BAX 326 Surgery Study in Hemophilia B Patients

• ClinicalTrials.gov Identifier: NCT01507896
• Recruitment Status: Completed
• First Posted: January 11, 2012
• Results First Posted: February 15, 2017
• Last Update Posted: May 19, 2021
• Sponsor: Baxalta now part of Shire
• Information provided by (Responsible Party): Takeda ( Baxalta now part of Shire )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia B	Biological: Recombinant factor IX	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 19, 2011
• Actual Primary Completion Date: May 15, 2014
• Actual Study Completion Date: May 15, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Intraoperative Hemostatic Efficacy [ Time Frame: On day of surgery ]
   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
2. Actual Intraoperative Blood Loss [ Time Frame: On day of surgery ]
   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.
3. Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon [ Time Frame: On day of surgery ]
   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.
4. Postoperative Hemostatic Efficacy at Drain Removal [ Time Frame: At drain removal (from 1-3 days postoperatively) ]
   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
5. Postoperative Hemostatic Efficacy at Postoperative Day 3 [ Time Frame: At postoperative day 3 (approximately 72 hours postoperatively) ]
   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
6. Postoperative Hemostatic Efficacy on Day of Discharge [ Time Frame: At discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) ]
   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
7. Actual Postoperative Blood Loss [ Time Frame: At drain removal (from 1-3 days postoperatively) ]
   Postoperative blood loss was based on the drainage fluid and was only assessed for participants who had a drain placed during surgery.
8. Actual Postoperative Blood Loss Compared to Average and Maximum Blood Loss Predicated Preoperatively by the Operating Surgeon [ Time Frame: At postoperative day 3 (approximately 72 hours postoperatively) ]
   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.
9. Daily Weight-Adjusted Dose of BAX326 Per Participant [ Time Frame: From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) ]
   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.
10. Total Weight-Adjusted Dose of BAX326 Per Participant [ Time Frame: From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) ]
    Assessed for the intra- and postoperative periods.
11. Number of Units of Blood Product Transfused [ Time Frame: From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) ]
    Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.
12. Volume of Blood Product Transfused [ Time Frame: From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) ]
    Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.
13. Safety: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX) [ Time Frame: Throughout the study period (approximately 2 years 5 months) ]
14. Safety: Number of Participants Who Developed Total Binding Antibodies to Factor IX (FIX) [ Time Frame: Throughout the study period (approximately 2 years 5 months) ]
    If there was more than 2-dilution increase as compared to pre-study level at screening.
15. Safety: Number of Adverse Events Related to BAX326 [ Time Frame: Throughout the study period (approximately 2 years 5 months) ]
16. Safety: Occurence of a Thrombotic Event [ Time Frame: Throughout the study period (approximately 2 years 5 months) ]
17. Pre-Surgical Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 72 Hours Post-infusion Per Dose [ Time Frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr ]
    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.
18. Pre-Surgical Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve Per Dose (Total AUC/Dose) [ Time Frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr ]
    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.
19. Pre-Surgical Pharmacokinetics (PK): Mean Residence Time (MRT) [ Time Frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr ]
    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.
20. Pre-Surgical Pharmacokinetics (PK): Factor IX (FIX) Clearance (CL) [ Time Frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr ]
    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).
21. Pre-Surgical Pharmacokinetics (PK): Incremental Recovery (IR) at 30 Min [ Time Frame: Within 30 mins pre-infusion and post-infusion at 30 minutes ]
    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.
22. Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2) [ Time Frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr ]
    T1/2 was determined as ln2 / λz.
23. Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) [ Time Frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr ]
    Vss was computed as CL·MRT.
24. Incremental Recovery (IR) at 15±5 Minutes Following Loading Dose Prior to Surgery [ Time Frame: Within 60 minutes prior to surgery and 15 ± 5 minutes after loading dose/rebolus, if applicable. ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Argentina

Instituto de Hematología y Medicina Clínica Rubén Dávoli

Rosario, Argentina, 2000

Bulgaria

Specialized Haematological Hospital "Joan Pavel"

Sofia, Bulgaria, 1233

Chile

Hospital Dr. Sotero del Rio

Santiago, Chile

Colombia

Centro Medico Imbanaco

Cali, Colombia

Czechia

Klinika detska hematologie a onkologie, Fakultni Nemocnice Motol

Prague, Czechia, 150 06

Poland

Medical University Lodz, Copernicus Hospital, Department of Hematology

Lodz, Poland, 93-510

Independent Public Pediatric Teaching Hospital, Clinical Department of Hematology and Pediatrics

Warsaw, Poland, 00-579

Institute of Haematology and Transfusion Medicine

Warsaw, Poland, 02-776

Romania

Louis Turcanu Emergency Clinical Children´s Hospital

Timisoara, Romania

Russian Federation

Federal State Institution Kirov, Hematology and Blood Transfusion Research Institute under the Federal Agency for High-Tech Medical Care

Kirov, Russian Federation, 610027

Children's Territorial Clinical Hospital

Krasnodar, Russian Federation, 350007

Hematology Research Center RAMS

Moscow, Russian Federation, 125167

Ukraine

State Institution "Institute of Blood Pathology and Transfusion Medicine under the Academy of Medical Sciences of Ukraine"

Lviv, Ukraine, 79044

United Kingdom

Royal Manchester Children's Hospital, Department of Hematology

Manchester, United Kingdom, M13 9WL

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

• Study Director: Study Director; Takeda

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT01507896
• Other Study ID Numbers: 251002; 2011-000413-39 ( EudraCT Number )
• First Posted: January 11, 2012
• Results First Posted: February 15, 2017
• Last Update Posted: May 19, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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.
• URL: https://vivli.org/ourmember/takeda/

Additional relevant MeSH terms:

Hemophilia A; Hemophilia B; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked