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

• ClinicalTrials.gov Identifier: NCT00916032
• Recruitment Status: Completed
• First Posted: June 8, 2009
• Results First Posted: September 5, 2013
• Last Update Posted: May 19, 2021
• Sponsor: Baxalta now part of Shire
• Information provided by (Responsible Party): Takeda ( Baxalta now part of Shire )

Study Description

Brief Summary:

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%).

Condition or disease	Intervention/treatment	Phase
Hemophilia A	Biological: Octocog alfa (recombinant human coagulation factor VIII) [ADVATE]	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 29, 2009
• Actual Primary Completion Date: April 1, 2010
• Actual Study Completion Date: April 1, 2010

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). Chromogenic Assay [ Time Frame: 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. ]
   Computed using the linear trapezoidal method.
2. Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). One-stage Activated Partial Thromboplastin Time (aPTT) Assay [ Time Frame: 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. ]
   Computed using the linear trapezoidal method.

Secondary Outcome Measures :

1. Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). Chromogenic Assay [ Time Frame: 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. ]
   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.
2. Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). One-stage aPTT Assay [ Time Frame: 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. ]
   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.
3. Incremental Recovery at Cmax - Chromogenic Assay [ Time Frame: 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. ]
   Determined as the highest Factor VIII (FVIII) activity achieved post-infusion
4. Incremental Recovery at Cmax - One-stage aPTT Assay [ Time Frame: 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. ]
   Determined as the highest FVIII activity achieved post-infusion
5. Incremental Recovery at 30 Minutes- Chromogenic Assay [ Time Frame: 30 minutes pre-infusion and 30 minutes post-infusion ]
   Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion
6. Incremental Recovery at 30 Minutes- One-stage aPTT Assay [ Time Frame: 30 minutes pre-infusion and 30 minutes post-infusion ]
   Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion
7. Elimination Phase Half-life- Chromogenic Assay [ Time Frame: 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. ]
   calculated as log_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model
8. Elimination Phase Half-life- One-stage aPTT Assay [ Time Frame: 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. ]
   calculated as log_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model
9. FVIII Clearance- Chromogenic Assay [ Time Frame: 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. ]
   computed as the dose divided by total AUC
10. FVIII Clearance- One-stage aPTT Assay [ Time Frame: 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. ]
    Computed as the dose divided by total AUC
11. Mean Residence Time (MRT)- Chromogenic Assay [ Time Frame: 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. ]
    Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC)
12. Mean Residence Time (MRT)- One-stage aPTT Assay [ Time Frame: 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. ]
    Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC)
13. Volume of Distribution at Steady State- Chromogenic Assay [ Time Frame: 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. ]
    computed as Clearance (CL) * Mean residence time (MRT)
14. Volume of Distribution at Steady State- One-stage aPTT Assay [ Time Frame: 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. ]
    computed as CL * MRT
15. Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- Chromogenic Assay [ Time Frame: 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. ]
    Determined as the highest FVIII activity achieved post-infusion.
16. Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- One-stage aPTT Assay [ Time Frame: 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. ]
    Determined as the highest FVIII activity achieved post-infusion.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Bulgaria

Sofia, Bulgaria, 1233

Russian Federation

Kirov, Russian Federation

Moscow, Russian Federation, 125167

St. Petersburg, Russian Federation, 195213

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

• Study Director: Study Director; Takeda

More Information

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT00916032
• Other Study ID Numbers: 060801; 2008-007347-13 ( EudraCT Number )
• First Posted: June 8, 2009
• Results First Posted: September 5, 2013
• Last Update Posted: May 19, 2021
• Last Verified: April 2021

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