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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02083965
Registration number
NCT02083965
Ethics application status
Date submitted
7/03/2014
Date registered
11/03/2014
Date last updated
19/12/2020
Titles & IDs
Public title
Pharmacokinetics of rFVIIIFc at Two Vial Strengths
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Scientific title
A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of 2 Vial Strengths of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in Previously Treated Subjects With Severe Hemophilia A
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Secondary ID [1]
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2013-003013-18
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Secondary ID [2]
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997HA307
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Severe Hemophilia A
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Condition category
Condition code
Blood
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Clotting disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - rFVIIIFc
Experimental: rFVIIIFc 1000 / 3000 PK Assessment - A single intravenous (IV) injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial followed by a single IV injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial.
Following the PK assessment, participants will receive either an episodic (on-demand) regimen with doses between 20 and 50 IU/kg based on the severity of the bleeding episode, or 1 of 2 prophylactic regimens: 50 IU/kg every 3 to 5 days or 65 IU/kg weekly. Participants will be allowed to switch from one regimen to another if approved by the Investigator.
Experimental: rFVIIIFc 3000 / 1000 PK Assessment - A single IV injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial followed by a single IV injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial.
Following the PK assessment, participants will receive either an episodic (on-demand) regimen with doses between 20 and 50 IU/kg based on the severity of the bleeding episode, or 1 of 2 prophylactic regimens: 50 IU/kg every 3 to 5 days or 65 IU/kg weekly. Participants will be allowed to switch from one regimen to another if approved by the Investigator.
Other interventions: rFVIIIFc
Administered as specified in the treatment arm.
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Intervention code [1]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay
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Assessment method [1]
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Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8).
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Timepoint [1]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Primary outcome [2]
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Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay
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Assessment method [2]
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The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
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Timepoint [2]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [1]
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Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay
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Assessment method [1]
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Maximum measured concentration of rFVIIIFc.
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Timepoint [1]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [2]
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Half-life (t½) as Measured by aPTT Clotting Assay
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Assessment method [2]
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Time required for the concentration of the drug to reach half of its original value.
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Timepoint [2]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [3]
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Clearance (CL) as Measured by the aPTT Clotting Assay
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Assessment method [3]
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The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
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Timepoint [3]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [4]
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Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay
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Assessment method [4]
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The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)
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Timepoint [4]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [5]
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Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay
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Assessment method [5]
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The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
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Timepoint [5]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [6]
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Time of Cmax (Tmax) as Measured by aPTT Clotting Assay
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Assessment method [6]
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Time at which maximum activity (Cmax) is observed.
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Timepoint [6]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [7]
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Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay
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Assessment method [7]
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Area under the plasma concentration time-curve from zero to the last measured concentration.
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Timepoint [7]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [8]
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Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay
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Assessment method [8]
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First order rate constant associated with the terminal portion of the curve (lambda z) .
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Timepoint [8]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [9]
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Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay
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Assessment method [9]
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Percentage of AUCinf extrapolated from the last data point to infinity.
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Timepoint [9]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [10]
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Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay
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Assessment method [10]
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Dose normalized area under the FVIII activity-time curve.
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Timepoint [10]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [11]
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Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT
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Assessment method [11]
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The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
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Timepoint [11]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [12]
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AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [12]
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Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8).
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Timepoint [12]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [13]
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IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [13]
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The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
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Timepoint [13]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [14]
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Cmax as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [14]
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Maximum measured concentration of rFVIIIFc.
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Timepoint [14]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [15]
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t½ as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [15]
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Time required for the concentration of the drug to reach half of its original value.
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Timepoint [15]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [16]
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CL as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [16]
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The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
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Timepoint [16]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [17]
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Vss as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [17]
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The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)
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Timepoint [17]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [18]
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MRT as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [18]
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The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
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Timepoint [18]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [19]
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Tmax as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [19]
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Time at which maximum activity (Cmax) is observed.
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Timepoint [19]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [20]
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AUClast as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [20]
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Area under the plasma concentration time-curve from zero to the last measured concentration.
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Timepoint [20]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [21]
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Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [21]
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First order rate constant associated with the terminal portion of the curve (lambda z).
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Timepoint [21]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [22]
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AUCext as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [22]
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Percentage of AUCinf extrapolated from the last data point to infinity.
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Timepoint [22]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [23]
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DNAUC as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [23]
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Dose normalized area under the FVIII activity-time curve.
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Timepoint [23]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [24]
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Vz as Measured by Two-Stage Chromogenic Clotting Assay
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Assessment method [24]
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The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
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Timepoint [24]
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Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
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Secondary outcome [25]
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Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay
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Assessment method [25]
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An inhibitor test result =0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of participants with confirmed inhibitor development was summarized overall.
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Timepoint [25]
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Predose, Month 3, Month 6/early withdrawal. Additionally: If inhibitor suspected; at 10-15 EDs; 2-4 weeks prior to scheduled surgery; preoperatively on day of surgery; 1-2 weeks post-surgery; at last postoperative visit (last 2 for major surgery only)
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Eligibility
Key inclusion criteria
Key
- Have severe hemophilia A
- Previously treated subject, defined as having at least 150 documented prior exposure
days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products
(other than any use of rFVIIIFc- study drug or commercial product) at Day 1. Fresh
frozen plasma treatment must not be considered in the count for documented exposure
days.
- No history of a positive inhibitor test or clinical signs of decreased response to
FVIII administrations. Family history of inhibitors will not exclude subjects.
- No measurable inhibitor activity using the Nijmegen-modified Bethesda assay at
Screening.
- Platelet count =100,000 platelets/µL at screening
- CD4 lymphocytes >200 mm3 if known as HIV antibody positive at screening.
- Viral load of <400 copies/mL if known HIV antibody positive at screening.
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Minimum age
12
Years
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Maximum age
No limit
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Sex
Males
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Subject is at high risk of bleeding during the 5-day period between the first and
second injections for PK analyses, as per Investigator discretion.
- Previous treatment with rFVIIIFc as study drug or commercial product.
- Other coagulation disorder(s) in addition to hemophilia A.
- History of hypersensitivity or anaphylaxis associated with any FVIII or IV
immunoglobulin administration.
- Currently taking (or likely to require during the study) acetylsalicylic acid (ASA),
except for low-dose ASA as prophylaxis (other nonsteroidal anti-inflammatory drugs are
permitted).
- Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to
Day 1. Exceptions to this include: ribavirin for treatment of hepatitis C virus (HCV),
and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more
than 7 days at a dose of =1 mg/kg within 12 weeks prior to Day 1) and/or inhaled
steroids.
NOTE: Other protocol-defined inclusion/exclusion Criteria May Apply
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Crossover
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/03/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/05/2015
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Sample size
Target
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Accrual to date
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Final
19
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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Research Site - Herston
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Recruitment hospital [2]
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Research Site - Perth
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Recruitment postcode(s) [1]
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- Herston
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Recruitment postcode(s) [2]
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- Perth
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Utah
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Country [3]
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United States of America
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State/province [3]
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Washington
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Country [4]
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United Kingdom
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State/province [4]
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Basingstoke
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Country [5]
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United Kingdom
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State/province [5]
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Cambridge
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Country [6]
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United Kingdom
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State/province [6]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Bioverativ Therapeutics Inc.
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The primary objective of the study is to characterize the pharmacokinetics (PK) of rFVIIIFc
administered at vial strengths of 1000 and 3000 IU in subjects with severe hemophilia A. The
secondary objective of the study is to evaluate the safety of rFVIIIFc beyond the PK
assessment for up to 6 months for a continued treatment period.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02083965
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Medical Director
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Address
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Bioverativ Therapeutics Inc.
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02083965
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