BAX 326 Surgery Study in Hemophilia B Patients

BAX 326 (Recombinant Factor IX): A Phase 3 Prospective, Multicenter Study Evaluating Efficacy and Safety in Previously Treated Patients With Severe (FIX Level < 1%) or Moderately Severe (FIX Level 1-2%) Hemophilia B Undergoing Surgical or Other Invasive Procedures

The purpose of the study is to assess the hemostatic efficacy and safety of BAX 326 in subjects with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B undergoing major or minor elective or emergency surgical, dental or other invasive procedures.

Study Overview

• Status: Completed
• Conditions: Hemophilia B
• Intervention / Treatment: Biological: Recombinant factor IX

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Rosario, Argentina, 2000
    • Instituto de Hematologia y Medicina Clinica Ruben Davoli
• Bulgaria
  • Sofia, Bulgaria, 1233
    • Specialized Haematological Hospital "Joan Pavel"
• Chile
  • Santiago, Chile
    • Hospital Dr. Sotero del Rio
• Colombia
  • Cali, Colombia
    • Centro Médico Imbanaco
• Czechia
  • Prague, Czechia, 150 06
    • Klinika detska hematologie a onkologie, Fakultni Nemocnice Motol
• Poland
  • Lodz, Poland, 93-510
    • Medical University Lodz, Copernicus Hospital, Department of Hematology
  • Warsaw, Poland, 02-776
    • Institute of Haematology and Transfusion Medicine
  • Warsaw, Poland, 00-579
    • Independent Public Pediatric Teaching Hospital, Clinical Department of Hematology and Pediatrics
• Romania
  • Timisoara, Romania
    • Louis Turcanu Emergency Clinical Children´s Hospital
• Russian Federation
  • Kirov, Russian Federation, 610027
    • Federal State Institution Kirov, Hematology and Blood Transfusion Research Institute under the Federal Agency for High-Tech Medical Care
  • Krasnodar, Russian Federation, 350007
    • Children's Territorial Clinical Hospital
  • Moscow, Russian Federation, 125167
    • Hematology Research Center RAMS
• Ukraine
  • Lviv, Ukraine, 79044
    • State Institution "Institute of Blood Pathology and Transfusion Medicine under the Academy of Medical Sciences of Ukraine"
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital, Department of Hematology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main Inclusion Criteria:

• Participant and/or legal representative has/have voluntarily provided signed informed consent.
• Participant has severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B (based on the one stage activated partial thromboplastin time (aPTT) assay), as tested at screening at the central laboratory.
• Participant requires surgery
• Participant has previously been treated with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 150 exposure days
• Participant has no evidence of a history of FIX inhibitors
• Participant is immunocompetent as evidenced by a CD4 count ≥ 200 cells/mm3.
• Participant is human immunodeficiency (HIV) negative or is HIV+ with a viral load < 200 particles/μL ~ < 400,000 copies/mL.

Main Exclusion Criteria:

• Participant has a history of FIX inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed in the respective local laboratory) at any time prior to screening.
• Participant has a detectable FIX inhibitor at screening, with a titer ≥0.6 Bethesda Units (BU) as determined by the Nijmegen modification of the Bethesda assay in the central laboratory.
• Participant has a history of allergic reaction or evidence of an ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
• Known hypersensitivity to hamster proteins or recombinant furin.
• Evidence of an ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
• Abnormal renal function
• Severe chronic liver disease
• Active hepatic disease with ALT or AST levels > 5 times the upper limit of normal.
• Diagnosis of an iherited or acquired hemostatic defect other than hemophilia B.
• Platelet count < 100,000/mL.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: BAX326 in Surgery; BAX 326 (recombinant factor IX) in Surgery

Biological: Recombinant factor IX; Following a loading dose with BAX326, participants will receive BAX326 as a bolus infusion. The treatment regimen will be determined by the intensity and duration of the hemostatic challenge and the institution´s standard of care. The dose will be tailored to raise FIX concentration to at least 80%-100% of normal for major surgeries and to at least 30%-60% of normal for minor surgeries.; Other Names: BAX326; RIXUBIS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative Hemostatic Efficacy	Assessment by the operating surgeon on a 4 point ordinal scale (according to the definitions provided below): - Excellent: Intraoperative blood loss was less than or equal to that expected for the type of procedure performed in a hemostatically normal participant (≤ 100% ) - Good: Intraoperative blood loss was up to 50% more than expected for the type of procedure performed in a hemostatically normal participant (101 - 150%) - Fair: Intraoperative blood loss was more than 50% of that expected for the type of procedure performed in a hemostatically normal participant (> 150%) - None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate	On day of surgery
Actual Intraoperative Blood Loss	Actual intraoperative blood loss was determined by the drainage volume, if a drain was placed, and the estimated blood loss into swabs and towels during the procedure.	On day of surgery
Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon	Predicted average/maximum blood loss minus actual blood loss. Prior to the surgery, the surgeon predicted the estimated volume (mL) of the expected average and maximum blood loss for the planned surgical intervention in a hemostatically normal individual of the same sex, age, and stature as the study participant for the intraoperative period.	On day of surgery
Postoperative Hemostatic Efficacy at Drain Removal	The postoperative hemostatic efficacy was to be assessed by the operating surgeon according to the following criteria (4-point ordinal scale): - Excellent: Volume in drain was less than or equal than that expected for the type of procedure performed in a hemostatically normal participant (≤ 100% ) - Good: Volume in drain was up to 50% more than expected for the type of procedure performed in a hemostatically normal participant (101% - 150%) - Fair: Volume in drain was more than 50% of that expected for the type of procedure performed in a hemostatically normal participant (> 150%) - None: Uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate	At drain removal (from 1-3 days postoperatively)
Postoperative Hemostatic Efficacy at Postoperative Day 3	Assessment by the operating surgeon on a 4 point ordinal scale: - Excellent: Postoperative hemostasis achieved with BAX326 was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal participant - Good: Postoperative hemostasis achieved with BAX326 was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal participant - Fair: Postoperative hemostasis with BAX326 was clearly less than optimal for the type of procedure performed but was maintained without the need to change the Factor IX concentrate - None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate	At postoperative day 3 (approximately 72 hours postoperatively)
Postoperative Hemostatic Efficacy on Day of Discharge	Assessment by the operating surgeon on a 4 point ordinal scale: - Excellent: Postoperative hemostasis achieved with BAX326 was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal participant - Good: Postoperative hemostasis achieved with BAX326 was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal participant - Fair: Postoperative hemostasis with BAX326 was clearly less than optimal for the type of procedure performed but was maintained without the need to change the Factor IX concentrate - None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate	At discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery)
Actual Postoperative Blood Loss	Postoperative blood loss was based on the drainage fluid and was only assessed for participants who had a drain placed during surgery.	At drain removal (from 1-3 days postoperatively)
Actual Postoperative Blood Loss Compared to Average and Maximum Blood Loss Predicated Preoperatively by the Operating Surgeon	Predicted average/maximum blood loss minus actual blood loss for participants who had a drain placed during surgery. Prior to the surgery, the surgeon will predict the estimated volume (mL) of the expected average and maximum blood loss for the planned surgical intervention in a hemostatically normal individual of the same sex, age, and stature as the study subject for the postoperative period until drain removal.	At postoperative day 3 (approximately 72 hours postoperatively)
Daily Weight-Adjusted Dose of BAX326 Per Participant	Daily weight-adjusted doses of BAX326 per participant were recorded from the day of surgery until postoperative Days 11+. Each category in outcome measure includes number of all, major and minor surgeries, respectively, if different from the totals.	From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery)
Total Weight-Adjusted Dose of BAX326 Per Participant	Assessed for the intra- and postoperative periods.	From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery)
Number of Units of Blood Product Transfused	Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.	From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery)
Volume of Blood Product Transfused	Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.	From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery)
Safety: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX)		Throughout the study period (approximately 2 years 5 months)
Safety: Number of Participants Who Developed Total Binding Antibodies to Factor IX (FIX)	If there was more than 2-dilution increase as compared to pre-study level at screening.	Throughout the study period (approximately 2 years 5 months)
Safety: Number of Adverse Events Related to BAX326		Throughout the study period (approximately 2 years 5 months)
Safety: Occurence of a Thrombotic Event		Throughout the study period (approximately 2 years 5 months)
Pre-Surgical Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 72 Hours Post-infusion Per Dose	AUC0-72h (area under the plasma concentration/time curve from time 0 to 72 hours) was computed using the linear trapezoidal method. The concentration at 72 hours was interpolated from the two nearest sampling time points or extrapolated using the last quantifiable concentration and the terminal rate constant λz. λz was estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R2.	Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Pre-Surgical Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve Per Dose (Total AUC/Dose)	Total AUC/Dose is also AUC0-inf (area under the plasma concentration/time curve from time 0 to infinity) and was defined as AUC0-t + Ct / λz, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration and λz is the terminal rate constant.	Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Pre-Surgical Pharmacokinetics (PK): Mean Residence Time (MRT)	The MRT is the average time that the study product stays in the body (or plasma) and is calculated as: AUMC 0-inf / AUC 0-inf, where AUMC 0-inf was determined in a similar manner as AUC 0-inf.	Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Pre-Surgical Pharmacokinetics (PK): Factor IX (FIX) Clearance (CL)	CL is the volume of plasma which is completely cleared of study product per unit time and is calculated as the dose divided by the total area under the curve from 0 to infinity (AUC0-inf).	Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Pre-Surgical Pharmacokinetics (PK): Incremental Recovery (IR) at 30 Min	IR was defined as (C post-infusion - C pre-infusion) / Dose, where C post-infusion is the measured concentration achieved at 30±5 minutes for pre-surgical PK.	Within 30 mins pre-infusion and post-infusion at 30 minutes
Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2)	T1/2 was determined as ln2 / λz.	Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss)	Vss was computed as CL·MRT.	Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Incremental Recovery (IR) at 15±5 Minutes Following Loading Dose Prior to Surgery	IR was defined as (C post-infusion - C pre-infusion) / Dose, where C post-infusion is the measured concentration achieved at 15±5 minutes for the loading dose.	Within 60 minutes prior to surgery and 15 ± 5 minutes after loading dose/rebolus, if applicable.

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire

Publications and helpful links

General Publications

• Windyga J, Lissitchkov T, Stasyshyn O, Mamonov V, Ghandehari H, Chapman M, Fritsch S, Wong WY, Pavlova BG, Abbuehl BE. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia. 2014 Sep;20(5):651-8. doi: 10.1111/hae.12419. Epub 2014 Apr 3.
• Windyga J, Timofeeva M, Stasyshyn O, Mamonov V, Lamas Castellanos JL, Lissitchkov T, Chojnowski K, Chapman M, Pavlova BG, Tangada S. Phase 3 Clinical Trial: Perioperative Use of Nonacog Gamma, a Recombinant Factor IX, in Previously Treated Patients With Moderate/Severe Hemophilia B. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620946839. doi: 10.1177/1076029620946839.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 19, 2011
• Primary Completion (ACTUAL): May 15, 2014
• Study Completion (ACTUAL): May 15, 2014

Study Registration Dates

• First Submitted: January 9, 2012
• First Submitted That Met QC Criteria: January 9, 2012
• First Posted (ESTIMATE): January 11, 2012

Study Record Updates

• Last Update Posted (ACTUAL): May 19, 2021
• Last Update Submitted That Met QC Criteria: April 30, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: 251002; 2011-000413-39 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR