Phase 3/4 Study of a Recombinant Protein-Free Factor VIII (rAHF-PFM): Comparison of Continuous Infusion Versus Intermittent Bolus Infusion in Hemophilia A Subjects Undergoing Major Orthopedic Surgery
Condition: Hemophilia A
MeSH terms: Hemophilia A
Intervention: Recombinant Protein-Free Factor VIII (rAHF-PFM); Recombinant Protein-Free Factor VIII (rAHF-PFM)
Intervention description: An initial loading dose will be administered intravenously over a period <= 5 minutes (maximum of infusion rate of 10 mL/minute) within 60 minutes prior to surgery dose in order to maintain a minimum target FVIII level of at least 80% of normal.
CI will start prior to surgery as soon as the loading dose has been administered, at a rate calculated according to a formula provided by the sponsor.
All study product must be administered with a syringe pump running at an infusion rate according to the dosing regimen, but always >= 0.4 mL/h.; The treatment schedule for intermittent BI of rAHF-PFM will begin with the administration of the loading dose according to the dose recommendations provided by the sponsor. If required by the hemostatic challenge, additional boluses may be administered after a blood sample for FVIII determination has been drawn. All infusions of rAHF PFM will be given over a period <= 5 minutes (maximum infusion rate, 10 mL/min).
Intervention MeSH terms: Factor VIII
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 85.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Hemophilia A (severe or moderately severe)

Summary:

      The purpose of this study is to compare the hemostatic efficacy and safety of continuous
      infusion versus intermittent bolus infusion in the peri- and post-operative setting,
      employing rAHF-PFM, a recombinant antihemophilic factor manufactured without added human or
      animal proteins, in previously treated patients with severe or moderately severe hemophilia A
      (baseline factor VIII level <= 2% of normal) who are undergoing unilateral major orthopedic
      surgery that requires drain placement. The total study period per subject (from consent to
      study completion) will vary from approximately 9 to 26 weeks and will involve clinical and
      laboratory assessments.
    

Eligibility criteria:

        Inclusion Criteria:

          -  The subject or the subject's legally authorized representative has provided signed
             informed consent.

          -  The subject is within 18 to 70 years of age.

          -  The subject has severe or moderately severe hemophilia A, defined by a baseline factor
             VIII level <= 2% of normal, as tested at screening. A subset of 15 subjects per group
             must have baseline factor VIII levels < 1% of normal.

          -  The aPTT must be within the range of normal after administration of FVIII concentrate,
             as determined in the preoperative pharmacokinetic evaluation, or as documented in the
             medical history, if available.

          -  The subject is scheduled to undergo an elective unilateral major orthopedic surgery
             that requires drain placement.

          -  The subject was previously treated with factor VIII concentrate(s) for a minimum of at
             least 150 exposure days (as estimated by the investigator) prior to study entry.

          -  Human immunodeficiency virus (HIV) positive subjects must be immunocompetent as
             determined with a CD4 count >= 200 cells/mm³ (CD4 count at screening), but HIV
             negative subjects with a CD4 count < 200 cells/mm³ qualify, if immunocompetency is
             documented.

          -  The subject has a life expectancy of at least 28 days from the day of surgery.

        Exclusion Criteria:

          -  The subject has a detectable factor VIII inhibitor at screening, with a titer >= 0.4
             BU (Nijmegen modification of the Bethesda assay) in the central laboratory.

          -  The subject has a history of factor VIII inhibitors with a titer >= 0.4 BU (by
             Nijmegen assay) or >= 0.5 BU (by Bethesda assay) at any time prior to screening.

          -  The subject is scheduled to undergo any other concurrent minor or major surgery during
             the course of the study. The placement of central venous lines and the performance of
             fine needle aspiration biopsies are permitted.

          -  Excluding hemophilia-related physical impairments, the subject is assigned to NYHA
             class >= III according to the New York Heart Association (NYHA).

          -  The subject has an abnormal renal function (serum creatinine > 1.5 mg/dL).

          -  The subject has active hepatic disease (alanine aminotransferase [ALT] or aspartate
             aminotransferase [AST] levels > 5 times the upper limit of normal).

          -  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 clinical and/or laboratory evidence of abnormal hemostasis from causes
             other than hemophilia A (e.g., late-stage chronic liver disease, immune
             thrombocytopenia purpura).

          -  The subject is currently receiving, or is scheduled to receive during the course of
             the study, an immunomodulating drug other than anti-retroviral chemotherapy (e.g.,
             alpha-interferon, corticosteroid agents at a dose equivalent to hydrocortisone greater
             than 10 mg/day).

          -  The subject has a known hypersensitivity to mouse or hamster proteins.

          -  The subject has received another investigational drug study within 30 days prior to
             screening and/or is scheduled to receive additional investigational drug during the
             course of the trial in the context of another investigational study.

          -  The subject is identified by the investigator as being unable or unwilling to
             cooperate with study procedures.