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

Study Overview
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Brief Summary
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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%).

Official Title
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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

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM)
* Drug: Recombinant Factor VIII (rAHF)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |