

Chicago, Illinois, United States, 60612

United States, Indiana

Research Site

Indianapolis, Indiana, United States, 46260

United States, Kentucky

Research Site

Louisville, Kentucky, United States, 40202

United States, Michigan

Research Site

East Lansing, Michigan, United States, 48823

United States, Missouri

Research Site

Saint Louis, Missouri, United States, 63104

United States, Utah

Research Site

Salt Lake City, Utah, United States, 84108

United States, Washington

Research Site

Seattle, Washington, United States, 98104

Australia, New South Wales

Research Site

Camperdown, New South Wales, Australia, 2050

Australia, Victoria

Research Site

Melbourne, Victoria, Australia, 3004

Australia, Western Australia

Research Site

Murdoch, Western Australia, Australia, 6150

New Zealand

Research Site

Grafton, Auckland, New Zealand, 1023

Research Site

Newtown, Wellington, New Zealand, 6021

Research Site

Christchurch, New Zealand, 8011

Research Site

Hamilton, New Zealand, 3200

Sponsors and Collaborators

Bioverativ Therapeutics Inc.

Swedish Orphan Biovitrum

Investigators

• Study Director: Medical Director; Bioverativ Therapeutics Inc.

  Study Documents (Full-Text)

Documents provided by Sanofi ( Bioverativ Therapeutics Inc. ):

Study Protocol  [PDF] September 21, 2015

Statistical Analysis Plan  [PDF] October 10, 2016

More Information

• Responsible Party: Bioverativ Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT02502149
• Other Study ID Numbers: 997HA309; 2014-003895-21 ( EudraCT Number )
• First Posted: July 20, 2015
• Results First Posted: April 6, 2018
• Last Update Posted: December 19, 2020
• Last Verified: March 2018

Keywords provided by Sanofi ( Bioverativ Therapeutics Inc. ):

rFVIIIFc; Eloctate; Hemophilia

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Factor VIII; Coagulants