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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

This study has been completed.
Information provided by (Responsible Party):
Baxalta US Inc. Identifier:
First received: July 25, 2006
Last updated: February 5, 2016
Last verified: February 2016
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.

Condition Intervention Phase
Hemophilia A
Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

Further study details as provided by Baxalta US Inc.:

Primary Outcome Measures:
  • Cumulative Packed Red Blood Cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery in subjects receiving rAHF-PFM by bolus or continuous infusion [ Time Frame: During the first postoperative 24 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon [ Time Frame: During the first postoperative 24 hours ] [ Designated as safety issue: No ]
  • Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon [ Time Frame: Postoperatively until drain removal ] [ Designated as safety issue: No ]
  • Number of bleeding episodes during treatment with continuous or bolus infusion [ Time Frame: Postoperative Day 7 ] [ Designated as safety issue: No ]
  • Number of units of Packed Red Blood Cells transfused [ Time Frame: During the first postoperative 24 hours ] [ Designated as safety issue: No ]
  • Number of adverse events related to the administration of the study product [ Time Frame: Until study completion ] [ Designated as safety issue: No ]
  • Incidence of Factor VIII inhibitory antibody (≥0.4 Bethesda Units using the Nijmegen modification of the Bethesda assay) formation [ Time Frame: Until study completion ] [ Designated as safety issue: No ]

Enrollment: 86
Study Start Date: June 2006
Study Completion Date: December 2015
Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BI
Bolus infusion of rAHF-PFM
Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM)
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).
Experimental: CI
Continuous infusion of rAHF-PFM
Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM)

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.


Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00357656

  Show 36 Study Locations
Sponsors and Collaborators
Baxalta US Inc.
Study Director: Leonard Valentino, MD Baxalta US Inc.
  More Information

Responsible Party: Baxalta US Inc. Identifier: NCT00357656     History of Changes
Other Study ID Numbers: 060402 
Study First Received: July 25, 2006
Last Updated: February 5, 2016
Health Authority: Netherlands: Medicines Evaluation Board (MEB)
United States: Food and Drug Administration
Norway: Norwegian Medicines Agency
Hungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
Russia: Ministry of Health of the Russian Federation
Austria: Federal Ministry for Health and Women
Spain: Ministry of Health and Consumption
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Belgium: Federal Agency for Medicinal Products and Health Products
Italy: The Italian Medicines Agency
Sweden: Medical Products Agency
Romania: National Medicines Agency
Portugal: National Pharmacy and Medicines Institute
Poland: National Institute of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Baxalta US Inc.:
Hemophilia A (severe or moderately severe)

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 processed this record on December 02, 2016