Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method (rAHF PFM): A Phase 3/4, Prospective, Controlled, Randomized, Multi-Center Study to Compare the Efficacy and Safety of Continuous Infusion (CI) Versus Intermittent Bolus Infusion (BI) in Subjects With Severe or Moderately Severe Hemophilia A Undergoing Major Orthopedic Surgery
- The subject or the subject's legally authorized representative has provided signed
- 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
- The subject has a life expectancy of at least 28 days from the day of surgery.
- 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
- 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.