Trial Outcomes & Findings for Phase 3 Efficacy and Safety Study of BAX 855 in Severe Hemophilia A Patients Undergoing Surgical Procedures (NCT NCT01913405)

NCT ID: NCT01913405

Last Updated: 2021-05-24

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 30 participants
• Primary outcome timeframe: 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).
• Results posted on: 2021-05-24

Participant Flow

Twelve study sites have enrolled participants in seven countries (US, Russia, UK, Bulgaria, Lithuania, Spain, Switzerland). There were 30 surgical enrollments in a total of 23 unique participants. Seven unique participants enrolled more than once, of whom five received study product for more than one surgical procedure.

A total of 23 participants provided informed consent and were screened for study participation. Of these, 22 unique participants (29 surgical enrollments) were exposed to study product. One participant discontinued prior to surgery and one subject discontinued after surgery.

Participant milestones

Measure	BAX855 Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and nature of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-100% FVIII trough level, and minor surgery will target an initial 30-60% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and nature of the surgery performed.
Overall Study STARTED	22
Overall Study COMPLETED	20
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Measure	BAX855 Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and nature of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-100% FVIII trough level, and minor surgery will target an initial 30-60% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and nature of the surgery performed.
Overall Study Withdrawal by Subject	1
Overall Study Adverse Event	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	BAX855 n=22 Participants Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and nature of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-100% FVIII trough level, and minor surgery will target an initial 30-60% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and nature of the surgery performed.
Age, Continuous	34.8 Years STANDARD_DEVIATION 13.47 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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).

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

Outcome measures

Measure	Full Analysis Group n=24 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=14 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=7 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery n=3 Surgeries All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group n=12 Surgeries All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings Treatment success (GHEA score excellent or good)	100.0 Percentage of surgeries Interval 88.3 to 100.0	100.0 Percentage of surgeries Interval 80.7 to 100.0	100.0 Percentage of surgeries Interval 65.2 to 100.0	100.0 Percentage of surgeries Interval 36.8 to 100.0	100.0 Percentage of surgeries Interval 77.9 to 100.0
Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings Excellent	100.0 Percentage of surgeries Interval 88.3 to 100.0	100.0 Percentage of surgeries Interval 80.7 to 100.0	100.0 Percentage of surgeries Interval 65.2 to 100.0	100.0 Percentage of surgeries Interval 36.8 to 100.0	100.0 Percentage of surgeries Interval 77.9 to 100.0
Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings Good	0.0 Percentage of surgeries Interval 0.0 to 11.7	0.0 Percentage of surgeries Interval 0.0 to 19.3	0.0 Percentage of surgeries Interval 0.0 to 34.8	0.0 Percentage of surgeries Interval 0.0 to 63.2	0.0 Percentage of surgeries Interval 0.0 to 22.1

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Full Analysis Group n=26 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=14 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=7 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery n=5 Surgeries All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Intraoperative Blood Loss Actual blood loss	10 Milliliter Interval 4.0 to 30.0	10 Milliliter Interval 10.0 to 30.0	4.5 Milliliter Interval 3.0 to 50.0	5 Milliliter Interval 0.0 to 15.0	—
Intraoperative Blood Loss Predicted average blood loss	20 Milliliter Interval 5.0 to 150.0	150 Milliliter Interval 10.0 to 150.0	10 Milliliter Interval 5.0 to 50.0	5 Milliliter Interval 0.0 to 15.0	—
Intraoperative Blood Loss Difference from predicted average blood loss	6 Milliliter Interval 0.0 to 135.0	125 Milliliter Interval 0.0 to 140.0	1.5 Milliliter Interval 0.0 to 6.0	0 Milliliter Interval 0.0 to 0.0	—
Intraoperative Blood Loss Predicted maximum blood loss	100 Milliliter Interval 7.0 to 300.0	300 Milliliter Interval 100.0 to 300.0	20 Milliliter Interval 5.0 to 150.0	5 Milliliter Interval 0.0 to 30.0	—
Intraoperative Blood Loss Difference from predicted maximum blood loss	100 Milliliter Interval 4.0 to 280.0	275 Milliliter Interval 95.0 to 290.0	25 Milliliter Interval 3.0 to 100.0	0 Milliliter Interval 0.0 to 15.0	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Full Analysis Group n=26 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=14 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=7 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery n=5 Surgeries All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Postoperative Blood Loss Actual blood loss	10 Milliliter Interval 0.0 to 825.0	750 Milliliter Interval 15.0 to 1100.0	1 Milliliter Interval 0.0 to 33.5	0 Milliliter Interval 0.0 to 4.0	—
Postoperative Blood Loss Predicted average blood loss	27.5 Milliliter Interval 0.0 to 300.0	213.5 Milliliter Interval 30.0 to 700.0	1 Milliliter Interval 0.0 to 25.0	0 Milliliter Interval 0.0 to 0.0	—
Postoperative Blood Loss Difference from predicted average blood loss	-7.5 Milliliter Interval -125.0 to 4.0	-50 Milliliter Interval -400.0 to -15.0	4 Milliliter Interval -7.5 to 16.5	0 Milliliter Interval 0.0 to 196.0	—
Postoperative Blood Loss Predicted maximum blood loss	75 Milliliter Interval 0.0 to 600.0	450 Milliliter Interval 100.0 to 1200.0	2 Milliliter Interval 0.0 to 50.0	0 Milliliter Interval 0.0 to 0.0	—
Postoperative Blood Loss Difference from predicted maximum blood loss	67.5 Milliliter Interval 0.0 to 148.0	100 Milliliter Interval 0.0 to 300.0	34 Milliliter Interval 9.0 to 67.5	0 Milliliter Interval 0.0 to 196.0	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Full Analysis Group n=26 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=14 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=7 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery n=5 Surgeries All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Overall Perioperative Blood Loss Actual blood loss	50 Milliliter Interval 5.0 to 305.0	246 Milliliter Interval 15.0 to 1210.0	5.5 Milliliter Interval 3.0 to 50.0	9 Milliliter Interval 0.0 to 15.0	—
Overall Perioperative Blood Loss Predicted average blood loss	40 Milliliter Interval 5.0 to 800.0	675 Milliliter Interval 30.0 to 1000.0	20 Milliliter Interval 5.0 to 50.0	0 Milliliter Interval 0.0 to 15.0	—
Overall Perioperative Blood Loss Difference from predicted average blood loss	0 Milliliter Interval -50.0 to 20.0	-5 Milliliter Interval -210.0 to 25.0	2.5 Milliliter Interval 0.0 to 14.0	0 Milliliter Interval 0.0 to 0.0	—
Overall Perioperative Blood Loss Predicted maximum blood loss	125 Milliliter Interval 20.0 to 1500.0	1500 Milliliter Interval 100.0 to 1500.0	20 Milliliter Interval 6.0 to 150.0	0 Milliliter Interval 0.0 to 30.0	—
Overall Perioperative Blood Loss Difference from predicted maximum blood loss	64 Milliliter Interval 6.0 to 250.0	122.5 Milliliter Interval 50.0 to 400.0	5.5 Milliliter Interval 0.0 to 64.0	0 Milliliter Interval 0.0 to 15.0	—

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Full Analysis Group n=4 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=3 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=1 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Transfusion Requirements	438.0 Milliliter Standard Deviation 152.86	384.0 Milliliter Standard Deviation 132.49	600.0 Milliliter Standard Deviation NA only 1 participant analyzed	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Full Analysis Group n=26 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=14 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=7 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery n=5 Surgeries All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes site mucosal	2 Events	0 Events	1 Events	1 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes site joint	1 Events	1 Events	0 Events	0 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes site gastrointestinal	1 Events	0 Events	1 Events	0 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes site muscle	1 Events	1 Events	0 Events	0 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes cause spontaneous	0 Events	0 Events	0 Events	0 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes cause inury	5 Events	2 Events	2 Events	1 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes severity mild	3 Events	1 Events	1 Events	1 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes severity moderate	1 Events	0 Events	1 Events	0 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Bleeding episodes severity severe	1 Events	1 Events	0 Events	0 Events	—
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention Additional need for surgery	0 Events	0 Events	0 Events	0 Events	—

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Full Analysis Group n=26 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=14 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=7 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery n=5 Surgeries All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Consumption of BAX855 Total weight adjusted BAX855 consumption	562.076 IU/kg Standard Deviation 343.7305	746.103 IU/kg Standard Deviation 320.4581	507.881 IU/kg Standard Deviation 161.8075	122.673 IU/kg Standard Deviation 20.0076	—
Consumption of BAX855 Preoperative	62.492 IU/kg Standard Deviation 15.7678	69.442 IU/kg Standard Deviation 14.4532	56.852 IU/kg Standard Deviation 14.8899	50.928 IU/kg Standard Deviation 12.2700	—
Consumption of BAX855 Postoperative Day 0	34.195 IU/kg Standard Deviation 13.6755	37.082 IU/kg Standard Deviation 16.0160	31.141 IU/kg Standard Deviation 7.5641	20.762 IU/kg Standard Deviation NA Standard deviation not calculated as only 1 surgery analyzed	—
Consumption of BAX855 Postoperative Day 1	56.409 IU/kg Standard Deviation 24.8718	62.005 IU/kg Standard Deviation 25.4147	50.698 IU/kg Standard Deviation 29.2373	45.388 IU/kg Standard Deviation 12.0692	—
Consumption of BAX855 Postoperative Day 2	51.697 IU/kg Standard Deviation 27.7558	52.445 IU/kg Standard Deviation 27.4771	50.076 IU/kg Standard Deviation 30.9322	—	—
Consumption of BAX855 Postoperative Day 3	45.023 IU/kg Standard Deviation 24.2793	47.139 IU/kg Standard Deviation 27.1069	39.943 IU/kg Standard Deviation 17.0764	—	—
Consumption of BAX855 Postoperative Day 4	36.593 IU/kg Standard Deviation 12.2194	38.009 IU/kg Standard Deviation 13.6782	32.345 IU/kg Standard Deviation 5.3374	—	—
Consumption of BAX855 Postoperative Day 5	32.240 IU/kg Standard Deviation 15.1497	32.333 IU/kg Standard Deviation 15.1071	31.775 IU/kg Standard Deviation 21.6822	—	—
Consumption of BAX855 Postoperative Day 6	34.135 IU/kg Standard Deviation 13.3132	35.198 IU/kg Standard Deviation 12.8578	30.415 IU/kg Standard Deviation 19.7589	—	—
Consumption of BAX855 Postoperative Day 7	22.955 IU/kg Standard Deviation 6.0531	24.866 IU/kg Standard Deviation 5.7495	17.223 IU/kg Standard Deviation NA Standard deviation not calculated as only 1 surgery analyzed	—	—
Consumption of BAX855 Postoperative Day 8+	136.808 IU/kg Standard Deviation 139.3781	136.808 IU/kg Standard Deviation 139.3781	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=25 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞) One-stage clotting assay	2743.3 IU*h/dL Standard Deviation 751.83	—	—	—	—
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞) Chromogenic assay	3201.8 IU*h/dL Standard Deviation 1019.13	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=25 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h) One-stage clotting assay	2701.3 IU*h/dL Standard Deviation 719.52	—	—	—	—
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h) Chromogenic assay	3153.7 IU*h/dL Standard Deviation 980.27	—	—	—	—

SECONDARY outcome

Timeframe: 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%.

Outcome measures

Measure	Full Analysis Group n=25 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Pharmacokinetics (PK) - Terminal Half-life (T1/2) One-stage clotting assay	14.63 Hours Standard Deviation 3.179	—	—	—	—
Pharmacokinetics (PK) - Terminal Half-life (T1/2) Chromogenic assay	14.53 Hours Standard Deviation 3.137	—	—	—	—

SECONDARY outcome

Timeframe: 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. 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.

Outcome measures

Measure	Full Analysis Group n=25 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Pharmacokinetics (PK) - Mean Residence Time (MRT) One-stage clotting assay	19.26 Hours Standard Deviation 4.901	—	—	—	—
Pharmacokinetics (PK) - Mean Residence Time (MRT) Chromogenic assay	18.68 Hours Standard Deviation 4.160	—	—	—	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Full Analysis Group n=25 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Pharmacokinetics (PK) - Clearance (CL) One-stage clotting assay	0.02347 dL/(kg*h) Standard Deviation 0.006821	—	—	—	—
Pharmacokinetics (PK) - Clearance (CL) Chromogenic assay	0.02042 dL/(kg*h) Standard Deviation 0.006041	—	—	—	—

SECONDARY outcome

Timeframe: 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. 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.

Outcome measures

Measure	Full Analysis Group n=25 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss) One-stage clotting assay	0.4316 dL/kg Standard Deviation 0.09633	—	—	—	—
Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss) Chromogenic assay	0.3673 dL/kg Standard Deviation 0.09559	—	—	—	—

SECONDARY outcome

Timeframe: 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. 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.

Outcome measures

Measure	Full Analysis Group n=25 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Pharmacokinetics (PK) - Incremental Recovery(IR) IR at 15 min post infusion - one-stage clotting	2.106 (IU/dL):(IU/kg) Standard Deviation 0.3823	—	—	—	—
Pharmacokinetics (PK) - Incremental Recovery(IR) IR at 15 min post infusion - chromogenic	2.721 (IU/dL):(IU/kg) Standard Deviation 0.5981	—	—	—	—
Pharmacokinetics (PK) - Incremental Recovery(IR) IR at Cmax - one-stage clotting	2.123 (IU/dL):(IU/kg) Standard Deviation 0.4041	—	—	—	—
Pharmacokinetics (PK) - Incremental Recovery(IR) IR at Cmax - chromogenic	2.677 (IU/dL):(IU/kg) Standard Deviation 0.5960	—	—	—	—

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Full Analysis Group n=22 Participants All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Development of Inhibitory Antibodies to Factor VIII (FVIII)	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=22 Participants All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG) Treatment emerging binding antibodies to FVIII IgG	0 Participants	—	—	—	—
Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG) Treatment emerging binding antibodies to FVIII IgM	0 Participants	—	—	—	—
Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG) Treatment emerging binding antibodies to BAX855IgG	0 Participants	—	—	—	—
Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG) Treatment emerging binding antibodies to BAX855IgM	0 Participants	—	—	—	—
Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG) Treatment emerging binding antibodies to PEG IgG	0 Participants	—	—	—	—
Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG) Treatment emerging binding antibodies to PEG IgM	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=22 Participants All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=22 Participants All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Occurrence of Thrombotic Events	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=22 Participants All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Incidence of Severe Allergic Reactions (e.g. Anaphylaxis)	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=22 Participants All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Other Investigational Product (IP) - Related Adverse Events	2 Participants	—	—	—	—

SECONDARY outcome

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

Outcome measures

Measure	Full Analysis Group n=29 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Clinically Significant Changes in Vital Signs - Body Temperature Pre-infusion	36.60 °Celsius Interval 36.3 to 36.7	—	—	—	—
Clinically Significant Changes in Vital Signs - Body Temperature 15 minutes post infusion	36.60 °Celsius Interval 36.2 to 36.7	—	—	—	—
Clinically Significant Changes in Vital Signs - Body Temperature Change at 15 minutes post infusion	0.00 °Celsius Interval -0.1 to 0.2	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=29 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) Systolic BP: Pre-infusion	120 mmHg Interval 115.0 to 125.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) Systolic BP: 15 minutes post infusion	115.0 mmHg Interval 110.0 to 125.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) Systolic BP: Change at 15 minutes post infusion	-5.0 mmHg Interval -5.0 to 4.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) Diastolic BP: Pre-infusion	75.0 mmHg Interval 69.0 to 80.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) Diastolic BP: 15 minutes post infusion	75.0 mmHg Interval 70.0 to 80.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) Diastolic BP: Change at 15 minutes post infusion	0.0 mmHg Interval -5.0 to 1.0	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=29 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Clinically Significant Changes in Vital Signs - Respiratory Rate Pre-infusion	14.0 breaths/minute Interval 12.0 to 16.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Respiratory Rate 15 minutes post infusion	14.0 breaths/minute Interval 12.0 to 16.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Respiratory Rate Change at 15 minutes post infusion	0.0 breaths/minute Interval 0.0 to 0.0	—	—	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Full Analysis Group n=29 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Clinically Significant Changes in Vital Signs - Pulse Rate Pre-infusion	70.0 beats/minute Interval 68.0 to 74.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Pulse Rate 15 minutes post infusion	70.0 beats/minute Interval 66.0 to 77.0	—	—	—	—
Clinically Significant Changes in Vital Signs - Pulse Rate Change at 15 minutes post infusion	-1.0 beats/minute Interval -3.0 to 2.0	—	—	—	—

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Measure	Full Analysis Group n=26 Surgeries All participants treated with BAX855 with available GHEA score.	Major Orthopedic Surgery n=25 Surgeries All participants treated with BAX855 for major orthopedic surgery.	Major Non-orthopedic Surgery n=26 Surgeries All participants treated with BAX855 for major non-orthopedic surgery.	Minor Surgery n=26 Surgeries All participants treated with BAX855 for minor surgery.	Per Protocol Analysis Group n=27 Surgeries All participants treated with BAX855 with all 3 hemostatic efficacy assessments available. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in this group.
Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry	1 Surgeries	1 Surgeries	1 Surgeries	1 Surgeries	1 Surgeries

Adverse Events

BAX855

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Measure	BAX855 n=22 participants at risk Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and nature of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-100% FVIII trough level, and minor surgery will target an initial 30-60% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and nature of the surgery performed.
Gastrointestinal disorders Diabetic gastroparesis	4.5% 1/22 • Number of events 2 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Infections and infestations Device related infection	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Gastrointestinal disorders Oesophageal ulcer	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.

Other adverse events

Measure	BAX855 n=22 participants at risk Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and nature of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-100% FVIII trough level, and minor surgery will target an initial 30-60% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and nature of the surgery performed.
Infections and infestations Peritonsillitis	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Infections and infestations Rhinitis	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Psychiatric disorders Anxiety	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Nervous system disorders Headache	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Ear and labyrinth disorders Hyperacusis	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
General disorders Non-cardiac chest pain	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Investigations Hepatic enzyme increased	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Injury, poisoning and procedural complications Tooth fracture	9.1% 2/22 • Number of events 2 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Injury, poisoning and procedural complications Procedural hypotension	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Injury, poisoning and procedural complications Procedural pain	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
Injury, poisoning and procedural complications Wound	4.5% 1/22 • Number of events 1 • Throughout the entire study period (2 years and 9 months). For each participant the duration of treatment and therefore the entire study period depended on the nature of each participants invasive procedure (ranged from 43 days to 162 days). Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after study treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication. The sponsor requires a review of results communication (e .g. for confidential information) \>= 30 days prior to submission and may request an additional delay of \<=180 days (e .g. for intellectual property protection).
• Publication restrictions are in place

Restriction type: OTHER