Pharmacokinetic Comparison of Advate rAHF-PFM With Recombinate rAHF in Patients With Severe Hemophilia A

Pharmacokinetic Comparison of Advate rAHF-PFM With Recombinate rAHF in Patients With Severe Hemophilia A: a Phase IV, Prospective, Randomized, Controlled, Cross-over, Single Center Study

The purpose of this study is to compare the pharmacokinetic parameters and safety of Advate rAHF-PFM versus Recombinate rAHF in well described previously treated patients with severe hemophilia A (factor VIII level < 1%).

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Drug: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM); Drug: Recombinant Factor VIII (rAHF)

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany, 53127

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent obtained from participant or legally authorized representative
• 15-60 years old
• Factor VIII level < 1% as documented by previously measured factor VIII and genotyping
• Previously treated with factor VIII concentrate(s) for a minimum of at least 150 exposure days (as documented by the study site investigator) prior to study entry
• Observed decrease of efficacy by subject and/or treating physician after being switched from Recombinate rAHF to Advate rAHF-PFM

Exclusion Criteria:

• The participant has a detectable factor VIII inhibitor at screening, with a titer >= 0.4 Bethesda Unit (BU) (Nijmegen modification of the Bethesda Assay) measured at the local and the central laboratory
• The participant has a known hypersensitivity to mouse or hamster proteins
• The participant is participating in another investigational drug study within 30 days prior to screening
• The participant is identified by the investigator as being unable or unwilling to cooperate with study procedures

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Advate rAHF-PFM	Drug: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM); Infusion of 50 +/- 5 IU/kg bodyweight; Other Names: Advate rAHF-PFM; Recombinant Protein-Free Factor VIII (rAHF-PFM)
Active Comparator: 2; Recombinate rAHF	Drug: Recombinant Factor VIII (rAHF); Infusion of 50 +/- 5 IU/kg bodyweight; Other Names: Recombinate rAHF; Antihemophilic Factor (Recombinant)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 48 Hours. One-Stage Activated Partial Thromboplastin Time (aPTT) -Based Assay Performed at Central Laboratory (Medical University Vienna)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.	0-30 minutes before infusion up to 48 hours post-infusion
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 48 Hours. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.	0-30 minutes before infusion up to 48 hours post-infusion
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 48 Hours. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.	0-30 minutes before infusion up to 48 hours post-infusion
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 48 Hours. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.	0-30 minutes before infusion up to 48 hours post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to Infinity. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve. FVIII activity measurement	0-30 minutes before infusion up to 48 hours post-infusion
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to Infinity. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.	0-30 minutes before infusion up to 48 hours post-infusion
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to Infinity. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.	0-30 minutes before infusion up to 48 hours post-infusion
Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to Infinity. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.	0-30 minutes before infusion up to 48 hours post-infusion
Systemic Clearance (Cl). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Systemic Clearance (Cl). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Systemic Clearance (Cl). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Systemic Clearance (Cl). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Maximum Plasma Concentration (C-max). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.	0-30 minutes before infusion up to 48 hours post-infusion
Maximum Plasma Concentration (C-max). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.	0-30 minutes before infusion up to 48 hours post-infusion
Maximum Plasma Concentration (C-max). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.	0-30 minutes before infusion up to 48 hours post-infusion
Maximum Plasma Concentration (C-max). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.	0-30 minutes before infusion up to 48 hours post-infusion
Terminal Half-life. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations (9 to 48 hours).	0-30 minutes before infusion up to 48 hours post-infusion
Terminal Half-life. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.	0-30 minutes before infusion up to 48 hours post-infusion
Terminal Half-life. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.	0-30 minutes before infusion up to 48 hours post-infusion
Terminal Half-life. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.	0-30 minutes before infusion up to 48 hours post-infusion
Incremental Recovery. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	Increase in factor VIII concentration from pre- to post-infusion.	0-30 minutes before infusion up to 48 hours post-infusion
Incremental Recovery. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Computed from the terminal or disposition rate constant obtained from log_e -linear fitting using the least squares deviation to the last five quantifiable concentrations.	0-30 minutes before infusion up to 48 hours post-infusion
Incremental Recovery. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Increase in factor VIII concentration from pre- to post-infusion	0-30 minutes before infusion up to 48 hours post-infusion
Incremental Recovery. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Increase in factor VIII concentration from pre- to post-infusion	0-30 minutes before infusion up to 48 hours post-infusion
Mean Residence Time (MRT). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Mean Residence Time (MRT). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Mean Residence Time (MRT). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Mean Residence Time (MRT). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.	0-30 minutes before infusion up to 48 hours post-infusion
Time to Reach the Maximum Plasma Concentration (Tmax). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).	0-30 minutes before infusion up to 48 hours post-infusion
Time to Reach the Maximum Plasma Concentration (Tmax). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).	0-30 minutes before infusion up to 48 hours post-infusion
Time to Reach the Maximum Plasma Concentration (Tmax). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).	0-30 minutes before infusion up to 48 hours post-infusion
Time to Reach the Maximum Plasma Concentration (Tmax). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).	0-30 minutes before infusion up to 48 hours post-infusion
Volume of Distribution at Steady State (Vss). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)	Computed as weight-adjusted Clearance * Mean Residence Time	0-30 minutes before infusion up to 48 hours post-infusion
Volume of Distribution at Steady State (Vss). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Computed as weight-adjusted Clearance (CL) * Mean Residence Time	0-30 minutes before infusion up to 48 hours post-infusion
Volume of Distribution at Steady State (Vss). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Computed as weight-adjusted CL * Mean Residence Time	0-30 minutes before infusion up to 48 hours post-infusion
Volume of Distribution at Steady State (Vss). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site)	Computed as weight-adjusted CL * Mean Residence Time	0-30 minutes before infusion up to 48 hours post-infusion

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2008
• Primary Completion (Actual): February 18, 2009
• Study Completion (Actual): February 18, 2009

Study Registration Dates

• First Submitted: April 22, 2008
• First Submitted That Met QC Criteria: April 22, 2008
• First Posted (Estimate): April 24, 2008

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: 060601; 2007-004834-18 (EudraCT Number)