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BAX 326 Surgery Study in Hemophilia B Patients

Primary Purpose

Hemophilia B

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Recombinant factor IX

About this trial

This is an interventional treatment trial for Hemophilia B

Eligibility Criteria

12 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Instituto de Hematología y Medicina Clínica Rubén Dávoli
Specialized Haematological Hospital "Joan Pavel"
Hospital Dr. Sotero del Rio
Centro Medico Imbanaco
Klinika detska hematologie a onkologie, Fakultni Nemocnice Motol
Medical University Lodz, Copernicus Hospital, Department of Hematology
Independent Public Pediatric Teaching Hospital, Clinical Department of Hematology and Pediatrics
Institute of Haematology and Transfusion Medicine
Louis Turcanu Emergency Clinical Children´s Hospital
Federal State Institution Kirov, Hematology and Blood Transfusion Research Institute under the Federal Agency for High-Tech Medical Care
Children's Territorial Clinical Hospital
Hematology Research Center RAMS
State Institution "Institute of Blood Pathology and Transfusion Medicine under the Academy of Medical Sciences of Ukraine"
Royal Manchester Children's Hospital, Department of Hematology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BAX326 in Surgery

Arm Description

BAX 326 (recombinant factor IX) in Surgery

Outcomes

Primary Outcome Measures

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

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.

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.

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

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

Postoperative Hemostatic Efficacy on Day of Discharge

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.

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.

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.

Total Weight-Adjusted Dose of BAX326 Per Participant

Assessed for the intra- and postoperative periods.

Number of Units of Blood Product Transfused

Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.

Volume of Blood Product Transfused

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)

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.

Safety: Number of Adverse Events Related to BAX326

Safety: Occurence of a Thrombotic Event

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.

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.

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.

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).

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.

Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2)

T1/2 was determined as ln2 / λz.

Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss)

Vss was computed as CL·MRT.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT01507896

First Posted

January 9, 2012

Last Updated

April 30, 2021

Sponsor

Baxalta now part of Shire

1. Study Identification

Unique Protocol Identification Number

NCT01507896

Brief Title

BAX 326 Surgery Study in Hemophilia B Patients

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

December 19, 2011 (Actual)

Primary Completion Date

May 15, 2014 (Actual)

Study Completion Date

May 15, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Baxalta now part of Shire

4. Oversight

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hemophilia B

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

BAX326 in Surgery

Arm Type

Experimental

Arm Description

BAX 326 (recombinant factor IX) in Surgery

Intervention Type

Biological

Intervention Name(s)

Recombinant factor IX

Other Intervention Name(s)

BAX326, RIXUBIS

Intervention Description

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.

Primary Outcome Measure Information:

Title

Intraoperative Hemostatic Efficacy

Description

Time Frame

On day of surgery

Title

Actual Intraoperative Blood Loss

Description

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.

Time Frame

On day of surgery

Title

Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon

Description

Time Frame

On day of surgery

Title

Postoperative Hemostatic Efficacy at Drain Removal

Description

Time Frame

At drain removal (from 1-3 days postoperatively)

Title

Postoperative Hemostatic Efficacy at Postoperative Day 3

Description

Time Frame

At postoperative day 3 (approximately 72 hours postoperatively)

Title

Postoperative Hemostatic Efficacy on Day of Discharge

Description

Time Frame

At discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery)

Title

Actual Postoperative Blood Loss

Description

Postoperative blood loss was based on the drainage fluid and was only assessed for participants who had a drain placed during surgery.

Time Frame

At drain removal (from 1-3 days postoperatively)

Title

Actual Postoperative Blood Loss Compared to Average and Maximum Blood Loss Predicated Preoperatively by the Operating Surgeon

Description

Time Frame

At postoperative day 3 (approximately 72 hours postoperatively)

Title

Daily Weight-Adjusted Dose of BAX326 Per Participant

Description

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)

Title

Total Weight-Adjusted Dose of BAX326 Per Participant

Description

Assessed for the intra- and postoperative periods.

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)

Title

Number of Units of Blood Product Transfused

Description

Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.

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)

Title

Volume of Blood Product Transfused

Description

Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.

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)

Title

Safety: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX)

Time Frame

Throughout the study period (approximately 2 years 5 months)

Title

Safety: Number of Participants Who Developed Total Binding Antibodies to Factor IX (FIX)

Description

If there was more than 2-dilution increase as compared to pre-study level at screening.

Time Frame

Throughout the study period (approximately 2 years 5 months)

Title

Safety: Number of Adverse Events Related to BAX326

Time Frame

Throughout the study period (approximately 2 years 5 months)

Title

Safety: Occurence of a Thrombotic Event

Time Frame

Throughout the study period (approximately 2 years 5 months)

Title

Pre-Surgical Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 72 Hours Post-infusion Per Dose

Description

Time Frame

Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr

Title

Pre-Surgical Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve Per Dose (Total AUC/Dose)

Description

Time Frame

Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr

Title

Pre-Surgical Pharmacokinetics (PK): Mean Residence Time (MRT)

Description

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.

Time Frame

Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr

Title

Pre-Surgical Pharmacokinetics (PK): Factor IX (FIX) Clearance (CL)

Description

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).

Time Frame

Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr

Title

Pre-Surgical Pharmacokinetics (PK): Incremental Recovery (IR) at 30 Min

Description

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.

Time Frame

Within 30 mins pre-infusion and post-infusion at 30 minutes

Title

Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2)

Description

T1/2 was determined as ln2 / λz.

Time Frame

Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr

Title

Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss)

Description

Vss was computed as CL·MRT.

Time Frame

Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr

Title

Incremental Recovery (IR) at 15±5 Minutes Following Loading Dose Prior to Surgery

Description

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.

Time Frame

Within 60 minutes prior to surgery and 15 ± 5 minutes after loading dose/rebolus, if applicable.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

Facility Name

Instituto de Hematología y Medicina Clínica Rubén Dávoli

City

Rosario

ZIP/Postal Code

2000

Country

Argentina

Facility Name

Specialized Haematological Hospital "Joan Pavel"

City

Sofia

ZIP/Postal Code

1233

Country

Bulgaria

Facility Name

Hospital Dr. Sotero del Rio

City

Santiago

Country

Chile

Facility Name

Centro Medico Imbanaco

City

Cali

Country

Colombia

Facility Name

Klinika detska hematologie a onkologie, Fakultni Nemocnice Motol

City

Prague

ZIP/Postal Code

150 06

Country

Czechia

Facility Name

Medical University Lodz, Copernicus Hospital, Department of Hematology

City

Lodz

ZIP/Postal Code

93-510

Country

Poland

Facility Name

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

City

Warsaw

ZIP/Postal Code

00-579

Country

Poland

Facility Name

Institute of Haematology and Transfusion Medicine

City

Warsaw

ZIP/Postal Code

02-776

Country

Poland

Facility Name

Louis Turcanu Emergency Clinical Children´s Hospital

City

Timisoara

Country

Romania

Facility Name

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

City

Kirov

ZIP/Postal Code

610027

Country

Russian Federation

Facility Name

Children's Territorial Clinical Hospital

City

Krasnodar

ZIP/Postal Code

350007

Country

Russian Federation

Facility Name

Hematology Research Center RAMS

City

Moscow

ZIP/Postal Code

125167

Country

Russian Federation

Facility Name

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

City

Lviv

ZIP/Postal Code

79044

Country

Ukraine

Facility Name

Royal Manchester Children's Hospital, Department of Hematology

City

Manchester

ZIP/Postal Code

M13 9WL

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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 URL

https://vivli.org/ourmember/takeda/

Citations:

PubMed Identifier

24697870

Citation

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.

Results Reference

result

PubMed Identifier

32816519

Citation

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.

Results Reference

derived

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BAX 326 Surgery Study in Hemophilia B Patients

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