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BAX 326 Surgery Study in Hemophilia B Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Baxalta US Inc.
ClinicalTrials.gov Identifier:
NCT01507896
First received: January 9, 2012
Last updated: July 26, 2016
Last verified: July 2016
  Purpose
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 Intervention Phase
Hemophilia B
Biological: Recombinant factor IX
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Baxalta US Inc.:

Primary Outcome Measures:
  • Intraoperative Hemostatic Efficacy [ Time Frame: On day of surgery ] [ Designated as safety issue: No ]

    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

  • Actual Intraoperative Blood Loss [ Time Frame: On day of surgery ] [ Designated as safety issue: No ]
    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.

  • Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon [ Time Frame: On day of surgery ] [ Designated as safety issue: No ]
    Predicted average/maximum blood loss minus actual blood loss.

  • Postoperative Hemostatic Efficacy at Drain Removal [ Time Frame: At drain removal (from 1-3 days postoperatively) ] [ Designated as safety issue: No ]

    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

  • Postoperative Hemostatic Efficacy at Postoperative Day 3 [ Time Frame: At postoperative day 3 (approximately 72 hours postoperatively) ] [ Designated as safety issue: No ]

    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

  • 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) ] [ Designated as safety issue: No ]

    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

  • Actual Postoperative Blood Loss [ Time Frame: At drain removal (from 1-3 days postoperatively) ] [ Designated as safety issue: No ]
    Postoperative blood loss was based on the drainage fluid and was only assessed for participants who had a drain placed during surgery.

  • 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) ] [ Designated as safety issue: No ]
    Predicted average/maximum blood loss minus actual blood loss for participants who had a drain placed during surgery.

  • 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) ] [ Designated as safety issue: No ]

    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.


  • 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) ] [ Designated as safety issue: No ]
    Assessed for the intra- and postoperative periods.

  • 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) ] [ Designated as safety issue: No ]
    Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.

  • 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) ] [ Designated as safety issue: No ]
    Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.

  • Safety: Number of Participants who Developed Inhibitory Antibodies to Factor IX (FIX) [ Time Frame: Throughout the study period (approximately 2 years 5 months) ] [ Designated as safety issue: Yes ]
  • Safety: Number of Participants who Developed Total Binding Antibodies to Factor IX (FIX) [ Time Frame: Throughout the study period (approximately 2 years 5 months) ] [ Designated as safety issue: Yes ]
    If there was more than 2-dilution increase as compared to pre-study level at screening.

  • Safety: Number of Adverse events Related to BAX326 [ Time Frame: Throughout the study period (approximately 2 years 5 months) ] [ Designated as safety issue: Yes ]
  • Safety: Number of Participants Who Have the Occurence of a Thrombotic Event [ Time Frame: Throughout the study period (approximately 2 years 5 months) ] [ Designated as safety issue: Yes ]
  • Presurgical 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 ] [ Designated as safety issue: No ]
    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.

  • Presurgical 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 ] [ Designated as safety issue: No ]
    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.

  • Presurgical 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 ] [ Designated as safety issue: No ]
    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.

  • Presurgical 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 ] [ Designated as safety issue: No ]
    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).

  • Presurgical Pharmacokinetics (PK): Incremental recovery (IR) at 30 min [ Time Frame: Within 30 mins pre-infusion and post-infusion at 30 minutes ] [ Designated as safety issue: No ]
    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.

  • Presurgical 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 ] [ Designated as safety issue: No ]
    T1/2 was determined as ln2 / λz.

  • Presurgical 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 ] [ Designated as safety issue: No ]
    Vss was computed as CL·MRT.

  • 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. ] [ Designated as safety issue: No ]
    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.


Enrollment: 41
Study Start Date: December 2011
Study Completion Date: May 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BAX326 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

  Eligibility

Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01507896

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
Czech Republic
Klinika detska hematologie a onkologie, Fakultni Nemocnice Motol
Prague, Czech Republic, 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 US Inc.
Investigators
Study Director: Baxalta Study Director Baxalta US Inc.
  More Information

Publications:
Responsible Party: Baxalta US Inc.
ClinicalTrials.gov Identifier: NCT01507896     History of Changes
Other Study ID Numbers: 251002  2011-000413-39 
Study First Received: January 9, 2012
Last Updated: July 26, 2016
Health Authority: United States: Food and Drug Administration
Chile: Instituto de Salud Pública de Chile
Czech Republic: State Institute for Drug Control
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Ukraine: State Pharmacological Center - Ministry of Health
Japan: Pharmaceuticals and Medical Devices Agency
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Russia: FSI Scientific Center of Expertise of Medical Application
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Romania: National Medicines Agency
Bulgaria: Bulgarian Drug Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

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

ClinicalTrials.gov processed this record on December 09, 2016