Phase 3 Efficacy and Safety Study of BAX 855 in Severe Hemophilia A Patients Undergoing Surgical Procedures

GHEA=Sum of 1-3 ratings: Excellent: 7-9 (no category \<2), Good: 5-7 (no category \<1), Fair: 3-4 (no category \<1) 1. Intraoperative and 2. Postoperative (postoperative day 1) hemostatic efficacy assessments: Excellent=3: Blood Loss (BL) ≤ than expected for procedure type in non-hemophilic population (NHP) (≤100%), Good=2: BL ≤50% more than expect. for procedure type in NHP (101-150%), Fair=1: BL \>50% more than expect. for procedure type in NHP (\>150%), None=0: Significant bleeding-requiring rescue therapy (RT) 3. Perioperative hemostatic efficacy assessment (day 14 or discharge, whatever is first): Excellent=3: BL and required blood transfusions (BT) less than or similar (≤100%) to that expected for procedure type in NHP, Good=2: BL ≤50% more (101-150%) and BT less than or similar to that expected for procedure type in NHP, Fair=1: BL \>50% more (\>150%) and BT greater than expected in NHP, None=0: Significant bleeding-requiring RT, BT substantially greater than expected in NHP

Time frame: Hemostatic efficacy assessments were performed intraoperatively, postoperatively on day 1 (approximately 24 hours after surgery) and perioperatively at day 14 or discharge (whichever was first).

Population: Full analysis group comprises groups major orthopedic and non-orthopedic and minor surgery. Main analysis was done on the full analysis group (at least one hemostatic assessment available) and supportive analysis was done on the per protocol analysis group (all hemostatic assessments available).

Changes in clinical chemistry and hematology parameters from a normal or abnormal not clinically significant (ncs) result at screening to an abnormal and clinically significant (cs) result at the end of study assessment (EOS) are listed. Changes did occur in the following laboratory parameters: Alanine Aminotransferase (ALT) (U/L), Hemoglobin (g/L), Hematocrit, Erythrocytes(TI/L), Eosinophils/Leucocytes.

Time frame: Throughout the entire study period from screening to completion/termination (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).

Population: The outcome measure data include surgical enrollments with results both at screening and at the end of the study for each assay.

Changes in body temperature were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.

Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855. Pre-infusion and 15 min post-infusion vital signs measurements are not available for all surgeries. 15 min. post-infusion measure includes 1 hour post infusion measure for 2 subjects.

Changes in the pulse rate (beats/minute) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.

Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855. Pre-infusion and 15 min post-infusion vital signs measurements are not available for all surgeries. 15 min. post-infusion measure includes 1 hour post infusion measure for 2 subjects.

Changes in Respiratory rate were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.

Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855. Pre-infusion and 15 min post-infusion vital signs measurements are not available for all surgeries. 15 min. post-infusion measure includes 1 hour post infusion measure for 2 subjects.

Changes in systolic and diastolic blood pressure (mmHg) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.

Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855. Pre-infusion and 15 min post-infusion vital signs measurements are not available for all surgeries. 15 min. post-infusion measure includes 1 hour post infusion measure for 2 subjects.

Daily and total weight-adjusted consumption of BAX855 per subject.

Time frame: From initial loading dose until discharge for daily weight-adjusted dose and from first infusion (PK/IR) until end of study for total weight-adjusted dose.

Population: The full analysis group comprises the groups with major orthopedic, major non-orthopedic and minor surgery. Number of surgeries/participants with BAX855 consumption varies on each postoperative day.

Immunogenicity assessment using FVIII inhibitor by Nijmegen method. A 72-hour washout period is required prior to immunogenicity tests.

Time frame: Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855.

A 72-hour washout period is required prior to immunogenicity tests.

Time frame: Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855.

A 72-hour washout period is required prior to immunogenicity tests.

Time frame: Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855.

Time frame: Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days).

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855.

Actual intraoperative blood loss was assessed at the end of surgery and was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected intraoperative blood loss was predicted preoperatively by the investigator/surgeon.

Time frame: From initiation of surgery until end of surgery.

Population: The full analysis group comprises the groups with major orthopedic, major non-orthopedic and minor surgery.

Any clinically relevant bleeding episodes (as assessed by the investigator) as well as the need for any further surgical interventions were recorded. If the subject had not resumed his previous treatment after discharge, the occurrence and treatment of bleeding episodes were recorded in the subject's diary.

Time frame: Intra- and post-operative period, until the last intensified treatment after hospital discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks)

Population: Only surgeries/participants that have encountered bleeding episodes are reported for the analysis of bleeding episodes (5 surgeries in 5 participants) and all surgeries/participants are reported for the analysis of the need for surgical intervention.

Time frame: Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days).

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855.

Time frame: Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days).

Population: The safety analysis data set was used for the analysis of this outcome measure including all participants who received at least one infusion of BAX855.

Actual overall perioperative blood loss (assessed at the end of surgery, at postoperative day 1 and until discharge or day 14 - whichever is first) was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected perioperative blood loss was predicted pre-operatively by the investigator/surgeon.

Time frame: From start of surgery until discharge or day 14, whichever occurred first.

Population: The full analysis group comprises the groups with major orthopedic, major non-orthopedic and minor surgery.

Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Apparent steady state volume of distribution (Vss) was calculated as dose multiplied with AUMC(0-inf) divided by AUC(0-inf) to square. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.

Time frame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.

Following at least a 72 hour (h) washout period a single dose of BAX855 will be administered. The PK profiles was used to guide dosing and dosing frequency during the perioperative time period. The area under the plasma concentration/time curve from time 0 to 96 hours postinfusion (AUC 0-96h) was computed using the linear trapezoidal rule. For the calculation of AUC 0-96h the levels at 96 hours were linearly interpolated/extrapolated from the 2 nearest sampling time points. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.

Time frame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.

Following at least a 72 hour washout period a single dose of BAX855 was administered. The PK profiles was used to guide dosing and dosing frequency during the perioperative time period. The area under the plasma concentration/time curve from time 0 to infinity (AUC 0-inf) and the area under the first movement curve from time 0 to infinity (AUMC 0-inf) was calculated as the sum of AUC and AUMC from time 0 to the time of the last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.

Time frame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.

Following a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Systemic clearance (CL) was calculated as the dose in IU/kg divided by the total AUC. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. h = hours

Time frame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.

Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Incremental recovery (IR) was calculated as C post infusion minus C pre-infusion divided by the dose. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.

Time frame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.

Population: For measurement at 15 min post-infusion only 23 surgeries in 18 participants were available for analysis.

Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Mean residence time (MRT) was calculated as total area under the moment curve divided by the total area under the curve. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.

Time frame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.

Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Terminal or disposition half-life (HL) was calculated as log e(2)/λz where the terminal or disposition rate constant (λz) was estimated as the slope of a log-linear least squares regression model. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.

Time frame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.

Actual post-operative blood loss assessed at postoperative day 1 was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected postoperative blood loss was predicted pre-operatively by the investigator/surgeon.

Time frame: From completion of surgery until 24 hours after surgery.

Population: The full analysis group comprises the groups with major orthopedic, major non-orthopedic and minor surgery.

Volume of blood, red blood cells, platelets, and other blood products transfused. Only packed red blood cells were transfused in this study.

Time frame: From initiation of the surgery to 24 hours after completion of the surgery.

Population: The full analysis group comprises the groups with major orthopedic, major non-orthopedic and minor surgery. Only participants who received blood transfusions are included in this analysis.