Clinical trial NCT00357656: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hemophilia A
Keywords: Hemophilia A (severe or moderately severe)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Baxalta Innovations GmbH, now part of Shire
First posted: 2006-07-27
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Cumulative Packed Red Blood Cell (PRBC) Volume in the Drainage Fluid During the First 24 Hours Following Surgery in Subjects Receiving ADVATE (rAHF-PFM) by Bolus (BI) or Continuous Infusion (CI)
timeFrame: During the first postoperative 24 hours every 8 hours ± 30 minutes the drainage fluid was to be recorded..
Secondary outcomes:
measure: Actual Postoperative Blood Loss During the First 24 Hours Compared With the Average Blood Loss as Predicted Preoperatively by the Operating Surgeon
timeFrame: During the first 24 postoperative hours blood loss was measured every 8 hours ± 30 minutes
measure: Actual Postoperative Blood Loss Compared to the Expected Average Blood Loss Until Drain Removal as Predicted Preoperatively by the Surgeon
timeFrame: From end of surgery (application of compressive dressing and release of tourniquet, if applicable) until drain removal (up to postoperative day 7).
measure: Number of Bleeding Episodes During Treatment With Continuous or Bolus Infusion
timeFrame: Through Postoperative Day 7
measure: Number of Units of Packed Red Blood Cells Transfused
timeFrame: During the first postoperative 24 hours
measure: Number of Adverse Events Related to the Administration of the Study Product.
timeFrame: From first study drug exposure until study completion/discontinuation (approximately 9-26 weeks per subject)
measure: Incidence of Factor VIII Inhibitory Antibody (≥0.4 Bethesda Units Using the Nijmegen Modification of the Bethesda Assay Formation)
timeFrame: Throughout the study period of approximately 9-26 weeks per participant
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Los Angeles Orthopaedic Hospital
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Chicago
country: United States
facility: Rush Presbyterian St. Lukes
state: Illinois
city: Louisville
country: United States
facility: James Graham Brown Cancer Center
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Medical Institutions
state: Maryland
city: Boston
country: United States
facility: Brigham and Women´s Hospital
state: Massachusetts
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston Medical School
state: Texas
city: Vienna
country: Austria
facility: University Hospital for Internal Medicine I (Hematology/Hemostaseology)
city: Brussels
country: Belgium
facility: Cliniques Universitaires St. Luc, Haematology Department
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Budapest
country: Hungary
facility: State Health Centre, National Hemophilia Centre
city: Debrecen
country: Hungary
facility: University of Debrecen, 2nd Dept of Internal Medicine
city: Pécs
country: Hungary
facility: PTE ÁOK I. Internal Medical Clinic, Dept of Hematology
city: Milano
country: Italy
facility: Centro Emofilia e Trombosi "Angelo Bianchi Bonomi"
city: Naples
country: Italy
facility: Department of Clinical & Experimental Medecine, AOU Federico II
city: Amsterdam
country: Netherlands
facility: AMC Medical Research BV, Department of Vascular Medicine
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Maastricht
country: Netherlands
facility: Academic Hospital Maastricht
city: Oslo
country: Norway
facility: Rikshospitalet
city: Krakow
country: Poland
facility: Krakowskie Centrum Rehabilitacji
city: Warsaw
country: Poland
facility: Instytut Hematologii i Transfuzjologii, Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych
city: Coimbra
country: Portugal
facility: Centro Hospitalar de Coimbra
city: Porto
country: Portugal
facility: Hospital Santo António
city: Bucharest
country: Romania
facility: Fundeni Clinical Institute, Clinical Laboratory "St. Berceanu" Hematology and Bone Marrow Transplantation Department
city: Bucharest
country: Romania
facility: National Blood Transfusion Institute
city: Timisoara
country: Romania
facility: "Louis Turcanu" Emergency Clinical Children´s Hospital, 3rd Pediatrics Department, Hemophilia Center
city: Kirov
country: Russian Federation
facility: Regional Hemophilia Center
city: Moscow
country: Russian Federation
facility: Hematology Research Center under Russian Academy of Medical Sciences, Department of Reconstructive Orthopedic Surgery for Hemophilia Patients
city: St. Petersburg
country: Russian Federation
facility: Russian Research Institute of Hematology and Transfusiology, Department of Surgical Hematology and Angiology
city: Barcelona
country: Spain
facility: Hospital Vall d´Hebron, Servei d´Hemofilia
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Malmo
country: Sweden
facility: University Hospital MAS, Department for Coagulation Disorders
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: