BAX 326 Surgery Study in Hemophilia B Patients

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hemophilia B

Intervention / Treatment
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* Biological: Recombinant factor IX


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAX326 in Surgery<br>BAX 326 (recombinant factor IX) in Surgery | Biological: Recombinant factor IX<br>* 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.<br>* Other names: RIXUBIS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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) |