Hemophilia B
Conditions
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.
Interventions
BIOLOGICALRecombinant 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.
Sponsors
Baxalta now part of Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intraoperative Hemostatic Efficacy | 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 |
| Actual Intraoperative Blood Loss | 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. |
| Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon | 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. |
| Postoperative Hemostatic Efficacy at Drain Removal | 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 |
| Postoperative Hemostatic Efficacy at Postoperative Day 3 | 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 |
| Postoperative Hemostatic Efficacy on Day of Discharge | 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 |
| Actual Postoperative Blood Loss | 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. |
| Actual Postoperative Blood Loss Compared to Average and Maximum Blood Loss Predicated Preoperatively by the Operating Surgeon | 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. |
| Daily Weight-Adjusted Dose of BAX326 Per Participant | 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. |
| Total Weight-Adjusted Dose of BAX326 Per Participant | 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. |
| Number of Units of Blood Product Transfused | 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. |
| Volume of Blood Product Transfused | 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. |
| 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) | 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. |
| 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 | 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. |
| Pre-Surgical Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve Per Dose (Total AUC/Dose) | 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. |
| Pre-Surgical Pharmacokinetics (PK): Mean Residence Time (MRT) | 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. |
| Pre-Surgical Pharmacokinetics (PK): Factor IX (FIX) Clearance (CL) | 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). |
| Pre-Surgical Pharmacokinetics (PK): Incremental Recovery (IR) at 30 Min | 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. |
| Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2) | 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. |
| Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | 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. |
| Incremental Recovery (IR) at 15±5 Minutes Following Loading Dose Prior to Surgery | 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. |
Countries
Argentina, Bulgaria, Chile, Colombia, Czechia, Poland, Romania, Russia, Ukraine, United Kingdom
Participant flow
Recruitment details
Enrollment was conducted at 10 clinical sites in 8 countries (Bulgaria, Czech Republic, Poland, Romania, Russia, Ukraine, Chile, Colombia).
Pre-assignment details
30 unique participants enrolled for 41 surgical procedures, of which 1 participant discontinued before treatment with BAX326 but re-enrolled later for another surgical procedure. Note: a unique participant can undergo more than one surgical procedure.
Participants by arm
| Arm | Count |
|---|---|
| Treatment With BAX326 Recombinant Factor IX (FIX): Following a loading dose with BAX326, participants received BAX326 as a bolus infusion. The treatment regimen was determined by the intensity and duration of the hemostatic challenge and the institution's standard of care. The dose was 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. Note: Treatment with BAX326 refers to unique participants treated with BAX326 which is less than the number of participants treated with BAX326 as unique participants could undergo more than one surgical procedure in this study. 30 unique participants were treated with BAX326 for 40 planned surgical procedures; of these, 2 unique participants were treated with BAX326 but did not undergo 2 surgical procedures (1 surgery per unique participant), therefore 28 unique participants underwent 38 surgical procedures. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | The surgery was denied by the sponsor. | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment With BAX326 |
|---|---|
| Age, Continuous | 39.7 years STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 30 |
| serious Total, serious adverse events | 0 / 30 |
Outcome results
Primary
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.
Time frame: On day of surgery
Population: All participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) treated with BAX326 per surgical procedure. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Actual Intraoperative Blood Loss | 191.1 mL | Standard Deviation 354.1 |
| Major Surgeries | Actual Intraoperative Blood Loss | 344.9 mL | Standard Deviation 420.1 |
| Minor Surgeries | Actual Intraoperative Blood Loss | 1.2 mL | Standard Deviation 1.1 |
Primary
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.
Time frame: On day of surgery
Population: All participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) treated with BAX326 per surgical procedure. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Surgeries | Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon | Difference from predicted average blood loss | -27.0 mL | Standard Deviation 158.9 |
| All Surgeries | Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon | Difference from predicted maximum blood loss | 128.3 mL | Standard Deviation 260.8 |
| Major Surgeries | Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon | Difference from predicted average blood loss | -50.9 mL | Standard Deviation 213 |
| Major Surgeries | Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon | Difference from predicted maximum blood loss | 222.0 mL | Standard Deviation 323.7 |
| Minor Surgeries | Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon | Difference from predicted average blood loss | 2.4 mL | Standard Deviation 4.9 |
| Minor Surgeries | Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon | Difference from predicted maximum blood loss | 12.5 mL | Standard Deviation 24.5 |
Primary
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.
Time frame: At drain removal (from 1-3 days postoperatively)
Population: Participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who had a drain placed during surgery (major surgeries only). Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Actual Postoperative Blood Loss | 603.6 mL | Standard Deviation 388.7 |
Primary
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.
Time frame: At postoperative day 3 (approximately 72 hours postoperatively)
Population: Participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who had a drain placed during surgery (major surgeries only). Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Surgeries | Actual Postoperative Blood Loss Compared to Average and Maximum Blood Loss Predicated Preoperatively by the Operating Surgeon | Difference from predicated average blood loss | -221.4 mL | Standard Deviation 331.7 |
| All Surgeries | Actual Postoperative Blood Loss Compared to Average and Maximum Blood Loss Predicated Preoperatively by the Operating Surgeon | Difference from predicted maximum blood loss | 147.1 mL | Standard Deviation 330.1 |
Primary
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.
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)
Population: All participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) treated with BAX326 per surgical procedure. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 2 (N=29,21,8) | 115.0 IU/kg | Standard Deviation 40.2 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 3 (N=26,21,5) | 111.6 IU/kg | Standard Deviation 43.9 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 4 (N=24,21,3) | 115.2 IU/kg | Standard Deviation 63 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 6 (N=21,20,1) | 105.6 IU/kg | Standard Deviation 44 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 8 (N=19,19,0) | 93.0 IU/kg | Standard Deviation 45.8 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 9 (N=19,19,0) | 93.0 IU/kg | Standard Deviation 46.9 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 11+ (N=15,15,0) | 75.3 IU/kg | Standard Deviation 44.8 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Day of Surgery | 144.8 IU/kg | Standard Deviation 70.3 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 1 | 103.9 IU/kg | Standard Deviation 44.6 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 5 (N=23,21,2) | 104.4 IU/kg | Standard Deviation 47.4 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 7 (N=21,20,1) | 94.6 IU/kg | Standard Deviation 46.7 |
| All Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 10 (N=18,18,0) | 89.9 IU/kg | Standard Deviation 49.7 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 1 | 136.7 IU/kg | Standard Deviation 30.1 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 2 (N=29,21,8) | 134.2 IU/kg | Standard Deviation 27.6 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 10 (N=18,18,0) | 89.9 IU/kg | Standard Deviation 49.7 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Day of Surgery | 191.5 IU/kg | Standard Deviation 50.6 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 3 (N=26,21,5) | 123.5 IU/kg | Standard Deviation 39.4 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 8 (N=19,19,0) | 93.0 IU/kg | Standard Deviation 45.8 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 4 (N=24,21,3) | 123.5 IU/kg | Standard Deviation 62.4 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 5 (N=23,21,2) | 108.6 IU/kg | Standard Deviation 46.6 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 11+ (N=15,15,0) | 75.3 IU/kg | Standard Deviation 44.8 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 7 (N=21,20,1) | 96.1 IU/kg | Standard Deviation 47.4 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 6 (N=21,20,1) | 106.6 IU/kg | Standard Deviation 44.9 |
| Major Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 9 (N=19,19,0) | 93.0 IU/kg | Standard Deviation 46.9 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 6 (N=21,20,1) | 86.0 IU/kg | Standard Deviation 0 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 8 (N=19,19,0) | 0 IU/kg | Standard Deviation 0 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 1 | 63.5 IU/kg | Standard Deviation 18 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 9 (N=19,19,0) | 0 IU/kg | Standard Deviation 0 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 10 (N=18,18,0) | 0 IU/kg | Standard Deviation 0 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 11+ (N=15,15,0) | 0 IU/kg | Standard Deviation 0 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 4 (N=24,21,3) | 56.9 IU/kg | Standard Deviation 29.3 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 2 (N=29,21,8) | 64.6 IU/kg | Standard Deviation 16.2 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 3 (N=26,21,5) | 61.6 IU/kg | Standard Deviation 20.8 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Day of Surgery | 87.2 IU/kg | Standard Deviation 42.9 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 5 (N=23,21,2) | 60.4 IU/kg | Standard Deviation 41.9 |
| Minor Surgeries | Daily Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Day 7 (N=21,20,1) | 65.5 IU/kg | Standard Deviation 0 |
Primary
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.
Time frame: Within 60 minutes prior to surgery and 15 ± 5 minutes after loading dose/rebolus, if applicable.
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided suitable hemostatic efficacy data) who provided data for incremental recovery (IR) after the loading dose prior to surgery. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Incremental Recovery (IR) at 15±5 Minutes Following Loading Dose Prior to Surgery | 0.910 [IU/dL] : [IU/kg] | Standard Deviation 0.1787 |
Primary
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
Time frame: On day of surgery
Population: All participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) treated with BAX326 and had surgery. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Surgeries | Intraoperative Hemostatic Efficacy | None | 0 surgeries |
| All Surgeries | Intraoperative Hemostatic Efficacy | Good | 1 surgeries |
| All Surgeries | Intraoperative Hemostatic Efficacy | Fair | 0 surgeries |
| All Surgeries | Intraoperative Hemostatic Efficacy | Excellent | 37 surgeries |
| Major Surgeries | Intraoperative Hemostatic Efficacy | Good | 1 surgeries |
| Major Surgeries | Intraoperative Hemostatic Efficacy | Excellent | 20 surgeries |
| Major Surgeries | Intraoperative Hemostatic Efficacy | None | 0 surgeries |
| Major Surgeries | Intraoperative Hemostatic Efficacy | Fair | 0 surgeries |
| Minor Surgeries | Intraoperative Hemostatic Efficacy | None | 0 surgeries |
| Minor Surgeries | Intraoperative Hemostatic Efficacy | Good | 0 surgeries |
| Minor Surgeries | Intraoperative Hemostatic Efficacy | Fair | 0 surgeries |
| Minor Surgeries | Intraoperative Hemostatic Efficacy | Excellent | 17 surgeries |
Primary
Number of Units of Blood Product Transfused
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)
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided suitable hemostatic efficacy data) who received blood product infusions during the intraoperative and/or postoperative period. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Surgeries | Number of Units of Blood Product Transfused | Intraoperative Period | 2.8 units | Standard Deviation 1.2 |
| All Surgeries | Number of Units of Blood Product Transfused | Postoperative Period | 1.5 units | Standard Deviation 0.7 |
Primary
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
Time frame: At drain removal (from 1-3 days postoperatively)
Population: Participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who had a drain placed during surgery (major surgeries only). Note: a unique participant could have more than one surgical procedure
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Surgeries | Postoperative Hemostatic Efficacy at Drain Removal | Good | 4 major surgeries with drain placed |
| All Surgeries | Postoperative Hemostatic Efficacy at Drain Removal | Fair | 0 major surgeries with drain placed |
| All Surgeries | Postoperative Hemostatic Efficacy at Drain Removal | None | 0 major surgeries with drain placed |
| All Surgeries | Postoperative Hemostatic Efficacy at Drain Removal | Excellent | 10 major surgeries with drain placed |
Primary
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
Time frame: At postoperative day 3 (approximately 72 hours postoperatively)
Population: Participants in the Full Analysis Set who were provided with a hemostatic efficacy assessment by the operating surgeon at post operative day 3 where no drain was employed. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Excellent | 7 surgeries |
| All Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Fair | 0 surgeries |
| All Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Good | 1 surgeries |
| All Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | None | 0 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | None | 0 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Good | 1 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Excellent | 6 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Fair | 0 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Good | 0 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Excellent | 1 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | Fair | 0 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy at Postoperative Day 3 | None | 0 surgeries |
Primary
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
Time frame: At discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery)
Population: All participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) treated with BAX326 per surgical procedure. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Excellent | 29 surgeries |
| All Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | None | 0 surgeries |
| All Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Good | 7 surgeries |
| All Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Fair | 2 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | None | 0 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Good | 7 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Fair | 2 surgeries |
| Major Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Excellent | 12 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Excellent | 17 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | None | 0 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Fair | 0 surgeries |
| Minor Surgeries | Postoperative Hemostatic Efficacy on Day of Discharge | Good | 0 surgeries |
Primary
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.
Time frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who underwent a pre-surgical PK assessment in this study i.e.not participants who underwent a PK assessment in the pivotal study (250901). Note: a unique participant could have a pre-surgical PK assessment for more than one surgery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Pre-Surgical Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 72 Hours Post-infusion Per Dose | 18.48 [IU•hour (hr)/dL] : IU/kg | Standard Deviation 6.43 |
Primary
Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2)
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
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who underwent a pre-surgical PK assessment in this study i.e.not participants who underwent a PK assessment in the pivotal study (250901). Note: a unique participant could have a pre-surgical PK assessment for more than one surgery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2) | 23.60 hours (hr) | Standard Deviation 3.6 |
Primary
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).
Time frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who underwent a pre-surgical PK assessment in this study i.e.not participants who underwent a PK assessment in the pivotal study (250901). Note: a unique participant could have a pre-surgical PK assessment for more than one surgery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Pre-Surgical Pharmacokinetics (PK): Factor IX (FIX) Clearance (CL) | 0.0523 dL/(kg•hr) | Standard Deviation 0.0126 |
Primary
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.
Time frame: Within 30 mins pre-infusion and post-infusion at 30 minutes
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who underwent a pre-surgical PK assessment in this study i.e.not participants who underwent a PK assessment in the pivotal study (250901). Note: a unique participant could have a pre-surgical PK assessment for more than one surgery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Pre-Surgical Pharmacokinetics (PK): Incremental Recovery (IR) at 30 Min | 1.00 IU/dL : IU/kg | Standard Deviation 0.29 |
Primary
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.
Time frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who underwent a pre-surgical PK assessment in this study i.e.not participants who underwent a PK assessment in the pivotal study (250901). Note: a unique participant could have a pre-surgical PK assessment for more than one surgery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Pre-Surgical Pharmacokinetics (PK): Mean Residence Time (MRT) | 27.17 hours (hr) | Standard Deviation 4.03 |
Primary
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.
Time frame: Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who underwent a pre-surgical PK assessment in this study i.e.not participants who underwent a PK assessment in the pivotal study (250901). Note: a unique participant could have a pre-surgical PK assessment for more than one surgery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Pre-Surgical Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve Per Dose (Total AUC/Dose) | 20.60 [IU•hour (hr)/dL] : IU/kg | Standard Deviation 7.32 |
Primary
Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss)
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
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) who underwent a pre-surgical PK assessment in this study i.e.not participants who underwent a PK assessment in the pivotal study (250901). Note: a unique participant could have a pre-surgical PK assessment for more than one surgery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Surgeries | Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | 1.41 dL/kg | Standard Deviation 0.38 |
Primary
Safety: Number of Adverse Events Related to BAX326
Time frame: Throughout the study period (approximately 2 years 5 months)
Population: All participants in the Safety Analysis Set (participants exposed to BAX326 during the study). Note: a unique participant could be treated with BAX326 for more than one surgical procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Surgeries | Safety: Number of Adverse Events Related to BAX326 | 1 adverse events |
Primary
Safety: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX)
Time frame: Throughout the study period (approximately 2 years 5 months)
Population: All participants in the Safety Analysis Set (participants exposed to BAX326 during the study). Note: a unique participant could be treated with BAX326 for more than one surgical procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Surgeries | Safety: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX) | 0 participants |
Primary
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.
Time frame: Throughout the study period (approximately 2 years 5 months)
Population: All participants in the Safety Analysis Set (participants exposed to BAX326 during the study). Note: a unique participant could be treated with BAX326 for more than one surgical procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Surgeries | Safety: Number of Participants Who Developed Total Binding Antibodies to Factor IX (FIX) | 0 participants |
Primary
Safety: Occurence of a Thrombotic Event
Time frame: Throughout the study period (approximately 2 years 5 months)
Population: All participants in the Safety Analysis Set (participants exposed to BAX326 during the study). Note: a unique participant could be treated with BAX326 for more than one surgical procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Surgeries | Safety: Occurence of a Thrombotic Event | 0 surgeries |
Primary
Total Weight-Adjusted Dose of BAX326 Per Participant
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)
Population: All participants in the Full Analysis Set (participants exposed to BAX326 and provided data suitable for hemostatic efficacy analysis) treated with BAX326 per surgical procedure. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Surgeries | Total Weight-Adjusted Dose of BAX326 Per Participant | Intraoperative Period | 145 IU/kg | Standard Deviation 70 |
| All Surgeries | Total Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Period | 808 IU/kg | Standard Deviation 766 |
| Major Surgeries | Total Weight-Adjusted Dose of BAX326 Per Participant | Intraoperative Period | 191 IU/kg | Standard Deviation 51 |
| Major Surgeries | Total Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Period | 1350 IU/kg | Standard Deviation 617 |
| Minor Surgeries | Total Weight-Adjusted Dose of BAX326 Per Participant | Intraoperative Period | 87 IU/kg | Standard Deviation 43 |
| Minor Surgeries | Total Weight-Adjusted Dose of BAX326 Per Participant | Postoperative Period | 138 IU/kg | Standard Deviation 136 |
Primary
Volume of Blood Product Transfused
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)
Population: Participants in the Full Analysis Set (exposed to BAX326 and provided suitable hemostatic efficacy data) who received blood product infusions during the intraoperative and/or postoperative period. Note: a unique participant could have more than one surgical procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Surgeries | Volume of Blood Product Transfused | Intraoperative period | 834.3 mL | Standard Deviation 358.7 |
| All Surgeries | Volume of Blood Product Transfused | Postoperative Period (2 surgeries) | 414.0 mL | Standard Deviation 227.7 |