Phase 3, Prospective, Randomized, Multi-center Clinical Study Comparing the Safety and Efficacy of BAX 855 Following PK-guided Prophylaxis Targeting Two Different FVIII Trough Levels in Subjects With Severe Hemophilia A
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: Baxalta now part of Shire

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CLINICAL STUDY PROTOCOL
PRODUCT: BAX 855 – Pegylated full-length recombinant factor VIII
STUDY TITLE: Phase 3, prospective, randomized, multi-center clinical study 
comparing the safety and efficacy of BAX 855 following PK-guided prophylaxis 
targeting two different FVIII trough levels in subjects with severe Hemophilia A
STUDY SHORT TITLE: BAX 855 PK-guided Dosing
PROTOCOL IDENTIFIER: 261303
CLINICAL TRIAL PHASE 3
AMENDMENT 3: 2015 SEP 04
Replaces: 
AMENDMENT 2: 2015 MAY 12
ALL VERSIONS:
AMENDMENT 3: 2015 SEP 04
AMENDMENT 2: 2015 MAY 12
AMENDMENT 1: 2015 MAR 20
ORIGINAL: 2015 JAN 13
OTHER ID(s)
NCT Number: To be Determined
EudraCT Number: 2014-005477-37
IND NUMBER: 15299
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA 91362
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA

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1. STUDY PERSONNEL
1.1 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (eg, investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.

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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) to the sponsor and/or ECs, as applicable. 
ALL SAEs ARE TO BE REPORTED ON THE ADVERSE EVENT ELECTRONIC 
CASE REPORT FORM (ECRF) 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT. IF THE 
ECRF IS NOT AVAILABLE THEN THE SAE MUST BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR TO MEET THE 24 HOUR TIMELINE 
REQUIREMENT. 
See SAE Protocol Sections for further information and SAER form for contact 
information. 
Further details are also available in the study team roster.
For definitions and information on the assessment of these events, refer to the following:

AE, Section 13.2

SAE, Section 13.2.1.1

Assessment of AEs, Section 13.2.4

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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational 
Product (IP)
BAX 855
Name(s) of Active Ingredient(s)
Pegylated full-length Recombinant Factor VIII
CLINICAL CONDITION(S)/INDICATION(S)
Treatment and prophylaxis of bleeding in severe Hemophilia A
PROTOCOL ID
261303
PROTOCOL TITLE
Phase 3, prospective, randomized, multi-center clinical study comparing 
the safety and efficacy of BAX 855 following PK-guided prophylaxis 
targeting two different FVIII trough levels in subjects with severe 
Hemophilia A
Short Title
BAX 855 PK-Guided Dosing
STUDY PHASE
Ph3
PLANNED STUDY PERIOD
Initiation
First subject in: Q4 2015
Primary Completion
Q2 2018
Study Completion
Q4 2018
Duration
3 years
STUDY OBJECTIVES AND PURPOSE
Study Purpose
1.
To compare the efficacy and safety of PK-guided treatment with BAX 855 targeting FVIII trough 
levels of 1-3% and approximately 10% (8-12%)
2.
To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855
Primary Objective
1.
The primary objective is to compare two prophylactic dosing regimens of BAX 855 targeting two 
different FVIII trough levels, by comparing the proportions of subjects achieving a total annualized 
bleeding rate (ABR) of 0 in the second 6-month study period
Secondary Objectives
Efficacy:

To compare the two prophylactic dosing regimens of BAX 855 targeting two different FVIII 
trough levels with respect to the following:

The proportion of subjects in each prophylactic dosing arm achieving a spontaneous ABR 
and spontaneousi joint bleeding rate (AJBR) of 0 in the second 6-month study period

The proportion of subjects in each prophylactic dosing arm with a total, spontaneous 
ABR and AJBR <2
                                                
i i.e. not trauma related.

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
The total, spontaneous, and trauma-related ABRs in the 12-month study period

The reduction in ABR between the two treatment arms and the historical ABR prior to 
study enrollment

The total weight-adjusted consumption of BAX 855 for each prophylactic regimen

The joint status using the Hemophilia Joint Health Score (HJHS) and over time 

HRQoL and pharmacoeconomic outcomes (including SF-36, EQ-5D, Haemo-SYM and 
healthcare resource utilization)

To determine the hemostatic efficacy of BAX 855 in the control of bleeding episodes

To evaluate the efficacy of BAX 855 for perioperative management, if surgery is required
Safety:

To determine the immunogenicity of BAX 855

To determine the safety of BAX 855
Pharmacokinetics: 

To determine the PK parameters of BAX 855 at baseline and steady state and the correlation 
with pre-infusion VWF antigen level

To determine IR over time
Patient Reported Outcomes

To assess the difference in the SF-36 physical domain and component change scores from 
baseline to follow-up between patients in the 10% trough arm and patients in the 1-3% trough 
arm 

To assess the difference in the change of days of physical activity participation from baseline to 
follow-up between patients in the 10% trough arm and patients in the 1-3% trough arm
Exploratory objectives:

To determine the potential correlation between thrombin generation assay (TGA) parameters, 
FVIII trough levels and ABR

To assess the change in bleed and pain severity scores as measured by the Haemo-SYM 
questionnaire

To assess the change in HRQoL using EQ-5D and mental domain and component score of the
SF-36

To assess the difference in the change in healthcare resource utilization from baseline to 
follow-up between patients in the 10% trough arm and patients in the 1-3% trough arm 
STUDY DESIGN
Study Type/ 
Classification/ Discipline
Efficacy, Pharmacokinetic, Safety including Immunogenicity, and 
Pharmacodynamic
Control Type
Dose-Response
Study Indication Type
Prevention, Treatment
Intervention model 
Parallel design
Blinding/Masking
Open label

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Study Design
This study is a Phase 3, prospective, randomized, open-label, multicenter study 
to compare the safety and efficacy of a PK-guided BAX 855 treatment regimen 
targeting two different FVIII trough levels in approximately 116 subjects with 
severe hemophilia A to have 96 subjects evaluable (48 per treatment arm).
Planned Duration of 
Subject Participation
The subject’s participation will last approximately 15-16 months and is based 
on the assumption that completion of screening procedures will require 
approximately 6 weeks; PK assessments, dose calculation and randomization 
will take 6-8 weeks and the treatment period from the baseline visit to study 
completion will be 12 months.
Primary Outcome Measure
1.
Presence or absence of any bleedings in the second 6-month study period
Secondary Outcome Measures
Efficacy
1.
Total, spontaneous, and traumatic ABR, and spontaneous AJBR
2.
Total weight-adjusted consumption of BAX 855
3.
Overall hemostatic efficacy rating at 8 (± 1) hours after the initiation of treatment and at resolution 
of bleed
4.
Number of BAX 855 infusions needed for the treatment of bleeding episodes
5.
HJHS
6.
Intra-, post- and perioperative hemostatic efficacy in case of surgery
7.
Intra- and postoperative blood loss in case of surgery
Safety 
1.
Occurrence of AEs and SAEs
2.
Clinically significant changes in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry, and lipids)
3.
Inhibitory antibodies to FVIII, and binding antibodies to FVIII, BAX 855, PEG, and CHO protein
Patient Reported Outcomes (PROs)
1.
Physical domain and component scores of the SF-36 Health Survey
Pharmacokinetics
1.
BAX 855 PK parameters based on FVIII activity at baseline and steady state:
a.
AUC0-∞ (Area under the plasma concentration versus time curve from time 0 to infinity), IR 
(incremental recovery) at 15 – 30 minutes post-infusion, T1/2 (plasma half-life), MRT (mean 
residence time), CL (clearance), maximum plasma concentration (Cmax) and time to maximum 
concentration in plasma (Tmax), Vss (Volume of distribution at steady state)
b.
Incremental recovery (IR) over time

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Exploratory Outcome Measures
1.
Thrombin generation assay (TGA) parameters (lag time, time to peak thrombin generation, peak 
thrombin generation, and endogenous thrombin potential [ETP])
2.
Bleed and pain severity scores as measured by the Haemo-SYM questionnaire
3.
HRQoL as assessed using EQ-5D and mental domain and component scores of the SF-36
4.
Healthcare resource utilization 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
BAX 855
Dosage form: injection, powder, lyophilized, for solution
Dose and Dosage frequency: 
BAX 855 dose will be PK-guided to maintain FVIII target trough levels of 
1-3% or approximately 10% (8-12%) at the following dosing frequencies:
FVIII trough levels of 1-3%: approximately twice weeklyii
FVIII trough levels of approximately 10% (8-12%): every other day
Mode of Administration: intravenous bolus
SUBJECT SELECTION 
Targeted Accrual
Approximately 116 subjects will be enrolled to have 96 subjects evaluable (48
in each prophylaxis dosing arm).
Number of 
Groups/Arms/Cohorts
2
Inclusion Criteria for Subjects Transitioning from Another BAX 855 study:
1.
Subject has completed the end of study visit of a BAX 855 study or is transitioning from the 
ongoing Continuation Study 261302
2.
Subject is either receiving on-demand or prophylactic treatment with BAX 855 and had an ABR of 
≥2 documented and treated during the past 12 months
3.
Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ 
count ≥200 cells/mm3, as confirmed by central laboratory
4.
Subject is willing and able to comply with the requirements of the protocol
Inclusion Criteria for Newly Recruited Subjects:
1.
Subject is 12 to 65 years old at the time of screening
2.
Subject has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory 
or by historically documented FVIII clotting activity performed by a certified clinical laboratory 
and/or a FVIII gene mutation consistent with severe hemophilia A 
3.
Subject has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII 
for ≥150 documented exposure days (EDs)
                                                
ii Twice weekly: infusion on day 3 or 4, at two different doses to cover the different treatment intervals, or 
every 3.5 days. According to individual PK, frequency may be adjusted based on FVIII trough levels.

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4.
Subject is either receiving on-demand treatment or prophylactic treatment and had an annual 
bleeding rate of ≥2 documented and treated during the past 12 months.
5.
Subject has a Karnofsky performance score of ≥60 at screening
6.
Subject is HIV-; or HIV+ with stable disease and CD4+ count ≥200 cells/mm3, as confirmed by 
central laboratory at screening
7.
Subject is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be 
performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis
8.
If female of childbearing potential, subject presents with a negative urine pregnancy test and agrees 
to employ adequate birth control measures for the duration of the study
9.
Subject is willing and able to comply with the requirements of the protocol
Exclusion Criteria
Exclusion Criteria for Subjects Transitioning from Another BAX 855 study:
1.
Subject has developed a confirmed inhibitory antibody to FVIII with a titer of ≥0.6 Bethesda Units 
(BU) using the Nijmegen modification of the Bethesda assay as determined at the central laboratory 
during the course of the previous BAX 855 study
2.
Subject has been diagnosed with an acquired hemostatic defect other than hemophilia A
3.
The subject’s weight is < 35 kg or > 100 kg
4.
Subject’s platelet count is < 100,000/mL
5.
Subject has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal)
6.
Subject has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) levels ≥5 times the upper limit of normal
7.
Subject is scheduled to receive a systemic immunomodulating drug (eg, corticosteroid agents at a 
dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral 
chemotherapy during the study
8.
Subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject’s safety or compliance
9.
Subject is planning to take part in any other clinical study during the course of the study.
10. Subject is a member of the team conducting this study or is in a dependent relationship with one of 
the study team members. Dependent relationships include close relatives (ie, children, 
partner/spouse, siblings, parents) as well as employees of the investigator or site personnel 
conducting the study
Exclusion Criteria for Newly Recruited Subjects
1.
Subject has detectable FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification of 
the Bethesda assay) as confirmed by central laboratory at screening
2.
Subject has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 BU (as determined by the
Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in 
the local laboratory) at any time prior to screening
3.
Subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A 
(eg, qualitative platelet defect or von Willebrand’s disease)
4.
The subject’s weight is < 35 kg or > 100 kg.

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5.
Subject’s platelet count is < 100,000/mL.
6.
Subject has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80
7.
Subject has severe chronic hepatic dysfunction [eg, ≥5 times upper limit of normal ALT and/ or
AST, as confirmed by central laboratory at screening, or a documented INR > 1.5]
8.
Subject has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal)
9.
Subject has current or recent (< 30 days) use of other pegylated drugs prior to study participation or 
is scheduled to use such drugs during study participation 
10. Subject is scheduled to receive during the course of the study, a systemic immunomodulating drug 
(eg, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-
interferon) other than anti-retroviral chemotherapy.
11. Subject has participated in another clinical study involving an IP or investigational device within 
30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or 
investigational device during the course of this study
12. Subject has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the 
opinion of the investigator, would affect subject safety or compliance
13. Subject is a member of the team conducting this study or is in a dependent relationship with one of 
the study team members. Dependent relationships include close relatives (ie, children, 
partner/spouse, siblings, parents) as well as employees of the investigator or site personnel 
conducting the study.
STATISTICAL ANALYSIS
Sample Size Calculation
For the sample size assessment the following assumptions were used: Approximately 40% of patients in 
BAX 855 regimen targeting 1-3% trough level are expected to be bleed free as shown in the ADVATE 
Prophylaxis study and the BAX 855 pivotal study 261201. For the BAX 855 regimen targeting 
approximately 10% (8-12%) trough level, an increase to 70% bleed-free patients is expected based on 
modeling the bleeding rates per FVIII level in the BAX 855 pivotal study 261201.
Under these assumptions 48 subjects per study group are needed to reject the null hypothesis of 
no difference between the study arms against a two-sided alternative at the 5% level of statistical 
significance with 80% power. Assuming a drop-out rate of close to 10%, and 10-15% of subjects being non-
compliant, approximately 116 subjects are planned to be randomized between the two BAX 855 regimens
with an allocation ratio of 1:1.
Planned Statistical Analysis
The proportion of subjects with ABR = 0 in the two prophylaxis treatment regimens in the second 6 months 
period will be compared using a chi-square test with continuity correction at a two-sided 5% level of 
significance. For all outcome measures, bleeding rates will be analyzed using a negative binomial model and 
descriptive statistics will be presented for the two dosing regimens for other outcomes. Point estimates 
(mean or median) and 95% confidence intervals (CIs) will be computed if feasible.

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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 10
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 19
6.1 Description of Investigational Product ............................................................... 19
6.2 Clinical Condition/Indication .............................................................................. 20
6.3 Population to be Studied ...................................................................................... 21
6.4 Findings from Nonclinical and Clinical Studies................................................. 22
6.4.1 Findings from Nonclinical Studies ............................................................... 22
6.4.2 Findings from Clinical Studies ..................................................................... 22
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product to 
Human Subjects .................................................................................................... 27
6.6 Authorized Representative (Signatory) / Responsible Party ............................ 29
6.7 Compliance Statement.......................................................................................... 29
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 30
7.1 Study Purpose ....................................................................................................... 30
7.2 Primary Objective................................................................................................. 30
7.3 Secondary Objectives ........................................................................................... 30
7.3.1 Efficacy ........................................................................................................... 30
7.3.2 Safety............................................................................................................... 31
7.3.3 Pharmacokinetics........................................................................................... 31
7.3.4 Patient Reported Outcomes.......................................................................... 31
7.4 Exploratory Objectives......................................................................................... 31
8. STUDY DESIGN......................................................................................................... 32
8.1 Brief Summary...................................................................................................... 32
8.2 Overall Study Design............................................................................................ 32
8.3 Duration of Study Period(s) and Subject Participation .................................... 33
8.4 Outcome Measures ............................................................................................... 33
8.4.1 Primary Outcome Measure .......................................................................... 33

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8.4.2 Secondary Outcome Measures ..................................................................... 33
Efficacy .................................................................................................... 33
8.4.2.1
Safety........................................................................................................ 34
8.4.2.2
Patient Reported Outcomes................................................................... 34
8.4.2.3
Pharmacokinetics.................................................................................... 34
8.4.2.4
8.4.3 Exploratory Outcome Measures .................................................................. 34
8.5 Randomization and Blinding............................................................................... 34
8.6 Study Stopping Rules............................................................................................ 35
8.7 Investigational Product(s).................................................................................... 35
8.7.1 Packaging, Labeling, and Storage................................................................ 35
8.7.2 Administration ............................................................................................... 36
8.7.3 Description of Treatment.............................................................................. 36
8.7.4 BAX 855 Dosing for PK Assessment............................................................ 37
8.7.5 BAX 855 Prophylaxis Dosing........................................................................ 37
8.7.6 BAX 855 Dose and/or Frequency Adjustments .......................................... 38
8.7.7 Treatment of Bleeding Episodes................................................................... 40
8.7.8 Treatment for Surgery or Dental Procedures............................................. 42
8.7.9 Investigational Product Accountability ....................................................... 42
8.8 Source Data ........................................................................................................... 42
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 43
9.1 Inclusion Criteria.................................................................................................. 43
9.1.1 Subjects Transitioning from another BAX 855 Study ............................... 43
9.1.2 Inclusion Criteria for Newly Recruited Subjects........................................ 43
9.2 Exclusion Criteria................................................................................................. 44
9.2.1 Exclusion Criteria for Subjects Transitioning from Another BAX 855 
Study............................................................................................................... 44
9.2.2 Exclusion Criteria for Newly Recruited Subjects....................................... 44
9.3 Withdrawal and Discontinuation ........................................................................ 46
10. STUDY PROCEDURES .......................................................................................... 47
10.1 Informed Consent and Enrollment ................................................................... 47
10.2 Subject Identification Code................................................................................ 47
10.3 Screening and Study Visits................................................................................. 47
10.3.1 Subjects Transitioning from Other BAX 855 Studies.............................. 48
10.3.2 Newly Recruited Subjects ........................................................................... 48
10.4 Medications and Non-Drug Therapies.............................................................. 48
10.5 Subject Diary and Patient Reported Outcomes............................................... 49
10.5.1 Patient Reported Outcomes........................................................................ 50
10.6 Subject Completion/Discontinuation ................................................................ 51
10.7 Procedures for Monitoring Subject Compliance............................................. 52
11. ASSESSMENT OF EFFICACY.............................................................................. 53

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11.1 Bleeding Assessment........................................................................................... 53
11.1.1 Hemostatic Efficacy Rating for Treatment of Bleeding Episodes........... 53
11.1.2 Number of BAX 855 Infusions Needed for the Treatment of Bleeding 
Episodes.......................................................................................................... 55
11.1.3 Hemophilia Joint Health Score (HJHS) .................................................... 55
11.1.4 Weight-Adjusted Consumption of BAX 855 ............................................. 55
11.1.5 Peri-operative efficacy assessments............................................................ 55
12. DETERMINATION OF FVIII AND VWF ANTIGEN, FVIII ACTIVITY AND 
TGA.............................................................................................................................. 56
12.1 PHARMACOKINETICS................................................................................... 56
12.2 Incremental Recovery (IR) ................................................................................ 57
12.3 Trough Levels...................................................................................................... 58
13. ASSESSMENT OF SAFETY INCLUDING IMMUNOGENICITY ................... 59
13.1 Immunogenicity .................................................................................................. 59
13.2 Adverse Events.................................................................................................... 60
13.2.1 Definitions..................................................................................................... 60
Serious Adverse Event.......................................................................... 60
13.2.1.1
Non-Serious Adverse Event ................................................................. 61
13.2.1.2
13.2.2 Unexpected Adverse Events........................................................................ 61
13.2.3 Preexisting Diseases..................................................................................... 61
13.2.4 Assessment of Adverse Events.................................................................... 61
13.2.5 Severity ......................................................................................................... 63
13.2.6 Causality ....................................................................................................... 63
13.3 Urgent Safety Measures ..................................................................................... 65
13.4 Untoward Medical Occurrences........................................................................ 65
13.5 Medical Device Safety reporting ....................................................................... 65
13.6 Non-Medical Complaints ................................................................................... 66
13.7 Medical, Medication, and Non-Drug Therapy History................................... 66
13.8 Physical Examinations........................................................................................ 67
13.9 Clinical Laboratory Parameters........................................................................ 67
13.9.1 Screening Laboratory Parameters............................................................. 67
Blood Type............................................................................................. 67
13.9.1.1
Genetics and HLA-Genotype............................................................... 67
13.9.1.2
Pregnancy Test...................................................................................... 68
13.9.1.3
CD4 Count............................................................................................. 68
13.9.1.4
Viral Serology........................................................................................ 68
13.9.1.5
13.9.2 Hematology, Clinical Chemistry and Lipid Panel.................................... 68
13.9.3 FVIII Activity, FVIII Antigen, VWF Antigen .......................................... 68
13.9.4 Thrombin Generation Assay ...................................................................... 69
13.9.5 Assessment of Laboratory Values .............................................................. 69
Assessment of Abnormal Laboratory Values..................................... 69
13.9.5.1
13.9.6 Biobanking.................................................................................................... 69

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13.10 Vital Signs.......................................................................................................... 70
14. STATISTICS............................................................................................................. 71
14.1 Sample Size and Power Calculations ................................................................ 71
14.1.1 Sample Size Calculation.............................................................................. 71
14.2 Datasets and Analysis Cohorts .......................................................................... 71
14.2.1 Full Analysis Set........................................................................................... 71
14.2.2 Per Protocol Analysis Set............................................................................ 71
14.2.3 Safety Analysis Set....................................................................................... 71
14.3 Handling of Missing, Unused, and Spurious Data........................................... 71
14.3.1 Handling of incomplete observation periods for ABR............................. 71
14.3.2 Handling of other variables ........................................................................ 72
14.4 Methods of Analysis............................................................................................ 72
14.4.1 Primary Outcome Measure......................................................................... 72
14.4.2 Secondary Outcome Measures ................................................................... 73
14.4.3 Exploratory Outcome Measures ................................................................ 75
15. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 76
16. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 77
16.1 Investigator’s Responsibility.............................................................................. 77
16.1.1 Final Clinical Study Report........................................................................ 77
16.2 Training ............................................................................................................... 77
16.3 Monitoring........................................................................................................... 77
16.4 Auditing ............................................................................................................... 77
16.5 Non-Compliance with the Protocol ................................................................... 78
16.6 Laboratory and Reader Standardization ......................................................... 78
17. ETHICS ..................................................................................................................... 79
17.1 Subject Privacy ................................................................................................... 79
17.2 Ethics Committee and Regulatory Authorities................................................ 79
17.3 Informed Consent ............................................................................................... 79
17.4 Data Monitoring Committee.............................................................................. 80
18. DATA HANDLING AND RECORD KEEPING................................................... 81
18.1 Confidentiality Policy ......................................................................................... 81
18.2 Study Documentation and Case Report Forms ............................................... 81
18.3 Document and Data Retention........................................................................... 81
19. FINANCING AND INSURANCE........................................................................... 82

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20. PUBLICATION POLICY........................................................................................ 82
21. SUPPLEMENTS....................................................................................................... 83
21.1 Study Flow Charts .............................................................................................. 83
21.2 Detailed Flow Diagram of Study Procedures................................................... 85
21.3 Schedule of Study Procedures and Assessments.............................................. 96
21.4 Clinical Laboratory Assessments ...................................................................... 99
22. PERIOPERATIVE MANAGEMENT.................................................................. 102
22.1 Types of Interventions...................................................................................... 102
22.1.1 Major Surgeries ......................................................................................... 102
22.1.2 Minor Surgeries ......................................................................................... 102
22.2 Dosing Schedule and Requirements for Major Surgery ............................... 103
22.3 FVIII Substitution Plan.................................................................................... 103
22.3.1 General........................................................................................................ 104
22.3.2 Preoperative and Loading Dose ............................................................... 105
22.4 Postoperative Dosing ........................................................................................ 106
22.5 Efficacy assessment........................................................................................... 107
22.5.1 Intra-, Post-, and Perioperative Hemostatic Efficacy............................. 107
22.5.2 Intra- and Postoperative Blood Loss........................................................ 109
23. DEFINITIONS........................................................................................................ 114
23.1 Joint Bleeds........................................................................................................ 114
23.2 Muscle Bleeds.................................................................................................... 114
24. REFERENCES........................................................................................................ 115
25. SUMMARY OF CHANGES.................................................................................. 119

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Tables
Table 1 BAX 855 Treatment Guidelines for Bleeding Episodes..................................... 41
Table 2 Efficacy Rating Scale for Treatment of Bleeding Episodes ............................... 54
Table 3 PK Time Points................................................................................................... 56
Table 4 IR Time Points.................................................................................................... 57
Table 5 Intraoperative Efficacy Assessment Scale........................................................ 108
Table 6 Postoperative Efficacy Assessment Scale (Postoperative Day 1) .................... 108
Table 7 Perioperative Efficacy Assessment Scale (at discharge or 14 days post-surgery, 
whichever is first) ................................................................................................... 109
Table 8 Flow Diagram of Surgical Procedures For Baxalta Clinical Study 261303..... 110
Table 9. Schedule of Study Procedures and Assessments for Surgery.......................... 113
Figures
Figure 1 Study Design for Baxalta Clinical Study 261303.............................................. 83
Figure 2 Study Flow Chart............................................................................................... 84
Figure 3 Dosing Recommendations for Major Surgeries .............................................. 104

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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
annualized bleeding rate
AE
adverse event
AJBR
annualized joint bleeding rate
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
AUC
area under the curve
AUC(0-∞)
area under the plasma concentration curve from 0 to infinity
BAX 855
product code name for Baxalta’s pegylated recombinant FVIII (rFVIII)
BU
Bethesda unit
(US) CFR
(US) Code of Federal Regulations
CHO
Chinese hamster ovary
CI
confidence interval
CL
total body clearance
Cmax
maximum plasma concentration
(e)CRF
(electronic) case report form
DI
dose intensification
DMC
data monitoring committee
EC
ethics committee
ED
exposure day
ELISA
enzyme-linked immunoabsorbent assay
EMA
European Medicines Agency
EQ-5D
EuroQol-5 dimension
ETP
endogenous thrombin potential
FAS
full analysis set
FVIII
factor VIII
GCP
Good Clinical Practice
GEE
general estimating equation
GLM
general linear model
H
hour(s)
HAV
hepatitis A virus
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody

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Abbreviation
Definition
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
hepatitis C virus antibody
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HJHS
hemophilia joint health score 
HRQoL
health-related quality of life
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IgA
immunoglobulin A
IgE
immunoglobulin E
IgG
immunoglobulin G
IgM
immunoglobulin M
INR
international normalized ratio
IP
investigational product
IR
incremental recovery over time
ITI
immune tolerance induction
IU
international unit (s)
i.v.
intravenous(ly)
LDL
low density lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MRT
mean residence time
NMC
non-medical complaint
PCR
polymerase chain reaction
PD
pharmacodynamic
pdFVIII
plasma-derived factor VIII
PEG
polyethylene glycol
PK
pharmacokinetic(s)
PKFAS
pharmacokinetic full analysis set
PP
per protocol

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Abbreviation
Definition
PPAS
per protocol analysis set
PRO
patient reported outcomes
PTP
previously treated patient
rFVIII
recombinant factor VIII
SAE
serious adverse event
SAER
serious adverse event report
SD
standard deviation
SF-36
Short form-36 questionnaire
SIC
subject identification code
SWFI
sterile water for injection
T1/2
half-life
TGA
thrombin generation assay
Tmax
time to maximum concentration in plasma
US
United States
VAS
visual analog scale
VLDL
very low density lipoprotein
Vss
volume of distribution at steady state
VWF
von Willebrand factor

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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
The investigational product (IP), BAX 855, is a polyethylene glycol (peg)-ylated 
full-length recombinant FVIII (rFVIII), intended for use as a FVIII replacement therapy 
with an extended half-life in the prophylaxis and treatment of bleeding episodes in 
patients with severe hemophilia A. 
Since the half-life of current FVIII products is in the range of 10-14 hours 1;2, current 
prophylaxis regimens call for infusion of FVIII every other day or every 2-3 days when 
based on each patient’s individual PK profile.3 pegylation of FVIII is designed to prolong 
the half-life of FVIII, with the intent of reducing the frequency of administration while 
maintaining similar therapeutic benefit as existing FVIII products; improving patient 
convenience and compliance with therapy; and thereby improving overall health 
outcomes. Prolongation of half-life of FVIII may also increase efficacy by increasing the 
FVIII trough levels while maintaining the frequency of administration of existing FVIII 
concentrates every other day. 
BAX 855 consists of rFVIII protein molecules with covalently bound PEG chains linked 
to the protein using a stable linker. The product is reconstituted with sterile water for 
injection (SWFI) and is administered intravenously (i.v.) as a solution by bolus infusion.
It uses the same stabilizing agents (mannitol, trehalose, histidine and glutathione) as the 
rFVIII product (octocog alfa, ADVATE) from which it is derived. Comprehensive 
preclinical studies as well as two successfully completed studies (Baxter clinical study 
261101 and 261201) have shown that the pegylation extends both the in vivo half-life and 
the measurable circulating activity of the product (as determined by chromogenic and 
1-stage clotting assays). Physiochemical characterization studies demonstrate that the 
functional activity of BAX 855 is comparable to that of ADVATE. Additional details can 
be found in the BAX 855 Investigator’s Brochure (IB).
No comparator drug product will be used in this study for prophylaxis or treatment of 
bleeding. Treatment regimens are based on individual PK parameters and FVIII trough 
levels with a target trough level of 1-3% given twice weekly, or approximately 10% 
(8-12%) FVIII given every other day.

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6.2 Clinical Condition/Indication
Hemophilia A is an X-chromosome-linked recessive, congenital bleeding disorder caused 
by deficient or defective coagulation due to deficiency of FVIII. The absence of FVIII 
leads to ‘spontaneous’ bleeding episodes (occurring primarily in joints, muscles, and less 
commonly, in soft tissues) and to excessive bleeding following trauma or injury. 
Hemophilia A is currently treated with FVIII replacement using either plasma-derived 
(pdFVIII) or rFVIII concentrates.4;5
The intended indication for BAX 855 is treatment and prophylaxis of bleeding in subjects 
with hemophilia A. The clinical program of BAX 855 is in compliance with the 
EMA/CHMP/BPWP/144533/2009 guidelines for FVIII in hemophilia A.6
The major objective of a prophylactic treatment in severe hemophilia A patients is to 
prevent bleeding episodes, in particular frequent joint bleeding. Bleeding episodes in a 
joint cause detrimental changes in synovial tissue and cartilage, which trigger synovial 
cell inflammation and proliferation, cartilage damage and bone erosion.7 Intra-articular 
bleeding is the most important risk factor and seems to play a key role not only for the 
inflammation but also for the direct destructive process in the joint.8 A number of 
prospective and retrospective clinical studies have demonstrated that prophylactic 
treatment reduced the number of break-through bleeds compared to on-demand 
treatment.9;10;11;12;13;14;15;16;17;18
Current management of severe hemophilia A includes on-demand treatment for bleeding 
episodes and prophylaxis to prevent bleeds.19;20 A prospective clinical study using 
individually pharmacokinetic (PK) adjusted prophylaxis dosing targeting a FVIII trough 
level of 1% can reduce the annualized bleed rate (ABR) from 44 during on demand 
treatment to 1 during standard prophylaxis. The optimal prophylaxis regimen is still
under scientific discussion but the frequency of break through bleedings during 
prophylactic treatment is assumed to depend on the time spent with a low FVIII level. 
Thus, dose recommendations used in prophylaxis are designed to keep the FVIII trough 
level above 1% of the normal level.21
However, the 1% level is not applicable to prevent bleeding episodes in all patients. 
Especially patients with damaged joints often bleed in spite of maintenance of a 1% 
trough level, although this association is difficult to access in clinical practice.22 A 
pioneering bench mark study by Den Uijl et al. has suggested that the annual number of 
bleeds is approaching zero when baseline levels of FVIII ≥ 10% are maintained.23

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Although there are no established criteria for determining how many joint bleeds can 
be tolerated before irreversible damage occurs, some studies reported that more than
2-5 joint bleeds in total lead to impaired joint scores 24;25;26 whereas annual bleed rates 
between 0.1 and 2.7 did not lead to joint damage.27;28;29
In an advanced stage these events accumulate and result in permanent loss of joint 
mobility leading to crippling arthropathy, the hallmark of advanced severe hemophilia A. 
For the assessment of joint impairment, joint scores have been developed. One of the best 
established scores is the Hemophilia Joint Health Score (HJHS). The HJHS is a validated
11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early 
signs and minor changes.30
6.3 Population to be Studied
Adolescent and adult subjects (aged 12 - 65 years) with severe hemophilia A 
(FVIII < 1%), of all races and ethnic groups, without history of or currently confirmed 
FVIII inhibitors (≥ 0.6 Bethesda Units [BU]) will be studied. All subjects will have 
been previously treated with pdFVIII or rFVIII concentrates with ≥150 documented 
exposure days (EDs) (previously treated patients; PTP). Subjects receiving prophylaxis 
and on-demand treatment will be included in this study and they must have had at least 
2 documented and treated bleeds within the 12 months prior to enrolment. 
Justification for enrollment of adolescent subjects is based on the nonclinical safety
requirements outlined in the ICH M3 Guideline, Section 12 as well as the ICH E11 
Guideline on clinical investigation of medicinal products in the pediatric population. 
Hemophilia is a serious and potentially life-threatening disease. Adolescent subjects, in 
particular if they are physically active, are expected to benefit from a new treatment 
approach with target FVIII trough levels of approximately 10% using a new recombinant 
full-length rFVIII molecule with an extended half-life. Moreover, results from nonclinical 
repeated toxicology studies, the core safety pharmacology package and the completed 
clinical phase 1 and phase 2/3 pivotal study have not raised any safety or tolerability 
concerns. Furthermore, the parent protein molecule ADVATE has been used extensively
in the entire pediatric population with no unforeseen adverse events (AEs) (see ADVATE 
Company Core data Sheet).

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6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Findings from Nonclinical Studies
BAX 855 is manufactured by covalently binding a branched PEG reagent with a 
molecular weight of 20 kDA to Baxalta’s rFVIII (octocog alfa, ADVATE). Baxalta’s 
octocog alfa is expressed in Chinese hamster ovary (CHO) cells by a plasma/albumin free 
cell culture method and is the active substance in Baxalta’s licensed product ADVATE. 
Thus, the viral safety of BAX 855 is ensured by the octocog alfa (ADVATE) bulk drug 
substance manufacturing process as any potential risk of contamination with viruses or 
adventitious agents during the subsequent manufacturing steps of BAX 855 has been 
minimized. No substances of animal or human origin are added throughout the entire
manufacturing process of BAX 855.
Preclinical studies have demonstrated BAX 855 to have comparable activity and other 
biochemical properties to ADVATE. The expected prolonged FVIII exposure by 
BAX 855 was demonstrated in PK studies with a mean residence time (MRT) longer than 
ADVATE in FVIII knock-out-mice (1.6 fold), rats (1.2 fold) and cynomolgus monkeys 
(1.5 fold). Prolonged efficacy was shown for BAX 855 in comparison to equivalent doses 
of ADVATE in two primary pharmacodynamic models in FVIII knock-out mice.
Additional data from nonclinical studies can be found in the BAX 855 IB.
6.4.2 Findings from Clinical Studies
A Phase 1, first in human study (Baxter clinical study 261101) to assess the safety and 
PK of BAX 855 in PTPs aged 18-65 years with severe hemophilia A with ≥150 EDs to 
FVIII products was conducted in Europe and Japan. The study investigated safety and PK 
of single doses of 30 IU/kg and 60 IU/kg BAX 855 compared to the same dose of 
ADVATE. Subjects were followed for 28 days after BAX 855 administration for safety. 
Safety assessments included AEs, changes in vital signs, clinical laboratory assessments, 
and immunogenicity.
A total of 24 subjects were enrolled; 19 were treated and 18 were evaluable for PK 
analysis. Nine were treated with 30 IU/kg (Cohort 1) and 10 were treated with 60 IU/kg 
(Cohort 2) of BAX 855, including 2 subjects from Japan.
No subjects developed inhibitors to FVIII or binding antibodies to PEG after BAX 855
infusion. Binding antibodies to FVIII and PEG-FVIII were present in some subjects after 
BAX 855 infusion but all were at the lowest detectable titers (ie, 1:20 or 1:40); these 
results could not be analyzed for specificity and were therefore interpreted as “low-titer 
indeterminate”. Furthermore, no increases in preexisting antibody titers were observed 
after BAX 855. There were no thrombosis-associated events or allergic reactions. 

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No deaths or other serious adverse events (SAEs) occurred, and none of the 11 non-
serious AEs (all mild or moderate) were considered treatment-related. AEs reported 
following BAX 855 administration included vomiting, nasopharyngitis, upper respiratory 
tract infection, influenza-like illness, arthralgia, headache, and localized swelling. No 
significant treatment-related changes in laboratory values or vital signs were recorded. 
There were no notable differences in the type or rate of AEs experienced by subjects after 
ADVATE infusion versus BAX 855 infusion.
Eighteen subjects (Cohort 1, n=8; Cohort 2, n=10) were evaluable for PK analysis. Based 
on the one-stage clotting assay, the median elimination phase half-life (T1/2; h) was 
longer for BAX 855 than for ADVATE in both Cohort 1 (13.60 vs 9.90) and Cohort 2 
(16.64 vs 11.11). Other PK parameters also supported an improved PK profile for 
BAX 855 compared to ADVATE. Refer to the ADVATE Company Core Data Sheet for 
more details on the clinical experience to date with ADVATE.
Based on these data, BAX 855 appears to be safe and well tolerated after a single dose 
administration. The mean T1/2 was 1.4 and 1.5-fold higher for BAX 855 compared to 
ADVATE in Cohorts 1 and 2, respectively, demonstrating prolonged circulation of 
BAX 855 compared to ADVATE. These data support the use of the BAX 855 dosing 
regimens planned in this study.
In phase 2/3 study 261201, BAX 855 was found to be safe and well tolerated in all 
137 treated subjects, with an accumulated total of 6717 EDs to BAX 855 and 21,803,981 
IU of BAX 855 infused. None of the subjects developed inhibitory antibodies to FVIII of 
≥0.6 BU/mL or persistent binding antibodies to FVIII, PEG-FVIII or PEG. No subjects 
developed antibodies to CHO proteins. Binding antibodies that were detected prior to 
exposure to BAX 855 or that transiently developed during the study could not be 
correlated to an impaired treatment efficacy, altered PK parameter, or temporally 
associated AE. Based on these data, no increased risk for PTPs with ≥150 EDs to develop 
inhibitory antibodies to FVIII, no immune responses with a clinical impact, and no 
evidence of allergic or hypersensitivity reactions were observed in this study.
Seven adverse reactions including headache, diarrhea, nausea, and flushing occurred in 
6 subjects. All adverse reactions were consistent with the pharmacology of ADVATE. 
There were no allergic reactions or deaths related to BAX 855 during the study. Although 
some changes were observed in laboratory assessments for liver enzymes (alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST)) these were attributed to 
preexisting disease, in particular to hepatitis C virus (HCV) infection. There were no 
related SAEs and no safety signals were observed during the study.

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PK parameters of BAX 855 and ADVATE at the same dose level in dose-escalation 
study 261101 and in the pivotal study 261201 suggest that pegylation offers prolonged 
circulating FVIII levels in subjects with severe hemophilia A. Duration of circulation at 
the 30 IU/kg, 45 IU/kg, and the 60 IU/kg dose level was longer for BAX 855 than for 
ADVATE. In addition, the PK profile demonstrated that AUC0-∞increases 
proportionally with increasing dose levels. 
In study 261201, at a prophylactic dose level of 45 ± 5 IU/kg, the estimated mean fold 
increase with BAX 855 compared to ADVATE was approximately 1.4-fold for T1/2, 
approximately 1.5-fold for MRT, and approximately 1.9-fold for AUC0-∞in the one-
stage clotting assay. Fold increases in PK parameters were consistent in adolescent and 
adult subjects. Using the chromogenic assay, fold increases were similar for the pegylated 
extended half-life product compared to the licensed rFVIII product. BAX 855 PK 
outcomes remained consistent between the initial and repeat PK infusions after ≥50 EDs 
indicating that repeated exposure did not affect the PK profile of BAX 855.
In terms of efficacy, study 261201 met its primary endpoint by demonstrating a reduction 
of the mean ABR for prophylaxis of more than 50% compared to on-demand treatment 
using a negative binomial model analysis as determined in the full analysis set (FAS) of 
all subjects who received BAX 855 for prophylaxis or on-demand. The ratio for the mean 
ABR for prophylaxis to the mean ABR for on-demand treatment was 0.10 (95% CI 0.06; 
0.19); the estimated mean ABRs were 4.3 (95% CI: 3.4; 5.5) for prophylaxis and 43.4 
(95% CI: 25.2; 74.8) for on-demand treatment with BAX 855. An analysis by age group 
was not feasible for the adolescents due to the small number of subjects in the on-demand 
treatment group (n=2), however, subjects aged 18 to 65 years demonstrated similar mean 
ABRs to the overall group and a statistically significant reduction in ABR for prophylaxis 
compared to on-demand treatment. 
A mean (SD) of 1.86 (0.31) and a median (Q1; Q3) of 1.96 (1.89; 1.99) prophylactic 
infusions per week were administered at a dose of mean (SD) of 44.36 (3.88) IU/kg and a 
median (95% CI) of 44.83 (44.19; 45.43) IU/kg dose per infusion, suggesting that the 
subjects in the study received BAX 855 for prophylaxis twice weekly at 45 ± 5 IU/kg as 
intended according to the protocol. 
A total of 39.6% (40/101) of subjects in the per protocol analysis set (PPAS) who were 
treated with their originally assigned prophylactic dose for the entire duration of study 
participation and who fulfilled pre-specified compliance requirements, had zero 
bleeding episodes, none (0/17) of the subjects in the on-demand arm was bleed-free. 

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In the prophylaxis arm, 57.4% (58/101) of subjects had no spontaneous bleeding episodes 
and 57.4% (58/101) had no joint bleeding episodes. 
The intervals between bleeding episodes were longer for subjects on prophylaxis 
than those treated on-demand (PPAS): 15.8% (16/101) of subjects on prophylaxis had 
≤1 month between bleeding episodes compared with 100% (17/17) of subjects treated 
on demand.
Descriptive statistics reflecting the PPAS demonstrated a lower median (Q1; Q3) 
ABR (1.9 [0.0; 5.8]) in the prophylaxis arm (n = 101) compared to the on-demand arm 
(41.5 [31.7; 51.1]; n = 17) for all bleeding episodes. 
These results demonstrate that BAX 855 used at the intended infusion interval and dose is 
efficacious in the reduction of the ABR in PTPs with severe hemophilia A compared to 
on-demand treatment. 
BAX 855 was also efficacious in the treatment of bleeding episodes. The pre-defined 
success rate at 24 h as assessed by the proportion of subject with bleeds (n = 70) rated 
excellent or good on a 4-point scale was 0.97 (95% CI 0.94; 0.98) which was 
significantly higher (p <0.0001) than the null hypothesis of a success rate of 70% which 
was considered to be the lowest clinically acceptable success rate.
Hemostatic efficacy at 24 hours after infusion was rated excellent or good in >90% of 
bleeding episodes across bleeding sites (joint and non-joint) and etiologies 
(spontaneous/unknown and injury-related). Across bleeding sites and etiologies, >90% of 
all bleeding episodes in the PPAS were treated with only 1 or 2 infusions.
Physical activity level participation was collected as an exploratory outcome measure in 
the pivotal trial and analyzed post hoc for patients who were previously on-demand and 
then switched to prophylaxis with BAX 855 in the study.  These patients (n=18) 
demonstrated an increase in their mean days of activity of 3.06 days per week (SD:5.90) 
from baseline to follow-up.  They also demonstrated clinically meaningful improvements 
in their physical health-related quality of life in the Role Physical, Bodily Pain, and 
Physical Component Scores.  
In Study 261204, a phase 3 study, efficacy is assessed in patients undergoing major or 
minor elective or minor emergency surgical, dental or other invasive procedures.  The 
dose and frequency of BAX 855 administered is individualized based on the subject’s PK 
parameters (determined from a presurgical assessment) for major surgeries and IR for 
minor surgeries and the FVIII target levels required for the planned procedure.

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In general, the dose is tailored to raise the plasma level of FVIII to 80-100% of normal
for major and to 30-60% of normal for minor procedures. The primary efficacy outcome 
measure is hemostatic efficacy; assessments are performed intraoperatively by the 
surgeon and postoperatively by the investigator at 24 hours as well as on Day 14 or at 
discharge, whichever is first. 
The results of the interim analysis are summarized by the Global Hemostatic Efficacy
Assessment (GHEA) score and rated “excellent”, “good”, “fair” or “none”. A treatment
success was defined as a rating of “excellent” and/or “good”. Point estimates and
corresponding 2-sided exact CIs at the 90% confidence level were calculated for the rate
of hemostatic efficacy assessments with an “excellent”/”good” outcome. Secondary
efficacy outcome measures were: intra- and post-operative blood loss; transfusion
requirements; bleeding episodes; additional need for surgical intervention; consumption
of BAX 855. All efficacy analyses were performed on the Full Analysis Set (FAS). A 
total of 15 surgeries in 15 subjects are included in the interim analysis. There were 
11 major and 4 minor surgeries. The 11 major surgeries comprised 3 knee replacements, 
2 arthroscopic synovectomies, 1 elbow cyst extirpation, 3 multiple tooth extractions 
including 1 radicular cyst removal, 1 port placement, and 1 gastric band insertion. The 
4 minor surgeries comprised 1 synoviorthesis, 1 radiosynovectomy, 1 tooth extraction, 
and 1 dermatological surgery.
Perioperative efficacy of BAX 855 was rated as “excellent” (blood loss was less than or
equal to that expected for the same type of procedure performed in a non-hemophilic
population, and required blood components for transfusions were less than or similar to
that expected in a non-hemophilic population, assessed at discharge or Day 14
(whichever was first) for all 15 procedures. Intraoperative hemostatic efficacy of 
BAX 855 was rated by the operating surgeon as “excellent” (intraoperative blood loss 
less than or equal to that expected for the same type of procedure performed in a non-
hemophilic patient) for all 15 procedures. The postoperative efficacy of BAX 855, as 
assessed by the operating surgeon on postoperative Day 1 (ie, the day following the day 
of surgery), was rated as “excellent” (postoperative blood loss less than or equal to that 
expected for the same type of procedure performed in a non-hemophilic patient) for 
13 procedures. One minor surgery was rated as “good” (minor dental surgery) due to a 
small amount of oozing of blood from the gums during the night following surgery, and 
another minor surgery (minor dermatological surgery) was not rated at the time of data 
cut-off.

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The median (Q1; Q3) observed intraoperative blood loss was lower than the predicted
average: 10.0 (5.0 ; 50.0) mL median actual blood loss vs. 50.0 (6.0 ; 150) mL predicted
average blood loss for major surgeries and 2.5 (0.0 ; 27.5) mL actual median blood loss
vs. 2.5 (0.0 ; 102.5) mL predicted average blood loss for minor surgeries. Postoperative 
blood loss was observed in 5 major surgeries. The median (Q1 ; Q3) blood loss observed 
in major surgeries on postoperative Day 1 was 65.0 (0.0 ; 1100) mL (maximum: 
1200 mL). This was higher than the median maximum blood loss of 50.0 (0.0 ; 1200) mL 
predicted preoperatively by the operating surgeons for the types of procedures, however, 
the estimated maximum postoperative blood loss of 1200 mL was not exceeded.
The estimated range of maximum perioperative blood loss for major surgeries, as
predicted preoperatively, was 5 to 1500 mL. Although 3 subjects had an overall
perioperative blood loss in the range of 1210 mL to 1430 mL, which was greater than the
average of 1000 mL, none of them exceeded the maximum predicted perioperative blood
loss of 1500 mL for major surgeries. Two subjects who underwent major surgeries 
received a total of 3 blood transfusions (packed red blood cells). The mean volume of 
transfused blood was 307.7 mL (range: 300-323 mL). Four subjects experienced pre- or 
post-surgical bleeding episodes; none of the postoperative bleeds occurred at the surgical 
site. None of the 15 subjects had a need for an additional surgical intervention. The 
results of these studies demonstrate that BAX 855 is safe and efficacious in treating 
bleeding episodes and in prophylaxis administered twice weekly in adults and 
adolescents with severe hemophilia A as well as in surgical prophylaxis. In addition, the 
data consistently demonstrate prolonged circulation of BAX 855 in comparison with the 
parent molecule ADVATE.
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product to 
Human Subjects
BAX 855 and ADVATE have undergone comparable preclinical single and repeated dose 
toxicology and pharmacology testing. The results suggest that BAX 855 has a 
comparable safety profile to ADVATE. Since the core protein of BAX 855 is identical to 
ADVATE, a safety profile similar to ADVATE is expected for BAX 855 when infused in 
humans. The most commonly reported adverse drug reactions described for ADVATE in 
post-marketing clinical studies include: FVIII inhibitors, pyrexia, and headache. Allergic-
type hypersensitivity reactions, including anaphylaxis, have been reported with 
ADVATE and have been manifested by dizziness, paresthesia, rash, flushing, face 
swelling, urticaria, and pruritus.iii Additional safety experience for ADVATE is provided 
in the ADVATE Company Core Data Sheet.
                                                
iii
ADVATE Company Core Data Sheet on file at Baxalta US Inc. (Westlake Village, CA).

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Since BAX 855 is a pegylated form of ADVATE, there is also the potential risk of 
inducing anti-PEG antibodies following BAX 855 administration. Binding antibodies 
against PEG are present in the healthy population and in patients with hemophilia A. 
BAX 855 may react with pre-existing anti-PEG antibodies, potentially resulting in a 
clinical hypersensitivity reaction or increased clearance of BAX 855 from circulation. 
BAX 855 and ADVATE showed a similar immunogenicity profile in preclinical in vitro 
and in vivo studies. Data from preclinical studies indicate that pegylated human FVIII 
can only induce antibodies against PEG when FVIII is recognized as a foreign protein 
that can provide immunogenic epitopes for CD4+ T cells. In the pivotal phase 2/3 studies 
it could be demonstrated that the presence of anti-PEG antibodies at screening or 
transiently occurring in some subjects did not have an impact on hemostatic efficacy or 
safety and that BAX 855 did not induce persistent antibodies to PEG or BAX 855. 
Previously treated patients (PTPs) with a high degree of previous exposure to FVIII 
should be immunetolerant to FVIII and are considered to have a low risk of developing 
antibodies against FVIII. Therefore, the risk for PTPs with severe hemophilia A who do 
not have neutralizing antibodies against FVIII (inhibitors) are also expected to be at low 
risk to develop antibodies against BAX 855. In the pivotal study 261201, 101 subjects 
accumulated ≥50 EDs and none of them developed inhibitory antibodies to FVIII 
≥0.6 BU at any time during the study. Also, none of the subjects developed persistent 
binding antibodies to FVIII, PEG-FVIII or PEG. Moreover, no immune responses with a 
clinical impact and no evidence of hypersensitivity reactions were observed.
BAX 855 has been administered as a single dose of 30 IU/kg to 9 subjects and a 
single dose of 60 IU/kg to 10 subjects with severe hemophilia A in a Phase 1 study 
(Baxter clinical study 261101). In a Phase 2/3 study (Baxter Pivotal study 261201),
the prophylactic treatment regimen of 45 ± 5 IU/kg twice weekly was planned to be 
administered for ≥ 50 EDs or 6 months ± 2 weeks, whichever occurred last. 
On-demand therapy with BAX 855 at a dose of 10 to 60 ± 5 IU/kg was to be 
administered for 6 months ± 2 weeks. BAX 855 was safe and well tolerated in all 
137 treated subjects, with an accumulated total of 6717 EDs to BAX 855 and 
21,803,981 IU of BAX 855 infused. BAX 855 was also safe and well-tolerated for 
perioperative management in 11 major and 4 minor surgeries in 15 subjects with 
hemophilia A (Baxalta Surgery Study 261204). The preoperative loading dose, which 
was to raise the pre-infusion plasma level of FVIII to 80-100% of normal for major 
surgeries and to 30-60% of normal for minor procedures, ranged from 36 to 99 IU/kg for 
major surgeries (n=11) and from 39 to 69 IU/kg for minor surgeries (n=4).  The mean ± 
SD daily weight-adjusted dose for major surgeries (n=11) was 34.35 ±16.756 IU/kg 

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(median: 30.26 IU/kg, range: 9.05-99.19 IU/kg). The mean ±SD daily weight-adjusted 
dose for minor surgeries (n=4) was 42.90 IU/kg ±14.839 IU/kg (median: 41.10 IU/kg; 
range: 20.76-69.31 IU/kg).
No related AEs occurred. There were no AEs considered thrombotic events or related 
AEs considered allergic reactions by the investigator. None of the subjects developed 
FVIII inhibitors and no new safety issues have been identified. Based on data from these 
studies (see Section 6.4.2), there currently are no anticipated risks of BAX 855, beyond 
those associated with ADVATE, when administered in human subjects.
The comparability of BAX 855 to ADVATE, the preclinical safety profile of BAX 855, 
and the clinical data from the Phase 1 and 2/3 studies, suggest an acceptable risk benefit 
profile for BAX 855. Additional details related to risks and benefits can be found in the 
BAX 855 IB.
6.6 Authorized Representative (Signatory) / Responsible Party
, MD
, Clinical Development
Baxalta US Inc.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International 
Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 
1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical 
Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local 
regulatory requirements.
PPD
PPD

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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is:

To compare the efficacy and safety of PK-guided treatment with BAX 855
targeting FVIII trough levels of 1-3% and approximately 10% (8-12%).

To further characterize PK and PD parameters of BAX 855
7.2 Primary Objective
The primary objective of the study is to compare two prophylactic dosing regimens of 
BAX 855 targeting two different FVIII trough levels, by comparing the proportions of 
subjects achieving a total ABR of 0 in the second 6-month study period.
7.3 Secondary Objectives
The secondary objectives are:
7.3.1 Efficacy
1.
To compare the two prophylactic dosing regimens of BAX 855 targeting two 
different FVIII trough levels with respect to the following:

The proportion of subjects in each prophylactic dosing arm achieving a 
spontaneousiv ABR and spontaneousiv joint bleeding rate (AJBR) of 0 in the 
second 6-month study period

The proportion of subjects in each prophylactic dosing arm with a total, 
spontaneous ABR and AJBR < 2

The total, spontaneous, and trauma-related ABRs in the 12-month study 
period

The reduction in ABR between the two treatment arms and the historical ABR 
prior to study enrollment

The total weight-adjusted consumption of BAX 855 for each prophylactic 
regimen

The joint status using the Hemophilia Joint Health Score (HJHS) and over 
time

HRQoL and pharmacoeconomic outcomes (including SF-36, EQ-5D, Haemo-
SYM and healthcare resource utilization)
                                                
iv i.e. not trauma-related

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2.
To determine the hemostatic efficacy of BAX 855 in the control of bleeding 
episodes
3.
To evaluate the efficacy of BAX 855 for perioperative management, if surgery is 
required
7.3.2 Safety
1.
To determine the immunogenicity of BAX 855
2.
To determine the safety of BAX 855
7.3.3 Pharmacokinetics
1. To determine the PK parameters of BAX 855 at baseline and steady state and the 
correlation with pre-infusion VWF antigen level
2. To determine IR over time
7.3.4 Patient Reported Outcomes
1.
To assess the difference in the SF-36 physical domain and component change 
scores from baseline to follow-up between patients in the 10% trough arm and 
patients in the 1-3% trough arm 
2.
To assess the difference in the change of days of physical activity participation 
from baseline to follow-up between patients in the 10% trough arm and patients in 
the 1-3% trough arm
7.4 Exploratory Objectives
1. To determine the potential correlation between thrombin generation assay (TGA) 
parameters, FVIII trough levels and ABR
2. To assess the change in bleed and pain severity scores as measured by the Haemo-
SYM questionnaire
3. To assess the change in HRQoL using EQ-5D and mental domain and component 
scores of the SF-36
4. To assess the difference in the change in healthcare resource utilization from 
baseline to follow-up between patients in the 10% trough arm and patients in the 
1-3% trough arm 

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8. STUDY DESIGN
8.1 Brief Summary
This study is a Phase 3, prospective, randomized, open-label, multicenter study to 
compare the safety and efficacy of a PK-guided BAX 855 treatment regimen targeting 
two different FVIII trough levels of 1-3% and approximately 10% (8-12%) in adolescent 
and adult PTPs with severe hemophilia A (<1% FVIII). Enrolled subjects will undergo an 
initial PK assessment following a single administration of BAX 855 to determine the 
subject’s individual PK parameters to tailor the dose for the targeted FVIII trough levels. 
Subjects will be randomized to one of 2 study arms of 58 subjects each, to target trough 
FVIII levels of 1-3% or approximately 10% (8-12%), for a treatment period of 
12 months. Repeat PK at steady state will be performed after 9 months of treatment.
8.2 Overall Study Design 
This study is a Phase 3, prospective, randomized, open-label, multicenter study to 
compare the safety and efficacy of PK and FVIII trough level-guided BAX 855 treatment 
targeting FVIII trough levels of 1-3% or approximately 10% (8-12%) in a total of 
96 evaluable (48 in each of two study arms) adolescent and adult PTPs with severe 
hemophilia A (<1% FVIII). Approximately 116 subjects will be enrolled for a total of 
96 evaluable subjects (assuming a dropout rate of close to 10% and 10-15% of subjects 
being non-compliant). Subjects from the BAX 855 continuation (261302) the BAX 855 
surgery (261204) study, the BAX 855 pediatric (261202) studyv, and newly recruited 
subjects including BAX 855-naïve subjects will participate.
Subjects will be screened per protocol inclusion/exclusion criteria and, following 
confirmation of eligibility, will undergo an initial PK assessment following a single 
administration of BAX 855 (60 ± 5 IU/kg) to determine PK parameters. Following the 
PK assessment subjects will be randomized to one of 2 dosing regimens: The standard
treatment arm with twice weekly dosing will target FVIII trough levels of 1-3% and the 
second, intensified treatment arm with dosing every other day will target trough levels of 
approximately 10% (8-12%) FVIII. The dose will be based on each subject’s individual 
PK. More frequent dosing should be considered if single doses of 80 IU/kg are required 
or regular FVIII peak levels of 200% would be reached. 
Subjects will complete study visits as follows to undergo efficacy, safety, and PRO 
assessments: Baseline Visit, Visit 1 at 4 weeks ± 5 days; Visit 2 at 8 weeks ± 1 week; 
Visit 3 at 3 months ± 2 weeks; Visit 4 at 4.5 months ± 2 weeks; Visit 5 at 6 months 
                                                
v In case subject is at least 12 years of age at the time of informed consent of this study.

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± 1 week (26±1 weeks); Visit 6 at 7.5 months ± 2 weeks; Visit 7 at 9 months ± 2 weeks;
Visit 8 at 10.5 months ± 2 weeks; and the Study Completion/Termination Visit for 
follow-up at 12 months ± 1 week (53 [±1] weeks). It must be ensured that the second 
6-month study period will consist of at least 26 weeks following the 6 month-study visit 
scheduled at 26 (±1) weeks and that the subject will have received his PK-tailored dosing 
regimen for at least 52 weeks. The following items are discussed with the subject: 
concomitant medications, non-drug therapies, adverse events, bleeding episodes and their 
treatment, including details of target joint bleedings, and to review the subject diary. For 
subjects without bleeding episodes, Visits 6 and 8 are phone visits. If, however, a subject 
has a bleeding episode, instead of a phone visit the subject must attend a site visit to 
assess FVIII trough levels and IR and re-evaluate the PK-guided regimen, the subject’s 
physical activity and compliance. In these cases the subject will undergo all planned 
assessments for a study visit, including assessment of vital signs, physical examination, 
and all laboratory assessments.
The overall study design is illustrated in Figure 1.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 3 years from study initiation (ie, first 
subject enrolled) to study completion. The recruitment period is expected to be
approximately 15 months.
The subject participation period is approximately 15 to 16 months from enrollment to 
subject completion (ie, last study visit), unless prematurely discontinued.
8.4 Outcome Measures
8.4.1 Primary Outcome Measure
The primary outcome measure is the presence or absence of any bleedings in the second 
6-month study period. 
8.4.2 Secondary Outcome Measures
Efficacy
8.4.2.1
1. Total, spontaneous, and traumatic ABR, and spontaneous AJBR
2. Total weight-adjusted consumption of BAX 855
3. Overall hemostatic efficacy rating at 8 (± 1) hours after the initiation of treatment 
and at resolution of bleed. 
4. Number of BAX 855 infusions needed for the treatment of bleeding episodes
5. HJHS

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6. Intra-, post- and perioperative hemostatic efficacy in case of surgery
7. Intra- and postoperative blood loss in case of surgery
Safety
8.4.2.2
1. Occurrence of AEs and SAEs
2. Clinically significant changes in vital signs and clinical laboratory parameters 
(hematology, clinical chemistry, and lipids)
3. Inhibitory antibodies to FVIII, and binding antibodies to FVIII, BAX 855, PEG, 
and CHO protein
Patient Reported Outcomes
8.4.2.3
1. Physical domain and component scores of the SF-36 Health Survey
Pharmacokinetics
8.4.2.4
1. BAX 855 PK parameters based on FVIII activity at baseline and steady state:

AUC0-∞ (Area under the plasma concentration versus time curve from time 0 
to infinity), IR (incremental recovery) at 15 - 30 minutes post-infusion, T1/2
(plasma half-life), MRT (mean residence time), CL (clearance), maximum 
plasma concentration (Cmax) and time to maximum concentration in plasma 
(Tmax), Vss (Volume of distribution at steady state)

Incremental recovery (IR) over time
8.4.3 Exploratory Outcome Measures
1. Thrombin generation assay (TGA) parameters (lag time, time to peak thrombin 
generation, peak thrombin generation, and endogenous thrombin potential [ETP])
2. Bleed and pain severity scores as measured by the Haemo-SYM questionnaire
3. HRQoL as assessed using EQ-5D and mental domain and component scores of
SF-36
4. Health resource utilization
8.5 Randomization and Blinding
This is a randomized, open-label, concurrent, dose regimen comparison clinical study. In 
order to minimize/avoid bias, once eligibility is confirmed, subjects will be randomly 
assigned to 1 of 2 treatment regimens with PK-guided dosing targeting FVIII trough 
levels of 1-3% or approximately 10% (8-12%) in a 1:1 ratio. Randomization occurs after 
the PK assessment and will be stratified according to subjects’ pre-study treatment 
regimen /ABR (prophylaxis with ABR<5 vs. prophylaxis with ABR>=5 vs. on-demand).

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8.6 Study Stopping Rules 
This study will be halted (enrollment and treatment temporarily stopped), pending further 
review by sponsor, or stopped if the following criterion is met:

If 2 or more subjects develop a high responder inhibitory antibody > 5 BU, 
confirmed by 2 measurements within a 2-4 week period at the central laboratory, 
after BAX 855 administration 

If 2 or more subjects develop anaphylaxis following exposure to BAX 855
The study may be terminated, if 1 or more of the following criteria are met:

The sponsor decides to terminate the study based upon its assessment of safety

The sponsor decides to terminate the study for administrative reasons
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
BAX 855 is formulated as a sterile, highly purified protein preparation in lyophilized 
form for i.v. infusion and is provided in single-dose vials with a vial of diluent (2 mL or 
5 mL SWFI, as available). A butterfly transfer set with luer-lock syringes and a 
needleless transfer device (BAXJECT II high-flow (HF) or BAXJECT III, as available) 
will be used for reconstitution and bolus i.v. delivery. The BAXJECT system is a 
needleless liquid transfer device with the primary function of transferring diluent from its 
vial into an evacuated vial containing product requiring reconstitution prior to infusion.
A minimum of 4 lots of BAX 855 manufactured for this study will be used. Four 
potencies of BAX 855 may be used, depending upon availability: 250, 500, 1,000 and 
2,000 IU/vial. Additional potencies of 750 IU/vial, 1500 IU/vial and 3000 IU/vial will be 
used once available.
The recommended storage conditions for BAX 855 are 2°C to 8°C (36°F to 46°F) and it 
should not be allowed to freeze. BAX 855 should be stored and protected from light. The 
reconstituted product should ideally be used immediately but no longer than 3 hours after 
reconstitution.
For additional information, such as reconstitution instruction, please refer to the 
BAX 855 IB and/or other specific instructions provided by the sponsor.

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8.7.2 Administration
Following reconstitution, BAX 855 should be administered using plastic syringes 
provided by the sponsor since proteins such as BAX 855 may adhere to the surface of 
glass syringes. BAX 855 will be administered i.v. using an appropriately sized syringe, as 
a bolus infusion with a maximum infusion rate of 10 mL/min, as described in the 
BAX 855 IB. The reconstituted BAX 855 must be administered at room temperature and 
within 3 hours.
BAX 855 dose calculation will be based on the stated actual potency of each vial.
PK assessment and determination of IR
For the PK assessment in individual subjects (initial and at steady state), only vials of the 
same lot with a nominal potency of 500 IU should preferably be used. If due to a 
subject’s weight, the PK or IR infusion volume will exceed 30 mL, 1000 IU vials should 
preferably be used to reduce the volume administered.
The total calculated dose may be rounded up or down to the nearest whole vial in case 
500 IU potency vials are used. However, in case vials with a nominal potency of 
1,000 IU/vial are used, the total calculated dose should not be rounded up or down to the 
nearest whole vial to ensure accurate dosing (eg, 2.5 vials).
Infusions for prophylaxis and treatment of bleeding episodes
Two different lots per infusion may be used, however, each vial must be reconstituted 
with its own kit. The total calculated dose can be rounded up or down to the nearest 
whole vial.
8.7.3 Description of Treatment
Subjects will be randomized to one of two PK-tailored prophylactic dose regimens (see 
Section 8.5) each of them targeting: 

FVIII trough levels of 1-3% with twice weekly dosing, or 

FVIII trough levels of approximately 10% (8-12%) with dosing every other day.
The individual subject’s dose will be calculated by the sponsor and provided to the study 
site. More frequent dosing should be considered if single doses of 80 IU/kg are required 
or regular FVIII peak levels of 200% would be reached or exceeded. 

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8.7.4 BAX 855 Dosing for PK Assessment
Following a 72-96 h washout period, depending on the FVIII concentrate, subjects will 
undergo an initial PK assessment with BAX 855vi:
At Visit 9 months, ie after 9 months of prophylactic treatment with BAX855, a repeat PK 
at steady state will be performed. No wash-out period will be required prior to the repeat 
PK determination; however, the PK infusion should preferably coincide with the 
prophylactic treatment schedule to ensure that the baseline FVIII trough level is reached.
The BAX 855 dose to be used for the PK assessment is 60 ± 5 IU/kg. It must be 
administered in the hospital/clinic setting under medical supervision.
8.7.5 BAX 855 Prophylaxis Dosing 
FVIII trough level of 1-3%:
BAX 855 will be administered twice weekly, with either:

Infusion with alternating 3-days and 4-days infusion intervals; the doses will be 
different if a 3 or a 4-days interval needs to be covered.

An infusion every 3.5 days.

More frequent dosing should be considered if single doses of 80 IU/kg are 
required or regular FVIII peak levels of 200% would be reached or exceeded. 
FVIII trough level of approximately 10% (8% - 12%):

BAX 855 will be infused every other day.

A daily dosing may be considered to prevent regular high FVIII peak levels
The required dose and frequency will be provided by the sponsor. Subjects must adhere 
as closely as possible to the dosing regimen. If a dose is missed, it must be documented 
and the next dose will be taken as soon as possible. After this dose, the regularly 
scheduled regimen will be resumed. Subjects requiring treatment for a breakthrough 
bleeding episode should resume their PK-tailored prophylaxis as soon as the bleeding 
episode is resolved. 
The days of the week on which treatment is administered may be selected by the subject 
and/or his/her physician and should provide maximum coverage for vigorous activities.
                                                
vi
In case a subject underwent a PK determination in any of the BAX855 studies, the PK assessment may 
have to be repeated based on the sponsor’s evaluation. 

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To provide some flexibility, the weekly schedule in terms of the days of the week may be 
changed during the course of the study to best accommodate potential changes in the 
subject’s life style. However, the initially calculated and adjusted, if applicable, dose 
regimen should be maintained. 
For each subject, the BAX 855 infusions to perform PKs, IRs and the first individualized 
prophylaxis dose of BAX 855 at the Baseline visit, which includes an IR assessment, 
must be administered in the hospital/clinic setting under medical supervision. All other 
treatments may be self-administered, administered by a parent or caregiver, or 
administered in the clinic or hospital setting. Each subject’s physician will determine the 
setting of treatment administration. If the subject will self-administer BAX 855, the 
investigator will ensure that the subject and/or his caregiver have been adequately 
trained.
The weight determined at screening will be the basis for dose calculation of BAX 855. If 
there is a ± 10% change in weight from the screening visit (as measured at a subsequent 
study visit), the total dose in IU will be recalculated. Similarly, any additional ± 10% 
change in weight from this new baseline will result in a dose recalculation.
8.7.6 BAX 855 Dose and/or Frequency Adjustments
In the first 6-month treatment period the regimen may be adjusted based on the FVIII 
trough level determined at each study visit. FVIII trough levels should always be 
determined immediately before the planned next scheduled prophylactic infusion which 
may coincide with an infusion for determination of IR. 
Before dose adjustment, if applicable, a confirmatory FVIII trough level determination at
an additional study visit within 2 weeks after receipt of the FVIII activity results has to be 
performedvii. This additional study visit should also occur after either a 48 h wash-out 
period in case of an every other day dosing or 72 or 96 hours in case of twice weekly 
infusions to coincide with the regular prophylactic infusion. After receipt of the repeat 
FVIII activity results, dose adjustments should be performed:

If the lower FVIII trough activity level is < 1% and < 8% respectively;

If the upper FVIII trough activity level exceeds 3% and 12% respectively. Given 
the assay variations, fluctuations of approximately 3% are possible.
                                                
vii
This additional visit may coincide with regular scheduled study visit.

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Approximately 2 weeks after the dose adjustment, a repeat FVIII trough level 
determination at an additional study visit has to be performed, if it does not coincide with 
the next scheduled study visit.  The blood draw for the FVIII trough level measurement 
should occur after a wash-out period of at least 48 h in case of an every other day dosing 
or 72 or 96 h in case of twice weekly infusions to coincide with the regular prophylactic 
infusion.
Dose adjustments in the second 6-month period may only be performed if FVIII trough 
levels are considerably below the required FVIII trough levels of 1% and 8%. Should the 
upper limit considerably exceed 3% and 12% respectively, a dose adjustment may be 
performed. Dose adjustments should only be performed in case out-of-range FVIII trough 
value is confirmed with a repeat FVIII trough level measurement.
Guidance for dose adjustment:

In case of FVIII levels < 1% in the low dose arm, the dose should be increased by 
approx. 30%. 

For FVIII levels > 3% in the low dose arm, or FVIII levels > 12% or < 8% in the 
high dose arm, the adjusted dose will be calculated as follows:
	
 =

		 
where TLtarget is the target trough level (1.7% or 10%) and TLpredicted is the TL predicted 
under the current dose. The latter will be calculated as
TLpredicted = 0.5*(TLmeasured,t1*2(t1-τ)/HL +TLmeasured,t2*2(t2-τ)/HL)
where TLmeasured,t1 and TLmeasured,t2 are the trough levels measured t1 and t2 hours post-
infusion, τ is the infusion interval and HL is the terminal half-life.
In case the FVIII levels are below the required lower limit, the BAX 855 dosage may be 
increased up to a maximum of 80 ± 5 IU/kg and/or the dosing frequency may be 
increased. Doses as high as 80 IU/kg may be used, provided the FVIII peak level does not 
exceed 200%. Otherwise, the frequency of prophylactic infusions has to be increased. 

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In subjects with severe hemophilic arthropathy and/or target jointsviii who continue 
to experience recurrent bleeding episodes, an imaging technology such as magnetic 
resonance imaging (MRI) or ultrasound of the affected joint(s) has to be applied to 
verify the presence of a bleed.
Also, if at any time during the course of the study, a subject starts to experience an 
unexpected high bleeding rate or experiences bleeding episodes that do not adequately 
respond to BAX 855 therapy, he/she will be evaluated for the presence of inhibitory and 
total binding antibodies to FVIII, BAX 855 and PEG, and clinically managed at the 
discretion of the investigator. It is also recommended to perform an IR determination.
8.7.7 Treatment of Bleeding Episodes
BAX 855 (10-60 ± 5 IU/kg) will be used for treatment of bleeding episodes (ie, 
breakthrough bleeding episodes during prophylaxis) according to the guidelines in 
Table 1. These guidelines may be adjusted by the investigator based upon his or her 
clinical judgment. 
It is critical that treatment of a bleed is initiated as soon as possible after occurrence 
of the bleeding episode.
When bleeding is controlled, additional infusions of BAX 855 to maintain hemostasis are 
permitted, if required. Infusions given to maintain hemostasis should be documented in 
the eCRF.
For a detailed description of bleeding episodes into different sites see Section 23.
                                                
viii A target joint is defined as a single joint (ankles, knees, hips, or elbows) with ≥ 4 spontaneous bleeding 
episodes in any consecutive 6-month period.

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Table 1
BAX 855 Treatment Guidelines for Bleeding Episodes
Type of Bleeding Episode
FVIII Level Required (%)
Dose (IU/kg)
Frequency of Dosing
Minor
Early hemarthrosis, mild muscle bleeding,
or mild oral bleeding, including, epistaxis
20 to 40%
10 to 20 (±5) IU/kg
Repeat infusions every 12 to
24 h for 1 to 3 days or until the
bleeding episode is resolved
Moderate
Moderate bleeding into muscles, bleeding
into the oral cavity, definite hemarthrosis,
and known trauma
30 to 60%
15 to 30 (±5) IU/kg
Repeat infusions every 12 to
24 h for 3 days or more until the
pain and acute disability/
incapacity are resolved
Major
Significant gastrointestinal bleeding, 
intracranial, intra-abdominal, or 
intrathoracic bleeding, central nervous
system bleeding, bleeding in the
retropharyngeal or retroperitoneal spaces
or iliopsoas sheath, fractures, head trauma
60 to 100%
30 to 60 (±5) IU/kg
In case of life-threatening 
bleeds, a dose of 80 (±5) IU/kg 
may be considered
Repeat infusions every 8 to 12 h
until the bleeding episode/threat
is resolved
The required units will be calculated according to the following formula:
body weight (kg) x desired FVIII rise (%) (IU/dL) x {reciprocal of observed recovery}
Whenever possible, the subject’s most recent individual IR should be used. In its absence, 
an anticipated recovery of 2.5 (IU/dL)/(IU/kg) based on the initial PK with BAX 855 in 
the Phase 2/3 pivotal study, should be assumed and the required units calculated using the 
following formula:
body weight (kg) x desired FVIII rise (% or (IU/dL) x 0.4 dL/kg
The amount to be administered and the frequency of administration should always be 
oriented to the clinical effectiveness in the individual case.
In subjects with severe hemophilic arthropathy and/or target joints with recurrent 
bleeding requiring more than 2 infusions per bleed and/or where efficacy ratings are 
generally fair or none, an imaging technology such as MRI or an ultrasound of the 
affected joint(s) has to be applied to verify the presence of a bleed.

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8.7.8 Treatment for Surgery or Dental Procedures
Subjects enrolled into this BAX 855 study (261303) and who require planned surgery or 
dental procedures will be treated according to the treatment recommendations including a 
FVIII substitution plan as described in Section 22. Subjects who undergo surgical 
procedures will only resume their PK tailored dosing regimen once rehabilitation
requiring intensified treatment will be completed. 
8.7.9 Investigational Product Accountability
The investigator will ensure that the IP (BAX 855) is stored as specified in the protocol 
and that the storage area is secured, with access limited to authorized study personnel. 
The investigator will maintain records that the IP was received, including the date 
received, drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP must be dispensed only at the study site or other suitable location (eg,
infusion center; home, as applicable per study design). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP will be returned to the sponsor or sponsor’s 
representative after study completion/termination, or destroyed with the permission of the 
sponsor in accordance with applicable laws and study site procedures. If IP is to be 
destroyed, the investigator will provide documentation in accordance with sponsor’s 
specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following: 
hospital records, medical records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries or evaluation checklists, outcomes reported by subjects, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medico-technical departments involved in 
the clinical study.
For additional information on study documentation and CRFs, see Section 18.2.
The use of subject diaries is described in Section 10.5.

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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
9.1.1 Subjects Transitioning from another BAX 855 Study
Subjects transitioning from another BAX 855 study who meet ALL of the following 
criteria are eligible for this study:
1. Subject has completed the end of study visit of a BAX 855 study or is transitioning 
from the ongoing Baxalta Continuation Study 261302.
2. Subject is either receiving on-demand treatment or prophylactic treatment with 
BAX 855 and had an ABR of ≥2 documented and treated during the past 
12 months.
3. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable 
disease and CD4+ count ≥200 cells/mm3, as confirmed by central laboratory.
4. Subject is willing and able to comply with the requirements of the protocol.
9.1.2 Inclusion Criteria for Newly Recruited Subjects
Newly recruited subjects including BAX 855 naïve subjects who meet ALL of the 
following criteria are eligible for this study:
1. Subject is 12 to 65 years old at the time of screening
2. Subject has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by 
central laboratory or by historically documented FVIII clotting activity performed 
by a certified clinical laboratory and/or a FVIII gene mutation consistent with 
severe hemophilia A 
3. Subject has been previously treated with plasma-derived FVIII concentrates or 
recombinant FVIII for ≥150 documented exposure days (EDs)
4. Subject is either receiving on-demand treatment or prophylactic treatment and had 
an annual bleeding rate of ≥2 documented and treated during the past 12 months.
5. Subject has a Karnofsky performance score of ≥60 at screening
6. Subject is HIV-; or HIV+ with stable disease and CD4+ count ≥200 cells/mm3, as 
confirmed by central laboratory at screening
7. Subject is hepatitis C virus negative (HCV-) by antibody (if positive, additional
PCR testing will be performed), as confirmed by central laboratory at screening; or 
HCV+ with chronic stable hepatitis
8. If female of childbearing potential, subject presents with a negative urine pregnancy 
test and agrees to employ adequate birth control measures for the duration of the 
study
9. Subject is willing and able to comply with the requirements of the protocol. 

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9.2 Exclusion Criteria
9.2.1 Exclusion Criteria for Subjects Transitioning from Another BAX 855 Study
Subjects transitioning from another BAX 855 study who meet ANY of the following 
criteria are not eligible for this study:
1. Subject has developed a confirmed inhibitory antibody to FVIII with a titer of 
≥0.6 BU using the Nijmegen modification of the Bethesda assay as determined at 
the central laboratory during the course of the previous BAX 855 study.
2. Subject has been diagnosed with an acquired hemostatic defect other than 
hemophilia A.
3. The subject’s weight is < 35 kg or > 100 kg.
4. Subject’s platelet count is < 100,000/mL.
5. Subject has an abnormal renal function (serum creatinine > 1.5 times the upper limit 
of normal).
6. Subject has active hepatic disease with alanine aminotransferase (ALT) and/or 
aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal.
7. Subject is scheduled to receive a systemic immunomodulating drug (e.g. 
corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, 
or α-interferon) other than anti-retroviral chemotherapy during the study.
8. Subject has a clinically significant medical, psychiatric, or cognitive illness, or 
recreational drug/alcohol use that, in the opinion of the investigator, would affect 
subject’s safety or compliance.
9. Subject is planning to take part in any other clinical study during the course of the 
study.
10. Subject is a member of the team conducting this study or is in a dependent 
relationship with one of the study team members. Dependent relationships include 
close relatives (ie, children, partner/spouse, siblings, parents) as well as employees 
of the investigator or site personnel conducting the study.
9.2.2 Exclusion Criteria for Newly Recruited Subjects 
Newly recruited subjects who meet ANY of the following criteria are not eligible for this 
study:
1. Subject has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen 
modification of the Bethesda assay) as confirmed by central laboratory at screening.

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2. Subject has a history of confirmed FVIII inhibitors with a titer ≥0.6 BU (as 
determined by the Nijmegen modification of the Bethesda assay or the assay 
employed with the respective cut-off in the local laboratory) at any time prior to 
screening.
3. Subject has been diagnosed with an inherited or acquired hemostatic defect other 
than hemophilia A (eg, qualitative platelet defect or von Willebrand’s disease).
4. The subject’s weight is < 35 kg or > 100 kg.
5. Subject’s platelet count is < 100,000/mL.
6. Subject has known hypersensitivity towards mouse or hamster proteins, PEG or 
Tween 80.
7. Subject has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal 
ALT and/or AST, as confirmed by central laboratory at screening, or a documented 
INR > 1.5].
8. Subject has severe renal impairment (serum creatinine > 1.5 times the upper limit of 
normal).
9. Subject has current or recent (< 30 days) use of other pegylated drugs prior to study 
participation or is scheduled to use such drugs during study participation.
10. Subject is scheduled to receive during the course of the study, a systemic
immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to 
hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral 
chemotherapy.
11. Subject has participated in another clinical study involving an IP or investigational 
device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this 
study.
12. Subject has a medical, psychiatric, or cognitive illness or recreational drug/alcohol 
use that, in the opinion of the investigator, would affect subject safety or 
compliance.
13. Subject is a member of the team conducting this study or is in a dependent 
relationship with one of the study team members. Dependent relationships include 
close relatives (ie, children, partner/spouse, siblings, parents) as well as employees 
of the investigator or site personnel conducting the study.

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9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study) 
consent for continued participation and data collection. The reason for withdrawal will be 
recorded on the End of Study CRF. Assessments to be performed at the termination visit 
(including in cases of withdrawal or discontinuation) are described in Section 10.6 and 
Section 21.3.
Discontinuation (ie, complete withdrawal from study participation) may be due to 
dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by 
subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject. 
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:

The subject develops a confirmed high responder inhibitory antibody to FVIII 
(> 5 BU by Nijmegen modification of the Bethesda assay) or a low responder 
inhibitory antibody (≤ 5 BU but ≥ 0.6 BU) that cannot be managed by the 
protocol-required prophylactic dosing.

The subject experiences a severe anaphylactic reaction to BAX 855.

The subject requires therapy with another pegylated product (eg, PEG-
Interferon).

The subject frequently misses administration of IP (misses more than 30% of 
planned prophylactic doses within any 3-month period).

The subject is non-compliant with study procedures, in the opinion of the 
investigator and/or sponsor.

The subject uses his/her usual FVIII therapy following the baseline infusion

The subject requires major emergency surgery during this study

The subject experiences a life-threatening bleeding episode (eg, any 
gastrointestinal hemorrhage or intracranial hemorrhage) requiring the use of a 
FVIII concentrate other than BAX 855.

The subject experiences severe trauma requiring extensive FVIII replacement 
therapy other than BAX 855

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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient, or their legal representatives, as required, who provides informed consent 
(ie, signs and dates the informed consent form and assent form, if applicable) is 
considered enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (ie, 261303) to 
be provided by the sponsor, 3-digit number study site number (eg, 002) to be provided by 
the sponsor, and 3-digit subject number (eg, 003) reflecting the order of enrollment 
(ie, signing the informed consent form). For example, the third subject who signed an 
informed consent form at study site 02 will be identified as Subject 261303-002003. 
All study documents (eg, CRFs, clinical documentation, sample containers, drug 
accountability logs, etc.) will be identified with the SIC. Additionally, a uniquely coded 
SIC(s) is permitted as long as it does not contain a combination of information that 
allows identification of a subject (eg, collection of a subject’s initials and birth date
would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining an enrollment/screening log that includes all 
subjects enrolled. The log also will serve to document the reason for screening failure. If 
a subject does not satisfy all screening criteria, the same subject may be re-screened at a 
later date. A complete or partial re-screen may also become necessary at the discretion of 
the investigator or sponsor. All screening data will be collected and reported in eCRFs, 
regardless of screening outcome. For the purpose of analysis, only the data from the most 
recent screening visit will be used. If a subject is re-screened, the End of Study CRF 
should be completed, and a new ICF, new SIC and new CRF are required for that subject.
The screening procedures including laboratory evaluations must be completed within 
56 days or repeated if more than 56 days have elapsed. Exemptions may be granted for 
administrative reasons, eg, delay in timely availability of laboratory results.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, can be found in Section 21.2 Detailed 
Flow Diagram of Study Procedures, Section 21.3 Schedule of Study Procedures and 
Assessments, and Section 21.4 Clinical Laboratory Assessments. Only explanatory 
details are provided in the section below.

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10.3.1 Subjects Transitioning from Other BAX 855 Studies
Subjects transitioning from other BAX 855 studiesix can use the end of study assessments 
in their previous BAX 855 study for screening visit assessments in this PK-guided study. 
Any additionally required screening assessments will be performed the same day. 
Subjects will return to the study site no later than 56 days for the conductance of the PK 
assessment, if applicable, provided eligibility has been confirmed. At the screening visit 
the subject will be supplied with study IP of study 261303. Until the baseline visit 
subjects will be treated according to their previous BAX 855 treatment regimen.
10.3.2 Newly Recruited Subjects
Newly recruited subjects will continue using their FVIII treatment regimen until 
baseline/start of PK guided prophylaxis, except for one infusion with BAX 855 for PK 
determination.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days
before study entry and during the course of the study:

Medications:
Any pegylated medication (eg, PEG-interferon) except BAX 855 for 
transitioning subjects
Any investigational drug, biologic, or device except BAX 855 for transitioning 
subjects
A subject who has taken any of these medications or received any of these non-drug 
therapies will be considered a protocol deviation.
The use of any FVIII concentrate other than BAX 855 during the course of the 
study following the first BAX 855 PK guided prophylactic infusion at baseline will 
result in the immediate withdrawal of the subject. Every effort should be made to 
have the Completion/Termination Visit performed. The use of (commercial) 
ADVATE may be permitted for a short period of time for administrative reasons.
                                                
ix
For subjects in the continuation study, data from a regular scheduled study visit can be used as long they 
are not older than 4 weeks prior to screening. 

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The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:

Medications:
Hemostatic agents, such as tranexamic acid, are permitted, as indicated by the 
subject’s treating physician, to treat mucosal bleeding or during perioperative 
management during the study
Any medications deemed necessary by the subject’s physician to treat or 
prevent any medical condition
Any over-the-counter medication used by the subject to treat symptoms or 
signs
Supplemental vitamins, minerals

Non-drug therapies:
Any non-drug therapy (eg, physiotherapy) deemed necessary by the subject’s 
physician to treat or prevent any medical condition
10.5 Subject Diary and Patient Reported Outcomes
A subject diary will be provided to each subject at the Screening Visit to record the 
following information:
1. Infusion record for BAX 855
2. Details of bleeding episodes and response to treatment. For a detailed description of 
bleeding episodes into different sites see Section 23.
3. Physical activity within 8 h prior to the occurrence of a bleeding episode
4. Untoward events
5. PROs (see Section 10.5.1)
For each bleeding episode, the following information will be recorded by the 
subject/subject’s caregiver or by authorized, qualified personnel at the study site:

Location of bleed, eg, joint, soft tissue, muscle, body cavity, intracranial, other.

Type of bleed, ie, spontaneous (i.e. not related to injury/trauma), injury (definitely 
due to injury/trauma).

Severity of bleed, eg, minor, moderate, major (see Table 1).

Date and time of onset of bleed.

Date and time of each infusion of BAX 855 required to achieve adequate 
hemostasis.

Date and time of resolution of bleeding episode.

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
Overall clinical efficacy rating according to the rating scale as described in 
Table 2 at 8 (±1) hours after initiation of treatment and at resolution of 
bleed.Physical activity within 8 h prior to the occurrence of the bleeding episodes.
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic or paper format and remain with the subject for 
the duration of the study. The investigator will review the diary for completeness and 
request missing information periodically and in a timely manner. Untoward events 
recorded in the diary will be reported as AEs according to the investigator’s discretion 
and clinical judgment. Subject entries in the diary will serve as source records. If e-
diaries are used, during study participation the investigator has access to the database 
holding the subject diary data. After study closure, the investigator will receive the diary 
records for their subjects, including audit trail records, in PDF format. The data will be 
transmitted to the CRF by a validated transfer.
10.5.1 Patient Reported Outcomes
The PRO instruments to be measured in this study are described below. These measures 
will be administered in this study at 3 time points: Screening or Baseline Visit, 6-month 
visit, and Completion/Termination Visit, whereas the EQ-5D, Patient Activity Level, and 
Health Resource Use will be measured at each study visit before study specific 
procedures are started. Note that due to the unavailability of linguistically validated 
translations of certain PRO measures in certain countries, some of these questionnaires 
may not be administered in all countries participating in this study. In addition, subjects 
who are younger than the minimal age limit required for these assessments will not be 
required to complete the assessment.
1. Haemo-SYM Questionnaire – This is a self-administered, validated questionnaire 
designed to assess symptom severity in patients with hemophilia. This measure 
contains 17 items and includes 2 domains: Bleeds and Pain. Scores for each of these 
2 domains can be calculated, with higher scores indicating more severe symptoms. 
This questionnaire will be administered only to subjects ≥18 years of age.
2. Short Form-36 (SF-36) – The SF-36 is a self-administered, validated questionnaire 
designed to measure generic HRQoL. This 36-item questionnaire measures 
8 domains, including: Physical functioning, Role-physical, Bodily pain, General 
health, Vitality, Social functioning, Role emotional, and Mental health. Two 
summary scores can be calculated, the Physical Component Score, and the Mental 
Component Score. Additionally, scores can be calculated for each of the 8 domains. 
Higher scores indicate better health status. This questionnaire will be administered 
only to subjects ≥14 years of age.

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3. EQ-5D Questionnaire – The EQ-5D is a self-administered, standardized measure 
of health status that provides a generic measure of health for clinical and economic 
appraisal consisting of the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression each with 5 levels. There is an 
additional EQ VAS to record how good or bad their health state is.
4. Patient Activity Level 
Subjects will also be asked to estimate their activity levels. This will consist of a 
few questions asking subjects to rate their current level of activity. These data will 
be collected for all age groups.
5. Health Resource Use – For each occurrence (throughout the study), the subject 
will record the following events: days missed from work/school (as appropriate) 
and days not able to perform normal activities outside of work/school due to 
hemophilia, physician office visits, hemophilia treatment site visits, emergency 
room visits (reason and number), and hospitalizations (reason, dates of 
hospitalization and associated length of stay).
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according to the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (eg, death), 
discontinuation by subject (eg, lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (eg, pregnancy, progressive 
disease, non-compliance with IP/protocol violation(s), recovery), study terminated by 
sponsor, or other (reason to be specified by the investigator, eg, technical problems). 
Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate eCRF. 
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an 
additional, unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a subject terminates participation in the study and 
does not return for the completion/termination visit, their last recorded assessments 
shall remain recorded with their last visit. The reason for discontinuation will 
be recorded, and the data collected up to the time of discontinuation will be used in 
the analysis and included in the clinical study report. 

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If additional assessments are required, the assessments shall be recorded separately.
Assessments to be performed at the termination visit (including in cases of withdraw or 
discontinuation) can be found in Section 21.2 Detailed Flow Diagram of Study 
Procedures, Section 21.3 Schedule of Study Procedures and Assessments, and 
Section 21.4 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the BAX 855 individualized treatment regimens will be 
monitored by review of subject diaries and by IP accountability.

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11. ASSESSMENT OF EFFICACY
11.1 Bleeding Assessment
Each individual bleed, spontaneous or traumatic, will be recorded in the subject’s diary, 
and/or recorded in physician/nurse/clinic notes. A bleed is defined as subjective (eg, pain 
consistent with a joint bleed) or objective evidence of bleeding which may or may not 
require treatment with FVIII. For further definitions of bleeds see Section 23. Bleeds 
occurring at the same anatomical location (eg, right knee) with the same etiology (ie, 
spontaneous vs. injury) within 72 h of onset of the first bleed will be considered a single 
bleed.31 A new bleed is defined as a bleed occurring > 72 hours after stopping treatment 
for the original bleed for which treatment was initiated and had an initial moderate to 
excellent response to treatment.31 Bleeding occurring at multiple locations related to the 
same injury (eg, knee and ankle bleeds following a fall) will be counted as a single 
bleeding episode.
The subject will also indicate in the diary on a preselected scale the type of activity 
within 8 hours prior to the bleeding episode.
For the primary assessment, the total bleed rate in the second 6-month study period will 
be calculated (ie, after the 6-month visit to the Completion/Termination Visit). The 
secondary outcome measures, spontaneous and traumatic ABR, and spontaneous AJBR
will also be calculated from the recorded bleeds.
11.1.1 Hemostatic Efficacy Rating for Treatment of Bleeding Episodes
The subject or their caregiver will rate the severity (minor, moderate, or major) of the 
bleeding episode and will rate the overall treatment response at 8 (± 1) hours after the 
initiation of treatment and at the resolution of bleed using a 4-point efficacy rating scale 
(Table 2). Since the efficacy rating is based to a large degree on cessation of pain, the 
investigator/subject shall, in particular in case of injury-related bleeding into one or more 
than one location, consider the injury-related symptoms when performing the efficacy 
rating 8 (±1) hours after initiating treatment and at resolution of bleed.
As per Table 2, multiple infusions of BAX 855 may be administered for the treatment of 
a bleeding episode. The overall response to all infusions combined is the rating that will 
be recorded at resolution of bleed.

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Table 2
Efficacy Rating Scale for Treatment of Bleeding Episodes
Excellent
Full relief of pain and/or cessation of objective signs of bleeding (eg, swelling,
tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage)
after a single infusion. No additional infusion is required for the control of bleeding.
Administration of further infusions to maintain hemostasis would not affect this
scoring.
Good
Definite pain relief and/or improvement in signs of bleeding after a single infusion. 
Possibly requires more than 1 infusion for complete resolution.
Fair
Probable and/or slight relief of pain and slight improvement in signs of bleeding after a 
single infusion. Required more than 1 infusion for complete resolution.
None
No improvement or condition worsens.
Details pertaining to all treatments for each bleed, including response to treatment, will 
be recorded by study subjects/subjects’ caregiver in subject diaries provided by the 
sponsor or sponsor’s representative. At each study visit, the investigator will review 
together with the subject/subject’s caregiver the response to treatment and evaluate the 
hemostatic efficacy rating. It may become necessary to re-discuss the rating with the 
subject/subject’s caregiver to ensure the Rating Scale is fully understood:

Any inconsistency between the efficacy rating and the number of infusions used 
to treat a bleeding episode, or a response to treatment rated as “none” must be 
immediately clarified.

If 2 or more responses to treatment of unique bleeding episodes are rated “fair”, 
the investigator may re-evaluate the dosing regimen and the time from bleeding 
onset to the start of treatment. If a bleeding episode requires only one infusion but 
response to treatment is rated “fair”, the rating should be evaluated and the Rating 
Scale should be reviewed with the subject/subject’s caregiver.
If more than one infusion was given to treat a bleeding episode, and the treatment was 
rated “excellent”, additional information should be provided about the severity of the 
bleeding episode (see Table 1) and/or whether additional infusions were given to 
maintain hemostasis. If infusions were given to maintain hemostasis after resolution of 
bleed, this should be recorded accordingly in the eCRF.

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11.1.2 Number of BAX 855 Infusions Needed for the Treatment of Bleeding 
Episodes
The number of BAX 855 infusions needed for each bleeding episode depends on the 
severity and location of the bleed and is determined by the subject, his/her caregiver, 
and/or clinician treating the subject, and is based upon the subject’s response to 
treatment, using the Efficacy Rating Scale for Treatment of Bleeding Episodes in 
Table 2. An infusion is defined as completion of administration of the calculated dose of 
BAX 855. If an infusion is interrupted, eg, due to vascular access issues, and must be re-
started, it will be recorded as 1 infusion. If an infusion is terminated for any reason prior 
to completion of infusion and not restarted, it will be recorded as an infusion; reasons for 
not completing the infusion will be recorded.
11.1.3 Hemophilia Joint Health Score (HJHS)
The HJHS will be assessed at Baseline, ie the first PK guided prophylactic infusion with 
BAX855, and the completion/termination visit. An X-ray of an impaired joint will be 
taken for assessment of joint status. In addition, the PI or a qualified staff member (e.g.
physiotherapist) will assess the following components of the elbow, knee, and ankle 
joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, 
extension loss, joint pain, and strength, together with an assessment of the global gait.
11.1.4 Weight-Adjusted Consumption of BAX 855 
Weight-adjusted consumption of BAX 855 will be determined based upon the record in 
subjects’ diaries of the amount of BAX 855 infused and the subject’s weight, as measured 
in the clinic.
11.1.5 Peri-operative efficacy assessments 
For the detailed description of intra-, post- and perioperative efficacy see Section 22.

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12. DETERMINATION OF FVIII AND VWF ANTIGEN, FVIII ACTIVITY AND
TGA 
12.1 PHARMACOKINETICS
An initial evaluation of PK parameters based on FVIII activity will be performed in all 
subjects prior to randomizationx. This PK will be performed following a wash-out period 
of at least 72-96 hours, depending on the type of FVIII concentrate used.
In all subjects, a repeat PK evaluation will be performed at the 9 month ± 2 weeks visit to 
assess PK at steady state. For the repeat PK no wash-out period will be required and the 
PK infusion should coincide with the scheduled prophylactic infusion to ensure that the 
trough FVIII activity level is determined, eg 2 days following the most recent infusion in 
the intensified treatment group with targeted FVIII trough levels between 8-12%. 
Samples will be taken to assess FVIII activity, FVIII antigen and TGA parameters pre-
infusion and at several time points post-infusion over a 4-day period following a single 
dose of 60 ± 5 IU/kg of BAX 855. VWF antigen will be also determined from the pre-
infusion blood sample. 
Blood samples are collected at the following time points:
Table 3
PK Time Points
FVIII (Activity 
and Antigen)
VWF Antigen
TGA
Pre-infusion
Within 30 minutes prior to infusio
+ 
+
+ 
Infusion
60±5 IU/kg of BAX855
Post-infusion
15 – 30 minutes
+
+
3 hours ± 30 minutes
+
+
8 hours ± 30 minutes
+
+
24 hours ± 2 hour
+
+
48 hours ± 4 hour
+
+
72 hours ± 4 hour
+
+
96 hours ± 4 hour
+
+
                                                
x
In case a subject underwent a PK determination in BAX855 surgery or continuation study, the PK 
assessment may have to be repeated based on the sponsor’s evaluation.

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The PK infusion may be administered via a central line or a peripheral vein. Upon 
completion of the infusion, the butterfly catheter should be flushed with at least 2 mL of 
saline solution. All PK samples will be collected through a peripheral vein. Blood 
samples drawn during the first 3 hours after BAX 855 administration will be drawn from 
a peripheral vein in an extremity distinct from the one that was used for product infusion. 
After that time, a vein in any appropriate extremity may be used. In the event that a blood 
sample must be drawn through the central or peripheral line used for administration of IP, 
the line must first be flushed with 5 mL normal saline or other suitable catheter flush 
solution that does not contain anticoagulant. At least 5 mL of whole blood must be 
collected and discarded prior to obtaining the blood sample.
For further details regarding analysis of FVIII activity see Section 13.9.3.
Subjects who have a bleeding episode during the PK assessment period will not have 
subsequent PK blood samples taken. They will be treated for the bleeding episode, as 
appropriate (ie, for subjects that transitioned from a previous BAX 855 study, the bleed
will be treated with BAX 855; for newly recruited subjects, the bleed will be treated with 
their current FVIII concentrate). Subsequently, once recovered, subjects will be re-
infused for PK assessment following a washout period of at least 84 to preferably 
96 hours following the previous dose of BAX 855 or at least 72 hours following the 
previous dose of another FVIII concentrate. However, depending on the time point of the 
bleeding episode during the PK evaluation, an exemption may be granted by the sponsor.
12.2 Incremental Recovery (IR)
IR will be determined at each study visit except study visit week 4±5 days, week 8±1,
and month 4.5 months ±2 weeks when only trough levels will be measured. Following a 
wash-out period required for the respective treatment group, blood samples for the 
determination of IR will be taken at the following time points: 
Table 4
IR Time Points 
FVIII (Activity 
and Antigen)
VWF Antigen
TGA
Pre-infusion
Within 30 minutes prior to infusion
+ 
+
+ 
Infusion
60±5 IU/kg of BAX855
Post-infusion
15 -30 minutes
+
+

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12.3 Trough Levels
At study visit week 4±5 days, week 8±1 and month 4.5 ±2 weeks, FVIII activity trough 
levels will be measured to ensure that FVIII trough levels are within their targeted range. 
The blood sampling for FVIII activity, TGA parameters and VWF antigen should be 
performed immediately prior to the next regular prophylactic infusion, thus maintaining 
the treatment regimen-specific interval defined for each subject. Following dose 
adjustments, a FVIII trough level has to be determined approximately 2 weeks following 
the dose adjustment. 
Details on the sampling of blood for determination of FVIII trough levels are presented in 
Section 21.3 and Section 21.4

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13. ASSESSMENT OF SAFETY INCLUDING IMMUNOGENICITY
13.1 Immunogenicity
Immunogenicity of BAX 855 will be assessed prior to the infusion of BAX 855 
following a washout period of at least 48 h (at steady state in case of every other day 
dosing) or 72-96 h (in case of twice weekly infusions) by measurement of the following 
antibodies (see also Section 21.4 for the time points):

Inhibitory antibodies to FVIII –using the Nijmegen modification of the Bethesda 
assay

Binding antibodies to FVIII, BAX 855, and PEG. Both IgG and IgM antibodies 
will be measured using an ELISA assay

Anti-CHO antibodies measured by an ELISA assay
In addition to the time points as described in Section 21.4, the subject should be 
evaluated for inhibitory and binding antibodies to FVIII, BAX855 and PEG if clinically 
indicated, eg lack of response to treatment. 
A low titer (responder) inhibitor is defined as ≥ 0.6 BU but ≤ 5 BU. A high titer 
(responder) inhibitor is defined as > 5 BU by Nijmegen modification of the Bethesda 
assay. Inhibitors must be documented at 2 separate time points within a 2 to 4 week 
period at a central laboratory. Every confirmed FVIII inhibitor ≥ 0.6 BU must be reported 
as an SAE. 
Based on the variability of the binding antibody tests, only samples with titers ≥ 1:80 can 
be confirmed and will be evaluated as positive. IgG subclass 1-4, IgA (using ELISA) and 
IgE antibodies (using ImmunoCaps, Thermo Fisher) may be assayed as clinically 
indicated.
The assay for antibodies to CHO protein will use CHO protein derived from cultures of 
untransfected cells. Testing for binding of anti-CHO protein antibodies will be performed 
on citrate-anti-coagulated plasma using an ELISA employing polyclonal anti-human IgG 
antibodies. Antibody-containing samples will be identified in a screening assay followed 
by a confirmatory assay to exclude false positive results.
All assays will be performed in a central laboratory.

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13.2 Adverse Events
13.2.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered an IP 
that does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom (eg, rash, pain, discomfort, fever, dizziness, etc.), disease (eg, peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP.
Serious Adverse Event
13.2.1.1
A serious adverse event (SAE) is defined as an untoward medical occurrence that at any 
dose meets one or more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (ie, a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 
Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse
Reviewed and confirmed seroconversion for human immunodeficiency 
virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C 
virus (HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
Development of a confirmed inhibitor to FVIII with an inhibitor level 
≥0.6 BU, as measured by the Nijmegen modification of the Bethesda 
assay
Severe hypersensitivity/allergic reactions to BAX 855

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Uncomplicated pregnancies, following maternal exposure to IP are not considered an 
(S)AE; however, any pregnancy complication or pregnancy termination by therapeutic, 
elective, or spontaneous abortion shall be considered an SAE. 
Non-Serious Adverse Event
13.2.1.2
A non-serious AE is an AE that does not meet the criteria of an SAE.
13.2.2 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (eg, IB, package insert). “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
For the purposes of this study, all AEs including unexpected AEs experienced by a 
subject undergoing study treatment will be recorded on the AE CRF.
13.2.3 Preexisting Diseases
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure, will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on
the AE CRF.
13.2.4 Assessment of Adverse Events
For the purposes of this study, the following non-serious events experienced after the first 
IP exposure will not be considered AEs, and thus, not included in the analysis of AEs:

Hospital or clinic visits for administration of BAX 855

Hospitalization for routine bleeding episode management that could be managed 
in the clinic or home-setting but for which the subject was hospitalized

Hospitalizations for planned medical or surgical procedures, eg, placement of a 
central venous line (however, when there is an increase in the severity, duration, 
or frequency of a preexisting disease, the event must be described on the AE 
CRF)

Hospitalization or prolongation of hospitalization intended only for social reasons.

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
Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period

Bleeding episodes/hemophilia-related events: Bleeding episodes are part of the 
underlying disease and therefore are not AEs. If a bleeding episode was caused by 
an injury (eg, a fall), the injury would not be reported as an AE, unless it resulted 
in a medical finding other than a bleeding episode (eg, abrasion of skin; fractured 
tibia). Therefore, any hemophilia-related event (eg, hemarthrosis, bruising, 
hemorrhage) will not be reported as an AE, but these events will be recorded on 
the bleeding event CRF. However, hemophilia-related events meeting the criteria 
for seriousness (eg, a gastrointestinal hemorrhage requiring hospitalization) will 
be reported as SAEs and described on the SAE report
All other AEs from the first IP exposure until study completion/discontinuation will be 
described on the AE CRF using the medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
expressions (see definition in Section 13.2). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 13.2.1.1

Severity as defined in Section 13.2.5

Causal relationship to IP exposure or study procedure as defined in Section 13.2.6
For each AE, the outcome (ie, recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (ie, dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution, medically stabilized, or 
30 days after the study completion/termination visit, whichever comes first. If the 
severity rating for an ongoing AE changes before the event resolves, the original AE 
report will be revised (ie, the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including overdosing, underdosing, 
abuse, and withdrawal, treatment errors (including incorrect route of administration, 
use of an incorrect product, and deviations from the protocol-defined dosing schedule), 
failures of expected pharmacological actions, and unexpected therapeutic or clinical 
benefits will be followed with regard to occurrence of AEs, lack of efficacy, and/or other 
observations because these events may be reportable to regulatory authorities.

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Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion, the SAE must be reported on the SAE Form within 24 hours after awareness; 
no additional reporting on CRFs is necessary.
13.2.5 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant 
manner with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require 
therapeutic intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to 
temporary inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
13.2.6 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, eg, 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

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
Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (ie, does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely 
alternative etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which 
may include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive 
re-challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related, and occurring within 24 hours of IP 
administration, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.

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13.3 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. In the 
event(s) of an apparent immediate hazard to the subject, the investigator will notify the 
sponsor immediately by phone and confirm notification to the sponsor in writing as soon 
as possible, but within 1 calendar day after the change is implemented. The sponsor will 
also ensure the responsible ethics committee is notified of the urgent measures taken in 
such cases according to local regulations.
13.4 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 13.2). However, each 
serious untoward medical occurrence experienced before the first IP exposure (ie, from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAE Report. These events will not be considered as SAEs and will not 
be included in the analysis of SAEs. 
For the purposes of this study, each non-serious untoward medical occurrence 
experienced by a subject undergoing study-related procedures (eg, during blood 
sampling) before the first IP exposure will be recorded on the AE CRF; these events will 
not be considered as AEs and will not be included in the analysis of AEs. 
13.5 Medical Device Safety reporting
The IP kit contains the BAXJECT device. All Serious Injuries (SI) and Unexpected 
Adverse Device Events (UADE) must be reported. Serious injury is defined as: 

Life-threatening injury or illness results in permanent impairment/ damage to 
body function/ structure. It requires medical or surgical intervention to preclude 
permanent impairment/ damage to body function/ structure.

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13.6 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, eg, reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (eg, potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
13.7 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 13.2.5) or surgery and start and end dates, 
if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal;
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary.
The historical ABR including treated and untreated bleeding episodes in the 12 months 
prior to study enrollment based on medical records should also be recorded in the eCRF. 
Only the treated bleeds will be the basis for inclusion in the study.
All medications taken and non-drug therapies received from 4 weeks before enrollment
until completion/termination will be recorded on the concomitant medications and non-
drug therapies CRFs.
Any prior use of any pegylated medication (name of drug, indication, and dates of use), at 
any time in the past, will be recorded on the eCRF.

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13.8 Physical Examinations
At screening and subsequent study visits (as described in the schedule in Section 21.2), a 
physical examination will be performed on the following body systems: general 
appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, skin, and neurological. At screening, if an abnormal 
condition is detected, the condition will be described on the medical history CRF. At 
screening, the Karnofsky performance score will be assessed.
At study visits, if a new abnormal or worsened abnormal pre-existing condition is 
detected, the condition will be described on the AE CRF. If the abnormal value was not 
deemed an AE because it was due to an error, due to a preexisting disease (described in 
Section 13.2.3), not clinically significant, a symptom of a new/worsened condition 
already recorded as an AE, or due to another issue that will be specified, the investigator 
will record the justification on the source record.
13.9 Clinical Laboratory Parameters
All assessments will be performed at a central laboratory, according to the laboratory 
manual.
At all laboratory assessments subjects must not be actively bleeding. In addition to the 
laboratory assessments planned in the protocol, appropriate clinical laboratory testing 
should be performed whenever clinically indicated.
Details on the visits and timing of blood sampling for the laboratory parameters are 
provided in Section 21.2 and Section 21.3.
13.9.1 Screening Laboratory Parameters
Blood Type
13.9.1.1
For subjects who do not have documentation of their blood type in their medical record, 
blood ABO blood type will be measured centrally at screening.
Genetics and HLA-Genotype
13.9.1.2
FVIII gene mutation analysis and HLA genotype will be analyzed at screening. If results 
of FVIII gene mutation analysis and HLA genotype are already available at the study site, 
they will be provided to the sponsor and a reanalysis will not be required in those 
subjects.

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Pregnancy Test
13.9.1.3
A pregnancy test should be performed as appropriate (serum pregnancy test in females of 
child-bearing potential if no urine sample is available). The pregnancy test might be 
repeated during the study in countries where mandated by national law.
CD4 Count
13.9.1.4
At screening only, CD4 levels will be determined in all HIV+ subjects using flow 
cytometry.
Viral Serology
13.9.1.5
Viral serology testing will include HIV-1 and HIV-2 antibody, HBsAb, HBsAg, HBcAb, 
and HCV Ab. HCV titer will be confirmed by PCR for all subjects reported as HCV 
positive. All assessments will be performed at screening only. A positive test for HBsAg 
will be repeated using a new blood sample.
13.9.2 Hematology, Clinical Chemistry and Lipid Panel
Hematology tests will be performed on EDTA-anticoagulated whole blood, and clinical 
chemistry assessments and the lipid panel will be performed on serum.
The hematology panel consists of complete blood count [hemoglobin, hematocrit, 
erythrocytes (ie, red blood cell count), and leukocytes (ie, white blood cell count)] with 
differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean 
corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and 
platelet count.
The clinical chemistry panel consists of sodium, potassium, chloride, bicarbonate, total 
protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.
The lipid panel consists of cholesterol, very low density lipoprotein (VLDL), low density 
lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides.
13.9.3 FVIII Activity, FVIII Antigen, VWF Antigen
Blood samples will be analyzed for FVIII activity (1-stage clotting assay and the 
chromogenic assay) at a central laboratory. The 1-stage clotting assay will serve as the 
primary assay; the chromogenic assay will be used to provide supportive data. In addition 
FVIII antigen will be measured by ELISA. VWF antigen will be determined using 
ELISA from pre-infusion samples. The detailed time points of FVIII activity, FVIII 
antigen and VWF antigen assessment are provided in Section 12.1, Section 12.2, and 
Section 21.4.

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13.9.4 Thrombin Generation Assay 
For TGA parameters (lag time, time to peak thrombin generation, peak thrombin 
generation, and endogenous thrombin potential [ETP]), plasma samples will be tested 
using the calibrated, automated thrombin generation method (CAT). For details on the 
individual time points for TGA assessment please see Section 12.1, Section 21.2, and 
Section 21.4.
13.9.5 Assessment of Laboratory Values
Assessment of Abnormal Laboratory Values 
13.9.5.1
The investigator’s assessment of each laboratory value (ie, hematology, clinical 
chemistry, and lipids) will be recorded on the CRF. For each abnormal laboratory value, 
the investigator will determine whether the value is considered clinically significant or 
not. For clinically significant values, the investigator will indicate if the value constitutes
a new AE (see definition in Section 13.2, and record the sign, symptom, or medical 
diagnosis on the AE CRF), is a symptom or related to a previously recorded AE, is due to 
a pre-existing disease (described in Section 13.2.3), or is due to another issue that will be 
specified. If the abnormal value was not clinically significant, the investigator will 
indicate the reason, ie because it is due to a preexisting disease, due to a lab error, or due 
to another issue that will be specified. Additional tests and other evaluations required to 
establish the significance or etiology of an abnormal value, or to monitor the course of an 
AE should be obtained when clinically indicated. Any abnormal value that persists 
should be followed at the discretion of the investigator.
13.9.6 Biobanking
Patients will consent for taking an extra blood sample at each study visit for additional 
analysis, if necessary. Additional backup samples that remain after study testing is done 
may be stored and used for additional testing (eg, further evaluation of an abnormal test 
or an AE). 
Also, an additional blood draw for further exploratory testing will be drawn pre-infusion 
and early in the morning , if feasible, otherwise at the same time point at the Baseline, 
Month 3, Month 6, Month 9 and  Completion/Termination study visit (see Clinical 
Laboratory Assessment Schedule in Section 21.4).
Samples will be stored in a coded form for no more than 2 years after the final study 
report has been completed and then the samples will subsequently be destroyed.

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13.10 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min), and systolic and diastolic blood pressure (mmHg). Height (in or cm) and 
weight (lb or kg) will also be collected at screening; weight will also be recorded before 
any IP infusions are administered at the study site, but at least at each study visit. Blood 
pressure will be measured when subjects are in the supine position.
Vital signs will be assessed within 15 minutes prior to start of infusion and 30±5 minutes 
following infusion at baseline and at each study visit. Vital signs should always be 
assessed before any blood sampling is done at a particular time point.
Vital sign values are to be recorded on the CRF. For each abnormal vital sign value, the 
investigator will determine whether or not to report an AE (see definition in Section 13.2
and record the medical diagnosis (preferably), symptom, or sign on the AE CRF). 
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.

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14. STATISTICS
14.1 Sample Size and Power Calculations
14.1.1 Sample Size Calculation
For the sample size assessment the following assumptions were used. Approximately 
40% of patients in BAX 855 regimen targeting 1-3% trough level are expected to be 
bleed-free as shown in the ADVATE Prophylaxis study and the BAX 855 pivotal study 
261201. For the BAX 855 regimen targeting approximately 10% (8-12%) trough level, an 
increase to 70% bleed-free patients is expected based on modeling the bleeding rates per 
FVIII level in the BAX 855 pivotal study 261201.
Under these assumptions 48 subjects per study arm are needed to reject the null 
hypothesis of no difference between the study arms against a two-sided alternative at the 
5% level of statistical significance with 80% power. Assuming a drop-out rate of close to 
10%, and 10-15% of subjects being non-compliant, approximately 116 subjects are 
planned to be randomized between the two BAX 855 regimens with an allocation ratio 
of 1:1.
14.2 Datasets and Analysis Cohorts
14.2.1 Full Analysis Set 
The Full Analysis Set (FAS) will comprise all subjects who were randomized and who 
were treated with BAX 855 prophylactically for any period of time. 
14.2.2 Per Protocol Analysis Set 
The Per Protocol Analysis Set will comprise all subjects who were randomized and 
completed the second 6 months of prophylactic treatment.
14.2.3 Safety Analysis Set
The Safety Analysis Set (SAS) will comprise all subjects treated with at least 1 BAX 855 
dose. All safety analyses for BAX 855 will be performed on the SAS.
14.3 Handling of Missing, Unused, and Spurious Data
Missing data will not be imputed in general, with the exceptions as detailed below.
14.3.1 Handling of incomplete observation periods for ABR
The primary endpoint requires complete data for the second 6 months of prophylaxis 
(Day 183 to Day 364). The multiple imputations technique will be used for the analysis 
of the primary endpoint and estimation of ABRs. As this is a statistical analysis 
technique, it will be described in the statistical analysis section.

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14.3.2 Handling of other variables
If body weight is missing for a subject then the last value of available body weight 
measurement will be carried forward in order to compute weight-adjusted BAX 855 
consumption. If the date of onset for an AE is missing completely then it will be imputed 
with the date of the first study drug application.
For PK data, if any concentration data are considered spurious (e.g. lack of biological 
plausibility), the reason for exclusion and the analysis from which the data point was 
excluded will be documented. 
Regarding missing data in AE records:

Handling of unknown causality assessment:
If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related”.

Handling of unknown severity grades:
If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, the severity of this AE will be counted as 
“severe”.

If a subject experiences more than one AE categorized under the same preferred 
term, one of them is categorized as “mild” or “moderate” and one of them is 
categorized as “unknown”, the severity of this AE will be counted as “unknown”.
14.4 Methods of Analysis
14.4.1 Primary Outcome Measure
The proportion of subjects with ABR = 0 in the two prophylaxis treatment regimens in 
the second 6 months period will be compared using a chi-square test with continuity 
correction at a two-sided 5% level of significance. 
The null hypotheses of no difference between the prophylactic regimens will be tested 
against a two-sided alternative.
The observation period for the primary endpoint will be the second 6 months of 
prophylaxis (Day 183 to Day 364). If the subject undergoes a surgical procedure the 
observation period is interrupted starting from the presurgical loading dose until the 
subject resumes his previous prophylactic treatment regimen, or until rehabilitation or 
any other surgery specific postoperative measures have been completed, whichever 
occurs last.

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Data analyses will follow the intent-to-treat principle, i.e. bleedings observed in the 
observation period will be used in the analyses irrespective of compliance with the 
treatment regimen of the protocol. Only if a subject refuses to provide any bleeding data, 
the multiple imputations (MI) technique will be used to handle observation periods 
shorter than 6 months, i.e. 182 days, as follows.
For subjects who terminated before Day 364 and refuse to provide data on bleeds, bleeds 
will be imputed for the unobserved period from a Poisson random variate. The subject 
specific Poisson parameter will be determined from estimating a negative binomial model 
for the bleed rate in the unobserved period with stratum, age, race as well as the number 
of bleeds from Day 92 to the end of the observed period of the subject as covariates in all 
subjects of the same Study Arm. For subjects with more than 21 weeks in the observation 
period, the number of bleeds occurring at a later time in other subjects might be very low 
or even zero. To avoid estimating from an unstable model, the negative binomial model 
will be for the number of bleed up to Day 329 with covariates of stratum, age, race and 
number of bleeds observed from Day 92 to Day329. At least 1000 imputation datasets 
will be generated. The chi-squared test statistics with continuity correction and its 
standard error will be used to compare the two study arms in each imputation dataset and 
the multiple imputations techniques will be used to derive an overall estimate with two-
sided 95% confidence interval.
The dataset to be analyzed is all subjects. For subjects who developed an inhibitor, 
missing observation periods will be imputed at twice the rate before the study.
The use of age and race in the imputation model will allow for subgroup analyses of the 
primary endpoint and ABRs.
Sensitivity analyses
Sensitivity analyses will be performed similar to the primary analysis except that the 
negative binomial distributions used for imputations will have an artificially increased 
Poisson parameter by 10%, 20%, 40% and 80%. In addition, a worst-case sensitivity 
analysis will be performed which imputes worst-case outcomes in all subjects with 
missing ABR data in the observation period.
14.4.2 Secondary Outcome Measures 

Total, spontaneous, and traumatic ABR, and spontaneous AJBR
For total ABR, spontaneous ABR, traumatic ABR and spontaneous JABR, separate 
negative binomial models will be used for the second 6 months treatment period
(Days 183 to 364) as well as for the complete 12-month treatment period (Days 1 to 364)

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The negative binomial model for the bleed rate will include covariates for study arm, 
stratum, age, and race. The multiple imputations technique will be used for incomplete 
observation periods as described for the primary endpoints analysis. Subgroups for age 
and race will be analyzed as well.
For all other outcome measures, descriptive statistics will be presented for the two dosing 
regimens. Point estimates (means and medians) and their 95% CIs will be computed to 
include: 

Total weight-adjusted consumption of BAX 855 for each prophylactic regimen

Overall hemostatic efficacy rating at 8 ±1 h after initiation of treatment and at 
resolution of bleed

Number of BAX 855 infusions needed for the treatment of bleeding episodes

HJHS

Physical domain and component scores of the SF-36

Physical Activity Levels
In case of surgeries, descriptive statistics will be performed for the following secondary 
outcome measures:

Intra-, post- and perioperative hemostatic efficacy in case of surgery (see 
Section 22.5.1 for details)

Intra- and postoperative blood loss in case of surgery (see Section 22.5.2 for
details)
PK parameters before randomization will be summarized descriptively over all subjects 
to include:
AUC0-∞(Area under the plasma concentration versus time curve from time 0 to 
infinity), IR (incremental recovery) at 15-30 minutes post-infusion, T1/2 (plasma 
half-life), MRT (mean residence time), CL (clearance), maximum plasma 
concentration (Cmax) and time to maximum concentration in plasma (Tmax), 
Vss (Volume of distribution at steady state)
PK parameters after 9 months will be summarized descriptively by prophylactic 
treatment regimen:
AUC0-∞(Area under the plasma concentration versus time curve from time 0 to 
infinity), IR (incremental recovery) at 15-30 minutes post-infusion, T1/2 (plasma 
half-life), CL (clearance), maximum plasma concentration (Cmax) and time to 
maximum concentration in plasma (Tmax), 

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Incremental recovery (IR) over time will be displayed as boxplots for the two 
prophylactic regimens.
Correlation of VWF:Ag and PK parameters will be assessed by boxplots and Spearman 
rank correlation coefficient.
Descriptive statistics will be used for the secondary safety outcome measures (see 
Section 8.4.2.2):

Occurrence of AEs and SAEs

Changes in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry, and lipids)

Inhibitory antibodies to FVIII, and binding antibodies to FVIII, BAX 855, PEG, 
and CHO protein
The methods of analysis for the secondary PROs measures (see Section 8.4.2.3) are 
described for the following PROs:

Physical domain and component scores of the SF-36 

Physical activity levels
Change scores from baseline to completion/follow-up will be assessed for each treatment 
arm and tested using the minimally important difference threshold and the Wilcoxon sign 
rank test. Differences in the change scores between treatment groups will be tested using 
the minimally importance difference threshold and the Mann-Whitney U Test.
14.4.3 Exploratory Outcome Measures 
Boxplots and Spearman rank correlation coefficient will be used to assess the correlation 
between the average of various coagulation parameters (thrombin generation assay 
(TGA) parameters: lag time, time to peak thrombin generation, peak thrombin generation, 
and endogenous thrombin potential [ETP] and FVIII trough levels) and ABR in the same 
time periods (first 6 months, second 6 months, overall).
Changes from baseline to completion/follow-up for patients for the two dosing arms will 
be tested using the minimally importance difference threshold and the Wilcoxon sign 
rank test for the following PROs:

Bleed and pain severity as measured by the Haemo-SYM questionnaire

HRQoL as assessed using the EQ-5D and mental domain and component scores 
of the SF-36 questionnaire

Health Resource Utilization 

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Differences in the change scores between treatment groups will be tested using the 
minimally importance difference threshold and the Mann-Whitney U Test for the 
following PROs:

Bleed and pain severity as measured by the Haemo-SYM questionnaire

HRQoL as assessed using the EQ-5D and mental domain and components scores 
of the SF-36 questionnaire

Health Resource Utilization 
15. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Study Agreement. If contacted by an 
applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the Clinical Study Agreement.

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16. QUALITY CONTROL AND QUALITY ASSURANCE
16.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The investigator is ultimately responsible for the conduct of 
all aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
16.1.1 Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
16.2 Training
The study monitor will ensure that the investigator and study site personnel understand 
all requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
16.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit the study monitor to visit the study site at appropriate 
intervals, as described in the Clinical Study Agreement. Monitoring processes specific to 
the study will be described in the clinical monitoring plan.
16.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit auditors to visit the study site, as described in the Clinical 
Study Agreement. Auditing processes specific to the study will be described in the 
auditing plan.

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16.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor will also ensure the responsible ethics committee is notified of 
the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
16.6 Laboratory and Reader Standardization
Not applicable; a central laboratory will be used for all clinical assessments.

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17. ETHICS 
17.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
17.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the Clinical Study 
Agreement. 
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
17.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable regulatory requirements and 
ICH GCP. An assent form may be provided and should be signed by patients less than 
18 years of age. Before use, the informed consent/assent form will be reviewed by the 
sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 17.2). The informed consent/assent form will include a comprehensive 
explanation of the proposed treatment without any exculpatory statements, in accordance 
with the elements required by ICH GCP and applicable regulatory requirements. Patients 
and/or their legally authorized representative(s) will be allowed sufficient time to 
consider participation in the study. By signing the informed consent/assent form, patients 
and/or their legally authorized representative(s) agree that they will complete all 
evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.

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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent/assent will be updated, if necessary. This new information and/or revised 
informed consent/assent form that have been approved by the applicable EC and 
regulatory authorities, where applicable, will be provided by the investigator to the 
subjects and/or the subjects’ legally authorized representative who consented to 
participate in the study (see Section 17.3).
17.4 Data Monitoring Committee
A Data Monitoring Committee (DMC) will not be used for this study as the expected 
related AEs in this study are anticipated to be similar to that of the licensed product 
ADVATE (of which the core protein is identical to that of BAX 855; see Section 6.5 for 
more details on anticipated risks and benefits of BAX 855). Additionally, the safety is not 
expected to differ from the safety observed in the BAX 855 pivotal and the ongoing 
BAX855 continuation study (Studies 261201 and 261302, respectively).

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18. DATA HANDLING AND RECORD KEEPING
18.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
18.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAE reports (SAERs), laboratory reports 
(if applicable), and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit, the data will be recorded on paper, and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 18.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (eg, ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
18.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the Clinical Study Agreement.

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19. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the Clinical Study 
Agreement.
20. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement. 

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21.2 Detailed Flow Diagram of Study Procedures
Before any study procedures are performed, informed consent must be obtained from 
each patient.
Screening Visit
The screening procedures differ according to whether the subject is transitioning from a previous 
BAX 855 study (see Section A) or is newly recruited (see Section B). If the sponsor decides a transitioning 
subject requires a PK Assessment, then from the screening visit onwards procedures are identical to those 
for newly recruited subjects. If no PK Assessment is required, the next visit for transitioning subjects is the 
Baseline Visit once randomization is performed.
Evaluations must be completed within 56 days of the screening visit.
No wash-out is required but whenever possible the screening visit should be scheduled shortly before the 
next scheduled prophylactic infusion when baseline FVIII trough levels are reached in case the subject 
receives prophylactic treatment.
A: Subjects transitioning from other BAX 855 studies
The screening visit coincides with the end of study visit of the previous BAX 855 study; the subject must 
not be actively bleeding. If applicable, BAX 855 will be administered for IR determination based on the 
protocol of the previous study.
Informed consent must be obtained at enrollment at the latest (prior to any study-specific procedure); to 
give the patient sufficient time to review the ICF, this document should preferably be provided prior to the 
end of study visit of the previous study.
The relevant data obtained at the end of study visit of the previous BAX 855 study will be transcribed to 
the screening visit eCRF of this PK-guided dosing study, and where possible, duplication of blood draws or 
evaluations will be avoided.
The following procedures will be performed:
Clinical Assessments:

Assessment of inclusion/exclusion criteria

PROs (or can be done at Baseline visit) should be determined prior to any other study specific 
procedures:
o
Haemo-SYM questionnaire
o
EQ-5D
o
SF-36
o
Physical activity questionnaire
o
Health Resource Use
Laboratory Assessments:
Blood will be drawn for the following additional assessments:

Screening tests:
o
CD4 count in subjects who are HIV positive
o
Viral serology (if any positive, test to be confirmed with a second sample) : 

HIV: HIV-1 and HIV-2 Ab

HBV: HBsAg, HBsAb, HBcAb

HCV: HCVAb (PCR to be performed if positive)

Pregnancy test, if applicable 

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The following data will be obtained/transcribed from the end of study visit of the previous BAX 855 study:

Medical history

Medication history

Concomitant medications

Non-drug therapies

Physical examination (including assessment of target joints)

Vital signs (body temperature (°C), respiratory rate (breaths/min), pulse rate (beats/min), and supine 
systolic and diastolic blood pressure (mmHg)).

Laboratory Data:
o
FVIII/VWF/TGA assays:

FVIII activity (activated partial thromboplastin-based 1-stage clotting assay and 
chromogenic assay)

FVIII antigen

VWF antigen 

TGA, if not available from previous study, an additional blood sample has to be 
drawn for TGA testing
o
Immunogenicity tests:

Inhibitory antibodies to FVIII (Nijmegen assay)

Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG

Anti-CHO antibodies
o
Hematology, clinical chemistry, and lipids
o
Gene mutation and HLA genotype if not available
o
Blood type (A, B, AB or O) if historical data not available
Subject diary:

Hand out subject diary and provide training to subject
Other procedures:

Dispense IP:
o
A sufficient quantity of IP of study 261303 will be dispensed to cover the period until the PK 
Assessment / Baseline visit (as applicable)
B: Newly recruited subjects

Ensure informed consent has been obtained

Medical history

Hemophilia history, including:
o
Confirmation of diagnosis and severity
o
Family history of hemophilia
o
Documentation of mutation, if known
o
The presence of any target joints will be documented. A target joint is defined as any single 
joint (ankles, knees, hips, or elbows) with ≥ 4 spontaneous bleeding episodes in any 
consecutive 6 month period.
o
Documentation of all FVIII replacement therapies used within the last year, including:

Date of last FVIII infusion prior to screening visit, type of FVIII product, dose infused 
and reason for administration

FVIII regimen (prophylaxis or on-demand)

Product name (or IP name and manufacturer, if applicable)

Dose (for prophylaxis, if applicable, and for treatment of bleeding episodes)

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
Frequency of administration (for prophylaxis)

Estimate of average number of infusions for each bleeding episode and usual response
o
Assessment of subject’s ABR based on documented and treated bleeding episodes within 12 
months before enrolment, based on subject’s medical records.

Concomitant medications for the last 30 days, and any prior history of use of any pegylated 
medication (eg, PEG-interferon) at any time in the past, including treatment indication, date of last 
administration, and duration of treatment(s), if known

Non-drug therapies for the last 30 days

Physical examination, including height and weight

Karnofsky performance score

Vital signs (body temperature (°C), respiratory rate (breaths/min), pulse rate (beats/min), and supine 
systolic and diastolic blood pressure (mmHg)).

PROs (or can be done at Baseline visit) should be determined before any other study specific 
procedures are performed:
o
Haemo-SYM questionnaire
o
EQ-5D
o
SF-36
o
Physical activity questionnaire
o
Health Resource Use
Laboratory Assessments:
Blood will be drawn for the following assessments:

Screening tests:
o
CD4 count in subjects who are HIV positive
o
Viral serology (if any positive, test to be confirmed with a second sample) : 

HIV: HIV-1 and HIV-2 Ab

HBV: HBsAg, HBsAb, HBcAb

HCV: HCVAb (PCR to be performed if positive)
o
Genetics (FVIII gene mutation analysis) and HLA-genotype if historical data not available
o
Blood type (A, B, AB or O) if historical data not available

FVIII/VWF/TGA assays:
o
FVIII activity (activated partial thromboplastin-based 1-stage clotting assay and chromogenic 
assay)
o
FVIII antigen
o
VWF antigen 
o
TGA

Immunogenicity tests:
o
Inhibitory antibodies to FVIII (Nijmegen assay)
o
Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG
o
Anti-CHO antibodies

Hematology, clinical chemistry, and lipids

Pregnancy test, if applicable
Subject diary:

Hand out subject diary and provide training to subject

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PK Assessment
Subjects transitioning from another BAX 855 study who have already had a PK assessment may have to 
repeat the PK assessment based on the sponsor’s evaluation. The PK assessment has to be performed after a 
wash-out period of at least 72-96 h depending on the FVIII concentrate used and the patient should not be 
actively bleeding. 
Blood sampling after infusion of BAX 855 for PK assessments will be performed over a 4-day period. 

Review and discuss subject diary
At the pre-infusion time point, the following assessments will be carried out:

Laboratory Assessments (within 30 minutes of start of infusion):
o
FVIII assays
o
VWF antigen
o
TGA

Vital signs (within 15 minutes of start of infusion)
Infusion:

Infusion of 60 ± 5 IU/kg BAX 855
Post-infusion:

Laboratory Assessments:
o
FVIII assays and TGA at the post-infusion time points, 15-30 min, 3±0.5 h, 8±0.5 h, 24±2 h , 
48±4 h, 72±4 h and 96±4 h
At 30 ± 5 min post-infusion:

Vital signs (body temperature, respiratory rate, pulse rate, and supine systolic and diastolic blood 
pressure)
Throughout the visit, the following assessments will be carried out:

Physical examination

Adverse events

Concomitant medications and non-drug therapies
Randomization
Once the FVIII activity results are available and the PK parameters calculated, subjects will be randomized 
to one of the treatment arms. 

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Baseline Visit
The washout periods are at least 72 – 96 h and the subject must not be actively bleeding. Evaluations must 
be completed within 56 days of the PK Assessment. Whenever possible the PRO questionnaires should be 
completed before all other study specific procedures are started. 
At the pre-infusion time point, the following assessments will be carried out:

PROs (if not done at Screening visit):
o
Haemo-SYM questionnaire
o
EQ-5D 
o
SF-36
o
Physical Activity questionnaire
o
Health Resource Use

Review and discuss subject diary

Physical examination, including body weight, and assessment of target joints

Vital signs (within 15 minutes of start of infusion)

Laboratory Assessments (within 30 minutes before start of infusion):
o
Hematology, clinical chemistry, and lipids
o
FVIII, VWF Ag and TGA assays
o
Immunogenicity tests:

Inhibitory antibodies to FVIII (Nijmegen assay)

Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG

Anti-CHO antibodies
o
Additional blood draw for further exploratory testing
Infusion:

Infusion of PK-guided dose of BAX 855
Post-infusion:
At 15-30 min post-infusion:

Laboratory Assessments
o
FVIII and TGA assays 
At 30±5 min post infusion:

Vital signs (body temperature, respiratory rate, pulse rate, and supine systolic and diastolic blood 
pressure)
Other procedures:

Dispense IP

HJHS joint score
Throughout the visit, the following assessments will be carried out:

Adverse events

Concomitant medications and non-drug therapies

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Visits at Study Site:
3 months ± 2 weeks
6 months ± 1 week (26±1 week)
For the procedures at 4 weeks ±5 days, 8 weeks ± 1 week and 4.5 months ± 2 weeks, see next section.
The procedures listed here will also be carried out at 7.5 months ± 2 weeks and 10.5 months ± 2 weeks if 
subject has bleeding and attends site rather than having a phone visit.
The washout periods are as follows: 

Low trough arm: 96 h (after the longer treatment interval of 4 days), 72 h (after the short treatment 
interval of 3 days) or 84 h (3.5 day intervals); 

High trough arm: at least 48 h or when the subject reaches his/her baseline value depending on the 
frequency of BAX 855 infusions.
The subject must not be actively bleeding.
Before any other study-specific procedures are carried out:

PROs at 6 month visit 
o
Haemo-SYM questionnaire
o
EQ-5D
o
SF-36 
o
Physical Activity
o
Health Resource Use

EQ-5D, Patient Activity Level, and Health Resource Use at each visit 

Physical examination, including body weight, and assessment of target joints

Review and discuss subject diary, including assessment of bleeding episodes and their treatment

Re-evaluation of PK regimen based on pre-dose FVIII trough level from previous visit, change in 
body weight. Note: before any dose adjustments are performed an additional visit should be 
scheduled within 14 days after receipt of the FVIII activity result to reassess trough levels.
At the pre-infusion time point:

Vital signs (within 15 minutes of start of infusion)

Laboratory Assessments (within 30 minutes before start of infusion):
o
Hematology, clinical chemistry, and lipids (clinical chemistry and lipids are not applicable at 
study visits 7.5 month ±2 weeks and 10.5 month ±2 weeks)
o
FVIII, VWF Ag and TGA assays
o
Immunogenicity tests:

Inhibitory antibodies to FVIII (Nijmegen assay)

Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG

Anti-CHO antibodies
o
Additional blood draw for further exploratory testing
Infusion:
Infusion of 60±5 IU/kg of BAX 855
Post-infusion:
At 15-30 min post-infusion:

FVIII and TGA assays
At 30±5 min post-infusion:

Vital signs (body temperature, respiratory rate, pulse rate, and supine systolic and diastolic blood 
pressure)

Pegylated full-length Recombinant Factor VIII
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Dispense IP
Throughout the visit, the following assessments will be carried out:
Adverse events
Concomitant medications and non-drug therapies

Pegylated full-length Recombinant Factor VIII
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Visits at Study Site:
4 weeks ± 5 days
8 weeks ± 1 week
4.5 months ± 2 weeks
Dose Readjustment Visit
Visits following dose adjustment
The washout periods are as follows: 

Low trough arm: 96 h (after the longer treatment interval of 4 days), 72 h (after the short treatment 
interval of 3 days) or 84 h (3.5 day intervals); 

High trough arm: at least 48 h or when the subject reaches his/her baseline value, depending on the 
frequency of BAX 855 infusions.
The subject must not be actively bleeding.
These procedures will also be followed if a subject attends an additional visit to check trough FVIII levels 
prior to any dose readjustment.
Before any other study-specific procedures are carried out:

EQ-5D, Patient Activity Level and Health Resource Use

Review and discuss subject diary, including assessment of bleeding episodes and their treatment

Re-evaluation of FVIII regimen based on pre-dose FVIII trough level from previous visit, if 
applicable, change in body weight. Note: before any dose adjustments are performed an additional 
visit should be scheduled in 14 days to reassess trough levels
At the pre-infusion time point, the following assessments will be carried out:

Vital signs (within 15 minutes of start of infusion)

Laboratory Assessments:
o
FVIII, VWF Ag and TGA assays (within 30 minutes of start of infusion)

Immunogenicity tests (within 30 minutes of start of infusion):
o
Inhibitory antibodies to FVIII (Nijmegen assay)
o
Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG
o
Anti-CHO antibodies
Infusion:

Infusion of PK-guided dose of BAX 855
FVIII trough level measurement following dose adjustment
Those subjects who had dose adjustment will undergo a repeat FVIII trough level measurement 
approximately 2 weeks following their dose adjustment. The measurement should be performed 
immediately prior to their next scheduled prophylactic infusion: 
Only the following assessment will be performed: 

Laboratory Assessments:
o
FVIII, VWF Ag and TGA assays (within 30 minutes of start of infusion)
Throughout the visit, the following assessments will be carried out:

Adverse events

Concomitant medications and non-drug therapies 
IP dispense

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Phone Visits:
7.5 months ± 2 weeks
10.5 months ± 2 weeks
If subjects experienced bleeding episodes between the last visit and visit 7.5 months± 2 weeks and
10.5 months ± 2 weeks, respectively, they must visit the site rather than having a phone visit
The subject will be contacted by phone and will be asked about the following:

Review and discuss subject diary

Bleeding episodes and their treatment

Adverse events

Concomitant medications and non-drug therapies
In case of bleeding episodes the laboratory assessment as described for study visit month 3 ± 2 weeks and 
month 6 ± 1 week may be performed.

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Visit at Study Site:
9 months ± 2 weeks
The washout periods are as follows: 

Low trough arm: at least 96 h (after the longer treatment interval of 4 days), 72 h (after the short 
treatment interval of 3 days) or 84 h (3.5 day intervals); prior to the subsequent prophylactic 
infusion

High trough arm: at least 48 h immediately prior to next prophylactic infusion or when the subject 
reaches his/her baseline value depending on the frequency of BAX 855 infusions.
The subject must not be actively bleeding.
Before any other study-specific procedures are carried out:

EQ-5D, Patient Activity Level, and Health Resource Use

Review and discuss subject diary, including assessment of bleeding episodes and their treatment

Physical examination, including body weight, and Assessment of target joints
At the pre-infusion time point, the following assessments will be carried out:

Vital signs (within 15 minutes of start of infusion)

Laboratory Assessments (within 30 minutes of start of infusion):
o
FVIII, VWF Ag and TGA assays 
o
Hematology, clinical chemistry, and lipids

Immunogenicity tests (within 30 minutes of start of infusion):
o
Inhibitory antibodies to FVIII (Nijmegen assay)
o
Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG
o
Anti-CHO antibodies

Additional blood draw for further exploratory testing
Infusion:

Infusion of 60±5 IU/kg BAX 855
Post-infusion:

Laboratory Assessments: 
o
FVIII assays and TGA at the post-infusion time points, 15-30 min, 3±0.5 h, 8±0.5 h, 24±2 h , 
48±4 h, 72±4 h and 96±4 h
o
At 30 ± 5 min post-infusion:

Vital signs (body temperature, respiratory rate, pulse rate, and supine systolic and diastolic blood 
pressure)
Dispense IP
Throughout the visit, the following assessments will be carried out:

Adverse events

Concomitant medications and non-drug therapies

Pegylated full-length Recombinant Factor VIII
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Completion/Termination Visit:
at 12 months ± 1 week (53 [±1] weeks)
When planning the Completion/Termination Visit, it must be ensured that the second 6-month study period 
will consist of a minimum of 26 weeks and that the subject will have received his PK-tailored dosing 
regimen for at least 52 weeks.
The washout periods are as follows: 

Low trough arm: at least 96 h (after the longer treatment interval of 4 days), 72 h (after the short 
treatment interval of 3 days) or 84 h (3.5 day intervals); 

High trough arm: at least 48 h or when the subject reaches his/her baseline value depending on the 
frequency of infusions.
The subject must not be actively bleeding.
Before any other study-specific procedures are carried out:

PROs:
o
Haemo-SYM questionnaire
o
SF-36
o
EQ-5D
o
Physical Activity
o
Health Resource Use

Return of subject diary and review and discuss entries with subject, including assessment of 
bleeding episodes and their treatment

Physical examination, including body weight; Assessment of target joints; HJHS joint score
At the pre-infusion time point, the following assessments will be carried out:

Vital signs (within 15 minutes of start of infusion)

Laboratory Assessments:
o
FVIII, VWF Ag and TGA assays (within 30 minutes of start of infusion)
o
Hematology, clinical chemistry, and lipids

Immunogenicity tests (within 30 minutes of start of infusion):
o
Inhibitory antibodies to FVIII (Nijmegen assay)
o
Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG
o
Anti-CHO antibodies

Additional blood draw for further exploratory testing
Infusion:

Infusion of 60 ±5 IU/kg BAX 855
Post-infusion:

Laboratory Assessments: 
o
FVIII assays and TGA (15-30 minutes after start of infusion)
At 30 ± 5 min post-infusion:

Vital signs (body temperature, respiratory rate, pulse rate, and supine systolic and diastolic blood 
pressure)
Throughout the visit, the following assessments will be carried out:

Adverse events

Concomitant medications and non-drug therapies 

PEGylated full-length Recombinant Factor VIII
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21.3 Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visit
PK Assessmenta
Pre infusion, 
15-30 min, 3±0.5 
h, 8±0.5 h, 24±2 h 
48±4 h, 72±4 h 
& 96±4 h 
Post- Infusion
Baseline Visit
Study Visits
Completion/
Termination
Visitc
12 Mo
(53 ±1 Wk)
Visit 
4Wk 
±5d
Visit 
8Wk 
±1Wk
Visit 
3 Mo 
±2Wk
Visit 
4.5 Mo 
±2Wk
Visit 
6 Mo 
±1Wk
(26±1Wk)
Phone 
Visit 
7.5 Mo 
±2Wkb
Visit
9 Mo 
±2Wk
+ PK
Phone 
Visit
10.5 Mo 
±2wkb
Washout
N/A
72-96 h
Low trough arm: 96 h (after the longer treatment interval of 4 days), 72 h (after the short treatment 
interval of 3 days) or 84 h (3.5 day intervals); High trough arm: at least 48 h or when the subject
reaches his/her baseline value
Informed consentd
X
Eligibility criteria
X
Medical and medication 
historye
X*
Concomitant medicationsf
X*
X
X
X
X
X
X
X
X
X
X
X
Non-drug therapiesf
X*
X
X
X
X
X
X
X
X
X
X
X
Physical examg
X*
X
X
X
X
(X)b
X
(X)b
X
Vital signsh
X*
X
X
X
X
X
X
X
(X)b
X
(X)b
X
Adverse eventsf
*
X
X
X
X
X
X
X
X
X
X
X
Bleeding episodes and 
their treatmentf,i
*
X
X
X
X
X
X
X
X
X
Assessment of target 
jointsj
X
X
X
X
(X)
X
(X)
X
Joint score (HJHS)
X
X
Subject diaryk
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessmentsl
X*
X
X
X
X
X
X
X
(X)b
X
(X)b
X
IP treatmentm
X
X
X
X
X
X
X
(X)b
X
(X)b
X
IP dispensen
Xn
(X)
X
X
X
X
X
X
X

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Procedures/
Assessments
Screening Visit
PK Assessmenta
Pre infusion, 
15-30 min, 3±0.5 
h, 8±0.5 h, 24±2 h 
48±4 h, 72±4 h 
& 96±4 h 
Post- Infusion
Baseline Visit
Study Visits
Completion/
Termination
Visitc
12 Mo
(53 ±1 Wk)
Visit 
4Wk 
±5d
Visit 
8Wk 
±1Wk
Visit 
3 Mo 
±2Wk
Visit 
4.5 Mo 
±2Wk
Visit 
6 Mo 
±1Wk
(26±1Wk)
Phone 
Visit 
7.5 Mo 
±2Wkb
Visit
9 Mo 
±2Wk
+ PK
Phone 
Visit
10.5 Mo 
±2wkb
Washout
N/A
72-96 h
Low trough arm: 96 h (after the longer treatment interval of 4 days), 72 h (after the short treatment 
interval of 3 days) or 84 h (3.5 day intervals); High trough arm: at least 48 h or when the subject
reaches his/her baseline value
Re-evaluation of PK 
regimen/dose adjustmentso
X
X
X
X
X
(X)b
(X)
(X)b
PROsp
(X)q
(X)
(X)q
(X)q
(X)q
(X)q
X
(X)q
(X)q
(X)q
X
*
The screening visit coincides with the end of study visit of the previous BAX 855 study. The procedures/assessments marked with an asterisk (*) will be 
transcribed from the end of study visit of the previous BAX 855 study. 
a
Subjects transitioning from another BAX 855 study may have to repeat the PK assessment if evaluated to be necessary by the sponsor. The wash-out 
period prior to the PK determination is 72 - 96 hours, depending on the FVIII concentrate. PK will also be assessed at the 9-month visit (steady state 
PK) with the same post-infusion sampling timepoints.
b
If a subject has a bleeding episode, instead of a phone visit the subject must attend a site visit to assess FVIII trough levels and IR and re-evaluate the 
PK-guided regimen (see Figure 2). In these cases the subject will undergo all planned assessments for a study visit, including assessment of vital signs, 
physical examination, and all laboratory assessments excluding clinical chemistry and the lipid panel.
c
Including subjects who withdraw or discontinue.  When planning the Completion/Termination Visit, it must be ensured that the second 6-month study 
period will consist of a minimum of 26 weeks and that the subject will have received his PK-tailored dosing regimen for at least 52 weeks.
d
Occurs at enrollment (prior to any study-specific procedure).
e
Medical history to include hemophilia history (confirmation of diagnosis & severity; family history of hemophilia; documentation of a mutation, if 
known; presence of any target joints; and historical ABR, blood group if available). Medication history to include documentation of all FVIII 
replacement therapies used within the last year, any prior history of use of any pegylated medication (eg, PEG-interferon) at any time in the past, and 
other medications in the last 30 days.
f
Indicates that adverse events, concomitant medications, non-drug therapies, bleeding episodes and their treatment as well as the physical activity levels 
8 hours prior to the occurrence of bleeding will be continuously monitored but specifically discussed and reviewed at these time points.
g
Includes height and weight at screening, weight at the pre-infusion assessments, and Karnofsky performance score at screening.
h
Pulse, respiration, supine blood pressure, and temperature to be assessed within 15 minutes prior to start of infusion and 30±5 minutes following 
infusion.
Continued on Next Page

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Continued
i
The physical activity level in the 8 hours before the start of the bleeding episode should also be recorded.
j
A target joint is defined as one in which there have been ≥ 4 bleeds in any consecutive 6-month period.
k
The subject diary will be handed out at screening and training will be provided at the subsequent visits and the entries are reviewed and discussed with 
subject. It will be used to document bleeds, physical activity in the 8 hours before the bleed, treatment administered and response to BAX 855, 
prophylactic infusions, untoward events, concomitant medications, PROs and health resource use data, if applicable.
l
For laboratory assessments, See Section 21.4. 
m
BAX 855 is administered in the clinic at the visits shown. At the PK assessment and for IR determination a set dose of 60 ± 5 IU/kg BAX 855 is used, in 
all other cases the dose is PK-guided according to the allocated regimen.
n
Transitioning subjects will receive IP of study 261303 as of the screening visit. Newly recruited subjects will continue with their previous treatment 
regimen until the first prophylactic PK guided infusion at baseline and the infusion for PK determination.
o
In the first 6-month period, adjustments can be made based on PK and FVIII trough levels from previous study visits. Dose adjustments in second 6-
month period are only permitted when FVIII trough levels are outside of the target window. Adjustments should be based on PK, pre-dose FVIII trough 
level from previous visit, any change in body weight, and assessment of any spontaneous bleeds. Before any dose adjustments are performed an 
additional visit should be scheduled within 14 days after receipt of FVIII activity results. Details of dose adjustments will be provided in a separate 
document.
p
PROs include: Haemo-SYM Questionnaire, EQ-5D questionnaire, Short-Form 36 (SF-36), Physical Activity, and Health Resource Use; PROs can be 
done either at screening visit or baseline visit. Should always be completed before any study visit specific procedure.
q
EQ-5D, Patient Activity Level and Health Resource Use will be determined at each study visit.

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21.4 Clinical Laboratory Assessments
Procedures/
Assessmentsa
Screening Visit
PK 
Assessmentb
Baseline Visit
Study Visitsc
Completion/
Termination
Visitd 12 Mo
(53±1Wk)
Pre Infusion, 15-
30 Min, 
3±0.5 h, 8±0.5 h, 
24±2 h, 48±4 h,
72±4 h 
& 96±4 h 
Post-Infusion
Visit 
4Wk 
±5d
Visit 
8Wk 
±1Wk
Visit 
3 Mo 
± 2Wk
Visit 
4.5 Mo 
±2Wk
Visit 
6 Mo 
±1Wk
(26±1 
Wk)
Visit 
7.5 Mo 
±2Wkq
Visit 
9 Mo 
±2Wk
+PK
Visit 
10.5 Mo 
±2Wkq
Washout for FVIII 
and immunogenicity 
testing
None
72-96 h
Low trough arm: 96 h (after the longer treatment interval of 4 days), 72 hours (after the short treatment 
interval of 3 days) or 84 hours (3.5 day intervals); High trough arm: at least 48 h, or when the subject 
reaches his/her baseline value.
CD4 counte
X
Genetics and 
HLA-genotypef
X
Viral serologyg
X
Blood typeh
X
Pregnancy Test 
(if applicable)i
X
FVIII and 
VWF:Ag assaysj
X
X
Xk
X
X
Xk
X
Xk
(Xk)
Xk
(Xk)
Xk
Immunogenicityl
X
X
X
X
X
X
X
(X)
X
(X)
X
Hematologym
X
X
X
X
(X)
X
(X)
X
Clinical chemistry 
and lipid paneln
X
X
X
X
X
X
TGAo
X
X
X
X
X
X
X
X
(X)
X
(X)
X

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Procedures/
Assessmentsa
Screening Visit
PK 
Assessmentb
Baseline Visit
Study Visitsc
Completion/
Termination
Visitd 12 Mo
(53±1Wk)
Pre Infusion, 15-
30 Min, 
3±0.5 h, 8±0.5 h, 
24±2 h, 48±4 h,
72±4 h 
& 96±4 h 
Post-Infusion
Visit 
4Wk 
±5d
Visit 
8Wk 
±1Wk
Visit 
3 Mo 
± 2Wk
Visit 
4.5 Mo 
±2Wk
Visit 
6 Mo 
±1Wk
(26±1 
Wk)
Visit 
7.5 Mo 
±2Wkq
Visit 
9 Mo 
±2Wk
+PK
Visit 
10.5 Mo 
±2Wkq
Washout for FVIII 
and immunogenicity 
testing
None
72-96 h
Low trough arm: 96 h (after the longer treatment interval of 4 days), 72 hours (after the short treatment 
interval of 3 days) or 84 hours (3.5 day intervals); High trough arm: at least 48 h, or when the subject 
reaches his/her baseline value.
Additional blood draw 
for further exploratory 
testingp
X
X
X
X
X
a
At all assessments subjects must not be actively bleeding. In addition to the assessments shown, clinical laboratory tests should be performed whenever 
clinically indicated.
b
Subjects transitioning from another BAX 855 study may have to repeat the initial PK assessment if evaluated to be necessary by the sponsor. The wash-
out period prior to the PK determination is 72 - 96 hours, depending on the FVIII concentrate. PK will also be assessed at the 9-month visit (steady state 
PK) with the same post-infusion sampling timepoints. 
c
If a subject has a bleeding episode since the last visit before the 7.5 month ± 2 week or 10.5 month ± 2 week visits, instead of a phone visit the subject 
must attend a site visit to assess FVIII trough levels and IR and re-evaluate the PK-guided regimen. In these cases, the subject will undergo all 
assessments as listed for the 3 and 6 month ± 2 week visits.
d
Including subjects who withdraw or discontinue. When planning the Completion/Termination Visit it must be ensured that the second 6-month study 
period will consist of a minimum of 26 weeks and that the subject will have received his PK-tailored dosing regimen for at least 52 weeks.
e
CD4 count is analyzed in HIV positive subjects only to determine eligibility.
f
If results of FVIII gene mutation analysis and HLA genotype are already available at the study site, they will be provided to the sponsor and an 
additional analysis will not be required.
g
Viral serology includes: HIV-1, HIV-2, HBcAb, HBsAb, HBsAg, HCVAb. Any HCV positive sample will be tested by PCR for viral titer.
h
If historical data on blood group type is available, this may be recorded in the CRF and blood type does not need to be determined. 
i
Pregnancy test as appropriate (serum pregnancy test in females of child-bearing potential if no urine sample is available). The pregnancy test might be 
repeated during the study in countries where mandated by national law.
Continued on Next Page

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Continued
j
Factor VIII assays include: 1-stage clotting FVIII activity, FVIII chromogenic activity, and FVIII antigen. For assessment of trough levels, a blood 
sample will be taken within 30 minutes before the IP infusion. VWF antigen level will only be determined pre-infusion at each study visit.
k
For assessment of FVIII IR, in addition to the pre-infusion sample a second sample will be taken 15-30 minutes after IP infusion. 
l
Immunogenicity assessments include: inhibitory antibodies to FVIII, binding antibodies to FVIII, BAX 855 and PEG, and anti-CHO antibodies. Both 
IgG and IgM binding antibodies will be measured. Blood draws have to be performed within 30 min before the IP infusion.
m
Hematology assessments include: hemoglobin, hematocrit, red blood cell count, and white blood cell count with differential (ie, basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and platelet count. 
Samples should be taken within 30 minutes before the start of IP infusion.
n
Clinical chemistry assessments include: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, and glucose. Lipid panel includes cholesterol, very 
low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides. Samples should be taken within 30 
minutes before the start of IP infusion.
o
TGA parameters are lag time, time to peak thrombin generation, peak thrombin generation, and endogenous thrombin potential [ETP] Samples will be 
taken together with blood samples for FVIII activity and antigen determination.
p
Blood draws for additional exploratory testing will be drawn pre-infusion and early in the morning if feasible, otherwise at the same time point at each 
study visit.
q
Only applicable for subjects who experience bleeding episodes since the previous study visit who have to perform a study site visit. 

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22. PERIOPERATIVE MANAGEMENT
22.1 Types of Interventions
22.1.1 Major Surgeries
Major surgeries involve surgeries which require moderate or deep sedation, general 
anesthesia, or major conduction blockade for patient comfort. It generally refers to major 
orthopedic (eg, joint replacement), major abdominal, intracranial, cardiovascular, spinal 
and any other surgery which has a significant risk of large volume blood loss or blood 
loss into a confined anatomical space. Extractions of several teeth or extraction of the 
third molar are generally considered as major. In children it may include adeno-
tonsillectomy. Examples include:

bone fixation for fractures

hip and knee replacements (arthroplasties)

arthrodeses (joint fusions)

open synovectomies

osteotomies

liver biopsy

pseudotumor removal, hepatectomy, colectomy, tumor removal, 

hardware removal (plates, intramedullary nails),etc.
Major surgeries/interventions are expected to require clinical surveillance or hospital 
treatment >3 days after the surgery/intervention.
22.1.2 Minor Surgeries
Minor surgeries comprise surgeries which can be safely and comfortably performed on a 
patient who has received local or topical anesthesia, without more than minimal 
preoperative medication or minimal intraoperative sedation. The likelihood of 
complications requiring hospitalization or prolonged hospitalization is remote. It refers to 
interventions such as:

removal of skin lesions

arthroscopy and arthroscopic procedures, like synovectomies

minor dental procedures or dental extractions (except extraction of several teeth 
or third molar extraction)

placement and/or removal of central venous catheters

synoviorthesis and arthrocentesis

nerve release

removal of osteophytes and small cysts

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Minor surgeries/interventions are expected to require clinical surveillance or hospital 
treatment ≤ 3 days after the surgery/intervention.
22.2 Dosing Schedule and Requirements for Major Surgery
A detailed list of procedures is shown in Table 8, and a summary schedule of assessments 
and laboratory sampling in Table 9.
22.3 FVIII Substitution Plan
Based on the category (minor or major) and type of surgery, the investigator must outline 
the expected FVIII substitution plan with target peak and trough levels covering the 
surgical, dental or invasive procedure until expected wound healing. The FVIII levels 
measured intra/postoperatively will be compared with the FVIII substitution plan. Slight 
deviations from the predefined substitution plan are allowed based on investigators 
clinical judgment and available laboratory FVIII data.
Figure 3 is a visualization of timing and target FVIII levels for major surgery.

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Figure 3
Dosing Recommendations for Major Surgeries
22.3.1 General
The dose and frequency of BAX 855 administered will be individualized based on the
subject’s IR and half-life, if available, and the required FVIII target levels.
The required units will be calculated according to the following formula:
Required units (IU) =
body weight (kg) x desired FVIII rise (IU/dL) x {reciprocal of IR} (IU/kg)/(IU/dL)
Example: In case of an IR of 2.0 [IU/dL]/[IU/kg], the required units would be calculated
using the following formula:
body weight (kg) x desired FVIII rise (IU/dL) x 0.5 (IU/kg)/(IU/dL)

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If at any time during the perioperative period, a subject does not respond to BAX 855 
therapy as anticipated either by the operating surgeon or hemophilia physician providing 
postoperative care, blood samples will be drawn for the determination of FVIII activity 
levels and inhibitory antibodies to FVIII. In the event of unexplained, excessive bleeding, 
the subject will be treated by whatever means necessary until adequate hemostasis is
achieved. The use of adjunct antifibrinolytic therapy such as e.g. tranexamic acid is 
allowed if clinically indicated by the investigator and/or according to the standard of care 
of the subject's institution.
22.3.2 Preoperative and Loading Dose
The subject will receive a loading dose calculated according to the formula described
above in order to maintain a minimum target FVIII level as required by the category and
type of surgery. The recommended loading dose will be calculated by the investigator.
The initial loading dose will be administered within 60 minutes prior to surgery (prior to
incision/intubation). Vials of varying potencies may be used to ensure adequate dosing. A
blood sample for post infusion FVIII at 15 ± 5 minutes after completion of the initial
loading dose will be drawn to ensure that the required FVIII levels have been obtained. 
Also, a pre-infusion blood sample may be drawn within 30 minutes prior to the loading 
dose. Activated partial thromboplastin time (aPTT) will also be determined from the post 
infusion blood sample. 
In case of major surgery, FVIII target levels should be 80-100% of normal, in case of
minor surgery FVIII levels should be at 30-60%.
If the FVIII activity results are not available within a reasonable time period prior to the
start of surgery, at least the post-infusion value of the aPTT must be obtained. The FVIII
activity level following the loading dose must be obtained within 4 hours of infusion of
BAX 855 and dose adjustments must be performed as needed.
The surgery may only start after normalization of the aPTT.
If the aPTT is not normalized or the desired FVIII activity is not attained, a supplemental
loading dose(s) of BAX 855 can be given at the discretion of the investigator.
Subsequent infusions of BAX 855 should be preceded by measurement of residual FVIII 
levels and dose adjustments must be based on the most recent residual FVIII activity 
levels.

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22.4 Postoperative Dosing
Major surgery
After the initial loading dose, an optional re-bolus sufficient to raise FVIII levels to the
appropriate level as defined for the type of surgery may be administered after a blood
sample for FVIII determination has been drawn and the required FVIII levels by the local
laboratory have been determined.
Note:
A second FVIII activity level should be determined within preferably 6-8 h following 
major surgery and within 12 h at the latest, with dose adjustments as necessary on the day 
of surgery.
ALL subsequent infusions of BAX 855 should be preceded by measurement of residual 
FVIII levels and the dose adjusted as needed. Dosing adjustments based on aPTT values 
are not allowed.
Based on each individual PK parameter, ie, IR and half-life, if available, it is 
recommended that the following FVIII trough levels should be targeted for major 
surgery:

The first postoperative 72 hours (Day 1- Day 3): ≥80%

Postoperative Day 4 – Day 7: ≥ 50% (if not yet discharged)

Postoperative Day 8 to discharge (if not yet discharged) including intensified 
treatment for rehabilitation, if applicable: it is recommended that the FVIII levels 
should not fall below 30% (left to the discretion of the investigator depending on 
the postoperative course)
General postoperative treatment recommendations:

Treatment intervals should be tailored in order not to exceed supraphysiological
peak FVIII levels of 180%. Therefore, the dose should be administered in 1-3
infusions over 24 hours, most commonly in 2 infusions.

The dose may be increased to a maximum of 100 IU/kg, however, the peak level
should not exceed 180%.
Any modifications of the FVIII replacement recommendations and the substitution plan 
that are deemed necessary during the postoperative period will be at the discretion of the 
investigator and will be documented on the eCRFs.

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Beginning postoperative Day 1 (ie, the day following the day of surgery) through
discharge, subjects will have a BAX 855 pre-infusion (within 30 minutes) and after 
15±5 minutes a post-infusion FVIII level measurement at least once per day in order to 
assess the adequacy of factor replacement therapy during the postoperative period. For
consistency, it is recommended that the daily blood draws are performed at the same time
of the day, eg, morning blood draws. At a minimum, a blood sample for FVIII
determination must be drawn prior to any supplemental unscheduled FVIII infusion. In 
order to ensure the timely availability of the results, FVIII levels will be determined at the 
local laboratory. A back-up sample should be drawn for FVIII measurement at the central 
laboratory.
Minor surgeries
Subjects undergoing minor surgery can be re-dosed postoperatively with BAX 855 at 
8-24 hour intervals. Trough levels of FVIII should be kept at 30- 60% of normal for the 
first 24 hours or longer as deemed necessary by the investigator. At least 1 postoperative 
dose should be given calculated based on the individual IR value determined prior to 
surgery. If the individual IR could not be not determined before surgery, the average IR 
value of 2.0 IU/dL: IU/kg for BAX 855 should be used.The investigator must outline the 
expected FVIII substitution plan with target peak and trough levels during and following 
the surgical procedure until expected wound healing. The FVIII levels measured 
intra/postoperatively will be compared with the FVIII substitution plan. Slight deviations 
from the predefined substitution plan are allowed based on investigators´ clinical 
judgment and available laboratory FVIII data.
In case the subject is hospitalized for more than 24 hours, daily pre- and post-infusion 
FVIII level determinations as described for major surgery have to be performed and the 
dose adjusted according to the residual FVIII levels. As with major surgeries, the target 
FVIII levels should preferably not exceed 180%, otherwise the frequency should be 
increased.
22.5 Efficacy assessment
22.5.1 Intra-, Post-, and Perioperative Hemostatic Efficacy
The hemostatic efficacy will be assessed at the end of surgery (Table 5), at postoperative 
day 1 (Table 6), and overall as a perioperative assessment (Table 7).

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Table 5
Intraoperative Efficacy Assessment Scale
Prior to the discharge from the recovery room, the operating surgeon will assess the 
intraoperative hemostatic efficacy compared to that expected for the type of procedure 
performed in a non-hemophilic population
Rating
Criteria
Excellent
Intraoperative blood loss was less than or equal to that expected (≤100%)
Good
Intraoperative blood loss was up to 50% more than expected (101-150%)
Fair
Intraoperative blood loss was more than 50% of that expected (>150%)
None
Uncontrolled hemorrhage that was the result of inadequate therapeutic response 
despite proper dosing, necessitating rescue therapy 
Table 6
Postoperative Efficacy Assessment Scale (Postoperative Day 1)
On postoperative Day 1, the operating surgeon will assess the postoperative hemostatic 
efficacy compared to that expected for the type of procedure performed in a non-hemophilic 
population
Rating
Criteria
Excellent
Postoperative blood loss was less than or equal to (≤100%) that expected
Good
Postoperative blood loss was up to 50% more (101-150%) than expected
Fair
Postoperative blood loss was more than 50% (>150%) of that expected
None
Significant postoperative bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating rescue therapy 

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Table 7
Perioperative Efficacy Assessment Scale (at discharge or 14 days post-surgery, 
whichever is first)
At discharge or 14 days post-surgery, whichever is first, a hematologist will assess the 
perioperative efficacy compared to that expected for the type of procedure performed in a non-
hemophilic population
Rating
Criteria
Excellent
Perioperative blood loss was less than or equal to (≤100%) that expected 
Required blood components for transfusions were less than or similar to that expected
Good
Perioperative blood loss was up to 50% more (101-150%) than expected
Required blood components for transfusions were less than or similar to that expected
Fair
Perioperative blood loss was more than 50% of that expected (>150%)
Required blood components transfusions were greater than that expected
None
Significant perioperative bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating rescue therapy 
Required blood components for transfusions were substantially greater than expected 
22.5.2 Intra- and Postoperative Blood Loss
The observed versus predicted operative blood loss will be described for the period from 
initiation of the intervention to discharge or 14 days after the intervention, whichever is 
first.
Prior to the surgery, the surgeon/investigator will predict the estimated volume (mL) of 
the expected average and maximum blood loss for the planned surgical intervention in a 
hemostatically normal individual of the same sex, age, and stature as the study subject, 
for intraoperative, postoperative and overall perioperative time periods. Every effort 
should be made to predict the volume as precisely as possible, also taking into account, 
for example, the use of a tourniquet or placement of a postoperative drain and whether or 
not suction is used. The estimate will be for the intraoperative time period, the 
postoperative time period from completion of the procedure until approximately 24 hours 
post-surgery and for the overall perioperative time period (assessed at discharge or 
14 days after the intervention, whichever is first).
The intraoperative blood loss will be measured by determining the volume of blood and 
fluid removal through suction into the collection container (waste box and/or cell saver) 
and the estimated blood loss into swabs and towels during the procedure, per the 
anesthesiologist’s record. Postoperatively, blood loss will be determined by the drainage 
volume collected, which will mainly consist of drainage fluid via vacuum or gravity 
drain, as applicable. In cases where no drain is present, blood loss will be determined by 
the surgeon’s clinical judgment, as applicable or entered as “not available”.

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Table 8
Flow Diagram of Surgical Procedures For Baxalta Clinical Study 261303
1.Prior to surgery
The following procedures should be performed before surgery and must be available at the latest by 2 hours 
before the start of surgery:

Accurate prediction of volume of expected blood loss intraoperatively, postoperatively (from 
completion of the procedure until approximately 24 hours post-surgery) and for the overall 
perioperative time period (start of surgical procedure up to discharge)

Outline the expected FVIII substitution plan with target peak and trough levels.
1.1 Loading Dose and Post Infusion Laboratory Assessment
Subjects will undergo the following procedures:
Prior to initial BAX 855 loading dose:

Record AEs, concomitant medication and non-drug therapy use

Physical examination, vital signs (pulse, respiratory rate, blood pressure and temperature) and 
weight

Laboratory Assessments including:
o
Hematology (without differential but including platelets)
o
Clinical Chemistry  
o
Within 30 minutes before loading dose, optional blood draw for:

FVIII activity and aPTT
Give loading dose within the 60 minutes prior to surgery:

Loading dose of BAX 855 to raise the plasma level of FVIII to 80–100 % of normal for major and 
to 30-60 % for minor surgical, dental and invasive procedures. Administer within 60 minutes prior 
to surgery (prior to incision/intubation). 
15±5 minutes after infusion of loading dose:

Laboratory assessment of FVIII activity and aPTT

Vital signs (pulse, respiratory rate, blood pressure and temperature) will be recorded 15±5 minutes 
after infusion
If aPTT not normalized or desired FVIII level not obtained, rebolus of BAX 855 as necessary. 
If FVIII activity results are not available within a reasonable time period prior to the start of surgery, 
at least the post-infusion value of aPPT must be obtained. The FVIII activity level must be obtained 
within 4 hours after infusion of BAX 855 and dose adjustments must be performed as needed. 
The surgery can begin only if aPTT has normalized.

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Table 8
Flow Diagram of Surgical Procedures For Baxalta Clinical Study 261303
2. Intraoperative Procedures
During the surgical procedure:

Record AEs and concomitant medication and non-drug therapy use

Record blood product usage, including salvaged blood, packed red blood cells (pRBC), platelets, 
and other blood products. 

Administer additional BAX 855 infusions according to the FVIII substitution plan 

Record intraoperative blood loss and transfusion requirements
If the subject has excessive or unexplained bleeding, blood draws for:

FVIII activity

FVIII inhibitory and binding antibodies
Treat by whatever means necessary until adequate hemostasis is achieved. If other FVIII concentrates 
become necessary, the subject will subsequently be withdrawn from the study.
After the surgical procedure:

Record the volume of blood loss during surgery and total blood product usage, including salvaged 
blood, packed red blood cells (pRBCs), platelets, and other blood products

Assess intraoperative hemostatic efficacy at the end of surgery (Table 5)

If the subject is undergoing major surgery take sample for FVIII activity within preferably 6-8 h 
following surgery and within 12 hours at the latest, with dose adjustments as necessary on the day of 
surgery.

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Table 8
Flow Diagram of Surgical Procedures For Baxalta Clinical Study 261303
3. Postoperative Procedures

For subjects undergoing major surgery: keep pre-infusion FVIII levels at least at 80% of normal 
for the first postoperative 72 hours and at least at 50% during postoperative Day 4- Day 7. From 
Day 8 until discharge the FVIII levels should not fall below 30% or according to the substitution 
plan.

Subjects undergoing minor surgery can be re-dosed postoperatively with BAX 855 at 8-24 hour 
intervals. Keep trough levels of FVIII at 30 – 60 % for the first 24 hours (or longer as deemed 
necessary). Give at least 1 postoperative dose or according to the substitution plan.
From Postoperative Day 1 (ie, the day following the day of the surgical/invasive procedure), and 
daily until discharge the following assessments will be performed:

Record AEs and concomitant medication and non-drug therapy use

Record blood loss on a daily basis and at drain removal, if applicable

Record transfusion requirements

Hemostatic Efficacy Assessment:

Table 6: assessment of postoperative hemostatic efficacy of  BAX 855 performed  at Day 1 by 
the operating surgeon/investigator

Table 7: assessment of perioperative hemostatic efficacy of BAX 855 at day of discharge or 
Day 14, whichever occurs first, performed by the investigator
If a subject leaves the facility on the day of the surgery/invasive procedure, he/she is required to 
have a site visit the next day to perform the assessments of postoperative and perioperative 
hemostatic efficacy.

Perform physical examination and vital signs (pulse, respiratory rate, blood pressure and 
temperature) on Day 1, 2, 3 and 7 post surgery (if a subject remains admitted) 

Blood draws for FVIII activity determination and hematology should be performed coincident with 
an early morning dose to the greatest extent possible.

FVIII activity assays at the local and the central laboratories (back-up sample) on each day of 
planned IP administration at least once per day pre infusion (within 30 minutes) and post infusion 
(15±5 minutes), and prior to any unscheduled BAX 855 infusion 

1-stage clotting and chromogenic for the central laboratory

1-stage clotting or chromogenic (whichever is available) for local laboratories

Samples for central laboratory testing will be taken daily during Day 1 to 7 post-surgery and later 
then once weekly:

Hematology

FVIII activity

Clinical chemistry to be taken at Day 1 and then weekly

If the subject has excessive or unexplained bleeding, blood draws for:
o
FVIII activity
o
FVIII inhibitory and binding antibodies 

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Table 9.
Schedule of Study Procedures and Assessments for Surgery
Preoperative 
Intraoperative 
Postoperative: Daily 
Procedure/ Assessment
~2 h Prior to Surgery
In OR
Medications and non-
drug therapies
x
x
x
Physical examination
x
x
Days 1, 2, 3 and 7, then 
weekly
Adverse events
x
x
x
Vital signs
xe
xa
(as required)
xa
Days 1, 2, 3 and 7
FVIII substitution plan
x
IP treatment
x
loading dose
x
(as required)
x
(as required) Give at 
least 1 postop dose
Hemostatic efficacy 
assessments
Table 5
Table 6 at Day 1
Table 7 at 14 days or on 
discharge x b
Blood loss
X
predicted
x
x
Transfusion 
requirements
x
x
Laboratory Assessments
FVIII activity (clotting 
and chromogenic assay 
at central lab; 
either clotting or
chromogenic assay at 
local lab)
L and C 
within 30 min before 
loading dose, 
then 
15±5 min after loading 
dose
Optional sampling, 
as deemed necessary: L 
C
Also, if subject has 
excessive or unexplained 
bleeding
L and Cc
aPTT
L and Cd
Same timepoints as for 
FVIII activity
Immunogenicity
C (L)e
C (L)e
Key: C = central laboratory; L = local laboratory;
a
Within 30 min pre, 15 ±5 min post-dose
b
Whichever is first.
c
If underwent major surgery take sample within preferably 6-8 h following surgery and within 12 h at 
the latest. Sample on each day of planned IP administration at least once per day pre infusion (within 
30 minutes) and post infusion (15±5 minutes), and prior to any unscheduled BAX 855 infusion. Also if 
subject has excessive or unexplained bleeding.
d
Surgery may only start if aPTT has normalized.
e
Only if subject has excessive or unexplained bleeding: FVIII inhibitory and binding Ab.

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23. DEFINITIONS
23.1 Joint Bleeds
Features of an acute joint bleed include some or all of the following: ‘aura’, pain, 
swelling, warmth of the skin over the joint, decreased range of motion and difficulty in 
using the limb compared with baseline or loss of function.
The earliest clinical signs of a joint bleed are increased warmth over the area and 
discomfort with movement, particularly at the ends of range. 
Later symptoms and signs include pain at rest, swelling, tenderness, and extreme loss of 
motion. 
In patients with advanced arthropathy it may be difficult to distinguish pain-related 
arthritis from that associated with an acute bleed. Rapid resolution of pain following 
infusion of factor concentrates (typical of an acute hemarthrosis) or improvement of pain 
associated with activity soon after a period of rest (typical of chronic arthritis) can help 
distinguish between the two. 
In infants and young children, reluctance to use the limb alone may be indicative of a 
joint/muscle bleed.
23.2 Muscle Bleeds
Muscle bleeds can occur in any muscle of the body, usually from a direct blow or a 
sudden stretch. A muscle bleed is defined as an episode of bleeding into a muscle, 
determined clinically and/or by imaging studies, generally associated with pain and/or
swelling and functional impairment over baseline. 
For further definitions of CNS, GI and abdominal hemorrhages see the Guidelines for the 
management of hemophilia from the world federation of hemophilia.31;32

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24. REFERENCES
1. Björkman S, Berntorp E. Pharmacokinetics of coagulation factors: clinical 
relevance for patients with haemophilia. Clin.Pharmacokinet. 2001;40:815-832.
2. Björkman S, Folkesson A, Jönsson S. Pharmacokinetics and dose requirements of 
factor VIII over the age range 3-74 years : A population analysis based on 50 
patients with long-term prophylactic treatment for haemophilia A. 
Eur.J.Clin.Pharmacol. 2009;65:989-998.
3. Valentino, L. A., Mamonov, V., Hellmann, A., Quon, D., Desmond, J. C., Schroth, 
P., and Wong, W. Y. Prophylaxis in haemophilia A: A multicenter, open-label, 
randomized, phase 4 clinical study of ADVATE.  2011. 
4. White GC, II, Rosendaal F, Aledort LM et al. Definitions in hemophilia. 
Recommendation of the scientific subcommittee on factor VIII and factor IX of the 
scientific and standardization committee of the International Society on Thrombosis 
and Haemostasis. Thromb.Haemost. 2001;85:560-575.
5. Boggio LN, Kessler CM. Hemophilia A and B. In: Kitchens C, Alving B, Kessler 
C, eds. Consultative Hemostasis and Thrombosis. Philadelphia: Saunders Elsevier; 
2007:43, 45-59.
6. Committee for Medicinal Products for Human Use. Guideline on the clinical 
investigation of recombinant and human plasma-derived factor VIII products. 
EMA/CHMP/BPWP/144533/2009. 7-21-2011.  European Medicines Agency 
(EMA). 
Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
1/08/WC500109692.pdf

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7. Acharya SS: Exploration of the pathogenesis of haemophilic joint arthropathy: 
understanding implications for optimal clinical management. Br.J.Haematol. In 
press.
8. Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic 
arthropathy. J.Thromb.Haemost. 2010;8:1895-1902.
9. Blanchette VS, Manco-Johnson M, Santagostino E, Ljungs R. Optimizing factor 
prophylaxis for the haemophilia population: where do we stand? Haemophilia. 
2004;10 Suppl 4:97-104.
10. Manco-Johnson M. Comparing prophylaxis with episodic treatment in haemophilia 
A: implications for clinical practice. Haemophilia. 2007;13 Suppl 2:4-9.
11. Gringeri A, Bianchi B. Evaluation study on prophylaxis: A randomised italian trial 
(ESPRIT). One-Year Report [abstract]. Haemophilia. 1998;4:171.
12. Gringeri A. Evaluation study on prophylaxis: a randomised Italian trial (Esprit). 
two-years report [abstract]. 1999;
13. Fischer K. Can we consider discontinuing primary prophylaxis in adults with severe 
haemophilia? Haemophilia. 2008;14 Suppl 4:10.
14. Fischer K, van der Bom JG, Mauser-Bunschoten EP et al. Changes in treatment 
strategies for severe haemophilia over the last 3 decades: effects on clotting factor 
consumption and arthropathy. Haemophilia. 2001;7:446-452.
15. Fischer K, van der Bom JG, Negrier C, Grobbee DE, van den Berg M. Comparing 
Prophylaxis to on Demand Treatment for Severe Hemophilia: Better Outcome at
Equal Costs [abstract]. Blood. 2001;98 Suppl 1:533a.
16. Fischer K, Astermark J, van der Bom JG et al. Comparison of the two prophylactic 
regimens for severe hemophilia: Intermediate dose versus high dose [abstract]. 
Blood. 2001;98 Suppl 1:532a.

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17. Manco-Johnson M, Abshire T, Brown D et al. Initial results of a randomized, 
prospective trial of prophylaxis to prevent joint disease in young children with 
factor VIII (FVIII) deficiency [abstract]. Blood. 2005;106:6a.
18. Gringeri A, Lundin B, von Mackensen S et al. A randomized clinical trial of 
prophylaxis in children with hemophilia A (the ESPRIT Study). 
J.Thromb.Haemost. 2011;9:700-710.
19. National Hemophilia Foundation. Recommendation concerning prophylaxis 
(Prophylactic administration of clotting factor concentrate to prevent bleeding). 
MASAC 117. 5-19-2001.  National Hemophilia Foundation (NSF). 
20. National Hemophilia Foundation. Recommendation Concerning Prophylaxis 
(Regular Administration of Clotting Factor Concentrate to Prevent Bleeding). 
MASAC 170. 4-22-2006.  National Hemophilia Foundation (NHF). 
21. National Hemophilia Foundation. Recommendation concerning prophylaxis 
(Regular administration of clotting factor concentrate to prevent bleeding). MASAC 
179. 4-11-2007.  National Hemophilia Foundation (NHF). 
Link to Publisher´s Site: 
https://www.hemophilia.org/sites/default/files/document/files/masac179.pdf
22. Ahnström J, Berntorp E, Lindvall K, Björkman S. A 6-year follow-up of dosing, 
coagulation factor levels and bleedings in relation to joint status in the prophylactic 
treatment of haemophilia. Haemophilia. 2004;10:689-697.
23. den Uijl IEM, Mauser Bunchoten EP, Roosendaal G et al. Clinical severity of 
haemophilia A: does the classification of the 1950s still stand? Haemophilia. 
2011;17:849-853.
24. Funk M, Schmidt H, Escuriola-Ettingshausen C et al. Radiological and orthopedic 
score in pediatric hemophilic patients with early and late prophylaxis. 
Ann.Hematol. 1998;77:171-174.

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25. Funk MB, Schmidt H, Becker S et al. Modified magnetic resonance imaging score 
compared with orthopaedic and radiological scores for the evaluation of 
haemophilic arthropathy. Haemophilia. 2002;8:98-103.
26. Lundin B, Ljung R, Pettersson H, The European Paediatric Network for 
Haemophilia Management (PEDNET). MRI scores of ankle joints in children with 
haemophilia - comparison with clinical data. Haemophilia. 2005;11:116-122.
27. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic 
outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome 
Study Group. J.Intern.Med. 1994;236:391-399.
28. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years' experience of 
prophylactic treatment in severe haemophilia A and B. J.Intern.Med. 1992;232:25-
32.
29. van Dijk K, Fischer K, van der Bom JG, Grobbee DE, van den Berg HM. 
Variability in clinical phenotype of severe haemophilia: the role of the first joint 
bleed. Haemophilia. 2005;11:438-443.
30. Feldman BM, Funk SM, Bergstrom BM et al. Validation of a new pediatric joint 
scoring system from the international hemophilia prophylaxis study group: Validity 
of the hemophilia joint health score (HJHS). Arthritis Care Res. 2011;63:223-230.
31. Blanchette VS, Key NS, Ljung LR et al. Definitions in hemophilia: Communication 
from the SSC of the ISTH. J.Thromb.Haemost. 2014;12:1935-1939.
32. World Federation of Hemophilia Treatment Guidelines Working Group and 
Srivastava, A. Guidelines for the management of hemophilia 2nd Edition.  2005.  
World Federation of Hemophilia (WFH). 
Link to Publisher´s Site: http://www1.wfh.org/publication/files/pdf-1472.pdf

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25. SUMMARY OF CHANGES 
Protocol 261303: Amendment 3 2015 SEP 03
Replaces: Amendment 2 2015 MAY 12
In this section, changes from the previous version of Amendment 2, dated 
2015 MAY 12, are described and their rationale is given.
1.
Throughout the document
Description of Change: Minor grammatical and/or administrative changes have 
been made. 
Purpose for Change: To improve the readability and/or clarity of the protocol. 
2.
Sections: Synopsis, Planned Study Period
Description of Change: First Subject In (FSI), primary and study completion have 
been revised.
Purpose for Change: To account for a later FSI.
3.
Sections: Synopsis, 14 Statistics
Description of Change: The statistics sections have been substantially revised.
Purpose for Change: To comply with regulatory requests
4.
Sections: Synopsis, 
8.4.1 Primary Outcome Measure
Description of Change: The term for the primary outcome measure was changed 
from “total ABR” to “Presence or absence of any bleedings in the second 6-
month study period”.
Purpose for Change: To provide a more precise definition of the primary 
outcome.
5.
Sections: Synopsis, 
7.3.2 Secondory Objectives, Efficacy
Description of Change: SF-36 Physical activity level was replaced by SF-36 
Health Survey
Purpose for Change: To match name of the survey

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6.
Sections Synopsis, 
8.4.5 Outcome Measures, Patient Reported Outcome Measures
Description of Change: HrQoL including SF-36, EQ-5D, Haemo-SYM and 
healthcare resource utilization was added to pharmacoeconomic outcomes.
Purpose for change: To clarify that also HrQoL was captured in addition to 
pharmacoecnomics.
7.
Section: 8.5 Randomization and Blinding
Description of Change: The randomization schedule has been changed.
Purpose for Change: To consider also ABR. 
8.
Sections: Synopsis, 
8.4.2 Secondary Outcome Measures, 
10.5 Subject Diary and Patient Reported Outcomes,
11.1.1 Hemostatic Efficacy Rating for Treatment of Bleeding Episodes, 
14.4.2 Secondary Outcome Measures
Description of Change: The time point for the initial hemostatic efficacy rating 
for treatment of bleeding episodes was changed from 24±2 hours to 8±1 hours. 
Purpose for Change: Regulatory request.
9.
Section: 6.4.2 Findings from Clinical Studies
Description of Change: Data from the interim study report of the Baxalta
BAX855 surgery study 261204 were added. 
Purpose for Change: To provide additional information.
10. Section: 6.5 Evaluation of Anticipated Risks and Benefits of the 
Investigational Product to Human Subjects
Description of Change: Safety data from the interim study report of the Baxalta
BAX855 surgery study 261204 were added. 
Purpose for Change: To provide additional information.

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11. Sections: 8.2 Overall Study Design, 
21.1 Study Flow Charts, 
21.2 Detailed Flow Diagram of Study Procedures, 
21.3 Schedule of Study Procedures and Assessments, 
21.4 Clinical Laboratory Assessments
Description of Change: It was made clear that the second 6-month study period 
will consist of at least 26 weeks following the 6 month-study visit scheduled at 26 
(±1) weeks and that the subject will have received his PK-tailored dosing regimen 
for at least 52 weeks. The protocol was modified to schedule the end-of-study 
visit for week 53 plus or minus one (53 ± 1) week, so that patients should 
complete the second six full months of prophylaxis.
Purpose for Change: To ensure that Completion/Termination Visit is not before 
52 weeks and that the second 6 month study period is not shorter than 26 weeks. 
12. Sections: 8.7.6 BAX855 Dose and Frequency Adjustments
Description of Change: Detailed guidance for dose adjustments are provided. 
Purpose for Change: To provide additional dosing information
13. Sections: 8.7.1 Packaging, Labeling, and Storage
Description of Change: Additional potencies of 750 IU/vial, 1500 IU/vial and 
3000 IU/vial will be used once available.
Purpose for Change: To update information
14. Sections: 8.7.9 Immune Tolerance Induction for Inhibitor Development
Description of Change: The section was deleted.
Purpose for Change: ITI is not in the scope of this study and no IP will be 
provided.
15. Section: 22 Perioperative Management
Description of Change: Further guidance has been provided for surgical 
procedures being part of this study. 
Purpose for Change: To provide additional information

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Protocol 261303: Amendment 2 2015 MAY 12
Replaces: Amendment 1 2015 MAR 20
In this section, changes from the previous version of Amendment 1, dated 
2015 MAR 20, are described and their rationale is given.
1. Throughout the document.
Description of Change: The term PEG written in capital letters for example
“PEGylation” and “PEGylated” was changed to lower case letters “pegylation” and 
“pegylated”. Minor grammatical and/or administrative changes have been made. 
Purpose for Change: To be consistent with internal guidelines and to improve the 
readability and/or clarity of the protocol. 
2. Sections: Synopsis, 6.4.2 Finding from Clinical Studies, 7.3.4 Patient Reported 
Outcomes, 7.4 Exploratory Objectives, 8.4.2.3 Patient Reported Outcomes, 
8.4.3 Exploratory Outcome Measures, 14.4.2 Secondary Outcome Measures, 
14.4.3 Exploratory Outcome Measures
Description of Change: Details on Patient Reported Outcomes and their use for 
assessment of secondary outcome measures were added
Purpose for Change: To provide additional information
3. Sections: Synopsis, 7.3.1 Objectives - Efficacy, 8.4.2.1 Outcome Measures -
Efficacy, 8.7.3.5 Treatment for Surgery or Dental procedures, 9.2 Exclusion 
Criteria, 9.3 Withdrawal and  Discontinuation, 10.4 Medications and Non-
Drug Therapies, 11.1.5 Perioperative Efficacy Assessments, 14.4.1 Primary 
Outcome Measure, 14.4.2 Secondary Outcome Measures, 22 Perioperative 
Management
Description of Change:
A surgery arm was included in the study protocol. Details for perioperative 
management are provided in Section 22. The necessary revisions are made 
throughout the protocol.
Purpose for Change: Surgeries are now in the scope of this study to avoid potential 
drop-outs in case major surgeries are required and the surgery protocol (study 
protocol 261204) is not in place.

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4. Sections: Synopsis, 14.1.1 Sample Size Calculation, 14.3 Handling of Missing, 
Unused and Spurious Data, 14.3.2 Handling of other variables, 14.4.1 Primary 
Outcome Measure, 14.4.2 Secondary Outcome Measures, 14.5 Planned Interim 
Analysis of the Study. 
Description of Change:
Details in statistical analysis were added:
a) Specifications for the handling of missing data, including assumptions how 
missing data will be used for the analysis methods and a plan for sensitivity 
analyses to assess the impact of assumptions regarding the missing data mechanism 
of the analysis results.
b) Subgroup analyses with respect to age and race will be included 
c) The Chi-squared test with continuity correction is used which results in a lower 
but acceptable power of 80%.
d) The section for the planned interim analysis was deleted
e) Definition of the interruption period in case of surgery. Description how the 
secondary outcome measures related to surgical procedures will be analyzed. 
Purpose for Change:
a) and b) Upon regulatory request
c) To account for a more conservative approach considering continuity correction.
d) A planned interim analysis will not be performed. 
e) To account for the surgical procedures.
5. Section 8.5 Randomization and blinding
Description of change: The following sentence was added: Randomization occurs 
after the PK assessment and will be stratified according to subjects’ pre-study 
treatment regimen (prophylaxis vs. on-demand).
Purpose for change: To account for pretreatment regimen. 

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6. Sections: 12.1 Pharmacokinetics, 21.2 Detailed Flow Diagram of Study 
Procedures, 21.3 Schedule of Study Procedure and Assessments, 21.4 Clinical 
Laboratory Assessments
Description of Change:
The blood sampling time points for PK study were modified as follows: Post-
infusion at 15-30 minutes and at 3, 8, 24, 48, 72 and 96 hours.
Purpose for Change: Upon regulatory request.
7. Sections: 8.7.3.3 BAX 855 Dose and/or Frequency Adjustments 12.3 Trough 
Levels, 21.3 Schedule of Study Procedures and Assessments
Description of Change:
A repeat FVIII trough level measurement will be performed approximately 2 weeks 
after dose adjustment. 
Purpose for Change:
Upon regulatory request: to ensure that the adjusted dose is adequate. After 
approximately 2 weeks the subject will have reached steady state.
8. Section 8.7.3.4 Treatment of bleeding episodes
Description of change: The dose calculation for treatment of bleeding episodes was 
revised.
Purpose for change: Inadvertently, FIX was written instead of FVIII.