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

• ClinicalTrials.gov Identifier: NCT00666406
• Recruitment Status: Completed
• First Posted: April 24, 2008
• Results First Posted: March 26, 2013
• Last Update Posted: May 19, 2021
• Sponsor: Baxalta now part of Shire
• Information provided by (Responsible Party): Takeda ( Baxalta now part of Shire )

Study Description

Brief Summary:

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%).

Condition or disease	Intervention/treatment	Phase
Hemophilia A	Drug: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM); Drug: Recombinant Factor VIII (rAHF)	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 31, 2008
• Actual Primary Completion Date: February 18, 2009
• Actual Study Completion Date: February 18, 2009

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
2. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
3. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
4. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.

Secondary Outcome Measures :

1. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   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
2. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
3. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
4. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
5. Systemic Clearance (Cl). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
6. Systemic Clearance (Cl). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
7. Systemic Clearance (Cl). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
8. Systemic Clearance (Cl). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
9. Maximum Plasma Concentration (C-max). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
   C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
10. Maximum Plasma Concentration (C-max). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
11. Maximum Plasma Concentration (C-max). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
12. Maximum Plasma Concentration (C-max). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
13. Terminal Half-life. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    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).
14. Terminal Half-life. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.
15. Terminal Half-life. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.
16. Terminal Half-life. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.
17. Incremental Recovery. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Increase in factor VIII concentration from pre- to post-infusion.
18. Incremental Recovery. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    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.
19. Incremental Recovery. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Increase in factor VIII concentration from pre- to post-infusion
20. Incremental Recovery. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Increase in factor VIII concentration from pre- to post-infusion
21. Mean Residence Time (MRT). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
22. Mean Residence Time (MRT). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
23. Mean Residence Time (MRT). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
24. Mean Residence Time (MRT). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
25. Time to Reach the Maximum Plasma Concentration (Tmax). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
26. Time to Reach the Maximum Plasma Concentration (Tmax). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
27. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
28. Time to Reach the Maximum Plasma Concentration (Tmax). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
29. Volume of Distribution at Steady State (Vss). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Computed as weight-adjusted Clearance * Mean Residence Time
30. Volume of Distribution at Steady State (Vss). Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Computed as weight-adjusted Clearance (CL) * Mean Residence Time
31. 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) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Computed as weight-adjusted CL * Mean Residence Time
32. Volume of Distribution at Steady State (Vss). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the Study Site) [ Time Frame: 0-30 minutes before infusion up to 48 hours post-infusion ]
    Computed as weight-adjusted CL * Mean Residence Time

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Germany

Bonn, Germany, 53127

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

• Study Director: Study Director; Takeda

More Information

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT00666406
• Other Study ID Numbers: 060601; 2007-004834-18 ( EudraCT Number )
• First Posted: April 24, 2008
• Results First Posted: March 26, 2013
• Last Update Posted: May 19, 2021
• Last Verified: April 2021

Additional relevant MeSH terms:

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