Dose-Response Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A - Full Text View

Sponsor:	Baxter Healthcare Corporation
Information provided by:	Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:	NCT00289536

Purpose

The purpose of this study is to determine the effect of 3 doses of ADVATE rAHF-PFM on initial recovery (% increase [IU/dL] per IU/kg infused) and major single-infusion pharmacokinetic parameters. The 3 doses are 15, 30, and 50 IU/kg. Prior to each infusion, subjects will not have received treatment with a factor VIII concentrate for at least 3 days. Blood samples will be drawn within 30 minutes pre-infusion and at 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32 and 48 hours post-infusion. A washout period of at least 3 days, but no more than 30 days between the last blood draw and the next infusion will be observed. During participation, subjects will maintain their preexisting treatment regimens with ADVATE rAHF-PFM or other factor VIII concentrate.

A secondary objective is to investigate the relationship between pharmacokinetic parameters at each dose level and the levels of von Willebrand factor ristocetin cofactor activity and von Willebrand factor antigen at baseline.

Condition	Intervention	Phase
Hemophilia A	Biological: Antihemophilic factor, recombinant, manufactured protein-free	Phase IV

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Advate Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (ADVATE rAHF-PFM): A Phase 4 Study to Determine the Pharmacokinetic Response of Patients Diagnosed With Severe Hemophilia A to Different Doses of ADVATE rAHF-PFM

Resource links provided by NLM:

Genetics Home Reference related topics: hemophilia Help Me Understand Genetics

MedlinePlus related topics: Hemophilia

Drug Information available for: Octocog alfa Moroctocog Alfa Factor VIII

U.S. FDA Resources

Further study details as provided by Baxter Healthcare Corporation:

Primary Outcome Measures:

Initial Recovery [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion to 30 minutes post-infusion ] [ Designated as safety issue: No ]
Percent increase in factor VIII concentration per dose from pre- to post-infusion

Secondary Outcome Measures:

Area Under the Curve/Dose [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Area under the plasma factor VIII concentration versus time curve (AUC) estimated by linear trapezoidal method per dose.
Terminal Half-life [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Computed from the regression slope in the terminal phase of the model (the slope is biphasic). Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.
Area Under the Curve [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
Total Area Under the Curve [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Total AUC with extrapolation using the slope of the β-phase
Total Area Under the Moment Curve [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Total area under the first moment curve (AUMC) estimated by linear trapezoidal methods
Weight-adjusted Clearance [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Computed as weight-adjusted dose divided by total AUC
Mean Residence Time [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Computed as total AUMC divided by total AUC
Volume of Distribution at Steady State [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Computed as weight-adjusted CL * Mean Residence Time
Maximum Plasma Concentration [ Time Frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion ] [ Designated as safety issue: No ]
Maximal factor VIII concentration after infusion
Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco) [ Time Frame: At baseline and before each pharmacokinetic evaluation ] [ Designated as safety issue: No ]
Percentage of normal VWF:Rco activity. Normal is a lab standard consisting of a non-hemophilic population. Relationships between baseline VWF:Rco and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically.
Pre-infusion Von Willebrand Factor Antigen (VWF:Ag) [ Time Frame: At baseline and before each pharmacokinetic evaluation ] [ Designated as safety issue: No ]
Percentage of VWF:Ag. Relationships between baseline VWF:Ag and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically.

Enrollment:	38
Study Start Date:	February 2006
Study Completion Date:	April 2007
Primary Completion Date:	April 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Low Dose	Biological: Antihemophilic factor, recombinant, manufactured protein-free 15 IU/kg rAHF-PFM
Experimental: Medium Dose	Biological: Antihemophilic factor, recombinant, manufactured protein-free 30 IU/kg rAHF-PFM
Experimental: High Dose	Biological: Antihemophilic factor, recombinant, manufactured protein-free 50 IU/kg rAHF-PFM

Eligibility

Ages Eligible for Study:	12 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

The subject has severe hemophilia A as defined by a baseline factor VIII activity <1% of normal; tested at screening. (A minimum washout period of 3 days is required before the blood sample can be drawn to determine baseline factor VIII levels.)
The subject has a documented history of at least 150 exposure days to factor VIII concentrates (either plasma-derived or recombinant).
The subject is within 12 to 65 years of age.
The subject has a Karnofsky performance score >60.
The subject is human immunodeficiency virus negative (HIV-) or HIV+ with CD4 count >=400 cells/mm3 (CD4 count determined at screening, if necessary).
The subject or subject´s legally authorized representative has provided written informed consent.

Exclusion Criteria:

The subject has a known hypersensitivity to mouse or hamster proteins or to factor VIII concentrates.
The subject has a history of factor VIII inhibitors with titer >=0.8 BU (Bethesda Assay) or >=0.4 BU (Nijmegen modification of the Bethesda Assay) any time prior to screening.
The subject has a detectable factor VIII inhibitor at screening, >=0.4 BU (Nijmegen modification of the Bethesda Assay), in the Baxter central laboratory.
The subject has severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) >1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices.
The subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (e.g. qualitative platelet defect or von Willebrand´s Disease).
The subject has participated in another investigational study within 30 days of enrollment.
The subject´s clinical condition may require a major or moderate surgery (estimated blood loss >500 mL) during the period of participation in the study.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00289536

Locations

United States, Arkansas

Little Rock, Arkansas, United States
United States, California

Los Angeles, California, United States
United States, Illinois

Peoria, Illinois, United States
United States, Iowa

Iowa City, Iowa, United States
United States, New Jersey

New Brunswick, New Jersey, United States
United States, Ohio

Cincinnati, Ohio, United States
United States, Oklahoma

Oklahoma City, Oklahoma, United States
United States, Texas

Houston, Texas, United States

Sponsors and Collaborators

Baxter Healthcare Corporation

Investigators

Principal Investigator:	Deborah Brown, MD	The University of Texas Health Science Center, Houston
Principal Investigator:	Ralph Gruppo, MD	Cincinnati Children´s Hospital Medical Center
Principal Investigator:	Michael Tarantino, MD	Comprehensive Bleeding Disorders Center
Principal Investigator:	Jorge Di Paola, MD	University of Iowa
Principal Investigator:	Claire Philipp, MD	University of Medicine & Dentistry of NJ, Robert Wood Johnson Medical School
Principal Investigator:	Kapil Saxena, MD	University of Oklahoma HSC
Principal Investigator:	Doris V Quon, MD	Los Angeles Orthopaedic Hospital
Principal Investigator:	Kimo Stine, MD	Arkansas Children´s Hospital

More Information

No publications provided

Responsible Party:	Jorge Escobar, Clinical Project Manager, Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:	NCT00289536 History of Changes
Other Study ID Numbers:	060403
Study First Received:	February 9, 2006
Results First Received:	September 30, 2010
Last Updated:	May 4, 2011
Health Authority:	United States: Food and Drug Administration

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
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 09, 2012