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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Biological: Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM). (Antihemophilic factor is also known as Factor VIII)

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Kentucky
    • Lexington, Kentucky, United States
    • Louisville, Kentucky, United States
  • Michigan
    • Detroit, Michigan, United States
  • New Jersey
    • New Brunswick, New Jersey, United States
  • New York
    • New York, New York, United States
  • Ohio
    • Cincinnati, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • Texas
    • Houston, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; 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); 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.; Other Names: ADVATE
ACTIVE_COMPARATOR: 2; 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); 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.; Other Names: ADVATE

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 8, 2008
• Primary Completion (ACTUAL): October 23, 2009
• Study Completion (ACTUAL): October 23, 2009

Study Registration Dates

• First Submitted: August 4, 2009
• First Submitted That Met QC Criteria: August 4, 2009
• First Posted (ESTIMATE): August 6, 2009

Study Record Updates

• Last Update Posted (ACTUAL): May 24, 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: 060702