BAX 326 Surgery Study in Hemophilia B Patients

NCT01507896 | Completed Phase 3 Results DMC

• 2 other identifiers: 2510022011-000413-39
• Study Type: interventional
• Target: 30
• Locations: 10 countries
• Sites: 14

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.

Conditions

Hemophilia B

Outcome Measures

Primary Outcomes (24)

• 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.

Study Arms (1)

BAX326 in Surgery

EXPERIMENTAL

BAX 326 (recombinant factor IX) in Surgery

Biological: Recombinant factor IX

Interventions

Recombinant factor IX BIOLOGICAL

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.

Also known as: BAX326, RIXUBIS

BAX326 in Surgery

Eligibility Criteria

• Age: 12 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Baxalta now part of Shire: lead

Study Sites (14)

Instituto de Hematología y Medicina Clínica Rubén Dávoli

Rosario, 2000, Argentina

Location

Specialized Haematological Hospital "Joan Pavel"

Sofia, 1233, Bulgaria

Location

Hospital Dr. Sotero del Rio

Santiago, Chile

Location

Centro Medico Imbanaco

Cali, Colombia

Location

Klinika detska hematologie a onkologie, Fakultni Nemocnice Motol

Prague, 150 06, Czechia

Location

Medical University Lodz, Copernicus Hospital, Department of Hematology

Lodz, 93-510, Poland

Location

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

Warsaw, 00-579, Poland

Location

Institute of Haematology and Transfusion Medicine

Warsaw, 02-776, Poland

Location

Louis Turcanu Emergency Clinical Children´s Hospital

Timișoara, Romania

Location

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

Kirov, 610027, Russia

Location

Children's Territorial Clinical Hospital

Krasnodar, 350007, Russia

Location

Hematology Research Center RAMS

Moscow, 125167, Russia

Location

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

Lviv, 79044, Ukraine

Location

Royal Manchester Children's Hospital, Department of Hematology

Manchester, M13 9WL, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 24697870 RESULT

• 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.

  PMID: 32816519 DERIVED

MeSH Terms

Conditions

Hemophilia B

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; Genetic Diseases, X-Linked

Limitations and Caveats

Data provided for surgical procedures, treatments with BAX326 etc. and for unique participants (one unique participant could undergo more than one surgical procedure).

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 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2012
• First Posted: January 11, 2012
• Study Start: December 19, 2011
• Primary Completion: May 15, 2014
• Study Completion: May 15, 2014
• Last Updated: May 19, 2021
• Results First Posted: February 15, 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

CL (1); GB (1); PL (3); AR (1); CZ (1); BU (1); RO (1); RU (3); UA (1); CO (1)