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
- Conditions
- Hemophilia A
- Interventions
- Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM)
- Registration Number
- NCT00357656
- Lead Sponsor
- Baxalta now part of Shire
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 85
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description CI Recombinant Protein-Free Factor VIII (rAHF-PFM) Continuous infusion of rAHF-PFM BI Recombinant Protein-Free Factor VIII (rAHF-PFM) Bolus infusion of rAHF-PFM
- Primary Outcome Measures
Name Time Method 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) During the first postoperative 24 hours every 8 hours ± 30 minutes the drainage fluid was to be recorded.. Drainage fluid volume was to be measured cumulatively and recorded every 8 hours ± 30 minutes during the first 24 hours following surgery. Unit of measure: Tera per Liter is the PRBC concentration in 10\^12 units per 1 liter of drainage fluid.
- Secondary Outcome Measures
Name Time Method Number of Units of Packed Red Blood Cells Transfused During the first postoperative 24 hours Actual Postoperative Blood Loss During the First 24 Hours Compared With the Average Blood Loss as Predicted Preoperatively by the Operating Surgeon During the first 24 postoperative hours blood loss was measured every 8 hours ± 30 minutes Drainage fluid volume was to be measured cumulatively and recorded every 8 hours ± 30 minutes during the first 24 hours following surgery. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject 1) for the intraoperative procedure (defined as the time period from incision to application of compressive dressing and release of tourniquet, if applicable), 2) for the first 24 hours postoperatively, and 3) for the postoperative period until drain removal, if drainage continued beyond 24 hours. Units: Milliliter of blood
Actual Postoperative Blood Loss Compared to the Expected Average Blood Loss Until Drain Removal as Predicted Preoperatively by the Surgeon From end of surgery (application of compressive dressing and release of tourniquet, if applicable) until drain removal (up to postoperative day 7). The total blood loss for the postoperative period (from end of surgery until drain removal) was adjusted for the expected blood loss by applying a log-transformation of the blood loss data. The drainage volume was measured every 8 hours +/- 30 minutes during the first 24 hours. If the drainage continued beyond 24 hours, the PRBC volume and hemoglobin was to be measured cumulatively every 24 hours or whenever the drainage bottle was emptied and at the time of drain removal. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject for the first 24 hours postoperatively, and for the postoperative period until drain removal, if drainage continued beyond 24 hours. Units: Milliliter of blood
Number of Bleeding Episodes During Treatment With Continuous or Bolus Infusion Through Postoperative Day 7 To simplify the results below: Bleeding episodes were reported for 4 subjects (3 subjects on bolus infusion: 2 in Stratum A and 1 in Stratum B, and 1 subject on continuous infusion/Stratum B). The 4 subjects had 1 bleeding episode each. No bleeding episodes were reported for Stratum C.
Number of Adverse Events Related to the Administration of the Study Product. From first study drug exposure until study completion/discontinuation (approximately 9-26 weeks per subject) All AEs from the first study drug exposure until the study completion/discontinuation date were to be recorded. Each AE was to be evaluated by the investigator for causal relationship (i.e., unrelated, possibly related or probably related) to the study product.
Incidence of Factor VIII Inhibitory Antibody (≥0.4 Bethesda Units Using the Nijmegen Modification of the Bethesda Assay Formation) Throughout the study period of approximately 9-26 weeks per participant Number of participants that developed Factor VIII inhibitory antibody during the study.
Trial Locations
- Locations (36)
Johns Hopkins Medical Institutions
🇺🇸Baltimore, Maryland, United States
Tulane University
🇺🇸New Orleans, Louisiana, United States
University Hospital for Internal Medicine I (Hematology/Hemostaseology)
🇦🇹Vienna, Austria
"Louis Turcanu" Emergency Clinical Children´s Hospital, 3rd Pediatrics Department, Hemophilia Center
🇷🇴Timisoara, Romania
Brigham and Women´s Hospital
🇺🇸Boston, Massachusetts, United States
Hôpital Edouard Herriot
🇫🇷Lyon, France
University Hospitals of Cleveland
🇺🇸Cleveland, Ohio, United States
Cliniques Universitaires St. Luc, Haematology Department
🇧🇪Brussels, Belgium
Academic Hospital Maastricht
🇳🇱Maastricht, Netherlands
State Health Centre, National Hemophilia Centre
🇭🇺Budapest, Hungary
PTE ÁOK I. Internal Medical Clinic, Dept of Hematology
🇭🇺Pécs, Hungary
University of Debrecen, 2nd Dept of Internal Medicine
🇭🇺Debrecen, Hungary
Department of Clinical & Experimental Medecine, AOU Federico II
🇮🇹Naples, Italy
Russian Research Institute of Hematology and Transfusiology, Department of Surgical Hematology and Angiology
🇷🇺St. Petersburg, Russian Federation
Hematology Research Center under Russian Academy of Medical Sciences, Department of Reconstructive Orthopedic Surgery for Hemophilia Patients
🇷🇺Moscow, Russian Federation
Los Angeles Orthopaedic Hospital
🇺🇸Los Angeles, California, United States
Rush Presbyterian St. Lukes
🇺🇸Chicago, Illinois, United States
James Graham Brown Cancer Center
🇺🇸Louisville, Kentucky, United States
Penn State Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
The University of Texas Health Science Center at Houston Medical School
🇺🇸Houston, Texas, United States
University Hospital Gasthuisberg
🇧🇪Leuven, Belgium
AMC Medical Research BV, Department of Vascular Medicine
🇳🇱Amsterdam, Netherlands
University Medical Centre Groningen
🇳🇱Groningen, Netherlands
Instytut Hematologii i Transfuzjologii, Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych
🇵🇱Warsaw, Poland
Krakowskie Centrum Rehabilitacji
🇵🇱Krakow, Poland
Centro Hospitalar de Coimbra
🇵🇹Coimbra, Portugal
Hospital Santo António
🇵🇹Porto, Portugal
Fundeni Clinical Institute, Clinical Laboratory "St. Berceanu" Hematology and Bone Marrow Transplantation Department
🇷🇴Bucharest, Romania
National Blood Transfusion Institute
🇷🇴Bucharest, Romania
Regional Hemophilia Center
🇷🇺Kirov, Russian Federation
Hospital Vall d´Hebron, Servei d´Hemofilia
🇪🇸Barcelona, Spain
Hospital Universitario La Fe
🇪🇸Valencia, Spain
University Hospital MAS, Department for Coagulation Disorders
🇸🇪Malmo, Sweden
Rikshospitalet
🇳🇴Oslo, Norway
Centro Emofilia e Trombosi "Angelo Bianchi Bonomi"
🇮🇹Milano, Italy
Georgetown University
🇺🇸Washington, District of Columbia, United States