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 2: 2015 MAY 12 
Replaces:  
AMENDMENT 1: 2015 MAR 20 
ALL VERSIONS: 
AMENDMENT 2: 2015 MAY 12 
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: Q3 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 
                                                 
i  i.e. not trauma related. 

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

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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 
6. Intra-, post- and perioperative hemostatic efficacy in case of surgery 
7. Intra- and postoperative blood loss in case of surgery 
Safety  
1. Occurrence of AEs and SAEs 
2. Clinically significant changes in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry, and lipids) 
3. Inhibitory antibodies to FVIII, and binding antibodies to FVIII, BAX 855, PEG, and CHO protein 
Patient Reported Outcomes (PROs) 
1. Physical domain and component scores of the SF-36 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. Bleed and pain severity scores as measured by the Haemo-SYM questionnaire 
3. HRQoL as assessed using EQ-5D and mental domain and component scores of the SF-36 
4. Healthcare resource utilization  

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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION 
Active Product 
BAX 855 
Dosage form: injection, powder, lyophilized, for solution 
Dose and Dosage frequency:  
BAX 855 dose will be PK-guided to maintain FVIII target trough levels of  
1-3% or approximately 10% (8-12%) at the following dosing frequencies: 
FVIII trough levels of 1-3%: approximately twice weeklyii 
FVIII trough levels of approximately 10% (8-12%): every other day 
Mode of Administration: intravenous bolus 
SUBJECT SELECTION  
Targeted Accrual 
Approximately 116 subjects will be enrolled to have 96 subjects evaluable (48 
in each prophylaxis dosing arm). 
Number of 
Groups/Arms/Cohorts 
2 
Inclusion Criteria for Subjects Transitioning from Another BAX 855 study: 
1. Subject has completed the end of study visit of a BAX 855 study or is transitioning from the 
ongoing Continuation Study 261302 
2. Subject is either receiving on-demand or prophylactic treatment with BAX 855 and had an ABR of 
≥ 2 documented and treated during the past 12 months 
3. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ 
count ≥ 200 cells/mm3, as confirmed by central laboratory 
4. Subject is willing and able to comply with the requirements of the protocol 
Inclusion Criteria for Newly Recruited Subjects: 
1. Subject is 12 to 65 years old at the time of screening 
2. Subject has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory 
or by historically documented FVIII clotting activity performed by a certified clinical laboratory 
and/or a FVIII gene mutation consistent with severe hemophilia A  
3. Subject has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII 
for ≥ 150 documented exposure days (EDs) 
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.  
                                                 
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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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 
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. 
 

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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 80% 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 with an 
allocation ratio of 1:1. 
Planned Statistical Analysis 
The proportion of subjects with ABR = 0 in the two prophylaxis treatment regimens will be compared using 
a chi-square test with continuity correction (at a two-sided 5% level of significance). For all outcome 
measures, bleeding rates will be analyzed using a negative binomial model and descriptive statistics will be 
presented for the two dosing regimens for other outcomes. Point estimates (mean or median) and 95% CIs 
will be computed if feasible. 

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4. TABLE OF CONTENTS 
1. STUDY PERSONNEL ................................................................................................. 2 
1.1 Study Organization ................................................................................................. 2 
2. SERIOUS ADVERSE EVENT REPORTING ........................................................... 3 
3. SYNOPSIS ..................................................................................................................... 4 
4. TABLE OF CONTENTS ........................................................................................... 10 
5. LIST OF ABBREVIATIONS .................................................................................... 15 
6. BACKGROUND INFORMATION .......................................................................... 18 
6.1 Description of Investigational Product ............................................................... 18 
6.2 Clinical Condition/Indication .............................................................................. 19 
6.3 Population To Be Studied..................................................................................... 20 
6.4 Findings from Nonclinical and Clinical Studies................................................. 21 
6.4.1 Findings from Nonclinical Studies ............................................................... 21 
6.4.2 Findings from Clinical Studies ..................................................................... 21 
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product to 
Human Subjects .................................................................................................... 25 
6.6 Authorized Representative (Signatory) / Responsible Party ............................ 26 
6.7 Compliance Statement .......................................................................................... 26 
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 27 
7.1 Study Purpose ....................................................................................................... 27 
7.2 Primary Objective ................................................................................................. 27 
7.3 Secondary Objectives ........................................................................................... 27 
7.3.1 Efficacy ........................................................................................................... 27 
7.3.2 Safety ............................................................................................................... 28 
7.3.3 Pharmacokinetics ........................................................................................... 28 
7.3.4 Patient Reported Outcomes .......................................................................... 28 
7.4 Exploratory Objectives ......................................................................................... 28 
8. STUDY DESIGN ......................................................................................................... 29 
8.1 Brief Summary ...................................................................................................... 29 
8.2 Overall Study Design ............................................................................................ 29 
8.3 Duration of Study Period(s) and Subject Participation .................................... 30 
8.4 Outcome Measures ............................................................................................... 30 
8.4.1 Primary Outcome Measure .......................................................................... 30 

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8.4.2 Secondary Outcome Measures ..................................................................... 30 
8.4.2.1 Efficacy .................................................................................................... 30 
8.4.2.2 Safety ........................................................................................................ 31 
8.4.2.3 Patient Reported Outcomes ................................................................... 31 
8.4.2.4 Pharmacokinetics .................................................................................... 31 
8.4.3 Exploratory Outcome Measures .................................................................. 31 
8.5 Randomization and Blinding ............................................................................... 31 
8.6 Study Stopping Rules ............................................................................................ 32 
8.7 Investigational Product(s) .................................................................................... 32 
8.7.1 Packaging, Labeling, and Storage ................................................................ 32 
8.7.2 Administration ............................................................................................... 33 
8.7.3 Description of Treatment .............................................................................. 33 
8.7.3.1 BAX 855 Dosing for PK Assessment ..................................................... 34 
8.7.3.2 BAX 855 Prophylaxis Dosing ................................................................. 34 
8.7.3.3 BAX 855 Dose and/or Frequency Adjustments ................................... 35 
8.7.3.4 Treatment of Bleeding Episodes ............................................................ 36 
8.7.3.5 Treatment for Surgery or Dental Procedures ...................................... 38 
8.7.3.6 Immune Tolerance Induction for Inhibitor Development. ................. 38 
8.7.4 Investigational Product Accountability ....................................................... 38 
8.8 Source Data ........................................................................................................... 39 
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 40 
9.1 Inclusion Criteria .................................................................................................. 40 
9.1.1 Subjects Transitioning from Another BAX 855 Study .............................. 40 
9.1.2 Inclusion Criteria for Newly Recruited Subjects ........................................ 40 
9.2 Exclusion Criteria ................................................................................................. 41 
9.2.1 Exclusion Criteria for Subjects Transitioning from Another BAX 855 
Study ............................................................................................................... 41 
9.2.2 Exclusion Criteria for Newly Recruited Subjects ....................................... 41 
9.3 Withdrawal and Discontinuation ........................................................................ 43 
10. STUDY PROCEDURES .......................................................................................... 44 
10.1 Informed Consent and Enrollment ................................................................... 44 
10.2 Subject Identification Code ................................................................................ 44 
10.3 Screening and Study Visits................................................................................. 44 
10.3.1 Subjects Transitioning from Other BAX 855 Studies .............................. 45 
10.3.2 Newly Recruited Subjects ........................................................................... 45 
10.4 Medications and Non-Drug Therapies .............................................................. 45 
10.5 Subject Diary and Patient Reported Outcomes ............................................... 46 
10.5.1 Patient Reported Outcomes ........................................................................ 47 
10.6 Subject Completion/Discontinuation ................................................................ 48 
10.7 Procedures for Monitoring Subject Compliance ............................................. 49 

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11. ASSESSMENT OF EFFICACY .............................................................................. 50 
11.1 Bleeding Assessment ........................................................................................... 50 
11.1.1 Hemostatic Efficacy Rating for Treatment of Bleeding Episodes ........... 50 
11.1.2 Number of BAX 855 Infusions Needed for the Treatment of Bleeding 
Episodes .......................................................................................................... 52 
11.1.3 Hemophilia Joint Health Score (HJHS) .................................................... 52 
11.1.4 Weight-Adjusted Consumption of BAX 855 ............................................. 52 
11.1.5 Peri-operative efficacy assessments ............................................................ 52 
12. DETERMINATION OF FVIII AND VWF ANTIGEN, FVIII ACTIVITY AND 
TGA .............................................................................................................................. 53 
12.1 PHARMACOKINETICS ................................................................................... 53 
12.2 Incremental Recovery (IR) ................................................................................ 54 
12.3 Trough Levels ...................................................................................................... 55 
13. ASSESSMENT OF SAFETY INCLUDING IMMUNOGENICITY ................... 56 
13.1 Immunogenicity .................................................................................................. 56 
13.2 Adverse Events .................................................................................................... 57 
13.2.1 Definitions ..................................................................................................... 57 
13.2.1.1 Serious Adverse Event .......................................................................... 57 
13.2.1.2 Non-Serious Adverse Event ................................................................. 58 
13.2.1.3 Unexpected Adverse Events ................................................................. 58 
13.2.1.4 Preexisting Diseases .............................................................................. 58 
13.2.2 Assessment of Adverse Events .................................................................... 58 
13.2.2.1 Severity .................................................................................................. 60 
13.2.2.2 Causality ................................................................................................ 60 
13.3 Urgent Safety Measures ..................................................................................... 62 
13.4 Untoward Medical Occurrences ........................................................................ 62 
13.5 Medical Device Safety reporting ....................................................................... 62 
13.6 Non-Medical Complaints ................................................................................... 63 
13.7 Medical, Medication, and Non-Drug Therapy History ................................... 63 
13.8 Physical Examinations ........................................................................................ 64 
13.9 Clinical Laboratory Parameters ........................................................................ 64 
13.9.1 Screening Laboratory Parameters ............................................................. 64 
13.9.1.1 Blood Type ............................................................................................. 64 
13.9.1.2 Genetics and HLA-Genotype ............................................................... 64 
13.9.1.3 Pregnancy Test ...................................................................................... 65 
13.9.2 CD4 Count .................................................................................................... 65 
13.9.3 Viral Serology ............................................................................................... 65 
13.9.4 Hematology, Clinical Chemistry and Lipid Panel .................................... 65 
13.9.5 FVIII Activity, FVIII Antigen, VWF Antigen .......................................... 65 
13.9.6 Thrombin Generation Assay ...................................................................... 66 
13.9.7 Assessment of Laboratory Values .............................................................. 66 

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13.9.7.1 Assessment of Abnormal Laboratory Values..................................... 66 
13.9.8 Biobanking .................................................................................................... 66 
13.10 Vital Signs .......................................................................................................... 67 
14. STATISTICS ............................................................................................................. 68 
14.1 Sample Size and Power Calculations ................................................................ 68 
14.1.1 Sample Size Calculation .............................................................................. 68 
14.2 Datasets and Analysis Cohorts .......................................................................... 68 
14.2.1 Full Analysis Set ........................................................................................... 68 
14.2.2 Per Protocol Analysis Set ............................................................................ 68 
14.2.3 Safety Analysis Set ....................................................................................... 68 
14.3 Handling of Missing, Unused, and Spurious Data ........................................... 68 
14.3.1 Handling of incomplete observation periods for ABR ............................. 68 
14.3.2 Handling of other variables ........................................................................ 69 
14.4 Methods of Analysis ............................................................................................ 69 
14.4.1 Primary Outcome Measure......................................................................... 69 
14.4.2 Secondary Outcome Measures ................................................................... 70 
14.4.3 Exploratory Outcome Measures ................................................................ 72 
15. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 73 
16. QUALITY CONTROL AND QUALITY ASSURANCE ...................................... 74 
16.1 Investigator’s Responsibility .............................................................................. 74 
16.1.1 Final Clinical Study Report ........................................................................ 74 
16.2 Training ............................................................................................................... 74 
16.3 Monitoring ........................................................................................................... 74 
16.4 Auditing ............................................................................................................... 74 
16.5 Non-Compliance with the Protocol ................................................................... 75 
16.6 Laboratory and Reader Standardization ......................................................... 75 
17. ETHICS ..................................................................................................................... 76 
17.1 Subject Privacy ................................................................................................... 76 
17.2 Ethics Committee and Regulatory Authorities ................................................ 76 
17.3 Informed Consent ............................................................................................... 76 
17.4 Data Monitoring Committee .............................................................................. 77 
18. DATA HANDLING AND RECORD KEEPING ................................................... 78 
18.1 Confidentiality Policy ......................................................................................... 78 
18.2 Study Documentation and Case Report Forms ............................................... 78 
18.3 Document and Data Retention........................................................................... 78 
19. FINANCING AND INSURANCE ........................................................................... 79 

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20. PUBLICATION POLICY ........................................................................................ 79 
21. SUPPLEMENTS ....................................................................................................... 80 
21.1 Study Flow Charts .............................................................................................. 80 
21.2 Detailed Flow Diagram of Study Procedures ................................................... 82 
21.3 Schedule of Study Procedures and Assessments .............................................. 92 
21.4 Clinical Laboratory Assessments ...................................................................... 94 
22. PERIOPERATIVE MANAGEMENT .................................................................... 96 
22.1 Dosing Schedule and requirements for major surgery ................................... 96 
22.1.1 General .......................................................................................................... 96 
22.1.2 Preoperative and Loading Dose ................................................................. 96 
22.1.3 Postoperative Dosing ................................................................................... 97 
22.2 Efficacy assessment ........................................................................................... 100 
22.2.1 Intra-, Post-, and Perioperative Hemostatic Efficacy ............................. 100 
22.2.2 Intra- and Postoperative Blood Loss ........................................................ 101 
23. DEFINITIONS ........................................................................................................ 102 
23.1 Joint Bleeds ........................................................................................................ 102 
23.2 Muscle Bleeds .................................................................................................... 102 
24. REFERENCES ........................................................................................................ 103 
25. SUMMARY OF CHANGES .................................................................................. 107 
 
Tables 
Table 1  BAX 855 Treatment Guidelines for Bleeding Episodes ..................................... 37 
Table 2  Efficacy Rating Scale for Treatment of Bleeding Episodes ............................... 51 
Table 3  PK Time Points ................................................................................................... 53 
Table 4  IR Time Points .................................................................................................... 54 
Table 5  Intraoperative Efficacy Assessment Scale ........................................................ 100 
Table 6  Postoperative Efficacy Assessment Scale (Postoperative Day 1) .................... 100 
Table 7  Perioperative Efficacy Assessment Scale (at discharge or 14 days post-surgery, 
whichever is first) ................................................................................................... 101 
 
Figures 
Figure 1  Study Design for Baxalta Clinical Study 261303.............................................. 80 
Figure 2  Study Flow Chart ............................................................................................... 81 
Figure 3  Dosing Recommendations for Major Surgeries ................................................ 99 

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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.  

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

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

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

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

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

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

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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. 
Since BAX 855 is a pegylated form of ADVATE, there is also the potential risk of 
inducing anti-PEG antibodies following BAX 855 administration. Binding antibodies 
against PEG are present in the healthy population and in patients with hemophilia A. 
BAX 855 may react with pre-existing anti-PEG antibodies, potentially resulting in a 
clinical hypersensitivity reaction or increased clearance of BAX 855 from circulation. 
BAX 855 and ADVATE showed a similar immunogenicity profile in preclinical in vitro 
and in vivo studies. Data from preclinical studies indicate that pegylated human FVIII 
can only induce antibodies against PEG when FVIII is recognized as a foreign protein 
that can provide immunogenic epitopes for CD4+ T cells. In the pivotal phase 2/3 studies 
it could be demonstrated that the presence of anti-PEG antibodies at screening or 
transiently occurring in some subjects did not have an impact on hemostatic efficacy or 
safety and that BAX 855 did not induce persistent antibodies to PEG or BAX 855.  
Previously treated patients (PTPs) with a high degree of previous exposure to FVIII 
should be immunetolerant to FVIII and are considered to have a low risk of developing 
antibodies against FVIII. Therefore, the risk for PTPs with severe hemophilia A who do 
not have neutralizing antibodies against FVIII (inhibitors) are also expected to be at low 
risk to develop antibodies against BAX 855. In the pivotal study 261201, 101 subjects 
accumulated ≥50 EDs and none of them developed inhibitory antibodies to FVIII ≥ 0.6 
BU at any time during the study. Also, none of the subjects developed persistent binding 
antibodies to FVIII, PEG-FVIII or PEG. Moreover, no immune responses with a clinical 
impact and no evidence of hypersensitivity reactions were observed. 
                                                 
iii ADVATE Company Core Data Sheet on file at Baxalta US Inc. (Westlake Village, CA). 

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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. 
6.6 Authorized Representative (Signatory) / Responsible Party 
, MD 
, Clinical Development 
Baxalta US Inc. 
6.7 Compliance Statement 
This study will be conducted in accordance with this protocol, the International 
Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 
1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical 
Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local 
regulatory requirements. 
PPD
PPD

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

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

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

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± 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 
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 
6. Intra-, post- and perioperative hemostatic efficacy in case of surgery 
7. Intra- and postoperative blood loss in case of surgery 

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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. Physical domain and component scores of the SF-36Physical activity level 
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. Bleed and pain severity scores as measured by the Haemo-SYM questionnaire 
3. HRQoL as assessed using EQ-5D and mental domain and component scores of  
SF-36 
4. Health resource utilization 
8.5  Randomization and Blinding 
This is a randomized, open-label, concurrent, dose regimen comparison clinical study. In 
order to minimize/avoid bias, once eligibility is confirmed, subjects will be randomly 
assigned to 1 of 2 treatment regimens with PK-guided dosing targeting FVIII trough 
levels of 1-3% or approximately 10% (8-12%) in a 1:1 ratio. Randomization occurs after 
the PK assessment and will be stratified according to subjects’ pre-study treatment 
regimen (prophylaxis vs. on-demand). 

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8.6 Study Stopping Rules  
This study will be halted (enrollment and treatment temporarily stopped), pending further 
review by sponsor, or stopped if the following criterion is met: 
• If 2 or more subjects develop a high responder inhibitory antibody > 5 BU, 
confirmed by 2 measurements within a 2-4 week period at the central laboratory, 
after BAX 855 administration  
• If 2 or more subjects develop anaphylaxis following exposure to BAX 855 
The study may be terminated, if 1 or more of the following criteria are met: 
• The sponsor decides to terminate the study based upon its assessment of safety 
• The sponsor decides to terminate the study for administrative reasons 
8.7 Investigational Product(s) 
8.7.1 Packaging, Labeling, and Storage 
BAX 855 is formulated as a sterile, highly purified protein preparation in lyophilized 
form for i.v. infusion and is provided in single-dose vials with a vial of diluent (2 mL or 
5 mL SWFI, as available). A butterfly transfer set with luer-lock syringes and a 
needleless transfer device (BAXJECT II high-flow (HF) or BAXJECT III, as available) 
will be used for reconstitution and bolus i.v. delivery. The BAXJECT system is a 
needleless liquid transfer device with the primary function of transferring diluent from its 
vial into an evacuated vial containing product requiring reconstitution prior to infusion. 
A minimum of 4 lots of BAX 855 manufactured for this study will be used. Four 
potencies of BAX 855 may be used, depending upon availability: 250, 500, 1,000 and 
2,000 IU/vial.  
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. 

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

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8.7.3.1 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 855vi: 
At Visit 9 months, ie after 9 months of prophylactic treatment with BAX855, a repeat PK 
at steady state will be performed. No wash-out period will be required prior to the repeat 
PK determination; however, the PK infusion should preferably coincide with the 
prophylactic treatment schedule to ensure that the baseline FVIII trough level is reached. 
The BAX 855 dose to be used for the PK assessment is 60 ± 5 IU/kg. It must be 
administered in the hospital/clinic setting under medical supervision. 
8.7.3.2 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.  
FVIII trough level of approximately 10% (8% - 12%): 
• BAX 855 will be infused every other day. 
• A daily dosing may be considered to prevent regular high FVIII peak levels  
The required dose and frequency will be provided by the sponsor. Subjects must adhere 
as closely as possible to the dosing regimen. If a dose is missed, it must be documented 
and the next dose will be taken as soon as possible. After this dose, the regularly 
scheduled regimen will be resumed. Subjects requiring treatment for a breakthrough 
bleeding episode should resume their PK-tailored prophylaxis as soon as the bleeding 
episode is resolved.  
The days of the week on which treatment is administered may be selected by the subject 
and/or his/her physician and should provide maximum coverage for vigorous activities. 
                                                 
vi In case a subject underwent a PK determination in any of the BAX855 studies, the PK assessment may 
have to be repeated based on the sponsor’s evaluation.  

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To provide some flexibility, the weekly schedule in terms of the days of the week may be 
changed during the course of the study to best accommodate potential changes in the 
subject’s life style. However, the initially calculated and adjusted, if applicable, dose 
regimen should be maintained.  
For each subject, the BAX 855 infusions to perform PKs, IRs and the first individualized 
prophylaxis dose of BAX 855 at the Baseline visit, which includes an IR assessment, 
must be administered in the hospital/clinic setting under medical supervision. All other 
treatments may be self-administered, administered by a parent or caregiver, or 
administered in the clinic or hospital setting. Each subject’s physician will determine the 
setting of treatment administration. If the subject will self-administer BAX 855, the 
investigator will ensure that the subject and/or his caregiver have been adequately 
trained. 
The weight determined at screening will be the basis for dose calculation of BAX 855. If 
there is a ± 10% change in weight from the screening visit (as measured at a subsequent 
study visit), the total dose in IU will be recalculated. Similarly, any additional ± 10% 
change in weight from this new baseline will result in a dose recalculation. 
8.7.3.3 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.  
Before dose adjustment, if applicable, a confirmatory FVIII trough level determination at 
an additional study visit within 2 weeks after receipt of the FVIII activity results has to be 
performedvii. This additional study visit should also occur after either a 48 h wash-out 
period in case of an every other day dosing or 72 or 96 hours in case of twice weekly 
infusions to coincide with the regular prophylactic infusion. After receipt of the repeat 
FVIII activity results, dose adjustments should be performed: 
• If the lower FVIII trough activity level is < 1% and < 8% respectively; 
• If the upper FVIII trough activity level exceeds 3% and 12% respectively. Given 
the assay variations, fluctuations of approximately 3% are possible. 
                                                 
vii 
This additional visit may coincide with regular scheduled study visit. 

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Approximately 2 weeks after the dose adjustment, a repeat FVIII trough level 
determination at an additional study visit has to be performed, if it does not coincide with 
the next scheduled study visit.  The blood draw for the FVIII trough level measurement 
should occur after a wash-out period of at least  48 h in case of an every other day dosing 
or 72 or 96 hours in case of twice weekly infusions to coincide with the regular 
prophylactic infusion. 
Dose adjustments in the second 6-month period may only be performed if FVIII trough 
levels are considerably below the required FVIII trough levels of 1% and 8%. Should the 
upper limit considerably exceed 3% and 12% respectively, a dose adjustment may be 
performed.  
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 jointsviii 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 
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. 
                                                 
viii A target joint is defined as a single joint (ankles, knees, hips, or elbows) with ≥ 4 spontaneous bleeding 
episodes in any consecutive 6-month period. 

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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 22. 
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} 
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 FVIII rise (%or (IU/dL) x 0.4 dL/kg 
The amount to be administered and the frequency of administration should always be 
oriented to the clinical effectiveness in the individual case.  

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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) and who require planned surgery or 
dental procedures will be treated according to the treatment recommendations including a 
FVIII substitution plan described in Supplement 22.  
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. 

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8.8 Source Data 
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following: 
hospital records, medical records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries or evaluation checklists, outcomes reported by subjects, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medico-technical departments involved in 
the clinical study. 
For additional information on study documentation and CRFs, see Section 18.2. 
The use of subject diaries is described in Section 10.5. 

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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION 
9.1 Inclusion Criteria 
9.1.1 Subjects Transitioning from Another BAX 855 Study 
Subjects transitioning from another BAX 855 study who meet ALL of the following 
criteria are eligible for this study: 
1. Subject has completed the end of study visit of a BAX 855 study or is transitioning 
from the ongoing Baxalta Continuation Study 261302. 
2. Subject is either receiving on-demand treatment or prophylactic treatment with 
BAX 855 and had an ABR of ≥ 2 documented and treated during the past 
12 months. 
3. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable 
disease and CD4+ count ≥ 200 cells/mm3, as confirmed by central laboratory. 
4. Subject is willing and able to comply with the requirements of the protocol. 
9.1.2 Inclusion Criteria for Newly Recruited Subjects 
Newly recruited subjects including 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 
8. If female of childbearing potential, subject presents with a negative urine pregnancy 
test and agrees to employ adequate birth control measures for the duration of the 
study 
9. Subject is willing and able to comply with the requirements of the protocol.  

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

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2. Subject has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 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. 
13. Subject is a member of the team conducting this study or is in a dependent 
relationship with one of the study team members. Dependent relationships include 
close relatives (ie, children, partner/spouse, siblings, parents) as well as employees 
of the investigator or site personnel conducting the study. 

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9.3 Withdrawal and Discontinuation 
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study) 
consent for continued participation and data collection. The reason for withdrawal will be 
recorded on the End of Study CRF. Assessments to be performed at the termination visit 
(including in cases of withdrawal or discontinuation) are described in Section 10.6 and 
Section 21.3. 
Discontinuation (ie, complete withdrawal from study participation) may be due to 
dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by 
subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.  
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons: 
• The subject develops a confirmed high responder inhibitory antibody to FVIII 
(> 5 BU by Nijmegen modification of the Bethesda assay) or a low responder 
inhibitory antibody (≤ 5 BU but ≥ 0.6 BU) that cannot be managed by the 
protocol-required prophylactic dosing. 
• The subject experiences a severe anaphylactic reaction to BAX 855. 
• The subject requires therapy with another pegylated product (eg, PEG- 
Interferon). 
• The subject frequently misses administration of IP (misses more than 30% of 
planned prophylactic doses within any 3-month period). 
• The subject is non-compliant with study procedures, in the opinion of the 
investigator and/or sponsor. 
• The subject uses his/her usual FVIII therapy following the baseline infusion 
• The subject requires major emergency surgery during this study 
• The subject experiences a life-threatening bleeding episode (eg, any 
gastrointestinal hemorrhage or intracranial hemorrhage) requiring the use of a 
FVIII concentrate other than BAX855. 
• The subject experiences severe trauma requiring extensive FVIII replacement 
therapy other than BAX855 

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

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

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 Hemostatic agents, such as tranexamic acid, are permitted, as indicated by the 
subject’s treating physician, to treat mucosal bleeding or during perioperative 
management during the study 
 Any medications deemed necessary by the subject’s physician to treat or 
prevent any medical condition 
 Any over-the-counter medication used by the subject to treat symptoms or signs 
 Supplemental vitamins, minerals 
• Non-drug therapies: 
 Any non-drug therapy (eg, physiotherapy) deemed necessary by the subject’s 
physician to treat or prevent any medical condition 
10.5 Subject Diary and Patient Reported Outcomes 
A subject diary will be provided to each subject at the Screening Visit to record the 
following information: 
1. Infusion record for BAX 855 
2. Details of bleeding episodes and response to treatment. For a detailed description of 
bleeding episodes into different sites see Supplement 22. 
3. Physical activity within 8 h prior to the occurrence of a bleeding episode 
4. Untoward events 
5. PROs (see Section 10.5.1) 
For each bleeding episode, the following information will be recorded by the 
subject/subject’s caregiver or by authorized, qualified personnel at the study site: 
• Location of bleed, eg, joint, soft tissue, muscle, body cavity, intracranial, other. 
• Type of bleed, ie, spontaneous (i.e. not related to injury/trauma), injury (definitely 
due to injury/trauma). 
• Severity of bleed, eg, minor, moderate, major (see Table 1). 
• Date and time of onset of bleed. 
• Date and time of each infusion of BAX 855 required to achieve adequate 
hemostasis. 
• Date and time of resolution of bleeding episode. 
• 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. 

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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. 
2. Short Form-36 (SF-36) – The SF-36 is a self-administered, validated questionnaire 
designed to measure generic HRQoL. This 36-item questionnaire measures 
8 domains, including: Physical functioning, Role-physical, Bodily pain, General 
health, Vitality, Social functioning, Role emotional, and Mental health. Two 
summary scores can be calculated, the Physical Component Score, and the Mental 
Component Score. Additionally, scores can be calculated for each of the 8 domains. 
Higher scores indicate better health status. This questionnaire will be administered 
only to subjects ≥14 years of age. 

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3. EQ-5D Questionnaire – The EQ-5D is a self-administered, standardized measure 
of health status that provides a generic measure of health for clinical and economic 
appraisal consisting of the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression each with 5 levels. There is an 
additional EQ VAS to record how good or bad their health state is. 
4. Patient Activity Level  
Subjects will also be asked to estimate their activity levels. This will consist of a 
few questions asking subjects to rate their current level of activity. These data will 
be collected for all age groups. 
5. Health Resource Use – For each occurrence (throughout the study), the subject 
will record the following events: days missed from work/school (as appropriate) 
and days not able to perform normal activities outside of work/school due to 
hemophilia, physician office visits, hemophilia treatment site visits, emergency 
room visits (reason and number), and hospitalizations (reason, dates of 
hospitalization and associated length of stay). 
10.6 Subject Completion/Discontinuation 
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according 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.  
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an 
additional, unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a subject terminates participation in the study and 
does not return for the completion/termination visit, their last recorded assessments 
shall remain recorded with their last visit. The reason for discontinuation will 
be recorded, and the data collected up to the time of discontinuation will be used in 
the analysis and included in the clinical study report.  

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If additional assessments are required, the assessments shall be recorded separately. 
Assessments to be performed at the termination visit (including in cases of withdraw or 
discontinuation) can be found in 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. 

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11. ASSESSMENT OF EFFICACY 
11.1 Bleeding Assessment 
Each individual bleed, spontaneous or traumatic, will be recorded in the subject’s diary, 
and/or recorded in physician/nurse/clinic notes. A bleed is defined as subjective (eg, pain 
consistent with a joint bleed) or objective evidence of bleeding which may or may not 
require treatment with FVIII. For further definitions of bleeds see Supplement 22. Bleeds 
occurring at the same anatomical location (eg, right knee) with the same etiology (ie, 
spontaneous vs. injury) within 72 h of onset of the first bleed will be considered a single 
bleed.31 A new bleed is defined as a bleed occurring > 72 hours after stopping treatment 
for the original bleed for which treatment was initiated and had an initial moderate to 
excellent response to treatment.31 Bleeding occurring at multiple locations related to the 
same injury (eg, knee and ankle bleeds following a fall) will be counted as a single 
bleeding episode.  
The subject will also indicate in the diary on a preselected scale the type of activity 
within 8 hours prior to the bleeding episode. 
For the primary assessment, the total bleed rate in the second 6-month study period will 
be calculated (ie, after the 6-month visit to the Completion/Termination Visit). The 
secondary outcome measures, spontaneous and traumatic ABR, and spontaneous AJBR 
will also be calculated from the recorded bleeds. 
11.1.1 Hemostatic Efficacy Rating for Treatment of Bleeding Episodes 
The subject or their caregiver will rate the severity (minor, moderate, or major) of the 
bleeding episode and will rate the overall treatment response at 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. 

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

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

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

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The PK infusion may be administered via a central line or a peripheral vein. Upon 
completion of the infusion, the butterfly catheter should be flushed with at least 2 mL of 
saline solution. All PK samples will be collected through a peripheral vein. Blood 
samples drawn during the first 3 hours after BAX 855 administration will be drawn from 
a peripheral vein in an extremity distinct from the one that was used for product infusion. 
After that time, a vein in any appropriate extremity may be used. In the event that a blood 
sample must be drawn through the central or peripheral line used for administration of IP, 
the line must first be flushed with 5 mL normal saline or other suitable catheter flush 
solution that does not contain anticoagulant. At least 5 mL of whole blood must be 
collected and discarded prior to obtaining the blood sample. 
For further details regarding analysis of FVIII activity see Section 13.9.5. 
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 
dose of another FVIII concentrate. However, depending on the time point of the bleeding 
episode during the PK evaluation, an exemption may be granted by the sponsor. 
12.2 Incremental Recovery (IR) 
IR will be determined at each study visit except study visit week 4±5 days, week 8±1, 
and month 4.5 months ±2 weeks when only trough levels will be measured. Following a 
wash-out period required for the respective treatment group, blood samples for the 
determination of IR will be taken at the following time points:  
Table 4  
IR Time Points  
 
 
FVIII (Activity 
and Antigen) 
VWF Antigen 
TGA 
Pre-infusion 
Within 30 minutes prior to infusion 
+  
+ 
+  
Infusion 
60±5 IU/kg of BAX855 
 
 
 
Post-infusion 
15 -30 minutes 
+ 
 
+ 
 

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

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

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13.2 Adverse Events 
13.2.1 Definitions 
An AE is defined as any untoward medical occurrence in a subject administered an IP 
that does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom (eg, rash, pain, discomfort, fever, dizziness, etc.), disease (eg, peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP. 
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 

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Uncomplicated pregnancies, following maternal exposure to IP are not considered an 
(S)AE; however, any pregnancy complication or pregnancy termination by therapeutic, 
elective, or spontaneous abortion shall be considered an SAE.  
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 
Information (eg, IB, package insert). “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 
For the purposes of this study, all AEs including unexpected AEs experienced by a 
subject undergoing study treatment will be recorded on the AE CRF. 
13.2.1.4 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 (however, when there is an increase in the severity, duration, 
or frequency of a preexisting disease, the event must be described on the AE 
CRF) 
• Hospitalization or prolongation of hospitalization intended only for social reasons. 

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• Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period 
• Bleeding episodes/hemophilia-related events: Bleeding episodes are part of the 
underlying disease and therefore are not AEs. If a bleeding episode was caused by 
an injury (eg, a fall), the injury would not be reported as an AE, unless it resulted 
in a medical finding other than a bleeding episode (eg, abrasion of skin; fractured 
tibia). Therefore, any hemophilia-related event (eg, hemarthrosis, bruising, 
hemorrhage) will not be reported as an AE, but these events will be recorded on 
the bleeding event CRF. However, hemophilia-related events meeting the criteria 
for seriousness (eg, a gastrointestinal hemorrhage requiring hospitalization) will 
be reported as SAEs and described on the SAE report 
All other AEs from the first IP exposure until study completion/discontinuation will be 
described on the AE CRF using the medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
expressions (see definition in Section 13.2). Each AE will be evaluated by the 
investigator for: 
• Seriousness as defined in Section 13.2.1.1 
• Severity as defined in Section 13.2.2.1 
• 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 

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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. 
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 

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

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

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13.6 Non-Medical Complaints 
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following: 
• A failure of a product to exhibit its expected pharmacological activity and/or 
design function, eg, reconstitution difficulty 
• Missing components 
• Damage to the product or unit carton 
• A mislabeled product (eg, potential counterfeiting/tampering) 
• A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims 
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures. 
13.7 Medical, Medication, and Non-Drug Therapy History 
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 13.2.2.1) 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. 

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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. 
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. 

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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. 
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. 

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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 
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. 

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

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14. STATISTICS 
14.1 Sample Size and Power Calculations 
14.1.1 Sample Size Calculation 
For the sample size assessment the following assumptions were used. Approximately 
40% of patients in BAX 855 regimen targeting 1-3% trough level are expected to be 
bleed-free as shown in the ADVATE Prophylaxis study and the BAX 855 pivotal study 
261201. For the BAX 855 regimen targeting approximately 10% (8-12%) trough level, an 
increase to 70% bleed-free patients is expected based on modeling the bleeding rates per 
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 80% power. Assuming a drop-out rate of close to 
10%, and 10-15% of subjects being non-compliant, approximately 116 subjects are 
planned to be randomized between the two BAX 855 regimens with an allocation ratio 
of 1:1. 
14.2 Datasets and Analysis Cohorts 
14.2.1 Full Analysis Set  
The Full Analysis Set (FAS) will comprise all subjects who were randomized and who 
were treated with BAX 855 prophylactically for any period of time.  
14.2.2 Per Protocol Analysis Set  
The Per Protocol Analysis Set will comprise all subjects who were randomized and 
completed the second 6 months of prophylactic treatment. 
14.2.3 Safety Analysis Set 
The Safety Analysis Set (SAS) will comprise all subjects treated with at least 1 BAX 855 
dose. All safety analyses for BAX 855 will be performed on the SAS. 
14.3 Handling of Missing, Unused, and Spurious Data 
Missing data will not be imputed in general, with the exceptions as detailed below. 
14.3.1 Handling of incomplete observation periods for ABR 
The primary endpoint requires complete data for the second 6 months of prophylaxis 
(Day 184 to Day 366). The multiple imputations technique will be used for the analysis 
of the primary endpoint and estimation of ABRs. As this is a statistical analysis 
technique, it will be described in the statistical analysis section. 

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14.3.2 Handling of other variables 
If body weight is missing for a subject then the last value of available body weight 
measurement will be carried forward in order to compute weight-adjusted BAX 855 
consumption. If the date of onset for an AE is missing completely then it will be imputed 
with the date of the first study drug application. 
For PK data, if any concentration data are considered spurious (e.g. lack of biological 
plausibility), the reason for exclusion and the analysis from which the data point was 
excluded will be documented.  
Regarding missing data in AE records:  
• Handling of unknown causality assessment: 
 If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related”. 
• Handling of unknown severity grades: 
 If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, the severity of this AE will be counted as 
“severe”. 
• If a subject experiences more than one AE categorized under the same preferred 
term, one of them is categorized as “mild” or “moderate” and one of them is 
categorized as “unknown”, the severity of this AE will be counted as “unknown”. 
14.4 Methods of Analysis 
14.4.1 Primary Outcome Measure 
The proportion of subjects with ABR = 0 in the two prophylaxis treatment regimens in 
the second 6 months period will be compared using a chi-square test with continuity 
correction at a two-sided 5% level of significance.  
The null hypotheses of no difference between the prophylactic regimens will be tested 
against a two-sided alternative. 
The observation period for the primary endpoint will be the second 6 months of 
prophylaxis (Day 184 to Day 366). If the subject undergoes a surgical procedure the 
observation period is interrupted starting from the presurgical loading dose until the 
subject resumes his previous prophylactic treatment regimen, or until rehabilitation or 
any other surgery specific postoperative measures have been completed, whichever 
occurs last. 

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The multiple imputations (MI) technique will be used to handle observation periods 
shorter than 6 months, i.e. 183 days, as follows. 
For subjects who terminated before Day 366, bleeds will be imputed for the unobserved 
period from a Poisson random variate. The subject specific Poisson parameter will be 
determined from estimating a negative binomial model for the bleed rate in the 
unobserved period with stratum, age, race as well as the number of bleeds in the observed 
period of the subject as covariates in all subjects of the same Study Arm. For subjects 
with more than 150 days in the observation period, the number of bleeds occurring at a 
later time in other subjects might be very low or even zero. To avoid estimating from an 
unstable model, the negative binomial model will be for the number of bleed up to Day 
150 with covariates of stratum, age, race and number of bleeds observed up to Day 150. 
At least 1000 imputation datasets will be generated. The chi-squared test statistics with 
continuity correction and its standard error will be used to compare the two study arms in 
each imputation dataset and the multiple imputations techniques will be used to derive an 
overall estimate with two-sided 95% confidence interval. 
The dataset to be analyzed is all subjects with any observation time between Day 184 and 
366 and all subjects who developed an inhibitor (at any time); the latter being considered 
to have had a bleed.  
The use of age and race in the imputation model will allow for subgroup analyses of the 
primary endpoint and ABRs. 
Sensitivity analyses 
Sensitivity analyses will be performed similar to the primary analysis except that the 
negative binomial distributions used for imputations will have an artificially increased 
Poisson parameter by 10%, 20% and 30%. 
14.4.2 Secondary Outcome Measures  
• Spontaneous and traumatic ABR, and spontaneous AJBR 
For total ABR, spontaneous ABR, traumatic ABR and spontaneous JABR, separate 
negative binomial models will be used for the second 6 months treatment period.  
The negative binomial model for the bleed rate with covariates of Study Arm, stratum, 
age, and race. The multiple imputations technique will be used for incomplete 
observation periods as described for the primary endpoints analysis. Subgroups for age 
and race will be analyzed as well. 

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For all other outcome measures, descriptive statistics will be presented for the two dosing 
regimens. Point estimates (means and medians) and their 95% CIs will be computed to 
include:  
• Total weight-adjusted consumption of BAX 855 for each prophylactic regimen 
• Overall hemostatic efficacy rating at 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 
• Physical domain and component scores of the SF-36 
• Physical Activity Levels 
In case of surgeries, descriptive statistics will be performed for the following secondary 
outcome measures:  
• 
Intra-, post- and perioperative hemostatic efficacy in case of surgery 
Intra- and postoperative blood loss in case of surgery 
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. 

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

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

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

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

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

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

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

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

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21. SUPPLEMENTS 
21.1 Study Flow Charts 
Figure 1  
Study Design for Baxalta Clinical Study 261303 
 
PHA = Patient with severe Hemophilia A 
PK = Assessment of individual PK parameters 
R = Randomization 
 

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

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

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

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PK Assessment 
Subjects transitioning from another BAX 855 study who have already had a PK assessment may have to 
repeat the PK assessment based on the sponsor’s evaluation. The PK assessment has to be performed after a 
wash-out period of at least 72-96 h depending on the FVIII concentrate used and the patient should not be 
actively bleeding.  
Blood sampling after infusion of BAX 855 for PK assessments will be performed over a 4-day period.  
• Review and discuss subject diary 
At the pre-infusion time point, the following assessments will be carried out: 
• Laboratory Assessments (within 30 minutes of start of infusion): 
o 
FVIII assays 
o 
VWF antigen 
o 
TGA 
• Vital signs (within 15 minutes of start of infusion) 
Infusion: 
• Infusion of 60 ± 5 IU/kg BAX 855 
Post-infusion: 
• Laboratory Assessments: 
o 
FVIII assays and TGA at the post-infusion time points, 15-30 min, 3±0.5 h, 8±0.5 h, 
24±2 h , 48±2 h, 72±4 h and 96±4 h 
At 30 ± 5 min post-infusion: 
• Vital signs (body temperature, respiratory rate, pulse rate, and supine systolic and diastolic blood 
pressure) 
Throughout the visit, the following assessments will be carried out: 
• Physical examination 
• Adverse events 
• Concomitant medications and non-drug therapies 
Randomization 
Once the FVIII activity results are available and the PK parameters calculated, subjects will be randomized 
to one of the treatment 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 
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 
Visits following dose adjustment 
The washout periods are as follows: Low trough arm: 96 h (after the longer treatment interval of 4 days), 
72 h (after the short treatment interval of 3 days) or 84 h (3.5 day intervals); High trough arm: at least 48 h 
or when the subject reaches his/her baseline value, depending on the frequency of BAX 855 infusions. 
The subject must not be actively bleeding. 
These procedures will also be followed if a subject attends an additional visit to check trough FVIII levels 
prior to any dose readjustment. 
Before any other study-specific procedures are carried out: 
• EQ-5D, Patient Activity Level and Health Resource Use 
• Review and discuss subject diary 
• Re-evaluation of FVIII regimen based on pre-dose FVIII trough level from previous visit, if 
applicable, change in body weight. Note: before any dose adjustments are performed an additional 
visit should be scheduled in 14 days to reassess trough levels 
At the pre-infusion time point, the following assessments will be carried out: 
• Vital signs (within 15 minutes of start of infusion) 
• Laboratory Assessments: 
o 
FVIII, VWF Ag and TGA assays (within 30 minutes of start of infusion) 
• Immunogenicity tests (within 30 minutes of start of infusion): 
o 
Inhibitory antibodies to FVIII (Nijmegen assay) 
o 
Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG 
o 
Anti-CHO antibodies 
Infusion: 
• Infusion of PK-guided dose of BAX 855 
FVIII trough level measurement following dose adjustment 
Those subjects who had dose adjustment will undergo a repeat FVIII trough level measurement 
approximately 2 weeks following their dose adjustment. The measurement should be performed 
immediately prior to their next scheduled prophylactic infusion:  
Only the following assessment will be performed:  
• Laboratory Assessments: 
o 
FVIII, VWF Ag and TGA assays (within 30 minutes of start of infusion) 
 
Throughout the visit, the following assessments will be carried out: 
• Adverse events 
• Concomitant medications and non-drug therapies  
IP dispense 

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Phone Visits: 
7.5 months ± 2 weeks 
10.5 months ± 2 weeks 
If 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, 8±0.5 h, 
24±2 h , 48±2 h, 72±4 h and 96±4 h 
o 
At 30 ± 5 min post-infusion: 
• Vital signs (body temperature, respiratory rate, pulse rate, and supine systolic and diastolic blood 
pressure) 
Dispense IP 
Throughout the visit, the following assessments will be carried out: 
• Adverse events 
• Concomitant medications and non-drug therapies 

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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, 
8±0.5 h, 24±0.5 h 
48±2 h, 72±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 
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 
Continued on Next Page 

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Continued 
* 
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). 
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 
Completion/ 
Termination 
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 
Additional blood draw 
for further exploratory 
testingp 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
Continued on Next Page 

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Continued 
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.  
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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22. PERIOPERATIVE MANAGEMENT 
22.1 Dosing Schedule and requirements for major surgery  
22.1.1 General 
The dose and frequency of BAX 855 administered will be individualized based on the 
subject’s IR and half-life, if available, and the required FVIII target levels. 
The required units will be calculated according to the following formula: 
Required units (IU) = 
body weight (kg) x desired FVIII rise (IU/dL) x {reciprocal of IR} (IU/kg)/(IU/dL) 
Example: In case of an IR of 2.0 [IU/dL]/[IU/kg], the required units would be calculated 
using the following formula: 
body weight (kg) x desired FVIII rise (IU/dL) x 0.5 (IU/kg)/(IU/dL) 
If at any time during the study, a subject does not respond to BAX 855 therapy as 
anticipated either by the operating surgeon or hemophilia physician providing 
postoperative care, blood samples will be drawn for the determination of FVIII activity 
levels and inhibitory antibodies to FVIII. In the event of unexplained, excessive bleeding, 
the subject will be treated by whatever means necessary until adequate hemostasis is 
achieved. The use of adjunct antifibrinolytic therapy such as e.g. tranexamic acid is 
allowed if clinically indicated by the investigator and/or according to the standard of care 
of the subject’s institution. 
22.1.2 Preoperative and Loading Dose 
The subject will receive a loading dose calculated according to the formula described 
above in order to maintain a minimum target FVIII level as required by the category and 
type of surgery. The recommended loading dose will be calculated by the investigator. 
The initial loading dose will be administered within 60 minutes prior to surgery (prior to 
incision/intubation). Vials of varying potencies may be used to ensure adequate dosing. A 
blood sample for post infusion FVIII at 15 ± 5 minutes after completion of the initial 
loading dose will be drawn to ensure that the required FVIII levels have been obtained. 
Also, pre-infusion blood sample may be drawn within 30 minutes prior to the loading 
dose. Activated partial thromboplastin time (aPTT) will also be determined from the post 
infusion blood sample.  
In case of major surgery, FVIII target levels should be 80-100% of normal, in case of 
minor surgery FVIII levels should be at 30 - 60%. 

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If the FVIII activity results are not available within a reasonable time period prior to the 
start of surgery, at least the post-infusion value of the aPTT must be obtained. The FVIII 
activity level following the loading dose must be obtained within 4 hours of infusion of 
BAX 855 and dose adjustments must be performed as needed. 
The surgery may only start after normalization of the aPTT. 
If the aPTT is not normalized or the desired FVIII activity is not attained, a supplemental 
loading dose(s) of BAX 855 can be given at the discretion of the investigator. 
Subsequent infusions of BAX 855 should be preceded by measurement of residual FVIII 
levels and dose adjustments must be based on the most recent residual FVIII activity 
levels. 
22.1.3 Postoperative Dosing 
After the initial loading dose, an optional re-bolus sufficient to raise FVIII levels to the 
appropriate level as defined for the type of surgery may be administered after a blood 
sample for FVIII determination has been drawn and the required FVIII levels by the local 
laboratory have been determined. 
Note: 
A second FVIII activity level should be determined within preferably 6-8 h following 
major surgery and within 12 h at the latest, with dose adjustments as necessary on the day 
of surgery. 
ALL subsequent infusions of BAX 855 should be preceded by measurement of residual 
FVIII levels and the dose adjusted as needed. Dosing adjustments based on aPTT values 
are not allowed. Based on each individual PK parameters, ie, IR and half-life, if 
available, it is recommended that the following FVIII trough levels should be targeted for 
major surgery: 
• 
The first postoperative 72 hours (Day 1- Day 3): ≥ 80% 
• 
Postoperative Day 4 – Day 7: ≥ 50% (if not yet discharged) 
• 
Postoperative Day 8 to discharge (if not yet discharged): it is recommended that the 
FVIII levels should not fall below 30% (left to the discretion of the investigator 
depending on the postoperative course) 

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General postoperative treatment recommendations: 
• 
Treatment intervals should be tailored in order not to exceed supraphysiological 
peak FVIII levels of 180%. Therefore, the dose should be administered in 1-3 
infusions over 24 hours, most commonly in 2 infusions. 
• 
The dose may be increased to a maximum of 100 IU/kg, however, the peak level 
should not exceed 180%. 
Beginning postoperative Day 1 (ie, the day following the day of surgery) through 
discharge, subjects will have a BAX 855 pre-infusion (within 30 minutes) and after 
15±5 minutes a post-infusion FVIII level measurement at least once per day in order to 
assess the adequacy of factor replacement therapy during the postoperative period. For 
consistency, it is recommended that the daily blood draws are performed at the same time 
of the day, eg, morning blood draws. At a minimum, a blood sample for FVIII 
determination must be drawn prior to any supplemental unscheduled FVIII infusion. 
Figure 3 is a visualization of timing and target FVIII levels for major surgery. 

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Figure 3  
Dosing Recommendations for Major Surgeries 
 

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22.2 Efficacy assessment 
22.2.1 Intra-, Post-, and Perioperative Hemostatic Efficacy 
The hemostatic efficacy will be assessed during (Table 5) and after (Table 6) any surgical 
or invasive procedures, and overall as a perioperative assessment (Table 7). 
Table 5  
Intraoperative Efficacy Assessment Scale 
 
Prior to the discharge from the recovery room, the operating surgeon will assess the 
intraoperative hemostatic efficacy compared to that expected for the type of procedure 
performed in a non-hemophilic population 
Rating 
Criteria 
Score 
Excellent 
Intraoperative blood loss was less than or equal to that expected (≤100%) 
3 
Good 
Intraoperative blood loss was up to 50% more than expected (101-150%) 
2 
Fair 
Intraoperative blood loss was more than 50% of that expected (>150%) 
1 
None 
Uncontrolled hemorrhage that was the result of inadequate therapeutic response 
despite proper dosing, necessitating rescue therapy  
0 
 
Table 6  
Postoperative Efficacy Assessment Scale (Postoperative Day 1) 
 
On postoperative Day 1, the operating surgeon will assess the postoperative hemostatic 
efficacy compared to that expected for the type of procedure performed in a non-hemophilic 
population 
Rating 
Criteria 
Score 
Excellent 
Postoperative blood loss was less than or equal to (≤100%) that expected 
3 
Good 
Postoperative blood loss was up to 50% more (101-150%) than expected 
2 
Fair 
Postoperative blood loss was more than 50% (>150%) of that expected 
1 
None 
Significant postoperative bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating rescue therapy  
0 
 

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Table 7  
Perioperative Efficacy Assessment Scale (at discharge or 14 days post-surgery, 
whichever is first) 
 
At discharge or 14 days post-surgery, whichever is first, a hematologist will assess the 
perioperative efficacy compared to that expected for the type of procedure performed in a non-
hemophilic population 
Rating 
Criteria 
Score 
Excellent 
Perioperative blood loss was less than or equal to (≤100%) that expected  
Required blood components for transfusions were less than or similar to that expected 
3 
Good 
Perioperative blood loss was up to 50% more (101-150%) than expected 
Required blood components for transfusions were less than or similar to that expected 
2 
Fair 
Perioperative blood loss was more than 50% of that expected (>150%) 
Required blood components transfusions were greater than that expected 
1 
None 
Significant perioperative bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating rescue therapy  
Required blood components for transfusions were substantially greater than expected  
0 
22.2.2 Intra- and Postoperative Blood Loss 
The observed versus predicted operative blood loss will be described for the period from 
initiation of the intervention to discharge or 14 days after the intervention, whichever is 
first. 
Prior to the surgery, the surgeon/investigator will predict the estimated volume (mL) of 
the expected average and maximum blood loss for the planned surgical intervention in a 
hemostatically normal individual of the same sex, age, and stature as the study subject, 
for intraoperative, postoperative and overall perioperative time periods. Every effort 
should be made to predict the volume as precisely as possible, also taking into account, 
for example, the use of a tourniquet or placement of a postoperative drain and whether or 
not suction is used. The estimate will be for the intraoperative time period from 
completion of the procedure until approximately 24 hours post-surgery and for the overall 
perioperative time period (assessed at discharge or 14 days after the intervention, 
whichever is first). 
The intraoperative blood loss will be measured by determining the volume of blood and 
fluid removal through suction into the collection container (waste box and/or cell saver) 
and the estimated blood loss into swabs and towels during the procedure, per the 
anesthesiologist’s record. Post-operatively, blood loss will be determined by the drainage 
volume collected, which will mainly consist of drainage fluid via vacuum or gravity 
drain, as applicable. In cases where no drain is present, blood loss will be determined by 
the surgeon’s clinical judgment, as applicable or entered as “not available”. 

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

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

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

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

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

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

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

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