Pharmacokinetic Study of ADVATE Reconstituted in 2 mL Sterile Water for Injection

Study Overview
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Brief Summary
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The purpose of this study is to determine the pharmacokinetics and safety of Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM) reconstituted in 2 mL sterile water for injection (SWFI) and compare with those of rAHF-PFM reconstituted in 5 mL of SWFI.

Official Title
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A Phase 1, Prospective, Randomized, Crossover Study to Compare the Pharmacokinetics and Safety of rAHF-PFM Reconstituted in 2 mL Versus 5 mL SWFI in Previously Treated Severe Hemophilia A Patients

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM). (Antihemophilic factor is also known as Factor VIII)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject or subject's legally authorized representative has provided written informed consent The subject has severe hemophilia A as defined by a baseline FVIII activity <= 1% of normal; tested at screening The adolescent/adult subject has a documented history of at least 150 exposure days to FVIII concentrates (either plasma-derived or recombinant), and the pediatric subject has at least 50 exposure days The subject is >= 12 to <= 65 years of age for the complete pharmacokinetic assessment and >= 2 to < 12 years for the incremental recovery assessment The subject has a Karnofsky performance score > 60 The subject is human immunodeficiency virus negative (HIV-) or HIV+ with stable CD4 count >= 200 cells/mm³ (CD4 count determined at screening, if necessary) Exclusion Criteria: The subject has a known hypersensitivity to mouse or hamster proteins or to FVIII concentrates The subject has a history of FVIII inhibitors with titer >= 0. 5 BU (Bethesda Assay) or >= 0.4 BU (Nijmegen modification of the Bethesda Assay) any time prior to screening The subject has a detectable FVIII inhibitor at screening, >= 0.4 BU (Nijmegen modification of the Bethesda Assay), in the 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 Disease) The subject has received another investigational product within 30 days of enrollment The subject's clinical condition may require major or moderate surgery (estimated blood loss > 500 mL) during the period of participation in the study Subjects with clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance The subject is a female of childbearing potential with a positive pregnancy test at screening

Ages Eligible for Study
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Minimum Age: 2 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>ADVATE reconstituted in 2 mL sterile water for infusion | Biological: Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM). (Antihemophilic factor is also known as Factor VIII)<br>* Subjects are randomized to receive an infusion of rAHF-PFM reconstituted in 2 mL sterile water for infusion (SWFI) followed (after a wash-out period) by rAHF-PFM reconstituted in 5 mL SWFI or in 5 mL then 2 mL SWFI(cross-over design). Each subject will receive 2 infusions.<br>* Other names: ADVATE;|
| Active Comparator: 2<br>ADVATE reconstituted in 5 mL sterile water for infusion | Biological: Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM). (Antihemophilic factor is also known as Factor VIII)<br>* Subjects are randomized to receive an infusion of rAHF-PFM reconstituted in 2 mL sterile water for infusion (SWFI) followed (after a wash-out period) by rAHF-PFM reconstituted in 5 mL SWFI or in 5 mL then 2 mL SWFI(cross-over design). Each subject will receive 2 infusions.<br>* Other names: ADVATE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve | Area under the factor VIII (FVIII) plasma concentration versus time curve (AUC) from 0 to 48 hours estimated using the linear trapezoidal method | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Area Under the Curve | Total AUC when the concentration is extrapolated to zero using the slope of the β-phase of the model | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Adjusted in Vivo Incremental Recovery | Increase in factor VIII concentration from pre- to post-infusion | Pharmacokinetic evaluations: 30 minutes pre-infusion to 30 minutes post-infusion | 
| Terminal Half-life | Computed from the regression slope in the terminal phase of the model. 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 | 
| Weight-Adjusted Clearance | Computed as the 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 area under the moment curve divided by the total AUC. 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 | 
| Volume of Distribution at Steady State | Computed as weight-adjusted clearance * mean residence time | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Maximum Plasma Concentration | Maximal factor VIII concentration post-infusion | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 
| Number and Severity of Infusion Site Reactions | Infusion-related local reactions (including pain, tenderness, erythema, induration, and bruising) and severity were evaluated according to an FDA-defined grading scale (FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials; 2007). | Within 5 minutes pre-infusion up to 24 hours post-infusion | 
| Infusion Site Pain | Pain was assessed by participants (≥5 years of age) on a visual analog scale (VAS) from 0 (no pain) to 100 (worst possible pain). | Within 5 minutes post-infusion up to 24 hours post-infusion |