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Completed

NCT Number: NCT00289536

Dose-Response Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A

The purpose of this study is to determine the effect of 3 doses of ADVATE rAHF-PFM on initial recovery (% increase [IU/dL] per IU/kg infused) and major single-infusion pharmacokinetic parameters. The 3 doses are 15, 30, and 50 IU/kg. Prior to each infusion, subjects will not have received treatment with a factor VIII concentrate for at least 3 days. Blood samples will be drawn within 30 minutes pre-infusion and at 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32 and 48 hours post-infusion. A washout period of at least 3 days, but no more than 30 days between the last blood draw and the next infusion will be observed. During participation, subjects will maintain their preexisting treatment regimens with ADVATE rAHF-PFM or other factor VIII concentrate.

A secondary objective is to investigate the relationship between pharmacokinetic parameters at each dose level and the levels of von Willebrand factor ristocetin cofactor activity and von Willebrand factor antigen at baseline.

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Key information

Conditions

Hemophilia A Blood Coagulation Disorders Blood Coagulation Disorders, Inherited Coagulation Protein Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemorrhagic Disorders

Age range

12 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Little Rock, Arkansas, United States

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • The subject has severe hemophilia A as defined by a baseline factor VIII activity <1% of normal; tested at screening. (A minimum washout period of 3 days is required before the blood sample can be drawn to determine baseline factor VIII levels.)
  • The subject has a documented history of at least 150 exposure days to factor VIII concentrates (either plasma-derived or recombinant).
  • The subject is within 12 to 65 years of age.
  • The subject has a Karnofsky performance score >60.
  • The subject is human immunodeficiency virus negative (HIV-) or HIV+ with CD4 count >=400 cells/mm3 (CD4 count determined at screening, if necessary).
  • The subject or subject´s legally authorized representative has provided written informed consent.

Exclusion criteria

  • The subject has a known hypersensitivity to mouse or hamster proteins or to factor VIII concentrates.
  • The subject has a history of factor VIII inhibitors with titer >=0.8 BU (Bethesda Assay) or >=0.4 BU (Nijmegen modification of the Bethesda Assay) any time prior to screening.
  • The subject has a detectable factor VIII inhibitor at screening, >=0.4 BU (Nijmegen modification of the Bethesda Assay), in the Baxter 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´s Disease).
  • The subject has participated in another investigational study within 30 days of enrollment.
  • The subject´s clinical condition may require a major or moderate surgery (estimated blood loss >500 mL) during the period of participation in the study.

Treatment and study plan

Antihemophilic factor, recombinant, manufactured protein-free

Biological

15 IU/kg rAHF-PFM

Primary outcomes

  1. Initial Recovery

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion to 30 minutes post-infusion

    Percent increase in factor VIII concentration per dose from pre- to post-infusion

Secondary outcomes

  1. Area Under the Curve/Dose

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Area under the plasma factor VIII concentration versus time curve (AUC) estimated by linear trapezoidal method per dose.

  2. Terminal Half-life

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Computed from the regression slope in the terminal phase of the model (the slope is biphasic). 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%.

  3. Area Under the Curve

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.

  4. Total Area Under the Curve

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Total AUC with extrapolation using the slope of the β-phase

  5. Total Area Under the Moment Curve

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Total area under the first moment curve (AUMC) estimated by linear trapezoidal methods

  6. Weight-adjusted Clearance

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Computed as weight-adjusted dose divided by total AUC

  7. Mean Residence Time

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Computed as total AUMC divided by total AUC

  8. Volume of Distribution at Steady State

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Computed as weight-adjusted CL * Mean Residence Time

  9. Maximum Plasma Concentration

    Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

    Maximal factor VIII concentration after infusion

  10. Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco)

    Time frame: At baseline and before each pharmacokinetic evaluation

    Percentage of normal VWF:Rco activity. Normal is a lab standard consisting of a non-hemophilic population. Relationships between baseline VWF:Rco and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically.

  11. Pre-infusion Von Willebrand Factor Antigen (VWF:Ag)

    Time frame: At baseline and before each pharmacokinetic evaluation

    Percentage of VWF:Ag. Relationships between baseline VWF:Ag and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically.

Sponsors and collaborators

Lead sponsor

Baxalta now part of Shire

Industry

Registry information

Official study title

Advate Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (ADVATE rAHF-PFM): A Phase 4 Study to Determine the Pharmacokinetic Response of Patients Diagnosed With Severe Hemophilia A to Different Doses of ADVATE rAHF-PFM

Important dates

Study start
2006
Primary completion
2007
Study completion
2007
First posted
Feb 10, 2006
Registry last updated
Jun 10, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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