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

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

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%).

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Biological: Octocog alfa (recombinant human coagulation factor VIII) [ADVATE]

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 4

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1233
• Russian Federation
  • Kirov, Russian Federation
  • Moscow, Russian Federation, 125167
  • St. Petersburg, Russian Federation, 195213

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; 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]; 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; Other Names: ADVATE; Antihemophilic Factor (Recombinant)- Plasma/albumin free method (rAHF-PFM)
Active Comparator: 2; 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]; 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; Other Names: ADVATE; Antihemophilic Factor (Recombinant)- Plasma/albumin free method (rAHF-PFM)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2009
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: June 5, 2009
• First Submitted That Met QC Criteria: June 5, 2009
• First Posted (Estimate): June 8, 2009

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: 060801; 2008-007347-13 (EudraCT Number)