Back to resultsPharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale (Elevate)
Primary Purpose
Severe Hemophilia A
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
rFVIIIFc
Sponsored by
About this trial
This is an interventional other trial for Severe Hemophilia A focused on measuring rFVIIIFc, Eloctate, Hemophilia
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.
Sites / Locations
- Research Site
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- Research Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
rFVIIIFc (15K scale) 1000 IU vial
rFVIIIFc (15K scale) 6000 IU vial
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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)
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).
Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
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
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
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).
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
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).
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
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).
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
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).
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
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.
Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
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.
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
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.
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
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.
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
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.
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
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.
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
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.
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)
AUCinf is area under the concentration-time curve from time zero to infinity.
Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
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).
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Cmax is defined as maximum activity of rFVIIIFc.
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 required for the concentration of the drug to reach half of its original value.
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
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]).
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)
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.
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)
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.
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)
AUCinf is area under the concentration-time curve from time zero to infinity.
Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
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).
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Cmax is defined as maximum activity of rFVIIIFc.
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 required for the concentration of the drug to reach half of its original value.
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
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]).
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)
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.
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)
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.
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
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).
Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
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).
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
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).
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
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).
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
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).
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
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).
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
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.
Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
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.
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
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.
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
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.
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
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.
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured the Two-stage Chromogenic Assay for PK2 and PK3
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.
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
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.
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)
AUCinf is area under the concentration-time curve from time zero to infinity.
Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
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).
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Cmax is defined as maximum activity of rFVIIIFc.
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 required for the concentration of the drug to reach half of its original value.
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
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]).
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)
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.
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)
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.
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)
AUCinf is area under the concentration-time curve from time zero to infinity.
Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
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).
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Cmax is defined as maximum activity of rFVIIIFc.
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 required for the concentration of the drug to reach half of its original value.
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
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]).
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)
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.
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)
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.
Development of Inhibitors as Measured by the Nijmegen-modified Bethesda Assay
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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) at 15K Manufacturing Scale
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.
Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) at 15K Manufacturing Scale
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.
Full Information
NCT ID
NCT02502149
First Posted
May 29, 2015
Last Updated
December 16, 2020
Sponsor
Bioverativ Therapeutics Inc.
Collaborators
Swedish Orphan Biovitrum
1. Study Identification
Unique Protocol Identification Number
NCT02502149
Brief Title
Pharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale
Acronym
Elevate
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
2. Study Status
Record Verification Date
March 2018
Overall Recruitment Status
Completed
Study Start Date
August 2015 (undefined)
Primary Completion Date
April 2017 (Actual)
Study Completion Date
June 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bioverativ Therapeutics Inc.
Collaborators
Swedish Orphan Biovitrum
4. Oversight
Data Monitoring Committee
No
5. 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.
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]).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Hemophilia A
Keywords
rFVIIIFc, Eloctate, Hemophilia
7. Study Design
Primary Purpose
Other
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
24 (Actual)
8. Arms, Groups, and Interventions
Arm Title
rFVIIIFc (15K scale) 1000 IU vial
Arm Type
Experimental
Arm Description
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.
Arm Title
rFVIIIFc (15K scale) 6000 IU vial
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
rFVIIIFc
Other Intervention Name(s)
Eloctate; BIIB031; efmoroctocog alfa; recombinant coagulation factor VIII Fc fusion protein; antihemophilic factor [recombinant], Fc fusion protein
Intervention Description
As per arm description
Primary Outcome Measure Information:
Title
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)
Description
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).
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
Title
Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Secondary Outcome Measure Information:
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
Description
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (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
Title
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
AUCinf is area under the concentration-time curve from time zero to infinity.
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
Title
Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Cmax is defined as maximum activity of rFVIIIFc.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Time required for the concentration of the drug to reach half of its original value.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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]).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
AUCinf is area under the concentration-time curve from time zero to infinity.
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
Title
Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Cmax is defined as maximum activity of rFVIIIFc.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Time required for the concentration of the drug to reach half of its original value.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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]).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Description
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (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
Title
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured the Two-stage Chromogenic Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
AUCinf is area under the concentration-time curve from time zero to infinity.
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
Title
Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Cmax is defined as maximum activity of rFVIIIFc.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Time required for the concentration of the drug to reach half of its original value.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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]).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
AUCinf is area under the concentration-time curve from time zero to infinity.
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
Title
Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Cmax is defined as maximum activity of rFVIIIFc.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
Time required for the concentration of the drug to reach half of its original value.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
Description
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]).
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
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)
Description
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.
Time Frame
Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
Title
Development of Inhibitors as Measured by the Nijmegen-modified Bethesda Assay
Description
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.
Time Frame
At screening and predose on Day 1, 13 and 26 weeks after PK2 injection or at Early Termination (Approximately 43 weeks)
Title
Number of Participants With Treatment Emergent Adverse Events (TEAEs) at 15K Manufacturing Scale
Description
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.
Time Frame
Approximately 43 weeks
Title
Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) at 15K Manufacturing Scale
Description
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.
Time Frame
Approximately 43 weeks
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Bioverativ Therapeutics Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90007
Country
United States
Facility Name
Research Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Research Site
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
Research Site
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
Research Site
City
East Lansing
State/Province
Michigan
ZIP/Postal Code
48823
Country
United States
Facility Name
Research Site
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
Research Site
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
Research Site
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
Research Site
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Facility Name
Research Site
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Facility Name
Research Site
City
Murdoch
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Facility Name
Research Site
City
Grafton
State/Province
Auckland
ZIP/Postal Code
1023
Country
New Zealand
Facility Name
Research Site
City
Newtown
State/Province
Wellington
ZIP/Postal Code
6021
Country
New Zealand
Facility Name
Research Site
City
Christchurch
ZIP/Postal Code
8011
Country
New Zealand
Facility Name
Research Site
City
Hamilton
ZIP/Postal Code
3200
Country
New Zealand
12. IPD Sharing Statement
Learn more about this trial
Pharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale
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