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 1: 2015 MAR 20
Replaces: ORIGINAL: 2015 JAN 13
ALL VERSIONS:
AMENDMENT 1: 2015 MAR 20
ORIGINAL: 2015 JAN 13
OTHER ID(s)
NCT Number: To be Determined
EudraCT Number: To be Determined
IND NUMBER: To be Determined
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 ECs. 
ALL SAEs ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT
See 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 13.2.2

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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: Q2 2015
Primary Completion
Q4 2017
Study Completion
Q2 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
The secondary objectives are 

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

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 

The pharmacoeconomic outcomes 

To determine the hemostatic efficacy of BAX 855 in the control of bleeding episodes
                                                
i i.e. not trauma related.

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
To determine the immunogenicity of BAX 855

To determine the safety of BAX 855

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

To assess the following Patient Reported Outcomes (PROs) over time for subjects receiving 
BAX 855: Bleeding and Pain Symptoms, Health-Related Quality of Life (HRQoL) and 
Physical Activity
Exploratory objectives:
2.
To determine the potential correlation between thrombin generation assay (TGA) parameters, 
FVIII trough levels and ABR
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
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. Total ABR
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 24 (± 2) 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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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.
Bleed and pain severity as measured using the Haemo-SYM questionnaire
2.
HRQoL as assessed using the EQ-5D and SF-36 questionnaires
3.
Physical activity level 
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 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
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.
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
                                                
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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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)
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. Participation in the 
assessment of activity using the accelerometer device is voluntary
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 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) or aspartate 
aminotransferase (AST) levels ≥5 times the upper limit of normal
7.
Subject is scheduled to receive an 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, with the 
exception of BAX 855 Surgery Study as described in this protocol

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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 Bethesda Units (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 alanine 
aminotransferase (ALT) and/ or aspartate aminotransferase (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, there are no reliable data available. However, an increase of 30%
in bleed free patients is considered clinically relevant.
If the above assumptions hold true 48 subjects per study group are needed to reject the null hypothesis of no 
difference between the study groups with 86% power. Significance level of the test is targeted at 5% two-
sided level. 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 in a ratio of 
1:1.

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Planned Statistical Analysis
The proportion of subjects with ABR = 0 in the two prophylaxis treatment regimens will be compared using 
a likelihood-ratio chi-square test (at a one-sided 5% level of significance). For all outcome measures, 
descriptive statistics will be presented for the two dosing regimens. Point estimates (mean or median) and 
95% CIs will be computed if feasible.
An interim analysis is planned for this study when 50% of the planned subjects have completed the first 6 
months of prophylactic treatment. Because only data from the first 6 months will be analyzed for the interim 
analysis, no adjustment for the primary endpoint will be needed.

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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 .................................................................................... 15
6. BACKGROUND INFORMATION .......................................................................... 18
6.1 Description of Investigational Product ............................................................... 18
6.2 Clinical Condition/Indication .............................................................................. 18
6.3 Population To Be Studied..................................................................................... 20
6.4 Findings from Nonclinical and Clinical Studies................................................. 20
6.4.1 Findings from Nonclinical Studies ............................................................... 20
6.4.2 Findings from Clinical Studies ..................................................................... 21
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product to 
Human Subjects .................................................................................................... 24
6.6 Authorized Representative (Signatory) / Responsible Party ............................ 26
6.7 Compliance Statement.......................................................................................... 26
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 26
7.1 Study Purpose ....................................................................................................... 26
7.2 Primary Objective................................................................................................. 26
7.3 Secondary Objectives ........................................................................................... 26
7.3.1 Efficacy ........................................................................................................... 26
7.3.2 Safety............................................................................................................... 27
7.3.3 Pharmacokinetics........................................................................................... 27
7.3.4 Patient Reported Outcomes.......................................................................... 27
7.4 Exploratory Objectives......................................................................................... 27
8. STUDY DESIGN......................................................................................................... 27
8.1 Brief Summary...................................................................................................... 27
8.2 Overall Study Design............................................................................................ 28
8.3 Duration of Study Period(s) and Subject Participation .................................... 29
8.4 Outcome Measures ............................................................................................... 29
8.4.1 Primary Outcome Measure .......................................................................... 29

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8.4.2 Secondary Outcome Measures ..................................................................... 29
8.4.2.1 Efficacy .................................................................................................... 29
8.4.2.2 Safety........................................................................................................ 29
8.4.2.3 Patient Reported Outcomes................................................................... 29
8.4.2.4 Pharmacokinetics.................................................................................... 30
8.4.3 Exploratory Outcome Measures .................................................................. 30
8.5 Randomization and Blinding............................................................................... 30
8.6 Study Stopping Rules............................................................................................ 30
8.7 Investigational Product(s).................................................................................... 30
8.7.1 Packaging, Labeling, and Storage................................................................ 30
8.7.2 Administration ............................................................................................... 31
8.7.3 Description of Treatment.............................................................................. 32
8.7.3.1 BAX 855 Dosing for PK Assessment..................................................... 32
8.7.3.2 BAX 855 Prophylaxis Dosing................................................................. 32
8.7.3.3 BAX 855 Dose and/or Frequency Adjustments ................................... 33
8.7.3.4 Treatment of Bleeding Episodes............................................................ 34
8.7.3.5 Treatment for Surgery or Dental Procedures...................................... 36
8.7.3.6 Immune Tolerance Induction for Inhibitor Development.................. 37
8.7.4 Investigational Product Accountability ....................................................... 37
8.8 Source Data ........................................................................................................... 37
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 38
9.1 Inclusion Criteria.................................................................................................. 38
9.1.1 Subjects Transitioning from Another BAX 855 Study .............................. 38
9.1.2 Inclusion Criteria for Newly Recruited Subjects........................................ 38
9.2 Exclusion Criteria................................................................................................. 39
9.2.1 Exclusion Criteria for Subjects Transitioning from Another BAX 855 
Study............................................................................................................... 39
9.2.2 Exclusion Criteria for Newly Recruited Subjects....................................... 40
9.3 Withdrawal and Discontinuation ........................................................................ 41
10. STUDY PROCEDURES .......................................................................................... 42
10.1 Informed Consent and Enrollment ................................................................... 42
10.2 Subject Identification Code................................................................................ 42
10.3 Screening and Study Visits................................................................................. 42
10.3.1 Subjects Transitioning from Other BAX 855 Studies.............................. 43
10.3.2 Newly Recruited Subjects ........................................................................... 43
10.4 Medications and Non-Drug Therapies.............................................................. 43
10.5 Subject Diary and Patient Reported Outcomes............................................... 44
10.5.1 Patient Reported Outcomes........................................................................ 45
10.6 Subject Completion/Discontinuation ................................................................ 46
10.7 Procedures for Monitoring Subject Compliance............................................. 47

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11. ASSESSMENT OF EFFICACY.............................................................................. 47
11.1 Bleeding Assessment........................................................................................... 47
11.1.1 Hemostatic Efficacy Rating for Treatment of Bleeding Episodes........... 48
11.1.2 Number of BAX 855 Infusions Needed for the Treatment of Bleeding 
Episodes.......................................................................................................... 49
11.1.3 Hemophilia Joint Health Score (HJHS) .................................................... 49
11.1.4 Weight-Adjusted Consumption of BAX 855 ............................................. 50
12. DETERMINATION OF FVIII AND VWF ANTIGEN, FVIII ACTIVITY AND 
TGA.............................................................................................................................. 50
12.1 PHARMACOKINETICS................................................................................... 50
12.2 Incremental Recovery (IR) ................................................................................ 52
12.3 Trough Levels...................................................................................................... 52
13. ASSESSMENT OF SAFETY INCLUDING IMMUNOGENICITY ................... 52
13.1 Immunogenicity .................................................................................................. 52
13.2 Adverse Events.................................................................................................... 53
13.2.1 Definitions..................................................................................................... 53
13.2.1.1 Serious Adverse Event.......................................................................... 54
13.2.1.2 Non-Serious Adverse Event ................................................................. 54
13.2.1.3 Unexpected Adverse Events................................................................. 54
13.2.1.4 Preexisting Diseases.............................................................................. 55
13.2.2 Assessment of Adverse Events.................................................................... 55
13.2.2.1 Severity .................................................................................................. 57
13.2.2.2 Causality................................................................................................ 57
13.3 Urgent Safety Measures ..................................................................................... 58
13.4 Untoward Medical Occurrences........................................................................ 59
13.5 Medical Device Safety reporting ....................................................................... 59
13.6 Non-Medical Complaints ................................................................................... 59
13.7 Medical, Medication, and Non-Drug Therapy History................................... 60
13.8 Physical Examinations........................................................................................ 60
13.9 Clinical Laboratory Parameters........................................................................ 61
13.9.1 Screening Laboratory Parameters............................................................. 61
13.9.1.1 Blood Type............................................................................................. 61
13.9.1.2 Genetics and HLA-Genotype............................................................... 61
13.9.1.3 Pregnancy Test...................................................................................... 61
13.9.2 CD4 Count.................................................................................................... 61
13.9.3 Viral Serology............................................................................................... 61
13.9.4 Hematology, Clinical Chemistry and Lipid Panel.................................... 62
13.9.5 FVIII Activity, FVIII Antigen, VWF Antigen .......................................... 62
13.9.6 Thrombin Generation Assay ...................................................................... 62
13.9.7 Assessment of Laboratory Values .............................................................. 62
13.9.7.1 Assessment of Abnormal Laboratory Values..................................... 62

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13.9.8 Biobanking.................................................................................................... 63
13.10 Vital Signs.......................................................................................................... 63
14. STATISTICS............................................................................................................. 64
14.1 Sample Size and Power Calculations ................................................................ 64
14.1.1 Sample Size Calculation.............................................................................. 64
14.2 Datasets and Analysis Cohorts .......................................................................... 64
14.2.1 Full Analysis Set........................................................................................... 64
14.2.2 Per Protocol Analysis Set............................................................................ 64
14.2.3 Safety Analysis Set....................................................................................... 64
14.3 Handling of Missing, Unused, and Spurious Data........................................... 64
14.4 Methods of Analysis............................................................................................ 65
14.4.1 Primary Outcome Measure......................................................................... 65
14.4.2 Secondary Outcome Measures ................................................................... 65
14.4.3 Exploratory Outcome Measures ................................................................ 67
14.5 Planned Interim Analysis of the Study ............................................................. 67
15. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 67
16. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 67
16.1 Investigator’s Responsibility.............................................................................. 67
16.1.1 Final Clinical Study Report........................................................................ 68
16.2 Training ............................................................................................................... 68
16.3 Monitoring........................................................................................................... 68
16.4 Auditing ............................................................................................................... 68
16.5 Non-Compliance with the Protocol ................................................................... 68
16.6 Laboratory and Reader Standardization ......................................................... 69
17. ETHICS ..................................................................................................................... 69
17.1 Subject Privacy ................................................................................................... 69
17.2 Ethics Committee and Regulatory Authorities................................................ 69
17.3 Informed Consent ............................................................................................... 69
17.4 Data Monitoring Committee.............................................................................. 70
18. DATA HANDLING AND RECORD KEEPING................................................... 70
18.1 Confidentiality Policy ......................................................................................... 70
18.2 Study Documentation and Case Report Forms ............................................... 70
18.3 Document and Data Retention........................................................................... 71
19. FINANCING AND INSURANCE........................................................................... 71

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20. PUBLICATION POLICY........................................................................................ 71
21. SUPPLEMENTS....................................................................................................... 72
21.1 Study Flow Charts .............................................................................................. 72
21.2 Detailed Flow Diagram of Study Procedures................................................... 74
21.3 Schedule of Study Procedures and Assessments.............................................. 86
21.4 Clinical Laboratory Assessments ...................................................................... 89
21.5 Definitions............................................................................................................ 92
21.5.1 Joint Bleeds................................................................................................... 92
21.5.2 Muscle Bleeds............................................................................................... 92
22. REFERENCES.......................................................................................................... 93
Tables
Table 1 BAX 855 Treatment Guidelines for Bleeding Episodes..................................... 35
Table 2 Efficacy Rating Scale for Treatment of Bleeding Episodes ............................... 48
Table 3 PK Time Points................................................................................................... 51
Table 4 IR Time Points.................................................................................................... 52
Figures
Figure 1 Study Design for Baxalta Clinical Study 261303.............................................. 72
Figure 2 Study Flow Chart............................................................................................... 73

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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
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
PPAS
per protocol analysis set

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Abbreviation
Definition
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.
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 

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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.9-12; 13-16; 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
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 scores24-26 whereas annual bleed rates between 
0.1 and 2.7 did not lead to joint damage.27-29

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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 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).
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 

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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. 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.

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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.
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. 

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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. 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.

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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.
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. 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 immunotolerant 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. 
Based on data from these two 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.

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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.
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
7.3.1 Efficacy
The secondary objectives are:
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 spontaneousv 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
                                                
v i.e. not trauma-related.
PPD
PPD

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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
The pharmacoeconomic outcomes
2. To determine the hemostatic efficacy of BAX 855 in the control of bleeding 
episodes
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 following Patient Reported Outcomes (PROs) over time for 
subjects receiving BAX 855: Bleeding and Pain Symptoms, Health-Related 
Quality of Life (HRQoL) and Physical Activity
7.4 Exploratory Objectives
1. To determine the potential correlation between thrombin generation assay (TGA) 
parameters, FVIII trough levels and ABR
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. 

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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) studyvi, 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 level 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 ± 
2 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 ± 2 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 
                                                
vi In case subject is at least 12 years of age at the time of informed consent of this study.

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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 total ABR. 
8.4.2 Secondary Outcome Measures
8.4.2.1 Efficacy
1. Total, spontaneous and traumatic ABR, and spontaneous AJBR
2. Total weight-adjusted consumption of BAX 855
3. Overall hemostatic efficacy rating at 24 ± 2 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
8.4.2.2 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
8.4.2.3 Patient Reported Outcomes
1. Bleed and pain severity as measured using the Haemo-SYM questionnaire
2. HRQoL as assessed using the EuroQol-5 dimension (EQ-5D) and SF-36 
questionnaires
3. Physical activity level

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8.4.2.4 Pharmacokinetics
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. 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 targeting FVIII trough levels of 1-
3% or approximately 10% (8-12%) in equal numbers. Randomization occurs after the PK 
assessment.
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 

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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. 
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 instructions, please refer to the 
BAX 855 IB and/or other specific instructions provided by the sponsor.
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).

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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. 
8.7.3.1 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 855vii:
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.
8.7.3.2 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. 
                                                
vii 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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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.
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.
8.7.3.3 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. 

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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 
performedviii. 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.
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. 
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. 
A detailed procedure for dose adjustment will be provided in a separate document. 
In subjects with severe hemophilic arthropathy and/or target jointsix who continue 
to experience recurrent bleeding episodes, an imaging technology such as MRI or
ultrasound of the affected joint(s) has be applied to verify the presence of a bleed.
Also, if at any time during the course of the study, a subject’s starts to experience an 
unexpected high bleeding rate or experience bleeding episodes that do not adequately 
respond to BAX855 therapy, he/she will be evaluated for the presence of inhibitory and 
total binding antibodies to FVIII, BAX855 and PEG, and clinically managed at the 
discretion of the investigator. It is also recommended to perform an incremental recovery.
8.7.3.4 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 
                                                
viii This additional visit may coincide with regular scheduled study visit.
ix 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. 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 Supplement 21.5.
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 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}

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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 BAX855 in 
the Phase 2/3 pivotal study, should be assumed and the required units calculated using the 
following formula:
body weight (kg) x desired FIX 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.
8.7.3.5 Treatment for Surgery or Dental Procedures
Subjects enrolled into this BAX 855 study (261303) who require planned surgery or 
dental procedures may be eligible to enroll in the surgery study (261204) if the study is 
open for enrollment. Subjects participating in the surgery study (261204) will continue to 
receive their study-specific treatment from this PK-guided dosing study (261303) from 
the surgery study’s screening visit until the pre-operative procedures in the surgery study.
During the period where subjects receive IP from this PK-guided dosing study (261303), 
the investigator from this study is responsible for the subject’s safety and treatment. Any 
data relevant for the maximum efficacy study analysis collected during the above listed 
time periods will be recorded as part of the PK-guided dosing study (261303).
During the period starting with the initial loading dose until the end of the predefined 
surgical substitution plan or once the subject can resume the prophylactic treatment 
regimen of this PK guided dosing study, subjects will be treated with BAX 855 from the 
surgery study (261204).
Upon completion of the surgery study, subjects will be transitioned back to the BAX 855
PK-guided dosing study (261303). 
Minor procedures and emergency interventions not requiring more than 2 prophylactic 
infusions can be performed as part of this study. However, any required major emergency
surgery will result in study termination.

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8.7.3.6 Immune Tolerance Induction for Inhibitor Development
Subjects who develop a confirmed (ie, 2 separate assessments within a 2 to 4 week period 
from the central laboratory) high responder inhibitor (>5 BU) or low responder inhibitor 
(≤5 BU but ≥0.6 BU) that cannot be adequately managed by the protocol-required 
prophylactic regimen with BAX 855 will be discontinued from this study. The decision to 
initiate immune tolerance induction (ITI) with ADVATE will be made by the subject’s 
physician, and may be discussed with the sponsor’s medical director prior to initiation. 
The regimen used for ITI will be determined by the treating physician but should be 
discussed with the sponsor’s medical director. ITI is not within the scope of this study.
8.7.4 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.

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For additional information on study documentation and CRFs, see Section 18.2. The use 
of subject diaries is described in Section 10.5.
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 BAX855 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

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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. 
Participation in the assessment of activity using the accelerometer device is 
voluntary
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) 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, with the exception of BAX 855 Surgery Study as described in this 
protocol.
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.

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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.
2. Subject has a history of confirmed FVIII inhibitors with a titer ≥0.6 Bethesda 
Units (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 alanine aminotransferase (ALT) or aspartate aminotransferase (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.

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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.
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 a major elective surgical or dental procedure and is not able 
to participate in the surgery study.

The subject requires major emergency surgery during this study

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
The subject experiences a life-threatening bleeding episode (eg, any 
gastrointestinal hemorrhage or intracranial hemorrhage) requiring the use of a 
FVIII concentrate other than BAX855.

The subject experiences severe trauma requiring extensive FVIII replacement 
therapy other than BAX855
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.

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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 Supplement 21.2
Detailed Flow Diagram of Study Procedures, Supplement 21.3 Schedule of Study 
Procedures and Assessments, and Supplement 21.4 Clinical Laboratory Assessments. 
Only explanatory details are provided in the section below.
10.3.1 Subjects Transitioning from Other BAX 855 Studies
Subjects transitioning from other BAX 855 studiesx 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 
                                                
x 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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have the Completion/Termination Visit performed. The use of (commercial) 
ADVATE may be permitted for a short period of time for administrative reasons.
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 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 Supplement 21.5.
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.

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
Date and time of each infusion of BAX 855 required to achieve adequate 
hemostasis.

Date and time of resolution of bleeding episode.

Overall clinical efficacy rating according to the rating scale as described in 
Table 2 at 24 (±2) 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 prior 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.

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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.
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 with 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. 

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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. 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 Supplement 21.2
Detailed Flow Diagram of Study Procedures, Supplement 21.3 Schedule of Study 
Procedures and Assessments, and Supplement 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.
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 Supplement 21.5. 
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.

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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 24 (± 2) 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 24 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.
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 

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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.
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.

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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.
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 randomizationxi. 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. 
                                                
xi 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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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
+
+
9 hours ± 30 minutes
+
+
32 hours ± 2 hour
+
+
56 hours ± 4 hour
+
+
96 hours ± 4 hour
+
+
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 13.9.5.
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 

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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
+
+
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.
Details on the sampling of blood for determination of FVIII trough levels are presented in 
Supplement 21.3 and Supplement 21.4
13. ASSESSMENT OF SAFETY INCLUDING IMMUNOGENICITY
13.1 Immunogenicity
Immunogenicity of BAX 855 will be assessed prior to the infusion of BAX855 following 
a washout period of at least 48 h (at steady state in case of every other day dosing) or 72-
96 hours (in case of twice weekly infusions) by measurement of the following antibodies
(see also Section 21.4 for the timepoints):

Inhibitory antibodies to FVIII –using the Nijmegen modification of the Bethesda 
assay

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
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.
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.

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13.2.1.1 Serious Adverse Event
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
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. 
13.2.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
13.2.1.3 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 

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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, each unexpected AE experienced by a subject undergoing 
study treatment will be recorded on the AE CRF.
13.2.1.4 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.
13.2.2 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

Hospitalization or prolongation of hospitalization intended only for social reasons.

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

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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 13.2.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 13.2.2.2
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.
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.

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13.2.2.1 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.
13.2.2.2 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:

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). 

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
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.
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 

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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.
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

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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 13.2.2.1) 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.
13.8 Physical Examinations
At screening and subsequent study visits (as described in the schedule in 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 13.2.1.4), 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.

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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 Supplement 21.2 and Supplement 21.3.
13.9.1 Screening Laboratory Parameters
13.9.1.1 Blood Type
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.
13.9.1.2 Genetics and HLA-Genotype
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.
13.9.1.3 Pregnancy Test
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.
13.9.2 CD4 Count
At screening only, CD4 levels will be determined in all HIV+ subjects using flow 
cytometry.
13.9.3 Viral Serology
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.

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13.9.4 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.
13.9.5 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 
Supplement 21.4.
13.9.6 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, Supplement 21.2, and 
Supplement 21.4.
13.9.7 Assessment of Laboratory Values
13.9.7.1 Assessment of Abnormal Laboratory Values 
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 

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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 13.2.1.4), 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.
13.9.8 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 exploratory testing will be drawn pre-
infusion and early in the morning at each study visit, if feasible, otherwise at the same 
time point at each study visit.
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.
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 

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indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
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 
factor VIII 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 86% 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 in a 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. However, 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.

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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 likelihood-ratio chi-square test 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.
14.4.2 Secondary Outcome Measures 
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: 

Spontaneous and traumatic ABR, and spontaneous AJBR

Total weight-adjusted consumption of BAX 855 for each prophylactic regimen

Overall hemostatic efficacy rating at 24 ±2 h after initiation of treatment and at 
resolution of bleed

Number of BAX 855 infusions needed for the treatment of bleeding episodes

HJHS

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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), 
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 
descriptive:
Changes between treatment arms in the following PROs:

Bleed and pain severity as measured using the Haemo-SYM questionnaire

HRQoL as assessed using the EQ-5D and SF-36 questionnaires

Physical activity levels

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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).
Health resource utilization between study arms will be compared descriptively in the first 
6 months and second 6 months.
14.5 Planned Interim Analysis of the Study
An interim analysis is planned for this study when 50% of the planned subjects have 
completed the first 6 months of prophylactic treatment. Because only data from the first 6 
months will be analyzed for the interim analysis, no adjustment for the primary endpoint 
will be needed.
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.
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.

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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.
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.

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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.
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 

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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.
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).
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.

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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.
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)

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Pregnancy test, if applicable 
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

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
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)

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

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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, 9±0.5 h, 
32±2 h, 56±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 arm. 

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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
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 ± 2 weeks
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
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

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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)
Dispense IP
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:
4 weeks ± 5 days
8 weeks ± 1 week
4.5 months ± 2 weeks
Dose Readjustment 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.
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
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
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 subject experienced bleeding episodes between the last visit and visit 7.5 months± 2 weeks and 10.5 
months ± 2 weeks, respectively visits they must attend 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 following laboratory assessment may be performed (see also procedures 
for study visit months 3 ± 2 weeks and 6± 2 weeks ):
FVIII, VWF, TGA assay
Hematology
IR
Immunogenicity
Before any study specific procedures:
EQ-5D, Patient Activity Level, and Health Resource Use

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Visits 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
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 
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 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, 9±0.5 h, 
32±2 h, 56±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)
Dispense IP
Throughout the visit, the following assessments will be carried out:
Adverse events
Concomitant medications and non-drug therapies

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Completion/Termination Visit:
at 12 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); 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
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)
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 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 

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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, 
9±0.5 h, 
32±2 h, 56±4 
h & 96±4 h 
Post-
Infusion
Baseline Visit
Study Visits
Completion/
Termination
Visitc
12 Mo 
±2Wk
Visit 
4Wk 
±5d
Visit 
8Wk 
±1Wk
Visit 
3 Mo 
±2Wk
Visit 
4.5 Mo 
±2Wk
Visit 
6 Mo 
±2Wk
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

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Procedures/
Assessments
Screening Visit
PK 
Assessmenta
Pre infusion, 
15-30 min, 
3±0.5 h, 
9±0.5 h, 
32±2 h, 56±4 
h & 96±4 h 
Post-
Infusion
Baseline Visit
Study Visits
Completion/
Termination
Visitc
12 Mo 
±2Wk
Visit 
4Wk 
±5d
Visit 
8Wk 
±1Wk
Visit 
3 Mo 
±2Wk
Visit 
4.5 Mo 
±2Wk
Visit 
6 Mo 
±2Wk
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
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
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 BAX855 study. The procedures/assessments marked with an asterisk (*) 
will be transcribed from the end of study visit of the previous BAX855 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.
d
Occurs at enrollment (prior to any study-specific procedure).
Continued on Next Page

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Continued
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.
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
Com-
pletion/
Termi-
nation
Visitd
12 Mo 
±2Wk
Pre Infusion, 
1530 Min, 
3±0.5 h, 9±0.5 h, 
32±2 h, 56±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 
±2Wk
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
Com-
pletion/
Termi-
nation
Visitd
12 Mo 
±2Wk
Pre Infusion, 
1530 Min, 
3±0.5 h, 9±0.5 h, 
32±2 h, 56±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 
±2Wk
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
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.
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.
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. 
Continued on Next Page

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Continued
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 have to perform a study site visit. 

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21.5 Definitions
21.5.1 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.
21.5.2 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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22. 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 LA, Mamonov V, Hellmann A, Quon D, Desmond J C, Schroth P, and 
Wong WY. 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.

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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. 21-7-2011. European Medicines Agency 
(EMA). 
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.

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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.
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. 19-5-2001. National Hemophilia Foundation (NSF). 

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20. National Hemophilia Foundation. Recommendation Concerning Prophylaxis 
(Regular Administration of Clotting Factor Concentrate to Prevent Bleeding). 
MASAC 170. 22-4-2006. National Hemophilia Foundation (NHF). 
21. National Hemophilia Foundation. Recommendation concerning prophylaxis 
(Regular administration of clotting factor concentrate to prevent bleeding). MASAC 
179. 11-4-2007. National Hemophilia Foundation (NHF). 
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.
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.

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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. In press.
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). 

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23. SUMMARY OF CHANGES 
Protocol 261303: Amendment 1 2015 MAR 20
Replaces: ORIGINAL: 2015 JAN 13
In this section, changes from the previous version of the Original Protocol , dated 
2015 JAN 13, are described and their rationale is given.
1. Throughout the document
Description of Change: Change of sponsor name/entity. 
Purpose for Change: Administrative. 

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INVESTIGATOR ACKNOWLEDGEMENT
BAX 855 – PEGylated Full-Length Recombinant Factor VIII
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
PROTOCOL IDENTIFIER: 261303
CLINICAL TRIAL PHASE 3
AMENDMENT 1: 2015 MAR 20
Replaces: ORIGINAL: 2015 JAN 13
ALL VERSIONS:
AMENDMENT 1: 2015 MAR 20
ORIGINAL: 2015 JAN 13
OTHER ID(s)
NCT Number: To be Determined
EudraCT Number: To be Determined
IND NUMBER: To be Determined
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD
, Clinical Development
PPD
PPD