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

NCT ID: NCT00357656

Last Updated: 2021-05-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 85 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-05-29
• Study Completion Date: 2015-12-09

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.

Conditions

Hemophilia A

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

BI

Bolus infusion of rAHF-PFM

Group Type: EXPERIMENTAL

Recombinant Protein-Free Factor VIII (rAHF-PFM)

Intervention Type: DRUG

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).

CI

Continuous infusion of rAHF-PFM

Group Type: EXPERIMENTAL

Recombinant Protein-Free Factor VIII (rAHF-PFM)

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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).

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baxalta Innovations GmbH, now part of Shire

INDUSTRY

Sponsor Role: collaborator

Baxalta now part of Shire

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Takeda

Locations

Los Angeles Orthopaedic Hospital

Los Angeles, California, United States

Georgetown University

Washington D.C., District of Columbia, United States

Rush Presbyterian St. Lukes

Chicago, Illinois, United States

James Graham Brown Cancer Center

Louisville, Kentucky, United States

Tulane University

New Orleans, Louisiana, United States

Johns Hopkins Medical Institutions

Baltimore, Maryland, United States

Brigham and Women´s Hospital

Boston, Massachusetts, United States

University Hospitals of Cleveland

Cleveland, Ohio, 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 for Internal Medicine I (Hematology/Hemostaseology)

Vienna, , Austria

Cliniques Universitaires St. Luc, Haematology Department

Brussels, , Belgium

University Hospital Gasthuisberg

Leuven, , Belgium

Hôpital Edouard Herriot

Lyon, , France

State Health Centre, National Hemophilia Centre

Budapest, , Hungary

University of Debrecen, 2nd Dept of Internal Medicine

Debrecen, , Hungary

PTE ÁOK I. Internal Medical Clinic, Dept of Hematology

Pécs, , Hungary

Centro Emofilia e Trombosi "Angelo Bianchi Bonomi"

Milan, , Italy

Department of Clinical & Experimental Medecine, AOU Federico II

Naples, , Italy

AMC Medical Research BV, Department of Vascular Medicine

Amsterdam, , Netherlands

University Medical Centre Groningen

Groningen, , Netherlands

Academic Hospital Maastricht

Maastricht, , Netherlands

Rikshospitalet

Oslo, , Norway

Krakowskie Centrum Rehabilitacji

Krakow, , Poland

Instytut Hematologii i Transfuzjologii, Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych

Warsaw, , 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

"Louis Turcanu" Emergency Clinical Children´s Hospital, 3rd Pediatrics Department, Hemophilia Center

Timișoara, , Romania

Regional Hemophilia Center

Kirov, , Russia

Hematology Research Center under Russian Academy of Medical Sciences, Department of Reconstructive Orthopedic Surgery for Hemophilia Patients

Moscow, , Russia

Russian Research Institute of Hematology and Transfusiology, Department of Surgical Hematology and Angiology

Saint Petersburg, , Russia

Hospital Vall d´Hebron, Servei d´Hemofilia

Barcelona, , Spain

Hospital Universitario La Fe

Valencia, , Spain

University Hospital MAS, Department for Coagulation Disorders

Malmo, , Sweden

Countries

United States; Austria; Belgium; France; Hungary; Italy; Netherlands; Norway; Poland; Portugal; Romania; Russia; Spain; Sweden

Other Identifiers

2005-005697-71

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

060402

Identifier Type: -

Identifier Source: org_study_id