Pharmacokinetic Study of ADVATE 3000 IU in Previously Treated Patients With Severe Hemophilia A

Study Overview
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Brief Summary
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The objective of this clinical study is to compare the pharmacokinetic parameters of 3000 IU Advate using one 3000 IU potency vial dissolved in 5 mL diluent with that of 3000 IU Advate using two vials of 1500 IU potency dissolved in 5 mL diluent each (administered in 10 mL diluent in total) in previously treated patients with severe hemophilia A (factor VIII level < 1%).

Official Title
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Pharmacokinetic Comparison of 3000 IU Advate (rAHF-PFM) (Using One 3000 IU Potency Vial) With 3000 IU Advate (rAHF PFM) (Using Two 1500 IU Potency Vials) in Previously Treated Patients With Severe Hemophilia A: a Phase 4, Open-label, Prospective, Randomized, Controlled, Crossover, Multiple Center Study

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Octocog alfa (recombinant human coagulation factor VIII) [ADVATE]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is 18 to 65 years old, at the time of screening Participant has provided signed informed consent Participant has severe hemophilia A, defined by a baseline FVIII level < 1% of normal, as tested at screening at the central laboratory Participant's weight is between 55-65 kg Participant was previously treated with FVIII concentrate(s) for a minimum of 150 exposure days prior to study entry If Participant is HIV positive, he must be immunocompetent as determined with a CD4 count ≥ 200 cells/mm³ (CD4 count at screening) Participant is willing and able to comply with the requirements of the protocol Exclusion Criteria: Participant has a detectable FVIII inhibitor at screening, with a titer ≥ 0.4 Bethesda unit (BU) (Nijmegen modification of the Bethesda Assay) measured at the central laboratory Participant has a history of FVIII inhibitors with a titer ≥ 0.4 BU (by Nijmegen assay) or ≥ 0.5 BU (by Bethesda Assay) at any time prior to screening Participant has undergone a surgery within 21 days prior to screening or within 6 weeks prior to the anticipated first pharmacokinetics(PK) infusion Participant has an abnormal renal function (serum creatinine > 1.5 mg/dL) Participant has active hepatic disease (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >5 times the upper limit of normal) Participant 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 Participant has clinical and/or laboratory evidence of abnormal hemostasis from causes other than hemophilia A (eg, late-stage chronic liver disease, immune thrombocytopenia purpura) Participant is currently receiving, or is scheduled to receive during the course of the clinical study, an immunomodulating drug other than anti-retroviral chemotherapy (eg, alfa-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day) Participant has a known hypersensitivity to mouse or hamster proteins Participant has participated in another clinical study involving an investigational product or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product or investigational device during the course of this clinical study Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures Participant is a member of the team conducting this clinical study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, or parents) as well as employees of the investigator or site personnel conducting the clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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 |
| --- | --- |
| Active Comparator: 1<br>One infusion using a 3000 IU potency vial of Advate dissolved and administered in 5 mL diluent followed by a second infusion of two 1500 IU potency vials of Advate dissolved in 5 mL diluent each (administered in 10 mL diluent in total) | Biological: Octocog alfa (recombinant human coagulation factor VIII) [ADVATE]<br>* Participants will receive 3000 IU Advate using one 3000 IU potency vial dissolved in 5 mL diluent followed by two 1500 IU potency vials dissolved in 5 mL diluent each (administered in 10 mL diluent in total) or the alternate sequence<br>* Other names: Antihemophilic Factor (Recombinant)- Plasma/albumin free method (rAHF-PFM);|
| Active Comparator: 2<br>One infusion of two 1500 IU potency vials of Advate dissolved in 5 mL diluent each (administered in 10 mL diluent in total) followed by a second infusion of one 3000 IU potency vial of Advate dissolved and administered in 5 mL diluent | Biological: Octocog alfa (recombinant human coagulation factor VIII) [ADVATE]<br>* Participants will receive 3000 IU Advate using one 3000 IU potency vial dissolved in 5 mL diluent followed by two 1500 IU potency vials dissolved in 5 mL diluent each (administered in 10 mL diluent in total) or the alternate sequence<br>* Other names: Antihemophilic Factor (Recombinant)- Plasma/albumin free method (rAHF-PFM);|

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 From 0 to 48 Hours (AUC 0-48h). Chromogenic Assay | Computed using the linear trapezoidal method. | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). One-stage Activated Partial Thromboplastin Time (aPTT) Assay | Computed using the linear trapezoidal method. | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). Chromogenic Assay | The total area under the plasma concentration versus time curve when the concentration is extrapolated to zero using the slope of the β-phase of the model. | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). One-stage aPTT Assay | The total area under the plasma concentration versus time curve when the concentration is extrapolated to zero using the slope of the β-phase of the model. | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Incremental Recovery at Cmax - Chromogenic Assay | Determined as the highest Factor VIII (FVIII) activity achieved post-infusion | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3 hours. | 
| Incremental Recovery at Cmax - One-stage aPTT Assay | Determined as the highest FVIII activity achieved post-infusion | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3 hours. | 
| Incremental Recovery at 30 Minutes- Chromogenic Assay | Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion | 30 minutes pre-infusion and 30 minutes post-infusion | 
| Incremental Recovery at 30 Minutes- One-stage aPTT Assay | Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion | 30 minutes pre-infusion and 30 minutes post-infusion | 
| Elimination Phase Half-life- Chromogenic Assay | calculated as log_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Elimination Phase Half-life- One-stage aPTT Assay | calculated as log_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| FVIII Clearance- Chromogenic Assay | computed as the dose divided by total AUC | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| FVIII Clearance- One-stage aPTT Assay | Computed as the dose divided by total AUC | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Mean Residence Time (MRT)- Chromogenic Assay | Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC) | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Mean Residence Time (MRT)- One-stage aPTT Assay | Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC) | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Volume of Distribution at Steady State- Chromogenic Assay | computed as Clearance (CL) * Mean residence time (MRT) | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Volume of Distribution at Steady State- One-stage aPTT Assay | computed as CL * MRT | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- Chromogenic Assay | Determined as the highest FVIII activity achieved post-infusion. | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | 
| Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- One-stage aPTT Assay | Determined as the highest FVIII activity achieved post-infusion. | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. |