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

NCT00357656 | Completed Phase 4 Results DMC

• 2 other identifiers: 0604022005-005697-71
• Study Type: interventional
• Target: 85
• Locations: 14 countries
• Sites: 36

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

Keywords

Hemophilia A (severe or moderately severe)

Outcome Measures

Primary Outcomes (1)

• 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)

  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.

  During the first postoperative 24 hours every 8 hours ± 30 minutes the drainage fluid was to be recorded..

Secondary Outcomes (6)

• 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

• 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).

• Number of Bleeding Episodes During Treatment With Continuous or Bolus Infusion

  Through Postoperative Day 7

• Number of Units of Packed Red Blood Cells Transfused

  During the first postoperative 24 hours

• 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)

Study Arms (2)

BI

EXPERIMENTAL

Bolus infusion of rAHF-PFM

Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM)

CI

EXPERIMENTAL

Continuous infusion of rAHF-PFM

Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM)

Interventions

Recombinant Protein-Free Factor VIII (rAHF-PFM) 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.

CI

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Baxalta now part of Shire: lead
• Baxalta Innovations GmbH, now part of Shire: collaborator

Study Sites (36)

Los Angeles Orthopaedic Hospital

Los Angeles, California, 90007, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20057, United States

Location

Rush Presbyterian St. Lukes

Chicago, Illinois, 60612, United States

Location

James Graham Brown Cancer Center

Louisville, Kentucky, 40202, United States

Location

Tulane University

New Orleans, Louisiana, 70112-2699, United States

Location

Johns Hopkins Medical Institutions

Baltimore, Maryland, 21205, United States

Location

Brigham and Women´s Hospital

Boston, Massachusetts, 02115, United States

Location

University Hospitals of Cleveland

Cleveland, Ohio, 44106-6010, United States

Location

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

The University of Texas Health Science Center at Houston Medical School

Houston, Texas, 77030, United States

Location

University Hospital for Internal Medicine I (Hematology/Hemostaseology)

Vienna, 1090, Austria

Location

Cliniques Universitaires St. Luc, Haematology Department

Brussels, 1200, Belgium

Location

University Hospital Gasthuisberg

Leuven, 3000, Belgium

Location

Hôpital Edouard Herriot

Lyon, 69437, France

Location

State Health Centre, National Hemophilia Centre

Budapest, 1134, Hungary

Location

University of Debrecen, 2nd Dept of Internal Medicine

Debrecen, 4012, Hungary

Location

PTE ÁOK I. Internal Medical Clinic, Dept of Hematology

Pécs, 7624, Hungary

Location

Centro Emofilia e Trombosi "Angelo Bianchi Bonomi"

Milan, 20122, Italy

Location

Department of Clinical & Experimental Medecine, AOU Federico II

Naples, 80129, Italy

Location

AMC Medical Research BV, Department of Vascular Medicine

Amsterdam, 1100, Netherlands

Location

University Medical Centre Groningen

Groningen, 9713, Netherlands

Location

Academic Hospital Maastricht

Maastricht, 6229, Netherlands

Location

Rikshospitalet

Oslo, 0027, Norway

Location

Krakowskie Centrum Rehabilitacji

Krakow, 30-224, Poland

Location

Instytut Hematologii i Transfuzjologii, Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych

Warsaw, 02-776, Poland

Location

Centro Hospitalar de Coimbra

Coimbra, 3040-316, Portugal

Location

Hospital Santo António

Porto, 4900-001, Portugal

Location

Fundeni Clinical Institute, Clinical Laboratory "St. Berceanu" Hematology and Bone Marrow Transplantation Department

Bucharest, 022328, Romania

Location

National Blood Transfusion Institute

Bucharest, 11156, Romania

Location

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

Timișoara, 022328, Romania

Location

Regional Hemophilia Center

Kirov, 610027, Russia

Location

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

Moscow, 125167, Russia

Location

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

Saint Petersburg, 191024, Russia

Location

Hospital Vall d´Hebron, Servei d´Hemofilia

Barcelona, 08035, Spain

Location

Hospital Universitario La Fe

Valencia, 46990, Spain

Location

University Hospital MAS, Department for Coagulation Disorders

Malmo, 20502, Sweden

Location

MeSH Terms

Conditions

Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 25, 2006
• First Posted: July 27, 2006
• Study Start: May 29, 2006
• Primary Completion: October 1, 2015
• Study Completion: December 9, 2015
• Last Updated: May 19, 2021
• Results First Posted: May 19, 2017

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

RO (3); AU (1); FR (1); HU (3); NL (3); NO (1); RU (3); PT (2); ES (2); SE (1); IT (2); PL (2); US (10); BE (2)