BAX 326 Surgery Study in Hemophilia B Patients

Primary outcomes

1. Intraoperative Hemostatic Efficacy

   Time frame: 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

2. Actual Intraoperative Blood Loss

   Time frame: 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.

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

   Time frame: 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.

4. Postoperative Hemostatic Efficacy at Drain Removal

   Time frame: 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

5. Postoperative Hemostatic Efficacy at Postoperative Day 3

   Time frame: 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

6. 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)

   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

7. Actual Postoperative Blood Loss

   Time frame: 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.

8. 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)

   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.

9. 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)

   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.

10. 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)

    Assessed for the intra- and postoperative periods.

11. 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)

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

12. 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)

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

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

    Time frame: Throughout the study period (approximately 2 years 5 months)

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

    Time frame: 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.

15. Safety: Number of Adverse Events Related to BAX326

    Time frame: Throughout the study period (approximately 2 years 5 months)

16. Safety: Occurence of a Thrombotic Event

    Time frame: Throughout the study period (approximately 2 years 5 months)

17. Pre-Surgical 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

    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.

18. Pre-Surgical 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

    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.

19. Pre-Surgical 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

    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.

20. Pre-Surgical 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

    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).

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

    Time frame: 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.

22. Pre-Surgical 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

    T1/2 was determined as ln2 / λz.

23. Pre-Surgical 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

    Vss was computed as CL·MRT.

24. 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.

    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.