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

• Sponsor: Baxalta now part of Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01913405
• Collaborator: (none)
• Enrollment: 30
• Locations: 22
• Arm: 1
• Actual Duration (Months): 33.1
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the efficacy and safety of BAX 855 in severe hemophilia A previously treated (PTP) males, 12 to 65 years of age who are undergoing elective surgical or other invasive procedures.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A	Biological: PEGylated Recombinant factor VIII (rFVIII)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multi-Center, Open Label Study of Efficacy and Safety of PEGylated rFVIII (BAX 855) in Previously Treated Patients With Severe Hemophilia A Undergoing Surgical or Other Invasive Procedures
• Actual Study Start Date: Dec 20, 2013
• Actual Primary Completion Date: Sep 23, 2016
• Actual Study Completion Date: Sep 23, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 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 character of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-150% FVIII trough level, and minor surgery will target an initial 30-100% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and character of the surgery performed.

Biological: PEGylated Recombinant factor VIII (rFVIII); Lyophilized powder and solvent for solution for injection; Other Names: BAX 855 ADYNOVATE

Outcome Measures

Primary Outcome Measures

1. Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings [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).]

   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

Secondary Outcome Measures

1. Intraoperative Blood Loss [From initiation of surgery until end of 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.

2. Postoperative Blood Loss [From completion of surgery until 24 hours after 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.

3. Overall Perioperative Blood Loss [From start of surgery until discharge or day 14, whichever occurred first.]

   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.

4. Transfusion Requirements [From initiation of the surgery to 24 hours after completion of the surgery.]

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

5. Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention [Intra- and post-operative period, until the last intensified treatment after hospital discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks)]

   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.

6. Consumption of BAX855 [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.]

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

7. Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞) [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.

8. Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h) [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.

9. Pharmacokinetics (PK) - Terminal Half-life (T1/2) [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%.

10. Pharmacokinetics (PK) - Mean Residence Time (MRT) [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.

11. Pharmacokinetics (PK) - Clearance (CL) [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

12. Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss) [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.

13. Pharmacokinetics (PK) - Incremental Recovery(IR) [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.

14. Development of Inhibitory Antibodies to Factor VIII (FVIII) [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).]

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

15. 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) [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).]

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

16. Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies [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).]

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

17. Occurrence of Thrombotic Events [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).]

18. Incidence of Severe Allergic Reactions (e.g. Anaphylaxis) [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).]

19. Other Investigational Product (IP) - Related Adverse Events [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).]

20. Clinically Significant Changes in Vital Signs - Body Temperature [Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.]

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

21. Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP) [Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.]

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

22. Clinically Significant Changes in Vital Signs - Respiratory Rate [Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.]

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

23. Clinically Significant Changes in Vital Signs - Pulse Rate [Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.]

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

24. Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry [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).]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant requires an elective major or minor surgical, dental or other invasive procedure (e.g. biopsy, endoscopy).

• Participant and/or legal representative has/have provided signed informed consent.

• Participant has severe hemophilia A (Factor VIII (FVIII) level <1%) as confirmed by the central lab at screening or a documented FVIII activity level <1%.

• Participant was previously treated with FVIII concentrates with ≥150 documented exposure days (EDs).

• Participant is currently receiving prophylaxis or on-demand therapy with FVIII concentrate.

• Participant has a Karnofsky performance score of ≥60 at screening.

• Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥200 cells/mm^3, as confirmed by central laboratory at screening.

• Participant is Hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis as assessed by the investigator.

• Participant is willing and able to comply with the requirements of the study protocol.

Exclusion Criteria:

• Participant has detectable FVIII inhibitory antibodies (≥0.4 Bethesda Unit (BU) using the Nijmegen modification of the Bethesda assay) at screening as determined by the central laboratory or at any timepoint prior to screening (≥0.4 BU using the Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay).

• History of ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).

• Participant has a platelet count <100 x 10^9/L, as confirmed by central laboratory at screening.

• Participant has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.

• Participant has severe chronic hepatic dysfunction (eg ≥5 X upper limit of normal alanine aminotransferase (ALT), as confirmed by the central laboratory at screening, or a documented International Normalized Ratio (INR) > 1.5).

• Participant has a known hypersensitivity towards mouse or hamster proteins, polysorbate 80 or to PEG.

• Participant is currently using or has recently (< 30 days) used pegylated drugs (other than BAX 855) prior to study participation or is scheduled to use such drugs during trial participation.

• Participant is currently participating in another clinical drug (other than BAX 855) or device study or use of another investigational product or device within 30 days prior to study entry.

• Participant has a diagnosis of an inherited or acquired hemostatic defect other than hemophilia A.

• Participant is currently receiving, or scheduled to receive during the course of the study, an immunomodulating drug (eg, systemic corticosteroid agent at a dose equivalent to hydrocortisone >10 mg/day, or alpha interferon) other than anti-retroviral chemotherapy.

• Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida College of Medicine	Gainesville	Florida	United States	32610
2	Bleeding and Clotting Disorders Institute	Peoria	Illinois	United States	61614
3	University of Louisville	Louisville	Kentucky	United States	40202
4	Children's Mercy Hospitals & Clinics	Kansas City	Missouri	United States	64108
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
6	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
7	University of Utah Health Sciences Center	Salt Lake City	Utah	United States	84132
8	University of Washington	Seattle	Washington	United States	98104
9	SHAT of Oncohaematology Diseases	Sofia		Bulgaria	1527
10	MHAT 'Sv. Marina', EAD	Varna		Bulgaria	9003
11	Vilnius University Hospital Santariskiu Clinics, Public Institution	Vilnius		Lithuania	08661
12	Academisch Medisch Centrum	Amsterdam		Netherlands	1105 AZ
13	FSHI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"	Kirov		Russian Federation	610000
14	Hospital Universitari Son Espases	Palma de Mallorca	Baleares	Spain	07010
15	Complejo Hospitalario Universitario A Coruña	A Coruña	La Coruña	Spain	15006
16	Hospital Regional Universitario de Malaga	Malaga	Málaga	Spain	29010
17	Hospital Universitari i Politecnic La Fe	Valencia		Spain	46026
18	Universitaetsspital Zuerich	Zuerich		Switzerland	8091
19	SI Institute of Blood Pathology and Transfusion Medicine of AMSU	Lviv		Ukraine	79044
20	Royal Free Hospital	London	Greater London	United Kingdom	NW3 2QG
21	Great Ormond Street Hospital for Children	London	Greater London	United Kingdom	WC1N 3JH
22	Royal Manchester Children's Hospital	Manchester	Greater Manchester	United Kingdom	M13 9WL

Sponsors and Collaborators

• Baxalta now part of Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT01913405
• Other Study ID Numbers: 261204; 2013-001359-11
• First Posted: Aug 1, 2013
• Last Update Posted: May 24, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Hemophilia A; Factor VIII; BAX 855

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Period Title: Overall Study
STARTED	22
COMPLETED	20
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	BAX855
Arm/Group Description	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 Participants	22
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	34.8 (13.47)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	22 100%

Outcome Measures

1. Primary Outcome

Title	Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings
Description	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).

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Full Analysis Group	Major Orthopedic Surgery	Major Non-orthopedic Surgery	Minor Surgery	Per Protocol Analysis Group
Arm/Group Description	All participants treated with BAX855 with available GHEA score.	All participants treated with BAX855 for major orthopedic surgery.	All participants treated with BAX855 for major non-orthopedic surgery.	All participants treated with BAX855 for minor surgery.	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.
Measure Participants	20	12	6	3	11
Measure Surgeries	24	14	7	3	12
Treatment success (GHEA score excellent or good)	100.0	100.0	100.0	100.0	100.0
Excellent	100.0	100.0	100.0	100.0	100.0
Good	0.0	0.0	0.0	0.0	0.0

2. Secondary Outcome

Title	Intraoperative Blood Loss
Description	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Full Analysis Group	Major Orthopedic Surgery	Major Non-orthopedic Surgery	Minor Surgery
Arm/Group Description	All participants treated with BAX855 with at least one available hemostatic assessment.	All participants treated with BAX855 for major orthopedic surgery.	All participants treated with BAX855 for major non-orthopedic surgery.	All participants treated with BAX855 for minor surgery.
Measure Participants	21	12	6	4
Measure Surgeries	26	14	7	5
Actual blood loss	10	10	4.5	5
Predicted average blood loss	20	150	10	5
Difference from predicted average blood loss	6	125	1.5	0
Predicted maximum blood loss	100	300	20	5
Difference from predicted maximum blood loss	100	275	25	0

3. Secondary Outcome

Title	Postoperative Blood Loss
Description	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Full Analysis Group	Major Orthopedic Surgery	Major Non-orthopedic Surgery	Minor Surgery
Arm/Group Description	All participants treated with BAX855 with at least one available hemostatic assessment.	All participants treated with BAX855 for major orthopedic surgery.	All participants treated with BAX855 for major non-orthopedic surgery.	All participants treated with BAX855 for minor surgery.
Measure Participants	21	12	6	4
Measure Surgeries	26	14	7	5
Actual blood loss	10	750	1	0
Predicted average blood loss	27.5	213.5	1	0
Difference from predicted average blood loss	-7.5	-50	4	0
Predicted maximum blood loss	75	450	2	0
Difference from predicted maximum blood loss	67.5	100	34	0

4. Secondary Outcome

Title	Overall Perioperative Blood Loss
Description	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Full Analysis Group	Major Orthopedic Surgery	Major Non-orthopedic Surgery	Minor Surgery
Arm/Group Description	All participants treated with BAX855 with at least one available hemostatic assessment.	All participants treated with BAX855 for major orthopedic surgery.	All participants treated with BAX855 for major non-orthopedic surgery.	All participants treated with BAX855 for minor surgery.
Measure Participants	21	12	6	4
Measure Surgeries	26	14	7	5
Actual blood loss	50	246	5.5	9
Predicted average blood loss	40	675	20	0
Difference from predicted average blood loss	0	-5	2.5	0
Predicted maximum blood loss	125	1500	20	0
Difference from predicted maximum blood loss	64	122.5	5.5	0

5. Secondary Outcome

Title	Transfusion Requirements
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Full Analysis Group	Major Orthopedic Surgery	Major Non-orthopedic Surgery	Minor Surgery
Arm/Group Description	All participants treated with BAX855 with at least one available hemostatic assessment.	All participants treated with BAX855 for major orthopedic surgery.	All participants treated with BAX855 for major non-orthopedic surgery.	All participants treated with BAX855 for minor surgery.
Measure Participants	3	2	1	0
Measure Surgeries	4	3	1	0
Mean (Standard Deviation) [Milliliter]	438.0 (152.86)	384.0 (132.49)	600.0 (NA)

6. Secondary Outcome

Title	Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Full Analysis Group	Major Orthopedic Surgery	Major Non-orthopedic Surgery	Minor Surgery
Arm/Group Description	All participants treated with BAX855 with at least one available hemostatic assessment.	All participants treated with BAX855 for major orthopedic surgery.	All participants treated with BAX855 for major non-orthopedic surgery.	All participants treated with BAX855 for minor surgery.
Measure Participants	21	12	6	4
Measure Surgeries	26	14	7	5
Bleeding episodes site mucosal	2	0	1	1
Bleeding episodes site joint	1	1	0	0
Bleeding episodes site gastrointestinal	1	0	1	0
Bleeding episodes site muscle	1	1	0	0
Bleeding episodes cause spontaneous	0	0	0	0
Bleeding episodes cause inury	5	2	2	1
Bleeding episodes severity mild	3	1	1	1
Bleeding episodes severity moderate	1	0	1	0
Bleeding episodes severity severe	1	1	0	0
Additional need for surgery	0	0	0	0

7. Secondary Outcome

Title	Consumption of BAX855
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Full Analysis Group	Major Orthopedic Surgery	Major Non-orthopedic Surgery	Minor Surgery
Arm/Group Description	All participants treated with BAX855 with at least one available hemostatic assessment.	All participants treated with BAX855 for major orthopedic surgery.	All participants treated with BAX855 for major non-orthopedic surgery.	All participants treated with BAX855 for minor surgery.
Measure Participants	21	12	6	4
Measure Surgeries	26	14	7	5
Total weight adjusted BAX855 consumption	562.076 (343.7305)	746.103 (320.4581)	507.881 (161.8075)	122.673 (20.0076)
Preoperative	62.492 (15.7678)	69.442 (14.4532)	56.852 (14.8899)	50.928 (12.2700)
Postoperative Day 0	34.195 (13.6755)	37.082 (16.0160)	31.141 (7.5641)	20.762 (NA)
Postoperative Day 1	56.409 (24.8718)	62.005 (25.4147)	50.698 (29.2373)	45.388 (12.0692)
Postoperative Day 2	51.697 (27.7558)	52.445 (27.4771)	50.076 (30.9322)
Postoperative Day 3	45.023 (24.2793)	47.139 (27.1069)	39.943 (17.0764)
Postoperative Day 4	36.593 (12.2194)	38.009 (13.6782)	32.345 (5.3374)
Postoperative Day 5	32.240 (15.1497)	32.333 (15.1071)	31.775 (21.6822)
Postoperative Day 6	34.135 (13.3132)	35.198 (12.8578)	30.415 (19.7589)
Postoperative Day 7	22.955 (6.0531)	24.866 (5.7495)	17.223 (NA)
Postoperative Day 8+	136.808 (139.3781)	136.808 (139.3781)

8. Secondary Outcome

Title	Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Group
Arm/Group Description	All participants who underwent a pharmacokinetic assessment with BAX855 infusion.
Measure Participants	20
Measure Surgeries	25
One-stage clotting assay	2743.3 (751.83)
Chromogenic assay	3201.8 (1019.13)

9. Secondary Outcome

Title	Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmocokinetic Analysis Group
Arm/Group Description	All participants who underwent a pharmacokinetic assessment with BAX855 infusion.
Measure Participants	20
Measure Surgeries	25
One-stage clotting assay	2701.3 (719.52)
Chromogenic assay	3153.7 (980.27)

10. Secondary Outcome

Title	Pharmacokinetics (PK) - Terminal Half-life (T1/2)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Group
Arm/Group Description	All participants who underwent a pharmacokinetic assessment with BAX855 infusion.
Measure Participants	20
Measure Surgeries	25
One-stage clotting assay	14.63 (3.179)
Chromogenic assay	14.53 (3.137)

11. Secondary Outcome

Title	Pharmacokinetics (PK) - Mean Residence Time (MRT)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Group
Arm/Group Description	All participants who underwent a pharmacokinetic assessment with BAX855 infusion.
Measure Participants	20
Measure Surgeries	25
One-stage clotting assay	19.26 (4.901)
Chromogenic assay	18.68 (4.160)

12. Secondary Outcome

Title	Pharmacokinetics (PK) - Clearance (CL)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Group
Arm/Group Description	All participants who underwent a pharmacokinetic assessment with BAX855 infusion.
Measure Participants	20
Measure Surgeries	25
One-stage clotting assay	0.02347 (0.006821)
Chromogenic assay	0.02042 (0.006041)

13. Secondary Outcome

Title	Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss)
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pharmacokinetic Analysis Group
Arm/Group Description	All participants who underwent a pharmacokinetic assessment with BAX855 infusion.
Measure Participants	20
Measure Surgeries	25
One-stage clotting assay	0.4316 (0.09633)
Chromogenic assay	0.3673 (0.09559)

14. Secondary Outcome

Title	Pharmacokinetics (PK) - Incremental Recovery(IR)
Description	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pharmacokinetic Analysis Group
Arm/Group Description	All participants who underwent a pharmacokinetic assessment with BAX855 infusion.
Measure Participants	20
Measure Surgeries	25
IR at 15 min post infusion - one-stage clotting	2.106 (0.3823)
IR at 15 min post infusion - chromogenic	2.721 (0.5981)
IR at Cmax - one-stage clotting	2.123 (0.4041)
IR at Cmax - chromogenic	2.677 (0.5960)

15. Secondary Outcome

Title	Development of Inhibitory Antibodies to Factor VIII (FVIII)
Description	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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Count of Participants [Participants]	0 0%

16. Secondary Outcome

Title	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)
Description	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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Treatment emerging binding antibodies to FVIII IgG	0 0%
Treatment emerging binding antibodies to FVIII IgM	0 0%
Treatment emerging binding antibodies to BAX855IgG	0 0%
Treatment emerging binding antibodies to BAX855IgM	0 0%
Treatment emerging binding antibodies to PEG IgG	0 0%
Treatment emerging binding antibodies to PEG IgM	0 0%

17. Secondary Outcome

Title	Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies
Description	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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Count of Participants [Participants]	0 0%

18. Secondary Outcome

Title	Occurrence of Thrombotic Events
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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Count of Participants [Participants]	0 0%

19. Secondary Outcome

Title	Incidence of Severe Allergic Reactions (e.g. Anaphylaxis)
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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Count of Participants [Participants]	0 0%

20. Secondary Outcome

Title	Other Investigational Product (IP) - Related Adverse Events
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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Count of Participants [Participants]	2 9.1%

21. Secondary Outcome

Title	Clinically Significant Changes in Vital Signs - Body Temperature
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Measure Surgeries	29
Pre-infusion	36.60
15 minutes post infusion	36.60
Change at 15 minutes post infusion	0.00

22. Secondary Outcome

Title	Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP)
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Measure Surgeries	29
Systolic BP: Pre-infusion	120
Systolic BP: 15 minutes post infusion	115.0
Systolic BP: Change at 15 minutes post infusion	-5.0
Diastolic BP: Pre-infusion	75.0
Diastolic BP: 15 minutes post infusion	75.0
Diastolic BP: Change at 15 minutes post infusion	0.0

23. Secondary Outcome

Title	Clinically Significant Changes in Vital Signs - Respiratory Rate
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Measure Surgeries	29
Pre-infusion	14.0
15 minutes post infusion	14.0
Change at 15 minutes post infusion	0.0

24. Secondary Outcome

Title	Clinically Significant Changes in Vital Signs - Pulse Rate
Description	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BAX855
Arm/Group Description	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.
Measure Participants	22
Measure Surgeries	29
Pre-infusion	70.0
15 minutes post infusion	70.0
Change at 15 minutes post infusion	-1.0

25. Secondary Outcome

Title	Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry
Description	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).

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Hemoglobin: Abnormal Ncs at Screening - Abnormal cs at EOS	Hematocrit: Abnormal Ncs at Screening - Abnormal cs at EOS	Erythrocytes: Normal at Screening - Abnormal cs at EOS	Eosinophils/Leucocytes: Normal at Screening Abnormal cs at EOS	ALT: Normal at Screening - Abnormal cs at EOS
Arm/Group Description	Hematology: The hemoglobin result was abnormal not clinically significant at the screening assessment and changed to abnormal clinically significant at the end of study assessment.	Hematology: The hematocrit result was abnormal not clinically significant at the screening assessment and changed to abnormal clinically significant at the end of study assessment.	Hematology: The Erythrocytes result was normal at the screening assessment and changed to abnormal clinically significant at the end of study assessment.	Hematology: The Eosinophils/Leucocytes result was normal at the screening assessment and changed to abnormal clinically significant at the end of study assessment.	Chemistry: The ALT result was normal at the screening assessment and changed to abnormal clinically significant at the end of study assessment.
Measure Participants	22	22	22	22	22
Measure Surgeries	26	25	26	26	27
Count of Units [Surgeries]	1	1	1	1	1

Adverse Events

Time Frame	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 Event Reporting Description	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.
Arm/Group Title	BAX855
Arm/Group Description	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.
All Cause Mortality
	BAX855
	Affected / at Risk (%)	# Events
Total	0/22 (0%)
Serious Adverse Events
	BAX855
	Affected / at Risk (%)	# Events
Total	2/22 (9.1%)
Gastrointestinal disorders
Diabetic gastroparesis	1/22 (4.5%)	2
Oesophageal ulcer	1/22 (4.5%)	1
Infections and infestations
Device related infection	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	BAX855
	Affected / at Risk (%)	# Events
Total	8/22 (36.4%)
Ear and labyrinth disorders
Hyperacusis	1/22 (4.5%)	1
General disorders
Non-cardiac chest pain	1/22 (4.5%)	1
Infections and infestations
Peritonsillitis	1/22 (4.5%)	1
Rhinitis	1/22 (4.5%)	1
Injury, poisoning and procedural complications
Tooth fracture	2/22 (9.1%)	2
Procedural hypotension	1/22 (4.5%)	1
Procedural pain	1/22 (4.5%)	1
Wound	1/22 (4.5%)	1
Investigations
Hepatic enzyme increased	1/22 (4.5%)	1
Nervous system disorders
Headache	1/22 (4.5%)	1
Psychiatric disorders
Anxiety	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/22 (4.5%)	1
Oropharyngeal pain	1/22 (4.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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).