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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Antihemophilic factor, recombinant, manufactured protein-free
* Biological: Antihemophilic factor, recombinant, manufactured protein-free
* Biological: Antihemophilic factor, recombinant, manufactured protein-free


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 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: Low Dose<br> | Biological: Antihemophilic factor, recombinant, manufactured protein-free<br>* 15 IU/kg rAHF-PFM<br>|
| Experimental: Medium Dose<br> | Biological: Antihemophilic factor, recombinant, manufactured protein-free<br>* 30 IU/kg rAHF-PFM<br>|
| Experimental: High Dose<br> | Biological: Antihemophilic factor, recombinant, manufactured protein-free<br>* 50 IU/kg rAHF-PFM<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial Recovery | Percent increase in factor VIII concentration per dose from pre- to post-infusion | Pharmacokinetic evaluations: 30 minutes pre-infusion to 30 minutes post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve/Dose | Area under the plasma factor VIII concentration versus time curve (AUC) estimated by linear trapezoidal method per dose. | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Terminal Half-life | 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%. | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Area Under the Curve | AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve. | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Total Area Under the Curve | Total AUC with extrapolation using the slope of the β-phase | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Total Area Under the Moment Curve | Total area under the first moment curve (AUMC) estimated by linear trapezoidal methods | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Weight-adjusted Clearance | Computed as weight-adjusted dose divided by total AUC | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Mean Residence Time | Computed as total AUMC divided by total AUC | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Volume of Distribution at Steady State | Computed as weight-adjusted CL * Mean Residence Time | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Maximum Plasma Concentration | Maximal factor VIII concentration after infusion | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco) | 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. | At baseline and before each pharmacokinetic evaluation | 
| Pre-infusion Von Willebrand Factor Antigen (VWF:Ag) | Percentage of VWF:Ag. Relationships between baseline VWF:Ag and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically. | At baseline and before each pharmacokinetic evaluation |