A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 50% Reduced Volume and of Faster Infusion Rates in Patients With Hemophilia A or B With Inhibitors
Phase: PHASE3
Conditions: Hemophilia A or B With Inhibitors
Sponsor: Baxalta now part of Shire

CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Protocol Versions and Date:
Version 4.0: 07 March 2018
Version 3.0: 14 September 2017
Version 2.0: 04 August 2017
Version 1.0: 03 March 2016
Original Protocol: 08 October 2015
NCT02764489 
A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in 
Regular or 50% Reduced Volume and of Faster Infusion Rates in 
Patients With Hemophilia A or B With Inhibitors 
091501
Study Number: 

16.1.1 Protocol and Protocol Amendments
091501 Original Protocol 2015Oct08 
091501 Protocol Amendment 1 2016Mar03 
091501 Protocol Amendment 2 2017Aug04 
091501 Protocol Amendment 3 2017Sep14 
091501 Protocol Amendment 4 2018Mar07 
Takeda 
FEIBA 
Clinical Study Report: 091501
CONFIDENTIAL 
Page 1 of 414 
Appendix 16.1.1
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CLINICAL STUDY PROTOCOL
PRODUCT: Anti-inhibitor Coagulant Complex, FEIBA
STUDY TITLE: A Two-part, Phase 4, Prospective, Multicenter, Open-label, 
Randomized, Crossover Study of the PK and Safety of FEIBA Reconstituted in 
Regular or 50% Reduced Volume and the Safety of Faster Infusion Rates in 
Patients with Hemophilia A or B with Inhibitors
STUDY SHORT TITLE: FEIBA Reconstitution Volume Reduction and Faster 
Infusion Study
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 4
ORIGINAL: 2015 OCT 08
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-004079-60
IND NUMBER: 13715
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA 91362, 
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, 
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory)/Responsible Party
 MD
 Clinical Development
Baxalta US Inc.
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g., 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 ADVERSE EVENT ELECTRONIC 
CASE REPORT FORM (ECRF) 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT. IF THE 
ECRF IS NOT AVAILABLE THEN THE SAE MUST BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR TO MEET THE 24 HOUR TIMELINE 
REQUIREMENT.
See SAE Protocol Sections for further information and SAER form for contact 
information. 
Further details are also available in the study team roster.
For definitions and information on the assessment of these events, refer to the following:

Adverse Event, Section 12.1

Serious Adverse Event, Section 12.1.1.1

Assessment of Adverse Events, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
FEIBA, Anti-Inhibitor Coagulant Complex 
Name(s) of Active Ingredient(s)
Coagulation factors II, X, IX, and VIIa
CLINICAL CONDITION(S)/INDICATION(S)

Hemophilia A or B with inhibitors
PROTOCOL ID
091501
PROTOCOL TITLE
A Two-part, Phase 4, Prospective, Multicenter, Open-label, 
Randomized, Crossover Study of the PK and Safety of 
FEIBA Reconstituted in Regular or 50% Reduced Volume and 
the Safety of Faster Infusion Rates in Patients with Hemophilia 
A or B with Inhibitors
Short Title
FEIBA Reconstitution Volume Reduction and Faster Infusion 
Study
STUDY PHASE
Phase 4 (postmarketing)
PLANNED STUDY PERIOD
Initiation
First Subject In: Q2 2016
Primary Completion
Last Subject In: Q1 2017 
Study Completion
Last Subject Last Visit: Q1 2018
Duration
21 months 
STUDY OBJECTIVES AND PURPOSE
Study Purpose
1. To compare the pharmacokinetics (PK) of FEIBA (Factor Eight Inhibitor Bypassing Activity) 
component (Factor II [FII]) and safety of FEIBA reconstituted in a reduced volume of sterile water 
for injection (SWFI) versus regular volume SWFI, administered at the standard infusion rate of 
2 U/min/kg
2. To evaluate the safety of infusing reduced volume FEIBA at increased rates of 4 and 10 U/min/kg 
in comparison to the standard rate of 2 U/min/kg in Part 1 
Primary Objectives
1. Determine PK equivalence of FEIBA component (FII) reconstituted in 50% reduced volume 
SWFI and regular volume SWFI on area under the curve from time zero (preinfusion) to time 
216 hours (AUC0-216 h)
2. Determine the occurrence of severe allergic reactions (e.g., anaphylaxis)
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Secondary Objectives
1. Determine the safety and tolerability of 50% reduced volume FEIBA administered at the standard 
and escalated infusion rates, based on the occurrence of adverse events (AE)
2. Monitor clinically apparent thromboembolic events, changes in vital signs, infusion rate-related 
events, and infusion site reactions 
3. Determine the effect of 50% reduced volume FEIBA component (FII) on incremental recovery 
(IR), area under the curve from time zero (preinfusion) extrapolated to infinity (AUC0-∞), area 
under the concentration-time curve from time zero (preinfusion) to time of last quantifiable 
concentration (AUC0-last), terminal half-life (t1/2), clearance (CL), mean residence time (MRT), 
volume of distribution at steady state (Vss), maximum plasma concentration (Cmax), and time to 
maximum observed plasma concentration (tmax)
Exploratory Objective
 
2. Evaluate subject treatment preference using Treatment Satisfaction Questionnaire for Medication 
(TSQM) and patient preference questionnaire
STUDY DESIGN
Study Type/ Classification/ 
Discipline
PK Equivalence, Pharmacokinetic, and Safety
Control Type
Active
Study Indication Type
Treatment
Intervention model
Part 1:  Crossover
Part 2:  Sequential
Blinding/Masking
Part 1:  Randomized, Open-label
Part 2:  Non-randomized, Open-label
Study Design
This study is a 2-part, Phase 4, prospective, open-label, multicenter 
study to be conducted in at least 24 evaluable hemophilia A or B 
subjects with inhibitors (≥0.4 Bethesda units [BU] in hemophilia A 
and ≥0.6 BU in hemophilia B) for the primary PK assessment, (i.e., 
having the AUC0-216 h of FEIBA component FII estimable from both 
PK infusions), with a planned enrollment of 32 subjects.
In Part 1, subjects will be administered 2 different volumes of 
FEIBA in a randomized, crossover manner with a washout period 
between the treatments. Part 1 will evaluate the PK (FEIBA 
component FII) and safety of FEIBA reconstituted in 50% reduced 
volume of SWFI and administered at the standard infusion rate of 
2 U/min/kg compared with FEIBA reconstituted in regular volume 
of SWFI at the standard infusion rate. All subjects will be screened 
for eligibility based on the listed inclusion and exclusion criteria.
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After a washout period (at least 12 days from last treatment with 
FEIBA, or at least 24 hours after last treatment with a recombinant 
activated clotting factor VII (rFVIIa) product [e.g., NovoSeven®]), 
eligible subjects will be randomized (1:1) to receive 3 infusions of 
FEIBA reconstituted in 50% reduced volume SWFI followed by 
regular volume SWFI or vice versa. Subjects will receive the first
infusion for PK and safety analysis and the second and third infusions 
for collection of additional safety data. After a washout period of at 
least 12 days following the third infusion, subjects will crossover to 
the next treatment group where the fourth infusion will be for PK and 
safety analysis and the fifth and sixth infusions for collection of 
additional safety data.
All evaluable subjects will be included in the safety analysis set. 
Pharmacokinetic equivalence of FEIBA reconstituted in reduced and
regular volumes of SWFI in terms of AUC0-216 h will be evaluated 
using the PK population. 
Once the first 12 subjects have completed Part 1, the data monitoring 
committee (DMC) will review the safety and PK data and will provide 
a recommendation on whether these subjects can proceed to Part 2 for 
evaluation of increased infusion rates. The DMC will meet again after 
the final subject has completed Part 1 of the study. The DMC will then 
review all safety and PK data from Part 1 and provide a 
recommendation on whether the remaining subjects can proceed to 
Part 2. During the interim period (while subjects are waiting to 
proceed to Part 2), subjects will be provided with standard of care 
FEIBA (by the sponsor) for the treatment or prevention of bleeding 
episodes as determined by the investigator. A soft database lock will 
be in place on the records of the subjects who are undergoing DMC 
review. Subject recruitment and subjects in other phases of the study 
will not be affected by this database lock.
Part 2 is a non-randomized study with sequential enrollment of 
subjects who complete Part 1, to evaluate the safety of infusing 
FEIBA reconstituted in 50% reduced volume of SWFI at increased 
rates of 4 and 10 U/min/kg compared with the current standard rate of 
2 U/min/kg. Subjects will first be administered 3 infusions (Infusions 
7, 8, and 9) of FEIBA at the 4 U/min/kg rate. The infusions will be 
administered every 48 hours (+48 hours) to allow time to monitor 
safety and tolerability of the higher infusion rate. After the first 
12 subjects have completed Infusion 9, the DMC will review the 
safety data and provide a recommendation on whether these subjects 
can proceed to the next higher infusion rate of 10 U/min/kg.
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The DMC will meet again after the final subject has completed 
Infusion 9, and provide a recommendation on whether the remaining 
subjects can proceed to the faster infusion rate. A soft database lock 
will be in place on the records of the subjects who are undergoing 
DMC review. Subject recruitment and subjects in other phases of the 
study will not be affected by this database lock. Once subjects have 
been approved by the DMC to continue, they will then be given 
3 infusions (Infusions 10, 11, and 12) of FEIBA at the 10 U/min/kg 
rate. Infusions will again be administered every 48 hours (+48 hours)
to allow time to monitor safety and tolerability of the higher infusion 
rate. Following the last infusion, a study termination visit will be 
conducted within 7 days but no sooner than 72 hours after the last 
infusion.
All IP infusions will be administered at the hemophilia care 
centers/study sites. Each subject will receive a maximum of 14 IP
infusions total (most subjects will receive 12 IP infusions, up to 14 is 
for subjects who have a bleeding episode during PK collections, and 
therefore have their PK infusion reinfused). Subjects will receive 
FEIBA at a dose of 85 U/kg ± 100 U for all PK infusions (Infusions 1 
and 4) and 85 ± 15 U/kg for all other infusions (Infusions 2, 3, 5, and 
6, and all Part 2 infusions). During study participation, subjects will be 
provided with standard of care FEIBA (by the sponsor) for the 
treatment of bleeding episodes, and will be provided with standard of 
care FEIBA prophylaxis and/or treatment (by the sponsor) during 
interim DMC breaks, as determined by the investigator.
Planned Duration of Subject 
Participation
Study enrollment is planned to initiate in Q2 of 2016. It is planned that 
each subject will spend approximately 60 days in each portion of the 
study.  Additional time may be needed depending on the elapsed time 
between infusions, obtaining 12 evaluable subjects for DMC review, 
and the length of the DMC review period.  
Primary Outcome Measure 
1. AUC0-216 h of FEIBA component FII in the subjects
2. Occurrence of severe allergic reactions (e.g., anaphylaxis) 
Secondary Outcome Measure(s) 
Efficacy/Pharmacokinetics
1. Incremental recovery of FEIBA component FII in subjects
2. AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, and tmax of FEIBA component FII in subjects
Safety 
1. Evaluate occurrence of product-related AEs
2. Evaluate occurrence of infusion site reactions
3. Evaluate occurrence of all AEs occurring within 24 to 72 hours of IP infusion
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4. Evaluate occurrence of thromboembolic AEs
5. Evaluation of thrombotic markers (e.g., D-Dimers, prothrombin fragment F 1.2, 
thrombin/anti-thrombin complex [TAT], and fibrinopeptide A)
6. Evaluate vital signs and clinical laboratory assessments
Exploratory Outcome Measure(s)
2. Evaluate responses to the TSQM and the patient preference questionnaire
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: kit; powder, lyophilized, for solution/suspension;
injection
Dosage frequency: 12-14 study infusions
Mode of Administration: intravenous bolus
SUBJECT SELECTION
Targeted Accrual
Enroll 32 subjects (at least 24 evaluable for the primary PK 
assessment)
Number of Groups/Arms/Cohorts
1 cohort: at least 24 evaluable adult subjects (≥18 to ≤65 years old) 
for PK and safety evaluation
Inclusion Criteria
1. Subject is ≥18 to ≤65 years old at the time of screening
2. Hemophilia A or B of any severity, with a documented history of inhibitors requiring the use of 
bypassing agents (FEIBA or rFVIIa) 
3. Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain reaction (PCR); 
or HCV positive with stable hepatic disease
4. Human immunodeficiency virus (HIV) negative; or HIV positive with stable disease and cluster of 
differentiation 4 (CD4) count ≥200 cell/mm3 at screening
5. Adequate peripheral venous access
6. Subject is willing and able to comply with the requirements of the protocol
Exclusion Criteria
1. Known hypersensitivity to FEIBA or any of its components
2. Clinically symptomatic liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites)
3. Planned elective surgery during participation in this study (excluding minor procedures that will 
not need preventative bleeding treatments, such as exchanges of peripherally inserted central 
catheters)
4. Platelet count < 100,000/mL
5. Clinical or laboratory evidence of disseminated intravascular coagulation
6. Prior history or evidence of thromboembolic event: acute myocardial infarction, deep vein 
thrombosis, pulmonary embolism, etc.
7. Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that may increase the 
subject’s risk of thromboembolic complications 
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8. Subject is taking any immunomodulating drug (e.g., corticosteroid agents at a dose equivalent to 
hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to enrollment except anti-
retroviral chemotherapy
9. 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
10. Subject is a family member or employee of the investigator
11. Clinically significant medical, psychiatric or cognitive illness, or recreational drug/alcohol use 
that, in the opinion of the investigator, would affect subject safety or compliance 
STATISTICAL ANALYSIS
Sample Size Calculation
Part 1 (crossover) of this study will evaluate PK equivalence of FEIBA component (FII) in FEIBA 
reconstituted in 50% reduced volume versus regular volume of SWFI as measured by AUC0-216 h. The 
sample size was calculated for Type-1 (α) error level of 0.05 and a Type-II (β) error level of 0.1 or 90% 
power, under the assumption that the true (population) means are equivalent, i.e., the 90% confidence 
interval (CI) for the ratio of the geometric means between the 2 treatments are contained completely in the 
margins of equivalence defined as 80% to 125%. The within-subject variability was estimated by using the 
square root of mean square error (0.222) as in previous studies of FVIII. The required sample size was 
estimated to be 24 evaluable subjects. In order to obtain the required 24 subjects, Part 1 will randomize 
approximately 32 subjects for the crossover design, allowing for a possible 25% dropout rate.
With approximately 100 infusions for each treatment (reduced or regular volume of SWFI) administered 
for the study, the upper limit of the 95% CI of the rate of infusions with a specific AE is less than 3.3%, if 
the specific AE is not observed. The upper limit of the 95% CI of the rate of infusions for a specific AE is 
about 5% if 1 AE is observed.
Planned Statistical Analysis
Primary Analysis
For Part 1, a formal equivalence test will be made for AUC0-216 h of FII. All other PK parameters will be 
reported using descriptive statistics.
Log-transformed PK parameter AUC0-216 h of FII from the Infusions 1 and 4 will be analyzed using a linear 
mixed-effects model with sequence, period, and treatment (FEIBA reconstituted in 50% reduced volume 
and regular volume of SWFI) as fixed effects and subject as a random effect. To establish the equivalence,
the 90% CI for the ratio of the geometric means between the 2 treatments has to be contained completely in 
the margins of equivalence defined as 80% to 125%.
For Parts 1 and 2, the safety of treatment infusions will be evaluated primarily by the occurrence of severe 
allergic reactions and infusion site reactions by treatment for each study part. These will be statistically 
described and a 95% CI will be provided. 
Secondary and Exploratory Analysis
Levels of FEIBA components FII, 
 will be displayed graphically over time for each 
subject and summarized by visit and treatment for each study part. 
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The AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, tmax, and IR of FEIBA component FII will be summarized 
descriptively by visit and treatment for each study part.
The number and proportion of subjects experiencing serious and non-serious AEs up to study completion or 
subject withdrawal will be summarized by treatment. The number of product related serious and non-
serious AEs will also be summarized by treatment for each study part. 
Subgroup analyses will also be performed for events categorized as thromboembolic AEs. Thrombotic 
markers (e.g., D-Dimers, prothrombin fragment F 1.2, TAT, and fibrinopeptide A) will be summarized 
using descriptive statistics by treatment. Mean concentration plots will be presented by treatment and visit 
for each thrombotic marker and study part.
The results of the TSQM and the patient preference questionnaires will be summarized by descriptive 
statistics as appropriate. 
Vital signs and clinical laboratory assessments will be summarized descriptively by treatment for each 
study part at each scheduled assessment and for the corresponding change from baseline. Shift tables will 
also be presented for clinical laboratory assessments by treatment for each study part at each scheduled 
assessment.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory)/Responsible Party................................ 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 11
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 19
6.1 Description of Investigational Product ............................................................... 19
6.2 Clinical Condition/Indication .............................................................................. 20
6.3 Population to Be Studied...................................................................................... 20
6.4 Findings from Nonclinical and Clinical Studies................................................. 21
6.4.1 Finding from Nonclinical Studies................................................................. 21
6.4.2 Findings from Clinical Studies ..................................................................... 21
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 22
6.6 Compliance Statement.......................................................................................... 22
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 23
7.1 Study Purpose ....................................................................................................... 23
7.2 Primary Objectives............................................................................................... 23
7.3 Secondary Objectives ........................................................................................... 23
7.4 Exploratory Objective.......................................................................................... 23
8. STUDY DESIGN......................................................................................................... 24
8.1 Brief Summary...................................................................................................... 24
8.2 Study Design Rationale ........................................................................................ 24
8.3 Overall Study Design............................................................................................ 25
8.4 Duration of Study Period(s) and Subject Participation .................................... 27
8.5 Outcome Measures ............................................................................................... 27
8.5.1 Primary Outcome Measures......................................................................... 27
8.5.2 Secondary Outcome Measures ..................................................................... 27
8.5.2.1 Efficacy/Pharmacokinetics..................................................................... 27
8.5.2.2 Safety........................................................................................................ 27
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8.5.3 Exploratory Outcomes Measure .................................................................. 27
8.6 Randomization and Blinding............................................................................... 28
8.7 Study Stopping Rules............................................................................................ 28
8.8 Investigational Product(s).................................................................................... 28
8.8.1 Packaging, Labeling, and Storage................................................................ 28
8.8.2 Administration ............................................................................................... 29
8.8.3 Description of Treatment.............................................................................. 30
8.8.4 Management and Treatment of Break-Through Bleeding ........................ 35
8.8.5 Investigational Product Accountability....................................................... 36
8.9 Source Data ........................................................................................................... 37
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 38
9.1 Inclusion Criteria.................................................................................................. 38
9.2 Exclusion Criteria................................................................................................. 39
9.3 Withdrawal and Discontinuation ........................................................................ 39
10. STUDY PROCEDURES .......................................................................................... 41
10.1 Informed Consent and Enrollment ................................................................... 41
10.2 Subject Identification Code................................................................................ 41
10.3 Screening and Study Visits................................................................................. 41
10.3.1 Screening and Baseline Assessments.......................................................... 41
10.3.2 Treatment Visits........................................................................................... 43
10.3.2.1 Infusion Visits ....................................................................................... 43
10.3.3 PK only Visits............................................................................................... 44
10.3.4 Study Completion/Termination Visit......................................................... 44
10.4 Medications and Non-Drug Therapies.............................................................. 45
10.5 Subject Questionnaires....................................................................................... 46
10.6 Subject Diary....................................................................................................... 46
10.7 Subject Completion/Discontinuation ................................................................ 47
10.8 Procedures for Monitoring Subject Compliance............................................. 48
11. ASSESSMENT OF PHARMACOKINETICS....................................................... 49
11.1 Sample Collection and Processing..................................................................... 49
11.2 Pharmacokinetic Evaluation and Pharmacokinetic Parameters ................... 49
12. ASSESSMENT OF SAFETY................................................................................... 51
12.1 Adverse Events.................................................................................................... 51
12.1.1 Definitions..................................................................................................... 51
12.1.1.1 Serious Adverse Event.......................................................................... 51
12.1.1.2 Non-Serious Adverse Event ................................................................. 52
12.1.1.3 Unexpected Adverse Events................................................................. 52
12.1.1.4 Pre-existing Diseases............................................................................. 52
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12.1.2 Assessment of Adverse Events.................................................................... 53
12.1.2.1 Severity .................................................................................................. 54
12.1.2.2 Causality................................................................................................ 54
12.1.2.3 Safety Reporting ................................................................................... 55
12.1.3 Medical Device Safety reporting ................................................................ 56
12.2 Urgent Safety Measures ..................................................................................... 57
12.3 Untoward Medical Occurrences........................................................................ 57
12.4 Non-Medical Complaints ................................................................................... 57
12.5 Medical, Medication, and Non-Drug Therapy History................................... 58
12.6 Physical Examinations........................................................................................ 58
12.7 Clinical Laboratory Parameters........................................................................ 59
12.7.1 Hematology and Clinical Chemistry.......................................................... 59
12.7.2 Coagulation Testing..................................................................................... 59
12.7.3 Viral Serology............................................................................................... 60
12.7.4 CD4 Levels.................................................................................................... 60
12.7.5 Assessment of Laboratory Values .............................................................. 60
12.7.5.1 Assessment of Abnormal Laboratory Values..................................... 60
12.7.6 Biobanking.................................................................................................... 60
12.8 Vital Signs............................................................................................................ 61
12.9 Karnofsky Performance Test............................................................................. 61
12.10 Infusion Site Evaluations.................................................................................. 61
12.11 Special Treatment Considerations .................................................................. 62
13. STATISTICS............................................................................................................. 63
13.1 Sample Size and Power Calculations ................................................................ 63
13.2 Datasets and Analysis Cohorts .......................................................................... 63
13.3 Handling of Missing, Unused, and Spurious Data........................................... 64
13.4 Methods of Analysis............................................................................................ 64
13.4.1 Primary Outcome Measure......................................................................... 65
13.4.1.1 Analysis of the Primary PK Outcome Measure (Part 1)................... 65
13.4.1.2 Analysis of the Primary Safety Outcome Measure (Parts 1 and 2) . 65
13.4.2 Secondary Outcome Measures ................................................................... 66
13.4.2.1 Analysis of the Pharmacokinetic Outcome Measures....................... 66
13.4.2.2 Analysis of the Safety Outcome Measures ......................................... 66
13.4.3 Exploratory Outcome Measures ................................................................ 67
13.5 Planned Interim Analysis of the Study ............................................................. 67
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 67
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 68
15.1 Investigator’s Responsibility.............................................................................. 68
15.1.1 Final Clinical Study Report........................................................................ 68
15.2 Training ............................................................................................................... 68
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15.3 Monitoring........................................................................................................... 68
15.4 Auditing ............................................................................................................... 69
15.5 Non-Compliance with the Protocol ................................................................... 69
15.6 Laboratory and Reader Standardization ......................................................... 69
16. ETHICS ..................................................................................................................... 70
16.1 Subject Privacy ................................................................................................... 70
16.2 Ethics Committee and Regulatory Authorities................................................ 70
16.3 Informed Consent ............................................................................................... 70
16.4 Data Monitoring Committee.............................................................................. 71
17. DATA HANDLING AND RECORD KEEPING................................................... 72
17.1 Confidentiality Policy ......................................................................................... 72
17.2 Study Documentation and Case Report Forms ............................................... 72
17.3 Document and Data Retention........................................................................... 72
18. FINANCING AND INSURANCE........................................................................... 73
19. PUBLICATION POLICY........................................................................................ 73
20. SUPPLEMENTS....................................................................................................... 74
20.1 Study Flow Chart Part 1 .................................................................................... 74
20.2 Study Flow Chart Part 2 .................................................................................... 75
20.3 Schedule of Study Procedures and Assessments (Part 1)................................ 76
20.4 Schedule of Study Procedures and Assessments (Part 2)................................ 79
20.5 Clinical Laboratory Assessments ...................................................................... 81
20.6 Pharmacokinetic Assessments ........................................................................... 82
21. REFERENCES.......................................................................................................... 83
INVESTIGATOR ACKNOWLEDGEMENT.............................................................. 85
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Tables
Table 1 Schedule of Study Procedures and Assessments (Part 1).................................... 76
Table 2 Schedule of Study Procedures and Assessments (Part 2)................................... 79
Table 3 Clinical Laboratory Assessments......................................................................... 81
Table 4 PK Assessments................................................................................................... 82
Figures
Figure 1 Study Design for Part 1 Baxalta Clinical Study 091501 ................................... 74
Figure 2 Study Design for Part 2 Baxalta Clinical Study 091501 .................................... 75
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AICC
anti-inhibitor coagulant complex
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC0-216 h
area under the curve from time zero (preinfusion) to time 216 hours
AUC0-last
area under the curve from time zero (preinfusion) to the last quantifiable concentration
AUC0-∞
area under the curve from time zero (preinfusion) to infinity
BU
Bethesda units
BUN
blood urea nitrogen
BW
body weight
CBC
complete blood count
CD4
cluster of differentiation 4
CI
confidence interval
CL
clearance 
Cmax
maximum plasma concentration
CRF
case report form
DMC
Data Monitoring Committee
EC
ethics committee
EOI
end-of-infusion
eCRF
electronic case report form
EDC
electronic data capture
EDTA
Ethylenediaminetetraacetic acid
FEIBA
Factor Eight Inhibitor Bypassing Activity
FEIBA NF
Factor Eight Inhibitor Bypassing Activity Nanofiltered
FEIBA VH
Factor Eight Inhibitor Bypassing Activity Vapor Heated
FII
Factor II
FIX
Factor IX
FVII
Factor VII
FVIII
Factor VIII
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Abbreviation
Definition
FVIII:CAg
Factor VIII C antigen
FX
Factor X
GCP
Good Clinical Practice
HAV
hepatitis A virus
HBsAg
hepatitis B surface antigen
HBV
hepatitis B
Hct
hematocrit
HCV
hepatitis C virus
Hgb
hemoglobin
HIV
human immunodeficiency virus 
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IgG
immumoglobulin G
IgM
immunoglobulin M
IP
investigational product
IR
incremental recovery
IRB
Institutional Review Board
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
Min
minutes
MRT
mean residence time 
NMC 
non-medical complaint
PCR
polymerase chain reaction
PK
Pharmacokinetic(s)
PT
prothrombin time
rFVIIa
recombinant activated clotting factor VII
RBC
red blood cell
Rsq
r2
SAE
serious adverse event
SAER
serious adverse event report
SIC
subject identification code
SI
serious injuries
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Abbreviation
Definition
SWFI
sterile water for injection
t1/2
terminal half-life
TAT
thrombin/anti-thrombin complex
tmax
Time to maximum observed plasma concentration
TSQM
Treatment Satisfaction Questionnaire for Medication
US CFR
US Code of Federal Regulations
Vss
volume of distribution at steady state
WBC
white blood cell
λz
terminal rate constant
%AUCex
percentage of AUC obtained by extrapolation
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Note: Labeling has been updated since the Investigator Brochure (IB), and Factor Eight 
Inhibitor Bypassing Activity Nanofiltered (FEIBA NF) referenced in the background 
section is now referenced as FEIBA throughout the rest of the protocol.
The investigational product (IP), FEIBA NFi is a plasma derived, activated prothrombin 
complex concentrate, generically identified as an anti-inhibitor coagulant complex 
(AICC). FEIBA was developed to treat bleeding episodes and cover surgical 
interventions in hemophilia A and B patients with inhibitors and in non-hemophilia 
patients with acquired inhibitors.ii FEIBA was marketed beginning in 1978 and was 
superseded in 1985 by a 2-stage vapor heat-treated product, FEIBA VH. Nanofiltration 
was introduced to the manufacturing process in 2006 to produce FEIBA NF. Factor Eight 
Inhibitor Bypassing Activity Nanofiltered shares the same indications as FEIBA VH 
(control of bleeding episodes and to cover surgical interventions in hemophilia A and B 
patients with inhibitors), and is also intended for use as a prophylactic treatment for 
hemophilia A and B subjects with high-responding inhibitors and frequent joint 
bleeding.iii,1,2,3
Replacement therapy for the treatment of hemophilia A, and less frequently 
hemophilia B, can be complicated by an immune response resulting in the production of 
inhibitory alloantibodies to Factor VIII (FVIII) or Factor IX (FIX), especially in patients 
with moderate to severe hemophilia. The development of such inhibitory antibodies 
currently represents the most serious complication of hemophilia treatment. The presence 
of inhibitors against FVIII generally precludes the efficacious use of human FVIII 
replacement therapy. A substantial portion of patients with FVIII inhibitors have 
high-responding, high-titer inhibitors (> 5 Bethesda units [BU]). These patients exhibit an 
anamnestic response after FVIII exposure, sometimes with a dramatic increase in 
inhibitory antibody titer.4,5 The inability to provide FVIII replacement therapy 
predisposes this group of patients to increased morbidity and mortality compared with 
hemophilia patients without inhibitors.4 Several therapeutic approaches are currently 
available in the management of hemorrhagic events in patients who have developed 
FVIII inhibitors. These include neutralization with high doses of human FVIII (low titer 
                                                
i
FEIBA NF is a trademark of Baxalta Inc. US and Baxalta Innovations GmbH.
ii
Anti-Inhibitor Coagulant Complex, FEIBA Vapor Heated. Package Insert, Baxalta US Inc., Westlake 
Village, CA.
iii
Protocol 090701. FEIBA NF: A Prospective, Open-label, Randomized, Parallel Study to Evaluate 
Efficacy and Safety of Prophylactic versus On-demand Treatment in Subjects with Hemophilia A and B 
and High Titer Inhibitor. 2013 Jan 14, Baxalta US Inc., (Westlake Village, CA).
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inhibitor only), and treatment with bypassing agents such as Activated Prothrombin 
Complex Concentrates (APCCs), or activated recombinant factor VII (rFVIIa). Among 
these treatment options, only APCCs and rFVIIa are able to control acute hemorrhages in 
hemophilia patients with high titer inhibitors. These agents control bleeding by promoting 
the conversion of prothrombin to thrombin with subsequent fibrin polymerization and 
clot formation via mechanisms that do not require FVIII or FIX. It has been proposed that 
FEIBA products achieve this goal principally by virtue of the presence of a “partial 
prothrombinase complex” consisting of activated Factor X (FX) and prothrombin.6
The active ingredient of FEIBA is a plasma-derived, freeze-dried APCC with FVIII 
inhibitor bypassing activity. The product FEIBA contains mainly non-activated forms of 
the 3 coagulation factors, Factor II (FII), FIX and FX, as well as activated FVII; and 
Factor III coagulant antigen present in a concentration of up to 0.1 U/1 U FEIBA. A 
solution containing 1 U FEIBA shortens the activated partial thromboplastin time (aPTT) 
of FVIII inhibitor plasma up to 50% of the buffer value. Additional details can be found 
in the FEIBA IB.iv
6.2 Clinical Condition/Indication 
Hemophilia is an X-linked, recessive, congenital bleeding disorder caused by deficient or 
defective coagulation due to a deficiency in FVIII (hemophilia A), or FIX 
(hemophilia B).The absence of FVIII or FIX leads to spontaneous bleeding episodes 
(occurring primarily in joints, muscles, and less commonly, in soft tissues) and to 
excessive bleeding following trauma or injury.7,8 A serious complication in the treatment 
of hemophilia is inhibitor formation. Patients with inhibitors experience more difficulty 
in treating bleeds than those patients who do not develop inhibitors.
The intended indication for FEIBA NF is treatment and prophylaxis of bleeding in 
hemophilia A and B patients with inhibitors, and to cover surgical interventions.
6.3 Population to Be Studied
Adult subjects (age ≥18 to ≤65 years) with hemophilia A or B of any severity, of all 
races and ethnic groups will be studied. All subjects will have a documented history of 
inhibitors requiring the use of bypassing agents (FEIBA or rFVIIa). Subjects will either 
be hepatitis C virus (HCV) negative or HCV positive with stable hepatic disease. 
Subjects will either be human immunodeficiency virus (HIV) negative or HIV positive 
with stable disease and a cluster of differentiation 4 (CD4) count ≥ 200 cell/mm3.
                                                
iv
Investigator’s brochure. Anti-inhibitor coagulant complex nanofiltered; FEIBA NF. 2013 APR 22. 
Baxalta US Inc., (Westlake Village, CA). 
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6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Finding from Nonclinical Studies
The nonclinical studies performed for FEIBA NF included a virus clearance study, which
was performed to investigate the virus reduction capacity of the nanofiltration step in the 
manufacturing of FEIBA NF. 
Preclinical studies have demonstrated FEIBA NF to have comparable activity and other 
biochemical properties to FEIBA VH.
Data from nonclinical studies can be found in the FEIBA NF IB.iv Preclinical studies 
have demonstrated FEIBA NF to have comparable activity and other biochemical 
properties to FEIBA VH.
6.4.2 Findings from Clinical Studies
The results of Baxalta clinical study 090701iii demonstrated that prophylaxis with 
FEIBA NF significantly reduced the annualized bleeding episode rates for spontaneous, 
traumatic, joint, non-joint, spontaneous-joint, spontaneous-non-joint, and traumatic-joint 
bleeding episodes when compared with on-demand treatment. A statistically significant 
reduction in the rate of bleeding episodes in new target joints in the prophylaxis arm 
versus the on-demand arm was also observed. An examination of adverse events (AEs), 
abnormal laboratory parameters for hematology and clinical chemistry and vital signs 
demonstrated that FEIBA NF was safe and well tolerated for prophylactic use. Clinically, 
these data suggest that both on-demand and prophylaxis regimens were safe and 
efficacious in the management of hemophilia A or B with persistent high- or low-titer 
inhibitors refractory to FVIII or FIX treatment, and further confirmed the safety and 
effectiveness of FEIBA NF for controlling and preventing bleeding episodes.
Baxalta clinical study 091002 was an open, uncontrolled, non-interventional 
observational cohort study of FEIBA NF in hemophiliacs with inhibitors. This study was
designed to document routine usage of FEIBA NF as an inhibitor-bypassing agent for on-
demand or prophylactic treatment in everyday clinical practice and in surgical 
intervention. The safety results of this postauthorization safety study showed that
treatment with FEIBA NF, administered in 81 subjects with hemophilia and requiring 
treatment with inhibitor-bypass therapy for bleed resolution or bleed prophylaxis, was 
well tolerated. Treatment-related AEs or serious adverse events (SAEs) were reported 
in 9.9% and in 3.7% of subjects, respectively. A deep venous thrombosis and a 
superficial thrombophlebitis were observed in 1 subject with acquired hemophilia.
The hemostatic effectiveness was rated by the physicians as excellent or good in more 
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than 90% of total subjects, with the highest rates reported in subjects with FEIBA NF 
prescribed as regular prophylaxis. Additional details on this study can be found in the 
clinical study report.v
Additional observational, non-interventional studies were conducted with FEIBA NF. 
Additional details on clinical studies can be found in the FEIBA NF IB.iv
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
The FEIBA NF products can precipitate allergic-type hypersensitivity reactions that have 
included, urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and a 
drop in blood pressure; these reactions can be severe and can be systemic (e.g., 
anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other 
infusion reactions, such as chills, pyrexia, and hypertension have also been reported. The 
most commonly reported adverse drug reactions described for FEIBA NF include
increase in inhibitor titer, somnolence, dizziness, dysgeusia, dyspnea, nausea, chills, 
pyrexia, chest pain, and chest discomfort. 
The possibility of thrombotic events should be considered when systemic 
anti-fibrinolytics such as aminocaproic acid and tranexamic acid are used in combination 
with FEIBA NF. Therefore, antifibrinolytics should not be used for approximately 6 to 
12 hours before or after the administration of FEIBA NF.
Animal reproduction studies have not been conducted with FEIBA NF. There are no 
adequate and well-controlled studies in pregnant women. It is also not known whether 
FEIBA NF can cause fetal harm when administered to a pregnant woman or an affect 
reproductive capacity. It is not known whether FEIBA NF is excreted in human milk.9
Subjects within the study should be warned regarding this labeling information.
Additional safety experience for FEIBA is provided in the FEIBA NF IB.iv
6.6 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.
                                                
v
Clinical Study Report. Post-Authorization Safety Study of FEIBA NF (Factor VIII Inhibitor Bypassing 
Activity). An open, uncontrolled, non-interventional observational cohort study of FEIBA NF in 
hemophiliacs with inhibitors. 10 Oct 2014. Baxalta Inc. US and Baxalta Innovations GmbH.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is:
1. To compare the pharmacokinetics (PK) of FEIBA component (FII) and safety of 
FEIBA reconstituted in a reduced volume of sterile water for injection (SWFI) 
versus regular volume SWFI, administered at the standard infusion rate of 
2 U/min/kg
2. To evaluate the safety of infusing reduced volume FEIBA at increased rates of 
4 and 10 U/min/kg in comparison to the standard rate of 2 U/min/kg in Part 1
7.2 Primary Objectives
The primary objectives are to determine PK equivalence of FEIBA component (FII)
reconstituted in 50% reduced volume SWFI and regular volume SWFI on area under the 
curve from time zero (preinfusion) to time 216 hours (AUC0-216 h), and to determine the 
occurrence of severe allergic reactions (e.g., anaphylaxis).
7.3 Secondary Objectives
1. Determine the safety and tolerability of 50% reduced volume FEIBA
administered at the standard and escalated infusion rates, based on the occurrence 
of AEs
2. Monitor clinically apparent thromboembolic events, changes in vital signs, 
infusion rate-related events, and infusion site reactions 
3. Determine the effect of 50% reduced volume FEIBA component (FII) on 
incremental recovery (IR), area under the curve from time zero (preinfusion) to 
extrapolated to infinity (AUC0-∞), area under the concentration time curve from 
time zero (preinfusion) to time of last quantifiable concentration (AUC0-last), 
terminal half-life (t1/2), clearance (CL), mean residence time (MRT), volume of 
distribution at steady state (Vss), maximum plasma concentration (Cmax), and time 
to maximum observed plasma concentration (tmax)
7.4 Exploratory Objective
 
2. Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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8. STUDY DESIGN
8.1 Brief Summary
This is a 2-part Phase 4, prospective, open-label, multicenter study to be conducted in 
at least 24 evaluable hemophilia A or B subjects with inhibitors (≥0.4 BU in 
hemophilia A and ≥0.6 BU in hemophilia B) for the primary PK assessment, (i.e., 
having the AUC0-216 h of FEIBA component FII estimable from both PK infusions), 
with a planned enrollment of 32 subjects. All subjects will receive 3 infusions of FEIBA 
reconstituted in a regular volume of SWFI, and 3 infusions of FEIBA reconstituted in 
50% reduced volume of SWFI, with all 6 of these infusions being given at a rate of 
2 U/min/kg within Part 1 of the study. In Part 2 of the study, all subjects will receive 
3 infusions of FEIBA reconstituted in 50% reduced volume of SWFI at 4 U/min/kg 
followed by 3 infusions FEIBA reduced volume at a rate of 10 U/min/kg. All subjects 
will undergo PK evaluation in Part 1 of the study.
8.2 Study Design Rationale
This study has been designed as a 2-way crossover study in order to assess for PK 
bioequivalence analysis. By designing it as a crossover study, subjects serve as their own 
controls, reducing the number of subjects needed for the study by half. This study is 
open-label because it is a change in infusion volume and infusion rate, which would be 
difficult to properly blind. The goal of the study is to demonstrate PK bioequivalence of 
FEIBA in reduced volume SWFI to FEIBA regular volume SWFI, and then to increase 
the rate that this reduced volume can be infused. By being able to reduce the volume and 
speed of the infusion, subjects will be able to spend less time infusing. 
As there are washout periods, and interim breaks within the study design in which 
subjects will not be receiving IP, steps have been taken to protect them from bleeding 
episodes. If a subject has a bleeding episode during a washout period, he or she will be 
treated with standard of care FEIBA to control the bleeding, with a washout period 
beginning after the last infusion of FEIBA.  Once the washout period is complete, the 
study can restart from the last infusion time point. During the interim period (data 
monitoring committee [DMC] review period), subjects will be provided with FEIBA (by 
the sponsor) for the treatment or prevention of bleeding episodes as determined by the 
investigator. Subjects will record their treatments and bleeding episodes in a subject diary 
for review by the study team.
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8.3 Overall Study Design 
This is a 2-part Phase 4, prospective, open-label, multicenter study to compare PK and 
safety of FEIBA reconstituted in reduced versus regular volume of SWFI, and to evaluate 
the safety of infusing reduced volume FEIBA at increased rates of 4 and 10 U/min/kg in 
comparison with the standard rate of 2 U/min/kg, in approximately 32 subjects (at least 
24 evaluable) with hemophilia A or B with inhibitors (≥0.4 BU in hemophilia A and 
≥0.6 BU in hemophilia B), with the AUC0-216 h of FEIBA component FII estimable from 
both PK infusions. The overall study design is illustrated in Figure 1 and Figure 2.
In Part 1, subjects will be administered 2 different volumes of FEIBA in a randomized, 
crossover manner with a washout period between the treatments. Both volumes will be 
given at the standard infusion rate of 2 U/min/kg. After infusion, subjects should be 
observed for 30 minutes in the clinic. For PK infusions and collections, accommodations 
can be made for convenience or to ensure compliance with PK sampling. See 
Section 10.3.2 for details. A DMC review will be conducted after the first 12 subjects 
have completed Part 1, and then again after the last subject has completed Part 1 of the 
study. The DMC will provide recommendations for proceeding to Part 2, for both subsets 
of subjects. During the interim period (DMC review period), subjects will be provided 
with FEIBA (by the sponsor) for the treatment or prevention of bleeding episodes as 
determined by the investigator. Subjects will record their treatments and bleeding 
episodes in a subject diary for review by the study team. A soft database lock will be in 
place on the records of the subjects who are undergoing DMC review. This soft lock will 
prevent new data or data changes for these subjects, which will be unlocked following 
DMC review. Subject recruitment and subjects in other phases of the study will not be 
affected by this soft database lock.
Treatments regimens during Part 1 of the study are:

Part 1 Sequence A: 
1. FEIBA 2 U/min/kg in regular volume SWFI (Infusions 1, 2, and 3)
2. Washout period
3. FEIBA 2 U/min/kg in 50% reduced volume SWFI (Infusions 4, 5, and 6)

Part 1 Sequence B: 
1. FEIBA 2 U/min/kg in 50% reduced volume SWFI (Infusions 1, 2, and 3) 
2. Washout period
3. FEIBA 2 U/min/kg in regular volume SWFI (Infusions 4, 5, and 6)
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
Infusion dose:
1. Infusions 1 and 4: 85 U/kg ± 100 U
2. All other infusions: 85 ± 15 U/kg
Prior to the first infusion of FEIBA (Sequence A or B), subjects will undergo a washout 
period of at least 12 days from last treatment with APCC (e.g., FEIBA), or at least 1 day 
after the last treatment with an rFVIIa product (e.g., NovoSeven®). 
Part 2 is a non-randomized study with sequential enrollment of subjects who complete 
Part 1 to evaluate FEIBA reconstituted in 50% reduced volume of SWFI at increased 
rates of 4 and 10 U/min/kg. All subjects will receive the 4 U/min/kg treatment during the 
first treatment phase, then there will be an interim period for a DMC review (after the
first 12 subjects have completed Infusion 9, and again after the last subject has completed 
Infusion 9). The DMC will then provide recommendations regarding each subset of 
subjects proceeding to the increased rate of 10 U/min/kg during the second treatment 
phase. During the interim period (DMC review period), subjects will be provided with 
FEIBA (by the sponsor) for the treatment or prevention of bleeding episodes as 
determined by the investigator. Subjects will record their treatments and bleeding 
episodes in a subject diary for review by the study team. A soft database lock will be in 
place on the records of the subjects who are undergoing DMC review. Subject 
recruitment and subjects in other phases of the study will not be affected by this database 
lock. The treatment phases within Part 2 of the study are as follows:

First treatment phase: 4 U/min/kg (3 infusions) 

Second treatment phase: 10 U/min/kg (3 infusions)
All infusions will be administered at the hemophilia care centers/study sites. 
Pharmacokinetic collections may be performed at the hemophilia care centers/study sites 
or appropriate ambulatory centers. Each subject will receive a maximum of 14 IP
infusions total (most subjects will receive 6 in Part 1 and 6 in Part 2, the additional 
2 infusions are for reinfusing PK infusions if a bleeding event occurred during the 9 day 
PK collection). Subjects will receive FEIBA at a dose of 85 U/kg ± 100 U for all PK 
infusions (Infusions 1 and 4) and 85 ± 15 U/kg for all other infusions (Infusions 2, 3, 5, 6, 
and all Part 2 infusions). After each infusion, subjects should be observed for 30 minutes 
in the clinic. During study participation, subjects will be provided FEIBA for treatment of 
break-through bleeding (by the sponsor). Additional details on study design and timing 
are described in Section 8.8.3. For additional details on managing bleeding episodes, see 
Section 8.8.4.
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8.4 Duration of Study Period(s) and Subject Participation
The overall duration of the study is 21 months from study initiation (i.e., first subject 
enrolled) to study completion (i.e., last subject last visit). The recruitment period is 
expected to be approximately 9 to 12 months.
The subject participation period is 8 to 10 months from enrollment to subject completion 
(i.e., last study visit), unless prematurely discontinued.
8.5 Outcome Measures
8.5.1 Primary Outcome Measures
The primary outcome measures are:
1. AUC0-216 h of FEIBA component FII in subjects
2. Occurrence of severe allergic reactions (e.g., anaphylaxis)
8.5.2 Secondary Outcome Measures
8.5.2.1 Efficacy/Pharmacokinetics 
1. Incremental recovery of FEIBA component FII in subjects
2. AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, and tmax of FEIBA component FII in 
subjects
8.5.2.2 Safety
1. Evaluate occurrence of product-related AEs
2. Evaluate occurrence of infusion site reactions
3. Evaluate occurrence of all AEs occurring within 24 to 72 hours of IP infusion
4. Evaluate occurrence of thromboembolic AEs
5. Evaluation of thrombotic markers (e.g., D-Dimers, prothrombin fragment F 1.2, 
thrombin/anti-thrombin complex [TAT], and fibrinopeptide A)
6. Evaluate vital signs and clinical laboratory assessments
8.5.3 Exploratory Outcomes Measure
 
 
2. Evaluate responses to the TSQM and the patient preference questionnaires
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8.6 Randomization and Blinding
Part 1 of this study is a randomized, crossover, active treatment clinical study. In order to 
minimize/avoid bias, subjects will be randomly assigned to 1 of 2 treatment regimens 
(Sequence A: FEIBA regular volume of SWFI followed by FEIBA reduced volume of 
SWFI or Sequence B: FEIBA reduced volume of SWFI followed by FEIBA regular 
volume SWFI) in equal numbers. Part 2 of this study is an open-label, sequential, active 
treatment clinical study. In Part 2, all subjects will receive FEIBA reduced volume of 
SWFI at 2 varying rates of infusion. 
8.7 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1. If 2 or more subjects develop anaphylaxis following exposure to FEIBA 
(enrollment and treatment temporarily stopped pending further review by the 
DMC)
2. The sponsor or investigator, based on emerging data, considers there to be an 
unfavorable risk benefit
3. The sponsor or investigator considers continuation of the study unjustifiable for 
medical or ethical reasons
4. The DMC recommends study termination
8.8 Investigational Product(s)
8.8.1 Packaging, Labeling, and Storage
Note: Labeling has been updated since the IB, and FEIBA NF as previously referenced in 
Section 6 is now referenced as FEIBA.
The active ingredient of FEIBA is a plasma-derived, freeze-dried, APCC with FVIII 
inhibitor bypassing activity. Factor Eight Inhibitor Bypassing Activity will be provided in 
vials containing 350 to 650 U/vial (nominal potency 500 U), 700 to 1300 U/vial 
(nominal potency 1,000 U) or 1750 to 3250 U/vial (nominal potency 2500 U). FEIBA 
contains mainly non-activated forms of the 3 coagulation factors, FII, FIX, and FX, as 
well as activated FVII; and Factor VIII coagulant antigen (FVIII:CAg) present in a 
concentration of up to 0.1 U/1 U FEIBA. The factors of the kallikrein-kinin system are 
present only in trace amounts, if at all. A solution containing 1 U FEIBA shortens the 
aPTT of FVIII inhibitor plasma to 50% of the buffer value. The product is supplied as 
freeze-dried powder or friable solid of white to off-white or pale green color.
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Factor Eight Inhibitor Bypassing Activity can be stored at room temperature, not to 
exceed 25°C (77°F). Factor Eight Inhibitor Bypassing Activity should not be allowed to 
freeze, and should be protected from light. Although the chemical and physical stability 
of the reconstituted product has been demonstrated for 6 hours at room temperature (up to 
25°C), in consideration of sterility, infusion of FEIBA should be commenced as promptly 
as practical, but must be completed within 3 hours following reconstitution. 
Reconstituted product must not be returned to the refrigerator.
Reconstitution can be performed using a BAXJECT II Hi-Flow needleless transfer 
device. For additional information, such as reconstitution instructions, please refer to the 
FEIBA product insert 9 and/or other specific instructions provided by the sponsor or 
sponsor’s representative.
8.8.2 Administration
Following reconstitution, FEIBA should be administered using an intravenous needle or 
infusion set with a winged adapter (ensure the use of plastic luer lock syringes as proteins 
within FEIBA can adhere to glass). The standard infusion rate of FEIBA is a slow bolus 
injection, with an infusion rate of 2 U/kg body weight (BW) per minute, which in a 75-kg 
subject, corresponds to an infusion rate of approximately 2.4 to 7.5 mL/minute depending 
on the potency (see label on vial). This rate will be modified depending on which part of 
the study the subject is in. Subjects will receive FEIBA at a dose of 85 U/kg ± 100 U for 
all PK infusions (Infusions 1 and 4) and 85 ± 15 U/kg for all other infusions (Infusions 2, 
3, 5, 6, and all Part 2 infusions). For additional details, see the FEIBA IB.iv Additional 
rates of 4 and 10 U/min/kg are also used in this study.
Mixing of FEIBA with other products or substances must be avoided. It is advisable to 
flush venous access lines with isotonic saline prior to and after infusion of FEIBA.
Dose calculation for FEIBA will be based on the stated actual potency on vials in 
respective lots. Information regarding lot used, the actual dose given, date of treatment, 
treatment start and stop times, as well as any infusion interruptions will be recorded in the 
electronic case report form (eCRF).
Subjects must be given the same lot for Infusion 1 and Infusion 4 in order to ensure 
comparable PK results.
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8.8.3 Description of Treatment
Part 1
Part 1 of the study uses a crossover design to evaluate the PK of FEIBA component FII 
and to evaluate the safety of FEIBA reconstituted in 50% reduced volume SWFI versus 
regular volume of SWFI (administered at the standard infusion rate of 2 U/min/kg). 
Part 2 is a non-randomized study with sequential enrollment of subjects who complete 
Part 1. Part 2 will evaluate the safety of infusing FEIBA reconstituted in 50% reduced 
volume of SWFI at increased rates of 4 and 10 U/min/kg.
All subjects will be screened for eligibility based on the listed inclusion and exclusion 
criteria. The subject’s medical history including hemophilia history, confirmation of 
inhibitors, bleeding episode history, and history of FEIBA or rFVIIa usage for the 
previous year will be collected at screening. Also recorded will be the date of last use of 
FEIBA or rFVIIa treatment. Results of the screening assessments will be used to establish 
a subject’s eligibility for the study.
After eligibility is established, the duration of the washout period will be determined. The 
washout period is based on the subject’s last dose of FEIBA or rFVIIa. Due to the 
varying lengths of the half-lives of the components, subjects who have received FEIBA
will need to wait 12 days from their last dose of FEIBA before they can receive Infusion 
1 of the study. Subjects who have previously been treated with rFVIIa (e.g., NovoSeven), 
will need to wait at least 24 hours from the last dose of rFVIIa treatment before they can 
begin Infusion 1 of the study (in agreement with the reported half-life of 2.6 to 3.9 hours
of FVII). Additional days beyond the minimum of 1 or 12 days (treatment dependent) is 
permissible since subjects have varying courses of treatments prior to their enrollment in 
the study (as long as screening procedures stay within the allotted time frame). Subjects 
who are on prophylactic therapy before the study, will need to have an appropriate 
washout period once eligibility is determined. For subjects who are on an on-demand
treatment to control bleeding, the washout begins from the last day they used treatment. If 
they have a bleeding episode that requires treatment during the washout period, the 
washout period must be restarted before they can proceed with the study. For additional 
details on bleeding control, see Section 8.8.4.
After the washout period is complete, eligible subjects will be randomized (1:1) into 
Part 1 of the study by interactive voice response system to receive 3 infusions of 
FEIBA reconstituted in 50% reduced volume SWFI followed by regular volume 
SWFI or vice versa. Subjects will receive the first infusion for PK and safety analysis 
and the second and third infusions for collection of additional safety data. 
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The first infusion will be given after randomization, and PK blood draws will be taken at 
the times described in Table 4. After the 216 hour PK draw (9 days after Infusion 1),
subjects will receive Infusion 2, and subjects will receive Infusion 3 forty-eight (+48) 
hours after Infusion 2. If bleeding occurs during the 9-day PK collection period, the PK 
collection will be stopped and the subject will be treated with FEIBA. Once bleeding is 
resolved, subjects will undergo a 12-day washout period before having the IP infusion 
and PK assessments repeated. If bleeding occurs again, the subject will be treated with 
FEIBA and subjects will continue to the next IP infusion, see Section 8.8.4.
After Infusion 3, subjects will go through a washout period of at least 12 days before 
crossing over to the next treatment group for Infusion 4. The 12 days is based on 
Infusion 3, since all subjects receive FEIBA at Infusion 3. If bleeding occurs during the 
washout period it will be treated with FEIBA and the washout period will be restarted. If 
bleeding has not resolved 72 hours after treatment with FEIBA, the investigator will treat 
the subject as appropriate to control the bleeding. If multiple bleeding episodes occur 
during the washout period, the investigator and sponsor should decide if it is more 
beneficial for the subject to be taken off study, see Section 8.8.4.
Infusion 4 will be the beginning of the new treatment regimen in the crossover scheme, 
and PK assessment will be completed for this infusion. Infusion 4 must be administered 
using the same lot of IP as Infusion 1. Infusion 4 will be given after the minimum of 
12-day washout period is complete, and PK blood draws will be taken at times described 
in Table 4. After the 216-hour PK draw (9 days after Infusion 4), subjects will receive 
Infusion 5, and subjects will receive Infusion 6 forty-eight (+48) hours after Infusion 5.
Part 1 Treatment Summary:

Part 1 Sequence A: 
1. FEIBA 2 U/min/kg in regular volume SWFI (Infusions 1, 2, and 3)
2. Washout period
3. FEIBA 2 U/min/kg in 50% reduced volume (Infusions 4, 5, and 6)

Part 1 Sequence B: 
1. FEIBA 2 U/min/kg in 50% reduced (Infusions 1, 2, and 3) 
2. Washout period
3. FEIBA 2 U/min/kg in regular volume SWFI (Infusions 4, 5, and 6)
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
Infusion dose
1. Infusions 1 and 4: 85 U/kg ± 100 U
2. All other infusions: 85 ± 15 U/kg
Additional details on study visits for Part 1 can be found in Section 10.3 and Table 1.
DMC of Part 1
All evaluable subjects will be included in the DMC review, however to help with subject 
retention in the study, the DMC review of Part 1 will be conducted twice; once after the 
first 12 subjects have completed Part 1, and then again after the last subject has 
completed Part 1. Once the first 12 subjects have completed Part 1, the DMC will review 
the safety and PK data and will provide a recommendation on whether these subjects can 
proceed to Part 2 for evaluation of increased infusion rates. The DMC will meet again 
after the final subject has completed Part 1 of the study. The DMC will then review all 
safety and PK data from Part 1 and provide a recommendation on whether the remaining 
subjects can proceed to Part 2. A soft database lock will be in place on the records of the 
subjects who are undergoing review. Subject recruitment and subjects in other phases of 
the study will not be affected by this database lock.
During the interim period, subjects who are on hold for DMC review will be provided 
with standard of care FEIBA (by the sponsor) for the treatment or prevention of bleeding 
episodes as determined by the investigator. The subject will continue completing the 
electronic subject diary during the interim break. The study team will be able to monitor 
the subject through real-time reporting from the electronic diary recording. No other 
study procedures beyond the diary completion will be conducted during the interim 
period. After the DMC review, subjects who have been reviewed and approved to 
continue by the DMC can then be scheduled to proceed with Part 2 of the study. No 
washout period will be required before the commencement of Part 2 since there is no PK 
analysis in Part 2 of the study; however, subjects should wait at least 48 hours after their 
last dose of FEIBA before restarting IP.
After each subset of subjects have completed Part 1, PK equivalence of FEIBA
reconstituted in reduced and regular volumes of SWFI in terms of AUC0-216 h of FII will 
be evaluated.
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Part 2
Part 2 is non-randomized and uses sequential enrollment of subjects who complete Part 1 
of the study. Subjects in Part 2 will first be administered 3 infusions (Infusions 7, 8, 
and 9) of FEIBA at the 4 U/min/kg rate. Infusion 7 can be given as soon as possible once 
the DMC has released the subjects from review; however, if they have received FEIBA
during the pause for DMC, they will need to wait at least 48 hours after their last FEIBA
dose before beginning Infusion 7. The infusions in Part 2 will be administered every 
48 hours (+48) to allow time to monitor safety and tolerability of the higher infusion rate. 
Infusion rates for the treatment phases in Part 2 are:

First treatment phase: 4 U/min/kg (Infusions 7, 8, and 9) 

Second treatment phase: 10 U/min/kg (Infusions 10, 11, and 12)
After the first 12 subjects have completed Infusion 9, the DMC will review the safety 
data and provide a recommendation on whether these subjects can proceed to the next 
higher infusion rate of 10 U/min/kg. The DMC will meet again after the final subject has 
completed Infusion 9, and provide a recommendation on whether the remaining subjects 
can proceed to the faster infusion rate. 
During the interim period, subjects who are on hold for DMC review will be provided 
with standard of care FEIBA (by the sponsor) for the treatment or prevention of bleeding 
episodes as determined by the investigator. The subject will continue completing the 
electronic subject diary during the interim break. The study team will be able to monitor 
the subject through real-time reporting from the electronic diary recording. No other 
study procedures beyond the diary completion will be conducted during the interim 
period. After the DMC review, subjects who have been reviewed and approved to 
continue by the DMC can be scheduled to begin the 10 U/min/kg infusion. No washout 
period will be required before the commencement of the 10 U/min/kg infusion since there 
is no PK analysis in Part 2 of the study; however, subjects should wait at least 48 hours 
after their last dose of FEIBA before restarting IP.
Once subjects have been approved by the DMC to continue, they will be given 
3 infusions (Infusions 10, 11, and 12) of FEIBA NF at the 10 U/min/kg rate. Infusions 
will be again administered every 48 (+48) hours to allow time to monitor safety and 
tolerability of the higher infusion rate. Following the last infusion, a study termination 
visit will be conducted within 7 days but no sooner than 72 hours after the last infusion.
Additional details on study visits for Part 2 can be found in Section 10.3 and Table 2.
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Additional Treatment and Visit Information
The Schedule of Study Procedures and Events Procedures listed in Table 1 and Table 2
have the visit windows listed in relation to the subjects’ previous infusions instead of by 
study date. This is due to the variability in each subjects schedule based on previous 
therapy, bleeding events, and interim break periods. 
All infusions will be administered at hemophilia care centers/study sites. Each subject 
will receive a maximum of 14 IP infusions (12 scheduled IP infusions, as well as the 
possibility of PK infusions being reinfused if the subject had a bleeding episode during 
PK collection). Subjects will receive FEIBA at a dose of 85 U/kg ± 100 U for all PK 
infusions (Infusions 1 and 4) and 85 ± 15 U/kg for all other infusions (Infusions 2, 3, 5, 6, 
and all Part 2 infusions). During study participation, FEIBA will be used for control of 
break-through bleeding episodes. For additional information on break-through bleeding 
control, see Section 8.8.4.
Study visits will be completed concurrently with study infusions. After subjects have 
completed the 12 study infusions, they will complete a Study Completion/Termination 
Visit within 7 days but no sooner than 72 hours after Infusion 12. In case of early 
withdrawal or discontinuation the Study Completion/Termination Visit will need to be 
completed within 7 days but no sooner than 72 hours after the last IP infusion received.
A subject diary will be utilized to capture break-through bleeding events, treatments, and 
AEs throughout the study and interim periods, for additional details see Section 10.6.
Two subject questionnaires will be administered during the study, a TSQM questionnaire 
and a patient preference questionnaire (see 10.5). These will be administered between 
Screening and Infusion 1, between Infusion 3 and Infusion 4, between Infusion 6 and 
Infusion 7, and after Infusion 12 to assess the subjects’ satisfaction and preferences for 
treatments.
During study participation, subjects will be provided with standard of care FEIBA (by the 
sponsor) for the treatment of bleeding episodes, prophylaxis and/or treatment during 
interim pauses for DMC, as determined by the investigator. For additional details, see 
Section 8.8.4.
Detailed study flowcharts are presented in Table 1 and Table 2.
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Investigational product may be interrupted or discontinued at any time during the study at 
the discretion of the investigator based on his/her evaluation of the subject’s condition or 
safety. No dose modification is permitted for this study.
Any infusion site reactions, regardless of causality, will be recorded on the AE eCRF. 
Any concomitant medications, including those used to treat AE(s), will be recorded on 
the appropriate eCRF.
8.8.4 Management and Treatment of Break-Through Bleeding
Bleeding episodes are managed as described below for each section of the study 
(screening, PK assessments, washout, DMC period). In all cases, if the bleeding episode, 
of whatever severity, is not resolved within 72 hours after an infusion to control bleeding, 
the subject must contact the study site for further treatment recommendations.
Screening Washout
During screening, subjects will be asked to keep track of any FEIBA or rFVIIa usage, as 
the last dose is used to determine the date of the first infusion of IP. If a subject is on 
prophylaxis before the study, once eligibility is determined, the subject will discontinue 
their routine prophylaxis upon instruction of the investigator for the start of the washout 
period. If a subject experiences a bleeding episode during the washout period, subjects 
will be treated for the bleeding episode with FEIBA as determined by the investigator, 
and the washout period will be restarted. If the subject has a second bleeding episode 
during the washout period, the investigator should consider whether it is appropriate to 
include the subject into the study or whether they would be better served to remain on 
their current treatment regimen.
Bleeding during PK Assessments
Subjects who have a bleeding episode during the PK assessment periods will not have 
subsequent PK blood samples collected in that specific PK assessment period and will be 
treated for the bleeding episode with FEIBA as determined by the investigator. Once the 
bleeding is resolved, subjects will have the IP infusion and PK assessments repeated. 
However, they should wait at least 12 days after their last dose of FEIBA before 
proceeding. If the subject bleeds again on the second PK collection attempt, bleeding will 
be treated with FEIBA as determined by the investigator, and subjects will move on to 
the next IP infusion after waiting at least 48 hours from their last dose of FEIBA. 
Subjects will have one re-attempt on each PK infusion and collection.
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Washout Periods before Infusion 4
After Infusion 3, subjects will go through a washout period of at least 12 days before 
crossing over to the next treatment group for Infusion 4. The 12 days is based on 
Infusion 3, since all subjects receive FEIBA at Infusion 3. If bleeding occurs during the 
washout period, it will be treated with FEIBA and the washout period will be restarted. If 
bleeding has not resolved 72 hours after treatment with FEIBA, the investigator will treat 
the subject as appropriate to control the bleeding. If multiple bleeding episodes occur 
during the washout period, the investigator and sponsor should decide if it is more 
beneficial for the subject to be taken off the study. 
DMC Periods
During the interim period, subjects who are on hold for DMC review will be provided 
with standard of care FEIBA (by the sponsor) for the treatment or prevention of bleeding 
episodes as determined by the investigator. For subjects who are being treated for 
bleeding, if bleeding has not resolved 72 hours after treatment with FEIBA, the 
investigator will treat the subject as appropriate to control the bleeding.
8.8.5 Investigational Product Accountability
The investigator will ensure that the IP(s) 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(s) was received, including the date received, 
drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP(s) must be dispensed only at the study site or other suitable location (e.g.,
infusion center; home, as applicable per study design). Records will be maintained that 
include the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) 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(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
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8.9 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 
study that are necessary for the reconstruction and evaluation of the study. 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 eCRFs, see Section 17.2. The use 
of subject diaries is described in Section 10.6.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject is ≥18 to ≤65 years old at the time of screening
2. Hemophilia A or B of any severity, with a documented history of inhibitors 
requiring the use of bypassing agents (FEIBA or rFVIIa) 
3. HCV negative, either by antibody testing or polymerase chain reaction (PCR); or 
HCV positive with stable hepatic disease
4. HIV negative; or HIV positive with stable disease and CD4 count ≥ 200 cell/mm3
at screening
5. Adequate peripheral venous access
6. Subject is willing and able to comply with the requirements of the protocol
7. If a female of childbearing potential, subject must have a negative blood 
pregnancy test and agrees to employ adequate birth control measures for the 
duration of the study, such as:
a. Abstain from sexual intercourse
b. Use a reliable method of contraception (contraception such as an 
intrauterine device, barrier method [e.g., diaphragm or sponge; female 
condom not permitted] with spermicide, oral contraceptive, injectable 
progesterone, sub dermal implant), and have their male partner use a 
condom
8. If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a. Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-
stimulating hormone levels within the laboratory-defined postmenopausal 
range or postmenopausal with amenorrhea for at least 24 months and on 
hormonal replacement therapy
b. Documentation of irreversible surgical sterilization by hysterectomy, 
bilateral oophorectomy, bilateral tubal ligation (with no subsequent 
pregnancy at least 1 year from bilateral tubal ligation), or bilateral 
salpingectomy
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. Known hypersensitivity to FEIBA or any of its components
2. Clinically symptomatic liver disease (e.g., liver biopsy confirmed diagnosis of 
cirrhosis, portal vein hypertension, ascites, prothrombin time [PT] 5 seconds 
above upper limit of normal)
3. Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4. Platelet count < 100,000/mL
5. Clinical or laboratory evidence of disseminated intravascular coagulation
6. Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
7. Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
8. Subject is taking any immunomodulating drug (e.g., corticosteroid agents at a 
dose equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days 
prior to enrollment except anti-retroviral chemotherapy 
9. 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
10. Subject is a family member or employee of the investigator
11. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., 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 case report form (eCRF). Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) are 
described in Section 10.7 and Section 20.3.
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., 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 becomes pregnant. IP exposure will be discontinued. Attempts will 
be made to follow the subject through completion of the pregnancy and up to
1 year postdelivery, if feasible. The investigator will record a narrative 
description of the course of the pregnancy and its outcome

In addition, any pregnancies in the partner of a male subject during the study or 
for 12 weeks after the last dose, should also be recorded following authorization 
from the subject’s partner

AE(s)/SAE(s) that in the investigator or sponsor opinion, poses an unacceptable 
risk for continued dosing in the subject

Participation in another clinical study involving an IP during the course of the 
study
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form [ICF] 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 (e.g., 091501) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the ICF). For example, the third subject who signed an ICF at 
study site 02 will be identified as Subject 091501-020003. All study documents (e.g., 
eCRFs, 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 (e.g., 
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. 
All screening data will be collected and reported in eCRFs, regardless of screening 
outcome. If a subject is re-screened, the End of Study eCRF should be completed, and a 
new ICF, new SIC and new eCRF are required for that subject.
The overall study design is illustrated in Figure 1 and Figure 2. Details on the procedures 
to be performed at each study visit, including screening, can be found in Supplement 20.3
and Supplement 20.4 Schedule of Study Procedures and Assessments (Part 1 and Part 2, 
respectively) and Supplement 20.5 Clinical Laboratory Assessments. Pharmacokinetic 
assessment scheduling can be found in Table 4.
10.3.1 Screening and Baseline Assessments
After ICF has been obtained, subjects will be screened on-site for eligibility based on the 
inclusion and exclusion criteria defined in Section 9.1 and Section 9.2, respectively. 
Screening procedures must be performed within 56 days of Infusion 1.
At screening, subjects will receive instruction and educational materials on the symptoms 
of thromboembolic events. They will be instructed to contact the treatment 
center/hospital if they experience any symptoms of thromboembolism.
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Screening assessments include the following:

Eligibility evaluation (review of inclusion/exclusion criteria)

Medical history, including
Hemophilia history, inhibitor development history, bleeding episodes
history, history of FEIBA or rFVIIAa usage for a year prior to screening
Relevant medical and surgical history and all medications taken 4 weeks 
prior to screening

Review of concomitant medications/non-drug therapies

Complete physical examination (see Section 12.6)

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and
measurement body weight and height (see Section 12.8)

Karnofsky performance test assessment (see Section 12.9)

Clinical laboratory assessments (hematology, clinical chemistry, coagulation 
testing, and serology testing; see Section 12.7)

PK assessments (see Section 11.1)

Serum pregnancy test (female subjects of childbearing potential only)

TSQM and patient preference questionnaires (see Section 10.5)
After screening and eligibility is determined, the duration of the washout period will be 
determined. The washout period is based on the subjects’ last dose of FEIBA or rFVIIa 
(e.g., NovoSeven). Due to the varying lengths of the half-lives of the components, 
subjects who have received FEIBA will need to wait 12 days from the last dose of FEIBA
that they received before they can begin Infusion 1. For subjects who have previously 
been treated with rFVIIa, they will need to wait at least 24 hours from the last dose of 
rFVIIa before they can begin Infusion 1 of the study. Additional days beyond the 
minimum of 1 or 12 days (treatment dependent) is permissible (as long as the screening 
assessments stay within the window to Infusion 1) since subjects have varying courses of 
treatments prior to their enrollment in the study. Subjects who are on prophylactic 
therapy before the study, will need to have an appropriate washout period once eligibility 
is determined. Subjects who are on an on-demand treatment to control bleeding, the 
washout begins from the last day they used treatment, if they have a bleeding episode that 
requires treatment during the washout period, the washout period must be restarted before 
they can proceed with the study. For additional details on bleeding, see Section 8.8.4.
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10.3.2 Treatment Visits
10.3.2.1 Infusion Visits
Randomization will occur at Infusion Visit 1 using interactive voice response system.

Randomization of eligible subjects to the following treatment sequences:
Part 1 Sequence A: FEIBA 2 U/min/kg in regular volume SWFI 
(3 infusions), washout period, FEIBA NF 2 U/min/kg in 50% reduced 
volume (3 infusions)
Part 1 Sequence B: FEIBA 2 U/min/kg in 50% reduced volume 
(3 infusions), washout period, FEIBA NF 2 U/min/kg in regular volume 
SWFI (3 infusions)
For additional details on the description of treatment, see Section 8.8.3.
At Infusion Visit 1, subjects will be given a subject diary as described in Section 10.6.
During the study (Infusion Visits 1 to 12), subjects will return to the study site according 
to the schedule presented in Table 1 and Table 2. Prior to administration of IP, the 
following assessments will be performed at all visits unless otherwise indicated:

Review of concomitant medications/non-drug therapies

Review of subject diary

AE monitoring

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and 
measure body weight)
Before administration of IP
30 minutes after administration of IP

Clinical laboratory assessments (coagulation testing)

PK assessments (Infusions 1 and 4): from 30 minutes before start of infusion 
through 8 hours after stop of infusion
At the discretion of the investigator, subjects may be given the option of 
staying overnight at study site facility and/or a hotel for convenience or to 
ensure compliance with the serial PK collections. Funding or 
reimbursement for hotel facilities may be provided as allowed by the 
Institutional Review Board (IRB) approved ICF and any applicable laws 
and regulations. Voluntary overnight stays by subjects in hospital or 
hospital-affiliated facilities for the convenience/compliance with study 
procedures unrelated to AEs will not be considered as hospitalizations for 
SAE reporting purposes.
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
IP administration (infusion site should be monitored for 30 minutes [± 10 min] 
after infusion)

Subjects should be reminded to complete their diaries between study visits, 
including monitoring of infusion site for 72 hours postinfusion, break-through 
bleeding episodes, AEs, and concomitant medications

Subjects will be administered the TSQM and patient preference questionnaires
after screening, between Infusion 3 and Infusion 4, between Infusion 6 and 
Infusion 7, and after Infusion 12
10.3.3 PK only Visits
Additional PK only visits will be performed between Infusion 1 and 2, and between 
Infusions 4 and 5 according to the schedule presented in Table 1 and Table 4. These 
times include 24 hours, 72 hours, 120 hours, 168 hours and 216 hours after Infusions
1 and 4. Exact time ranges can be found in Table 4. For details on treatment of bleeding 
episodes during PK assessments, see Section 8.8.4.
10.3.4 Study Completion/Termination Visit
The Study Completion/Termination Visit will be performed within 7 days but no sooner 
than 72 hours after Infusion 12, or within 7 days but no sooner than 72 hours after the last 
infusion if the subject is discontinuing early. The following assessments will be 
performed:

Review of concomitant medications/non-drug therapies

AE monitoring

Clinical laboratory assessments (hematology, clinical chemistry, coagulation 
testing, serology testing)

Review of subject diary

Subject diaries will be collected

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and 
body weight)
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10.4 Medications and Non-Drug Therapies 
Once subject eligibility has been confirmed for the study, subjects will begin a washout 
period as described in Section 8.8.3. The subject will discontinue their routine 
prophylaxis upon instruction of the investigator at the beginning of the washout period. 
Throughout the course of the study and during the interim periods of the study, subjects 
will be provided with FEIBA for break-through bleeding, as well as FEIBA for 
prophylaxis if indicated by the investigator. See Section 8.8.4 for instructions on bleeding 
control.
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 immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) except anti-
retroviral chemotherapy
Any investigational drug or device
A subject who has taken any of these medications or received any of these non-drug 
therapies will be withdrawn from further study participation.
Antifibrinolytics should not be used approximately 6 to 12 hours before or after the 
administration of FEIBA.
The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:

Medications:
Hemostatic agents, such as tranexamic acid, are permitted, as indicated by 
the subject’s treating physician, to treat mucosal bleeding during the 
study (these are permitted; however, they should not be taken within 
12 hours before or after administration of FEIBA)
Any medications deemed necessary by the subject’s physician to treat or 
prevent any medical condition (with the exception of those listed as not 
permitted)
Any over-the-counter medication used by the subject to treat symptoms 
or signs of any medical condition
Supplemental vitamins, minerals
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
Non-drug therapies:
Any non-drug therapy (e.g., physiotherapy) deemed necessary by the 
subject’s physician to treat or prevent any medical condition
10.5 Subject Questionnaires
Two questionnaires will be administered to subjects within this study (TSQM 10 and a 
patient preference questionnaire). These questionnaires will be used to assess the 
subject’s preferences on the IP, as well as their satisfaction with the IP, and will be 
collected in the eCRF or in the subject electronic diary. Both questionnaires will be 
administered after screening, between Infusion 3 and Infusion 4, between Infusion 6 and 
Infusion 7, and after Infusion 12.
10.6 Subject Diary
An electronic subject diary will be provided to each subject at the Infusion 1 visit to 
record the following information: The subject diary will be reviewed at each infusion 
visit and the Study Completion/Termination Visit.

Break-through bleeding episodes (duration, severity, treatment)
Date and time of bleeding episode
Anatomic location of the bleeding episode: joint (identify exact joint), 
body cavity, deep muscle, superficial
Date and time of all infusions with dose and batch number of FEIBA used 
to control bleeding
Use of alternative hemostatic agents, if any

Infusion site reactions:  subjects will monitor the infusion site for 72 hours after 
each infusion and answer questions regarding AEs after infusion (see 
Section 10.5).

Treatments and AEs during DMC interim break
Date and time of infusion with dose and batch number of FEIBA

Untoward medical events

Concomitant medications (including immunizations) and non-drug therapies
If the subject feels that the bleeding is severe, he must notify the study site. If the 
bleeding episode, of whatever severity, is not resolved within 72 hours after an infusion 
to control bleeding, the subject must contact the study site for further treatment 
recommendations.
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Subjects will be trained on use of the diary. The diary will be provided in electronic 
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. 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 Investigator will review the diary for completeness and ask for missing information. 
Any unclear or implausible information should be immediately clarified with the subject 
at each study visit and instructions related to treatment and data entry should be 
reinforced.
10.7 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 eCRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems), DMC recommends a subject should not continue. 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 Study Completion/Termination Visit is done as 
an additional, unscheduled visit, the assessment results shall be recorded with the 
Study Completion/Termination Visit. If a subject terminates participation in the 
study and does not return for the Study 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 20.3 Schedule of Study Procedures and 
Assessments and Supplement 20.5 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. 
10.8 Procedures for Monitoring Subject Compliance
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures will be used to monitor subject compliance.
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11. ASSESSMENT OF PHARMACOKINETICS
11.1 Sample Collection and Processing
Blood PK samples for the determination of FEIBA components FII, 
 
will be taken at screening, at 30 and 15 minutes preinfusion, at end of infusion, 
and 30 and 60 minutes, 3, 8, 24, 72, 120, 168, and 216 hours after stop of infusion 
(see Table 4 for sampling time points and allowed sampling time deviations) following 
Infusions 1 and 4. The date and time of each sample collections will be documented in 
the subject’s eCRF. Blood sample processing and handling details will be presented in 
a separate laboratory manual.
At the discretion of the investigator and with sponsor’s approval, subjects may be given 
the option of staying overnight at study sites and/or a hotel for convenience or to ensure 
compliance with the serial PK collections. Funding or reimbursement for hotel facilities 
may be provided as allowed by the IRB-approved ICF and any applicable laws and 
regulations. Voluntary overnight stays by subjects in hospital or hospital-affiliated 
facilities for the convenience/compliance with study procedures unrelated to AEs will 
not be considered as hospitalizations for SAE reporting purposes.
11.2 Pharmacokinetic Evaluation and Pharmacokinetic Parameters
For PK assessments (Infusion 1 and 4), subjects will receive an infusion of 
85 U/kg ± 100 U FEIBA reconstituted in 50% reduced volume SWFI followed by regular 
volume SWFI or vice versa. There will be a washout period of at least 12 days following 
the Infusion 3 before subjects cross over to the next treatment group. For PK assessments, 
subjects are required to not be actively bleeding at the time of infusion.
Subjects who have a bleeding episode during the PK assessment periods will not have 
subsequent PK blood samples collected in that specific PK assessment period and will be 
treated for the bleeding episode with FEIBA as determined by the investigator. After a 
washout period of at least 12 days, the IP infusion and PK assessments will be repeated.
Pharmacokinetic parameters will be derived for baseline-corrected FII, 
 
 activity. Baseline-corrected FII, 
 activities will be calculated by 
subtracting the preinfusion value (or average of preinfusion values) from each 
measurement after infusion.
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The following PK parameters will be calculated for FII, 
using 
standard noncompartmental methods after administration with FEIBA reconstituted in 
regular volume of SWFI or FEIBA reconstituted in 50% reduced volume of SWFI:

AUC0-216 h

AUC0-∞

AUC0-last

t1/2

MRT

CL

Vss

Cmax

tmax

IR at Cmax; defined as (observed Cmax - Cpreinfusion)/[total dose/body weight]
Additional PK parameters may be calculated at the discretion of the PK scientist and/or 
sponsor.
The following PK parameters will be calculated for diagnostic purposes and listed, but 
will not be summarized:
t1/2, Interval
The time interval of the log-linear regression used to determine the terminal 
rate constant lambda_z (λz)
t1/2, N
Number of data points included in the log-linear regression analysis to 
determine λz
Rsq
Goodness-of-fit statistic for calculation of λz (coefficient of determination). If 
Rsq  < 0.800, then λz and associated parameters will not be reported
%AUCex
Percentage of AUC0-∞obtained by extrapolation. If % AUCex > 20.00%, then 
AUC0-∞and associated parameters will not be reported
All PK analyses will use the actual sampling times, wherever possible. Actual sampling 
times will be defined as time from the start of infusion to the collection time of blood. 
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 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 (e.g., an abnormal laboratory finding), 
symptom (e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP.
12.1.1.1 Serious Adverse Event
A SAE is defined as an untoward medical occurrence that at any dose meets 1 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 (i.e., 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 1 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
Additional events which should be reported as SAEs are as follows:

Reviewed and confirmed seroconversion for HIV, hepatitis A virus, hepatitis B 
virus, HCV, hepatitis E virus, or parvovirus B19
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
Hospitalization for planned port placement or removal is not considered an SAE, 
however, any hospitalization required for an emergency port removal is 
considered an SAE

Thromboembolic events (myocardial infarction, deep vein thrombosis, pulmonary 
embolism, stroke, transitory ischemic attack, etc.)
Uncomplicated pregnancies, following maternal or paternal 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. Any 
pregnancy occurring during the study should be reported to the sponsor within 24 hours 
of the site learning about the pregnancy. The pregnancy should be followed until
completion of the pregnancy and up to 1 year postdelivery, if feasible. Pregnancies not 
considered an (S)AE as described above will be captured in the eCRF.
Voluntary overnight stays by subjects in hospital or hospital-affiliated facilities for the 
convenience/compliance with study procedures as described in Section 10.3.2 for reasons 
unrelated to AEs will not be considered as hospitalization for SAE reporting purposes.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., 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.
12.1.1.4 Pre-existing Diseases
Pre-existing 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 pre-existing disease, the event must be described on 
the AE eCRF.
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12.1.2 Assessment of Adverse Events
Each AE from the first IP exposure until study termination/completion will be described 
on the AE eCRF 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 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
eCRF. Recovering/resolving AEs will be followed until resolution, it is medically 
stabilized, or 30 days after the Study Completion/Termination Visit, whichever comes 
first, and the follow-up information is to be documented in the eCRF. If the severity 
rating for an ongoing AE changes before the event resolves, the original AE report will 
be revised (i.e., 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 (20% higher than the 
highest permitted dose), underdosing (20% lower than the lowest permitted dose), 
treatment errors (including incorrect route of administration, use of an incorrect product, 
and deviations from the protocol-defined dosing schedule), failures of expected 
pharmacological actions, and unexpected therapeutic or clinical benefits will be followed 
with regard to occurrence of AEs, lack of efficacy, and/or other observations because 
these events may be reportable to regulatory authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and 1 year postdelivery, if 
feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion/termination, the SAE must be reported on the provided SAE Report Form 
within 24 hours after awareness; no additional reporting on eCRFs is necessary.
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12.1.2.1 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.
12.1.2.2 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, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely 
alternative etiology). 
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
Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which 
may include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
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 72 hours after 
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.
12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 2) and Section 12.1.
Adverse Events/SAEs are to be recorded on the AE page of the eCRF.  Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event).  All SAEs must be reported via the EDC system by 
completing the relevant eCRF page(s) in English.  Once the SAE has been recorded in the 
EDC system, the Sponsor and other designated recipients will be informed of the event 
automatically.  For instances in which the EDC may become unavailable, SAEs must be 
reported using the back-up paper SAE Report Form to meet the 24 hour timeline
requirement (contacts and instructions to be provided in separate documentation).  
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Once the EDC becomes available, the site must enter all SAE data as reported on the 
back-up paper SAE report form on the applicable eCRF pages.
The initial SAE information reported on the applicable eCRF pages (or back-up SAE 
Report Form, if applicable) must at least include the following:

Protocol Number

Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)

Investigational product exposure

Medical Term for Event (Diagnosis preferably) 

Description of the (S)AE, including:
Date of onset
(S)AE treatment (drug, dose, route of administration)
Causal relationship by the Investigator
Measures taken (i.e., action taken regarding IP in direct relationship to the 
AE)

Seriousness criteria (i.e., death, life-threatening, or other criterion)

Cause of death

Autopsy findings (if available)

Name, address, fax number, email, and telephone number of the reporting 
Investigator (for paper SAE Report Forms) 
12.1.3 Medical Device Safety reporting
The IP kit contains the BaxJect device. All Serious Injuries (SI) and Unexpected Adverse 
Device Events (UADE) must be reported to the Sponsor as an SAE in the same process 
as described above.
Serious injury is defined as:

Life-threatening injury or illness results in permanent impairment/ damage to 
body function/ structure.

Requires medical or surgical intervention to preclude permanent impairment/ 
damage to body function/ structure.
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12.2 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 study 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 study or studies

Any other immediate action taken in order to protect clinical study 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 (EC) is notified of the urgent measures 
taken in such cases according to local regulations.
12.3 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 12.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the AE eCRF (and SAE Report Form if eCRF is not available). These 
events will be considered as SAEs and will not be included in the analysis of SAEs. 
12.4 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, e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)
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
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.
12.5 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 12.1.2.1) 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.
General medical history will be collected for 4 weeks prior to screening. Any information 
on the subjects’ hemophilia history will be collected a year prior to screening including 
documented history of hemophilia, confirmation of inhibitors, bleeding episodes history, 
and history of FEIBA or rFVIIa usage.
All medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies eCRFs.
12.6 Physical Examinations
At screening (as described in Table 1 and Table 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 eCRF. At study visits, if a new abnormal or 
worsened abnormal pre-existing condition is detected, the condition will be described on 
the AE eCRF. If the abnormal value was not deemed an AE because it was due to an 
error, due to a pre-existing disease (described in Section 12.1.1.4), not clinically 
significant, a symptom of a new/worsened condition already recorded as an AE, or due to 
another issue that will be specified, the investigator will record the justification on the 
source record.
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12.7 Clinical Laboratory Parameters
Where applicable (see Section 15.6), assessments will be performed at a central 
laboratory, according to the laboratory manual. Blood samples that remain after study 
testing is done may be stored and used for additional testing. Samples will be destroyed 
after a maximum of 2 years from the time the final study report has been completed. 
Details of blood sampling volumes are presented in the laboratory manual and master 
ICF.
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count [hemoglobin, hematocrit, 
erythrocytes (i.e., red blood cell count), and leukocytes (i.e., white blood cell count)] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) mean 
corpuscular volume, mean corpuscular hemoglobin concentration, and platelet counts. 
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
aspartate aminotransferase (AST), total protein, albumin, alanine aminotransferase
(ALT), total bilirubin, alkaline phosphatase (ALP), blood urea nitrogen (BUN), 
creatinine, glucose, gamma-glutamyl transpeptidase (GGT), and 5’-nucleotidase.
Blood will be obtained for assessment of hematology and clinical chemistry parameters at 
screening and at study completion/termination. Hematology and clinical chemistry 
assessments will be performed on EDTA-anticoagulated whole blood and serum, 
respectively, at the central laboratory. 
In addition, serum samples for pregnancy tests for females of childbearing potential will 
be collected at screening.
12.7.2 Coagulation Testing
Blood will be obtained for the assessment of coagulation testing will consist of aPTT, PT, 
thrombotic markers (D-Dimers, prothrombin fragment F 1.2, TAT, fibrinopeptide A), FII, 
FX, FIX, FVII, and FVIII or FIX inhibitor level (Nijmegen assay).  All coagulation 
testing will be performed at screening, during the study (Infusion Visits 1 to 12), and at 
the Study Completion/Termination Visit.
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12.7.3 Viral Serology
Viral serology testing will include HIV-1 and HIV-2 antibody, hepatitis A virus (HAV)
antibody, hepatitis B virus (HBV) antibody, hepatitis B surface antigen (HBsAg), HCV 
antibody, parvovirus B19 (immunoglobulin M [IgM] and immunoglobulin G [IgG] 
antibodies), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus 
antibodies (IgM and IgG). The HCV titer will be confirmed by PCR for all subjects 
reported as HCV positive. All viral serology assessments will be performed at screening
and at the Study Completion/Termination Visit.
12.7.4 CD4 Levels
At screening only, CD4 levels will be determined using flow cytometry in the case of a 
subject being HIV positive.
12.7.5 Assessment of Laboratory Values
12.7.5.1 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value will be recorded on the eCRF. 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 an new AE (see definition in Section 12.1, and record 
the sign, symptom, or medical diagnosis on the AE eCRF), is a symptom or related to a
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.4), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e., because it is due to a 
pre-existing 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.
12.7.6 Biobanking
Backup samples should be taken and stored appropriately for additional analysis, if 
necessary. These samples may be used for re-testing, further evaluation of an AE, or 
follow-up of other test results. The following samples are planned:

Backup samples for FII, 
 will be taken at screening, and at all 
pre and postinfusion timepoints for PK assessments
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Backup samples that remain after study testing is done may be stored and used for 
additional testing (e.g., further evaluation of an abnormal test or an AE. 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.
12.8 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) 
measured once at screening and weight (lb or kg) will also be collected.
Vital signs will be measured at screening and within 30 minutes before and after 
administration of IP, at each Infusion study visit, and at study completion/termination. 
Blood pressure will be measured when subjects are in the supine position.
Vital sign values are to be recorded on the eCRF. For each abnormal vital sign value, the 
investigator will determine whether or not to report an AE (see definition in Section 12.1
and record the medical diagnosis (preferably), symptom, or sign on the AE eCRF). 
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.
12.9 Karnofsky Performance Test
The Karnofsky Performance Test is a status scale (0-100) utilized to measure the level of 
activity and medical care requirements in subjects. It is an investigator based assessment 
of subject status which evaluates the subjects’ ability to carry on normal life activities, as 
well as the symptoms of their disease. In this scale, a high number performance status 
represents high functionality, and a lower number represents low functionality and likely 
rapid progression of disease.11 Subjects will be scored using this scale at screening.
12.10 Infusion Site Evaluations
The current site of IP infusion will be assessed for immediate local reactions 30 minutes 
(±10 min) after infusion. In addition, infusion sites will be monitored by the subject for 
72 hours after infusion, and any AEs will be captured in the subject electronic diary as 
described in Section 10.6.
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Infusion sites will be monitored for pain, tenderness, erythema, and swelling. Infusion 
site evaluations will be made by clinical staff or by the subject or caregiver. If an infusion 
site reaction is observed, a physician will characterize and document the reaction as an 
AE. Infusion sites will continue to be reviewed at each study visit, and any infusion site 
reactions will be followed until resolution. Each infusion site reaction will be categorized 
using the intensity grading described for AEs in Section 12.1.2.1.
12.11 Special Treatment Considerations
Subjects will be screened for eligibility in the study as described in Section 8.2 and
Section 8.8.3, and will be informed of the study specific restrictions and requirements of 
the study. Subjects who are not willing to comply with the study requirements and 
restrictions of the study will not be eligible for enrollment.
All biological agents carry the risk of systemic allergic/hypersensitivity reactions. 
Clinical manifestations of these reactions may include, but are not limited to:

Skin rash

Pruritus (itching)

Urticaria (hives)

Angioedema (for example, swelling of the lips and/or tongue)

Anaphylactic reaction
Proteins may also cause redness, itching, swelling, or pain locally at the infusion site.  
Sometimes, these reactions can be life-threatening. Therefore, all subjects should be 
closely monitored for signs or symptoms that could result from such reactions, educated 
on the signs or symptoms of these types of reactions, and instructed to contact the study 
site immediately if any of the symptoms are experienced following an injection. If a 
subject experiences an acute allergic/hypersensitivity reaction after an infusion of IP, he 
or she should be managed appropriately and given instruction to receive relevant 
supportive care. Additionally, for an event judged by the investigator to be a potential 
systemic allergic/hypersensitivity reaction, a blood sample should be drawn to test for 
anti-drug antibodies.
Subjects who experience a potentially severe allergic reaction will be discontinued from 
IP. They will complete a Termination/Study Completion Visit, and will be monitored for 
stabilization or resolution of the AE. Premedication to prevent allergic reactions will not 
be permitted, as severe allergic reactions are an outcome measure for this study.
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13. STATISTICS
Data handling will be the responsibility of the contract research organization. The data 
will be inspected for inconsistencies by performing validation checks.
All details regarding the statistical analysis and the preparation of tables, listings, and 
figures will be described in the statistical analysis plan prepared by the contract research 
organization and approved by the sponsor before database lock.
13.1 Sample Size and Power Calculations
Part 1 (cross-over) of this study will evaluate PK equivalence of FEIBA component (FII) 
in FEIBA reconstituted in 50% reduced volume SWFI versus regular volume of SWFI as 
measured by AUC0-216 h. The sample size was calculated for a Type-1 (α) error level of 
0.05 and a Type-II (β) error level of 0.1 or 90% power, under the assumption that the true 
(population) means are equivalent, i.e., the 90% confidence interval (CI) for the ratio of 
the geometric means between the 2 treatments are contained completely in the margins of 
equivalence defined as 80% to 125%. The within-subject variability was estimated by 
using the square root of mean square error (0.222) as in previous studies of FVIII. The 
required sample size was estimated to be 24 evaluable subjects. In order to obtain the 
required 24 subjects, Part 1 will randomize approximately 32 subjects for the crossover 
PK study, allowing for a possible 25% dropout rate.
With approximately 100 infusions for each treatment (reduced or regular volume of 
SWFI) administered for the study, the upper limit of the 95% CI of the rate of infusions 
with a specific AE is less than 3.3%, if the specific AE is not observed. The upper limit 
of 95% CI of the rate of infusions for a specific AE is about 5% if 1 AE is observed.
13.2 Datasets and Analysis Cohorts
Classification into the analysis sets will be conducted prior to the soft database lock for 
DMC in Part 1. For Part 2, the classification of the analysis sets will be conducted prior 
to database lock.
Major protocol violations will include, but are not limited to: violation of 
inclusion/exclusion criteria, administration of prohibited medications, and erroneous 
administration of study treatment. Subjects will be assigned to treatment groups based on 
randomization.
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Safety: The safety population will include all subjects who received at least 1 dose of IP
(FEIBA). All safety analyses will be performed on the safety population. Subjects will be 
evaluated according to the treatment received. The safety population will be defined 
separately for each part of the study.
PK: The PK population will include all subjects who received at least 1 dose of IP and 
have at least 1 measured concentration at a scheduled PK time point after start of dosing 
without protocol violations or events with potential to affect PK. If any subjects are found 
to be noncompliant with respect to dosing or have incomplete data, a decision will be 
made on a case-by-case basis as to their inclusion in the analysis. Statistical analyses of 
the primary PK endpoint will be based on the PK population.
13.3 Handling of Missing, Unused, and Spurious Data
All data will be evaluated as observed; no imputation method for missing values will be 
used. A subject who withdraws prior to the last planned observation in a study period will 
be included in the analyses up to the time of withdrawal.
13.4 Methods of Analysis
For qualitative parameters, the population size (N for sample size and n for available 
data) and the percentage (of available data) for each class of parameters will be 
presented. Quantitative parameters will be summarized by the population size (N for 
sample size and n for available data), mean, standard deviation, median, minimum, and 
maximum values. All PK parameters will be summarized by treatment using n, mean, 
standard deviation, geometric mean, % geometric coefficient of variation, minimum, 
median, and maximum, except that tmax will be reported with n, minimum, median, and 
maximum only. 
A listing of PK blood sample collection times by individual, as well as derived sampling 
time deviations, will be provided. Pharmacokinetic concentrations/activities and derived 
PK parameters for FII, 
 will be summarized using descriptive statistics 
by treatment and nominal sampling time point. Plots of individual and mean plasma 
concentration-time profiles will be presented by treatment and visit. Plots of individual
and geometric mean AUC0-216 h will also be presented by treatment.
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13.4.1 Primary Outcome Measure
13.4.1.1 Analysis of the Primary PK Outcome Measure (Part 1)
The primary PK outcome measure is the AUC0-216 h of FEIBA component FII. AUC0-216 h
will be derived using noncompartmental methods as described in Section 11.2 and will be 
summarized by treatment using descriptive statistics. The 216 hour timepoint is critical 
and no imputation, interpolation, or extrapoloation of the FII concentration at time = 216 
hours will be performed if no bioanalytical result is available or the sample is not 
quantifiable at that specific timepoint. In such cases, AUC0-216 h will be set to missing.
Missing datapoints may not prevent the calculation of AUC0-216 h. If at least the 
pre-infusion, end-of-infusion, 216 hour and at least one other timepoint is collected,
AUC0-216 h may be able to be calculated.
For subjects that require re-infusion due to bleeding episodes during the PK assessment, 
PK parameters will only be listed for the first, interrupted infusion, while those from the 
repeated infusion (if deemed evaluable) will be listed and used for descriptive and 
statistical analysis.
Statistical analyses of the primary PK endpoint will be based on the PK population with 
evaluable AUC0-216 h parameters.
Log-transformed PK parameter AUC0-216 h from Infusions 1 and 4 will be analyzed using 
a linear mixed-effects model with sequence, period, and treatment (FEIBA reconstituted 
in 50% reduced volume and regular volume of SWFI) as fixed effects and subject as a 
random effect. Least-squares means with corresponding 95% CIs for the 2 treatments will 
be determined. The difference in least-squares means between the 2 treatments with 
reduced and standard volumes and corresponding 90% CI will also be determined. Back 
transformation will provide the ratio of the geometric means and corresponding CI for the 
treatment comparison (reduced to standard volumes). To establish the equivalence, the 
90% CI for the ratio of the geometric means between the 2 treatments has to be contained 
completely in the margins of equivalence defined as 80% to 125%.
13.4.1.2 Analysis of the Primary Safety Outcome Measure (Parts 1 and 2)
The safety of treatment infusions will be evaluated primarily by the occurrence of severe 
allergic reactions and infusion site reactions. The number and proportion (95% exact CI) 
of subjects experiencing severe allergic reactions and infusion site reactions will be 
summarized by treatment for each study part.
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13.4.2 Secondary Outcome Measures 
13.4.2.1 Analysis of the Pharmacokinetic Outcome Measures
Secondary efficacy/PK outcome measures consist of the IR of FEIBA component FII in 
subjects as well as PK measurements (AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, and 
tmax) of FEIBA component FII. Pharmacokinetic parameters will be derived using 
noncompartmental methods as described in Section 11.2. The secondary outcome 
measures will be descriptively summarized by treatment.
13.4.2.2 Analysis of the Safety Outcome Measures
Adverse events will be coded using the Medical Dictionary for Regulatory Activities and 
will be summarized by presenting the number and percentage of subjects having any AE, 
having an AE in each system organ class, and having each individual AE as reported by 
preferred term. In the summaries, AEs will be counted only once per subject and 
treatment for each study part. If a subject reports the same AE more than once, it will be 
counted with its worst severity and closest relationship to the IP.
The number and proportion of subjects experiencing serious and non-serious AEs up to 
study completion or subject withdrawal will be summarized by treatment for each study 
part. The number of product related serious and non-serious AEs will also be summarized 
by treatment for each study part. 
Subgroup analyses will also be performed for events categorized as thromboembolic 
AEs. Thrombotic markers (e.g., D-Dimers, prothrombin fragment F 1.2, TAT, and 
fibrinopeptide A) will be summarized using descriptive statistics by treatment for each 
study part. Mean concentration plots will be presented by treatment and visit for each 
thrombotic marker and study part.
Vital signs and clinical laboratory assessments as well as the corresponding changes from 
baseline will be summarized descriptively by treatment at each scheduled assessment for 
each study part. Baseline will be defined as the last value prior to the first infusion for 
each treatment. Laboratory abnormalities will be analyzed by shift tables where each 
subject will be counted only once with the worst grade in the summary tables by 
treatment at each scheduled assessment for each study part. All laboratory data will be 
listed with abnormal values flagged.
Individual listings presenting subjects by treatment will be presented for the safety 
parameters. The listings will be created for both change and absolute values, if 
appropriate.
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13.4.3 Exploratory Outcome Measures 
 
 
 
 
The results of the TSQM and the patient preference questionnaires will be summarized 
by descriptive statistics as appropriate.
13.5 Planned Interim Analysis of the Study
There is no planned interim analysis other than a safety and PK data review by the DMC.
14. 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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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 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.
15.1.1 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. 
15.2 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.
15.3 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.
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15.4 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.
15.5 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 (Baxalta) will also ensure the responsible EC 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.
15.6 Laboratory and Reader Standardization
Not applicable; a central laboratory/reader will be used for all clinical assessments.
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16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, ICF, 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.
16.3 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 must sign an ICF before entering into the study according to applicable 
regulatory requirements and ICH GCP. Before use, the ICF will be reviewed by the 
sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The ICF 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 will be allowed sufficient 
time to consider participation in the study. By signing the ICF, patients 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 will be updated, if necessary. This new information and/or revised ICF, that have 
been approved by the applicable EC and regulatory authorities, where applicable, will be 
provided by the investigator to the subjects who consented to participate in the study (see 
Section 16.3).
16.4 Data Monitoring Committee
This study will be monitored by and internal Data Monitoring Committee (DMC). The 
DMC is a group of individuals with pertinent expertise that reviews on a regular basis 
accumulating data from an ongoing clinical study. For this study, the Baxalta DMC will 
be composed by appropriate members of clinical, safety, and biostatistics division that are 
not involved in the active execution of the trial. This internal DMC can stop a study if it 
finds toxicities or if treatment is proven to be not beneficial. The DMC will meet at 2 
predetermined timepoints through the study for 2 subsets of subjects (subjects 1 through 
12, and again for all subjects through the final subject), for a total of 4 meetings. 
Baxalta internal DMC Part 1
All evaluable subjects will be included in the DMC review, however to help with subject 
retention on the study, the DMC review of Part 1 will be conducted twice; once after the 
first 12 subjects have completed Part 1, and then again after the last subject has 
completed Part 1. Once the first 12 subjects have completed Part 1, the DMC will review 
the safety and PK data and will provide a recommendation on whether these subjects can 
proceed to Part 2 for evaluation of increased infusion rates. The DMC will meet again 
after the final subject has completed Part 1 of the study. The DMC will then review all 
safety and PK data from Part 1 and provide a recommendation on whether the remaining 
subjects can proceed to Part 2. A soft database lock will be in place on the records of the 
subjects who are undergoing review. Subject recruitment and subjects in other phases of 
the study will not be affected by this database lock.
Baxalta internal DMC Part 2
After the first 12 subjects have completed Infusion 9, the DMC will review the safety 
data and provide a recommendation on whether these subjects can proceed to the next 
higher infusion rate of 10 U/min/kg. The DMC will meet again after the final subject has 
completed Infusion 9, and provide a recommendation on whether the remaining subjects 
can proceed to the faster infusion rate. 
Additional Baxalta internal DMC Meetings
Additional ad hoc meetings of the DMC may be convened as required.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 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 8.9), records detailing the progress of the study for each subject, signed 
ICFs, correspondence with the EC and the study monitor/sponsor, enrollment and 
screening information, eCRFs, 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 eCRFs are provided by the sponsor, only authorized study site personnel will record or 
change data on the eCRFs. If data is not entered on the eCRFs during the study visit, the 
data will be recorded on paper, and this documentation will be considered source 
documentation. Changes to an eCRF will require documentation of the reason for each 
change. An identical (electronic/paper) version of the complete set of eCRFs for each 
subject will remain in the investigator file at the study site in accordance with the data 
retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., 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.
17.3 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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18. 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.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement.
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20.3 Schedule of Study Procedures and Assessments (Part 1)
Table 1
Schedule of Study Procedures and Assessments (Part 1)
Procedures/
Assessments
Screening 
Assessments
Study Visitsa
DMC Reviewg
Washout Period 1e
Infusion 
#1
PK Visitsb
Infusion 
#2 
Infusion 
#3
Washout Period 2f
Infusion 
#4
PK Visitsa
Infusion 
#5 
Infusion 
#6
Study Visit Windowsc
A maximum 
of -56 days 
to 0
Day 1
Multiple 
Visits Day 
1 through 9
9 (+1)
days from 
Infusion 1
48 hr 
(+48) from 
Infusion 2
At least 
12 days 
from 
Infusion 3
Multiple 
Visits up to 
9 Days from 
Infusion 4
9 (+1) days 
from 
Infusion 4
48 hr (+48) 
from 
Infusion 5
Informed Consentd
X
Eligibility Criteria
X
Medical History
X
Medication and Non-drug 
Therapies
X
X
X
X
X
X
X
Dispense/Collect Subject 
Diary
X
Review Subject Diary
X
X
X
X
X
Physical Examination
X
Pregnancy Test
X
Vital Signsh
X
X
X
X
X
X
X
Karnofsky Performance 
Test
X
Laboratory Assessmentsi
X
X
X
X
X
X
X
PK Assessmentsj
X
X
X
X
X
Adverse Events
Xk
X
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient 
preference questionnairesl
X
X
X
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Continued
Abbreviations:DMC=Data Monitoring Committee; FEIBA=Factor Eight Inhibitor Bypassing Activity; ICF=informed consent form; IP=investigational 
product; PK=pharmacokinetic; rFVIIa=recombinant activated clotting factor VII; SAE=serious adverse event.
a
A Study Completion/Termination Visit is to be completed in Part 1 only for subjects who withdraw or discontinue prior to the end of the study. If a 
subject withdraws or discontinues, this visit should be done in within 7 days but no sooner than 72 hours from the last infusion that he or she receives.
Otherwise, the Study Completion/Termination Visit will occur at the end of Part 2 (see Table 2).
b
Additional PK visits will occur between Infusions 1 and 2, and between Infusions 4 and 5, at 24, 72, 120, 168, and 216 hours after Infusion 1 or Infusion 
4 as described in Table 4.
c
Study Visit Windows:
1.
Infusion 1: Infusion 1 can be scheduled after screening assessments have been completed and the appropriate washout period as defined in 
washout (footnote e) below has occurred. Scheduling will also need to ensure that PK timepoints can be collected as described in footnote a and
Table 4.
2.
Infusion 2: Infusion 2 is scheduled for 9 days (+1) after Infusion 1. All PK samples must be completed before Infusion 2 can begin. If the subject 
has a bleeding episode during the 9-day PK collection period, bleeding will be controlled as described in Section 8.8.4, and after a washout of at 
least 12 days, Infusion 1 and PK assessments will be repeated.
3.
Infusion 3: Infusion 3 should be scheduled 48 hours (+48 hours) after Infusion 2.
4.
Infusion 4: Infusion 4 should be at least 12 days after Infusion 3 (See footnote f on Washout Period 2 for restrictions).
5.
Infusion 5: Infusion 5 should be 9 days (+1) after Infusion 4. All PK samples must be completed before Infusion 4 can begin. If the subject has a 
bleeding episode during the 9-day PK collection, bleeding will be controlled as described in Section 8.8.4, and after a washout of at least 12 days, 
Infusion 4 and PK assessments will be repeated..
6.
Infusion 6: Infusion 6 should be scheduled for 48 hours (+48) after Infusion 5.
d
Occurs at enrollment (prior to any study-specific procedure).
e
Washout Period 1: Washout Period 1 is based on the subject’s last dose of FEIBA or rFVIIa (e.g., NovoSeven). Due to the varying lengths of the half-
lives of the drugs, subjects who have received FEIBA will need to wait 12 days from the last dose of FEIBA that they received before they can begin 
Infusion 1. For subjects who have previously been treated with rFVIIa, they will need to wait at least 24 hours from the last dose of rFVIIa before they 
can begin Infusion 1 of the study. Additional days of washout beyond the minimum of 12 days or 1 day for FEIBA or rFVIIa treatment subjects, 
respectively, are permissible (as long as the screening assessments stay within the window to Infusion 1). Subjects who are on prophylactic therapy 
before the study, will need to have an appropriate washout period once eligibility is determined. For subjects who are on an on-demand treatment to 
control bleeding, the washout begins from the last day of treatment. If the subject has a bleeding episode that requires treatment during the washout 
period, the washout period must be restarted before they can proceed with the study.
f
Washout Period 2: Washout Period 2 is a minimum of 12 days from Infusion 3, since all subjects receive FEIBA at Infusion 3. If bleeding occurs during 
the washout period, the subject will be treated with FEIBA and the washout period will be restarted.
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Continued
g
DMC break after Part 1: The DMC review of Part 1 will be conducted twice; once after the first 12 subjects have completed Part 1, and then again after 
the last subject has completed Part 1. Once the first 12 subjects have completed Part 1, the DMC will review the safety and PK data and will provide a 
recommendation on whether these subjects can proceed to Part 2 for evaluation of increased infusion rates. Therefore, subjects will be held in a DMC 
interim period until review as described in Section 8.8.3 after completion of Infusion 6. During this time subjects who are on hold will be provided with 
standard of care FEIBA (by the sponsor) for the treatment or prevention of bleeding episodes as determined by the investigator, see Section 8.8.4. The 
DMC process will not affect enrollment of new subjects or subjects who are in other parts of the study.
h
Vital signs will include body temperature, pulse rate, blood pressure, respiratory rate, and weight.  Blood will be measured when subjects are in the 
supine position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within 30 minutes after completion of 
the infusion. Height, measured once at Screening, will also be collected.
i
For laboratory assessments, see Table 3.
j
For PK assessments, see Section 11 for details.
k
The infusion site will be monitored for AEs for 30 ±10 minutes after the infusion. See Section 12.10 for details. SAEs will be collected from ICF signing 
but will not be included in the analysis of SAEs. See Section 12.3 for details.
l
Questionnaires (TSQM and patient preference questionnaire) will be administered between Screening and Infusion 1, between Infusion 3 and 4, and 
between Infusion 6 and 7.
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20.4 Schedule of Study Procedures and Assessments (Part 2)
Table 2
Schedule of Study Procedures and Assessments (Part 2)
Procedures/
Assessments
Study Visits
Infusions 7, 8, and 9
Rate: 4 U/min/kg
DMC Reviewd
Infusions 10, 11, and 12
Rate: 10 U/min/kg
Study Completion/
Termination
Visita
Study Visit Windows
48 hours (+48) from previous 
infusionb
48 hours (+48) from 
previous infusionc
3 days (+ 4) from Infusion 12 (or 
last infusion)a
Medications and Non-drug Therapies
X
X
X
Review Subject Diary
X
X
X
Pregnancy Test
Vital Signse
X
X
X
Laboratory Assessmentsf
X
X
X
Adverse Eventsg
X
X
X
IP Treatment
X
X
TSQM and patient preference 
questionnairesh
Xh
Abbreviations: DMC=Data Monitoring Committee; FEIBA=Factor Eight Inhibitor Bypassing Activity; IP=investigational product.
a
The Study Completion/Termination Visit includes cases of withdrawal or discontinuation. This visit should be done within 7 days but no sooner than 
72 hours after Infusion 12). If a subject withdraws or discontinues, this visit should be done within 7 days but no sooner than 72 hours after the last 
infusion that the subject receives.
b
Infusions 7, 8, and 9:
1.
Infusion 7 will be scheduled as soon as possible from the subject being approved to proceed to Part 2 of the study by the DMC. However, if 
they have been receiving FEIBA treatment during the DMC interim period, wait at least 48 hours after the subject’s previous infusion before 
Infusion 7 is given.
2.
Infusion 8 will be scheduled 48 hours (+48) after Infusion 7.
3.
Infusion 9 will be scheduled 48 hours (+48) after Infusion 8.
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Continued
c
Infusions 10, 11, and 12:
Infusion 10 will be scheduled as soon as possible from the subject being approved to proceed to the next treatment arm (Infusion 10) of the study by the 
DMC. However, if they have been receiving FEIBA treatment during the DMC interim period, wait at least 48 hours after the subject’s 
previous infusion before Infusion 10 is given.
Infusion 11 will be scheduled 48 hours (+48) after Infusion 10.
Infusion 12 will be scheduled 48 hours (+48) after Infusion 11.
d
DMC review in Part 2: The DMC review of Part 2 treatment 1 will be conducted twice, once after the first 12 subjects have completed Infusion 9, and
then again after the last subject has completed Infusion 9. The DMC will review the safety data for each subset of subjects and provide a 
recommendation on whether the subjects under review can proceed to Infusion 10. Once subjects have completed Infusion 9, they will be held in an 
interim period until the DMC review as described in Section 8.8.3. During this time, subjects who are on hold will be provided with standard of care 
FEIBA (by the sponsor) for the treatment or prevention of bleeding episodes as determined by the investigator. Subjects will continue to fill out their 
subject diary at this time. Subjects will move to the next treatment arm (Infusion 10) of the study upon approval by the DMC. The DMC process will 
not affect enrollment of new subjects or subjects who are in other parts of the study.
e
Vital signs will include body temperature, pulse rate, blood pressure, respiratory rate, and weight.  Blood will be measured when subjects are in the 
supine position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within 30 minutes after completion of 
the infusion. Height, measured once at Screening, will also be collected.
f
For laboratory assessments, see Table 3.
g
The infusion site will be monitored for AEs for 30 ±10 minutes after the infusion. See Section 12.10 for details. SAEs will be collected from ICF 
signing but will not be included in the analysis of SAEs. See Section 12.3 for details.
h
Subject questionnaires (TSQM and patient preference questionnaire) will be administered after Infusion 12.
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20.5 Clinical Laboratory Assessments
Table 3
Clinical Laboratory Assessments
Assessments
Screening Visit
Infusions 1 and 4 
PK Visitsa
(multiple visits 
Day 1 through 9)
Infusions 
2, 3, 5, 6, 7, 8, 9, 10, 
11, and 12
Study Completion/
Termination
Visitb
Hematologyc
X
X
Clinical Chemistryd
X
X
Coagulation Testinge
X
X
X
X
Serology Testingf
X
X
PK Assessmentsg
X
X
X
Pregnancy Testh
X
Abbreviations: ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
CBC=complete blood count; FII=Factor II; FIX=Factor IX; FVII=Factor VII; FVIII=Factor VIII; FX=Factor X; GGT=gamma-glutamyl transpeptidase; 
HAV=hepatitis A virus; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; Hct=hematocrit; HCV=hepatitis C virus; Hgb=hemoglobin; 
HIV=human immunodeficiency virus; IgG=immunoglobulin G; IgM=immunoglobulin M; MCHC=mean corpuscular hemoglobin concentration; 
MCV=mean corpuscular volume; PK=pharmacokinetic; PT=prothrombin time; RBC=red blood cell; TAT=thrombin/anti-thrombin complex; 
WBC=white blood cell.
a
Additional PK visits will occur between Infusions 1 and 2, and between Infusions 4 and 5, at 24, 72, 120, 168, and 216 hours after Infusion 1 or Infusion 
4 as described in Table 4.
b
Includes cases of withdraw or discontinuation.
c
Hematology assessments include:  CBC (Hct, Hgb, RBC count, WBC count ) with differential, MCV, MCHC, and platelet count.
d
Clinical chemistry assessments include sodium, chloride, potassium, bicarbonate, AST, ALT, albumin, total protein, alkaline phosphatase, total 
bilirubin, BUN, creatinine, glucose, GGT, 5’-nucleotidase.
e
Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1.2, TAT, fibrinopeptide A), FII, FX, FIX, FVII, 
and FVIII or FIX inhibitor level (Nijmegen assay).
f
Serological testing will include: HIV-1 and HIV-2 antibodies (HIV+, check CD4 count–screening visit only), HAV antibodies, HBV antibody, HBsAg, 
HCV antibody, parvovirus B19 (IgM and IgG), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus antibodies (IgM and IgG).
g
PK assessments will include coagulation activity testing of:  Factors II, 
 as described in Table 4.
h
A serum pregnancy test will be performed for females of childbearing potential.
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20.6 Pharmacokinetic Assessments
Table 4
PK Assessments
Procedures/
Assessments
Screening Visit
Infusion 1
Infusion 4
Day from 
Infusion
PK Assessments:
Factor II
 
X
X
Preinfusion
30 ± 5 min
30 ± 5 min
Day 0
15 ± 5 min
15 ± 5 min
Postinfusiona
EOI
EOI
Day 0
30 ± 5 minb
30 ± 5 minb
60 ± 5 min
60 ± 5 min
3 h ± 30 min
3 h ± 30 min
8 h ± 30 min
8 h ± 30 min
24 ± 4 hb
24 ± 4 hb
Day 1
72 ± 4 h
72 ±4 h
Day 3
120 ± 6 h
120 ± 6 h
Day 5
168 ± 6 h
168 ± 6 h
Day 7
216 ± 6 h
216 ± 6 h
Day 9
Abbreviations: EOI=end-of-infusion; Factor II=FII; 
 
h=hours; min=minutes; PK=pharmacokinetic.
Notes: PK assessments will be completed on FII, 
 at screening and all timepoints 
indicated before and after Infusion 1 and Infusion 4.
a
Postinfusion sampling times are relative to the end of infusion.
b
Blood sample for thrombotic marker analysis will be collected at either the 30-minute or 24-hour 
timepoint.
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21. REFERENCES
1. Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity 
(FEIBA®): 10-year compilation of thrombotic adverse events. Haemophilia. 
2002;8:83-90.
2. Hilgartner M, Aledort L, Andes A, Gill J. Efficacy and safety of vapor-heated anti-
inhibitor coagulant complex in hemophilia patients. FEIBA Study Group. 
Transfusion. 1990;30:626-630.
3. Hilgartner MW, Knatterud GL, FEIBA Study Group. The use of factor eight 
inhibitor by-passing activity (FEIBA immuno) product for treatment of bleeding 
episodes in hemophiliacs with inhibitors. Blood. 1983;61:36-40.
4. Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. 
Haemophilia. 1998;4:558-563.
5. Ehrenforth S, Kreuz W, Scharrer I et al. Incidence of development of factor VIII 
and factor IX inhibitors in haemophiliacs. Lancet 1992;339:594-598.
6. Turecek PL, Varadi K, Gritsch H et al. Factor Xa and prothrombin: mechanism of 
action of FEIBA. Vox Sang. 1999;77 Suppl 1:72-79.
7. 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.
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8. Boggio LN, Kessler CM. Hemophilia A and B. In: Kitchens C, Alving BM, Kessler 
CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier 
Saunders; 2007:45-59.
9. Baxter Healthcare Corporation. FEIBA (Anti-inhibitor coagulant complex) for 
intravenous use, lyophylized powder for solution. 15. 2013. FEIBA. United States. 
Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/Appr
ovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM221749.pd
f. Accessed on 09 September 2015.
10. Bharmal M, Payne K, Atkinson MJ et al. Validation of an abbreviated treatment 
satisfaction questionnaire for medication (TSQM-9) among patients on 
antihypertensive medications. Health Qual.Life Outcomes 2009;7:36.
11. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents 
in cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. New 
York: Columbia University Press; 1949:191-205.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered, FEIBA NF
STUDY TITLE: A Two-part, Phase 4, Prospective, Open-label, Randomized, 
Crossover Study of the PK and Safety of FEIBA Reconstituted in Regular or 50% 
Reduced Volume and the Safety of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 4
ORIGINAL: 2015 OCT 08
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-004079-60
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered, FEIBA NF
STUDY TITLE: A Two-part, Phase 4, Prospective, Open-label, Randomized, 
Crossover Study of the PK and Safety of FEIBA Reconstituted in Regular or 50% 
Reduced Volume and the Safety of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 4
ORIGINAL: 2015 OCT 08
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-004079-60
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD
, Clinical Development
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CLINICAL STUDY PROTOCOL
PRODUCT: Anti-inhibitor Coagulant Complex, activated prothrombin complex 
concentrate, FEIBA
STUDY TITLE: A Two-part, Phase 4, Prospective, Multicenter, Open-label, 
Randomized, Crossover Study of the PK and Safety of FEIBA Reconstituted in 
Regular or 50% Reduced Volume and the Safety of Faster Infusion Rates in 
Patients with Hemophilia A or B with Inhibitors
STUDY SHORT TITLE: FEIBA Reconstitution Volume Reduction and Faster 
Infusion Study
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 4
AMENDMENT 1 (Global): 2016 Mar 03
Replaces: Original: 2015 OCT 08
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA 91362, 
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, 
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory)/Responsible Party
 MD
 Clinical Development
Baxalta US Inc.
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g., 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 ADVERSE EVENT ELECTRONIC 
CASE REPORT FORM (ECRF) 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT. IF THE 
ECRF IS NOT AVAILABLE THEN THE SAE MUST BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR TO MEET THE 24 HOUR TIMELINE 
REQUIREMENT.
See SAE Protocol Sections for further information and SAER form for contact 
information. 
Further details are also available in the study team roster.
For definitions and information on the assessment of these events, refer to the following:

Adverse Event, Section 12.1

Serious Adverse Event, Section 12.1.1.1

Assessment of Adverse Events, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT (IP)
Name of IP
FEIBA, Anti-Inhibitor Coagulant Complex 
Name(s) of Active Ingredient(s)
Coagulation factors II, X, IX, and VIIa
CLINICAL CONDITION(S)/INDICATION(S)

Hemophilia A or B with inhibitors
PROTOCOL ID
091501
PROTOCOL TITLE
A Two-part, Phase 4, Prospective, Multicenter, Open-label, 
Randomized, Crossover Study of the PK and Safety of 
FEIBA Reconstituted in Regular or 50% Reduced Volume and 
the Safety of Faster Infusion Rates in Patients with Hemophilia 
A or B with Inhibitors
Short Title
FEIBA Reconstitution Volume Reduction and Faster Infusion 
Study
STUDY PHASE
Phase 4 (postmarketing)
PLANNED STUDY PERIOD
Initiation
First Subject In: Q2 2016
Primary Completion
Last Subject In: Q1 2017 
Study Completion
Last Subject Last Visit: Q1 2018
Duration
13 to 16 months 
STUDY OBJECTIVES AND PURPOSE
Study Purpose
1. To compare the pharmacokinetics (PK) of Factor Eight Inhibitor Bypassing Activity (FEIBA
component Factor II (FII) and safety of FEIBA reconstituted in a reduced volume of sterile water 
for injection (SWFI) versus regular volume SWFI, administered at the standard infusion rate of 
2 U/min/kg
2. To evaluate the safety of infusing reduced volume FEIBA at increased rates of 4 and 10 U/min/kg 
in comparison to the standard rate of 2 U/min/kg
Primary Objectives
1. Determine PK equivalence of FEIBA component FII reconstituted in 50% reduced volume SWFI 
and regular volume SWFI on area under the concentration-time curve from time zero (preinfusion) 
to time 216 hours (AUC0-216 h)
2. Determine the occurrence of thromboembolic events and allergic-type hypersensitivity reactions 
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Secondary Objectives
1. Determine the safety and tolerability of 50% reduced volume FEIBA administered at the standard 
and escalated infusion rates, based on the occurrence of adverse events (AEs)
2. Monitor clinically apparent changes in vital signs, infusion rate-related events, and infusion site 
reactions 
3. Determine the effect of 50% reduced volume FEIBA component FII on incremental recovery (IR), 
area under the concentration-time curve from time zero (preinfusion) extrapolated to infinity
(AUC0-∞), area under the concentration-time curve from time zero (preinfusion) to time of last 
quantifiable concentration (AUC0-last), terminal half-life (t1/2), clearance (CL), mean residence time 
(MRT), volume of distribution at steady state (Vss), maximum plasma concentration (Cmax), and 
time to maximum observed plasma concentration (tmax)
Exploratory Objective
 
2. Evaluate subject treatment preference using Treatment Satisfaction Questionnaire for Medication 
(TSQM) and patient preference questionnaire
STUDY DESIGN
Study Type/ Classification/ 
Discipline
PK Equivalence, Pharmacokinetic, and Safety
Control Type
Active
Study Indication Type
Treatment
Intervention model
Part 1:  Crossover
Part 2:  Sequential
Blinding/Masking
Part 1:  Randomized, Open-label
Part 2:  Non-randomized, Open-label
Study Design
This study is a 2-part, Phase 4, prospective, open-label, multicenter 
study to be conducted in up to 24 evaluable hemophilia A or B 
subjects with inhibitors (≥0.6 Bethesda units [BU] in hemophilia A 
and ≥0.6 BU in hemophilia B) for the primary PK assessment, (i.e., 
having the AUC0-216 h of FEIBA component FII estimable from both 
PK infusions), with a planned enrollment of up to 32 subjects.
In Part 1, subjects will be administered 2 different volumes of 
FEIBA in a randomized, crossover manner with a washout period 
between the treatments. Part 1 will evaluate the PK (FEIBA 
component FII) and safety of FEIBA reconstituted in 50% reduced 
volume of SWFI and administered at the standard infusion rate of 
2 U/min/kg compared with FEIBA reconstituted in regular volume 
of SWFI at the standard infusion rate. All subjects will be screened for 
eligibility based on the listed inclusion and exclusion criteria.
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After a washout period (at least 12 days from last treatment with 
APCC (e.g., FEIBA), or at least 24 hours after last treatment with a 
recombinant activated clotting factor VII (rFVIIa) product [e.g., 
NovoSeven®]), eligible subjects will be randomly assigned (1:1) to 
receive 3 infusions of FEIBA reconstituted in 50% reduced volume 
SWFI followed by regular volume SWFI or vice versa. Subjects will 
receive the first infusion for PK and safety analysis and the second and 
third infusions for collection of additional safety data. After a washout 
period of at least 12 days following the third infusion, subjects will 
crossover to the next treatment group where the fourth infusion will be 
for PK and safety analysis and the fifth and sixth infusions for 
collection of additional safety data.
All subjects who received at least 1 dose of FEIBA will be included in 
the safety analysis set. 
Pharmacokinetic equivalence of FEIBA reconstituted in reduced and
regular volumes of SWFI in terms of AUC0-216 h will be evaluated 
using the PK population. 
Part 2 is non-randomized with sequential enrollment of subjects who 
complete Part 1, to evaluate the safety of infusing FEIBA reconstituted 
in 50% reduced volume of SWFI at increased rates of 4 and 
10 U/min/kg. FEIBA Infusions 7, 8, and 9 will be administered at the
4 U/min/kg rate. The infusions will be administered every 48 hours 
(+48 hours) to allow time to monitor safety and tolerability of the 
higher infusion rate. Subjects will follow with 3 infusions (Infusions 
10, 11, and 12) of FEIBA at 10 U/min/kg rate. The infusions will be 
administered every 48 hours (+48 hours) to allow time to monitor 
safety and tolerability of the higher infusion rate.
Following the last infusion, a study termination visit will be conducted 
within 7 days but no sooner than 72 hours after the last infusion.
All IP infusions will be administered at the hemophilia care 
centers/study sites. Each subject will receive a maximum of 14 IP
infusions total (most subjects will receive 12 IP infusions, up to 14 is 
for subjects who have a bleeding episode during PK collections, and 
therefore have their PK infusion reinfused). Subjects will receive 
FEIBA at a dose of 85 U/kg ± 100 U for all PK infusions (Infusions 1 
and 4) and 85 ± 15 U/kg. For PK infusions, every measure should be 
taken to ensure consistent dosing between Infusion 1 and Infusion 4. 
Partial vials may be used in order to maintain a consistent dose in case 
85 U/kg ± 100 U can not be achieved by administration of whole vials. 
For infusions that are not PK infusions, whole vials should be rounded 
up or down to be as close as possible to the accurate dosage, as 
appropriate. Please refer to study documents for detailed instructions.
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Safety monitoring for this study will be conducted by an Internal 
Safety Monitoring Committee (ISMC). All SAEs that occur will be 
reviewed by the Chair of the ISMC. Additionally, there are 
3 scheduled ISMC meetings:
1. At least 48 hours after 6 subjects in Part 1 (3 subjects in each 
group) have completed Infusion 5
2. At least 48 hours after 6 subjects have completed Infusion 8 
(Part 2)
3. At least 48 hours after 6 subjects have completed Infusion 11
(Part 2)
ISMC preplanned meetings will be held concurrently with the ongoing 
study.
Planned Duration of Subject 
Participation
Study enrollment is planned to initiate in Q2 of 2016. It is planned that 
each subject will spend approximately 60-90 days in the study.  
Primary Outcome Measure 
1. AUC0-216 h of FEIBA component FII in the subjects
2. Occurrence of thromboembolic events
3. Occurrence of allergic-type hypersensitivity reactions 
Secondary Outcome Measure(s) 
Efficacy/Pharmacokinetics
1. Incremental recovery of FEIBA component FII in subjects
2. AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, and tmax of FEIBA component FII in subjects
Safety 
1. Evaluate occurrence of all AEs and SAEs
2. Evaluate occurrence of AEs leading to discontinuation
3. Evaluate occurrence of infusion site reactions
4. Evaluate occurrence of all AEs occurring within 24 to 72 hours of IP infusion
5. Evaluation of thrombotic markers (e.g., D-Dimers, prothrombin fragment F 1.2, 
thrombin/anti-thrombin complex [TAT], and fibrinopeptide A)
6. Evaluate vital signs and clinical laboratory assessments
Exploratory Outcome Measure(s)
2. Evaluate responses to the TSQM and the patient preference questionnaire
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: kit; powder, lyophilized, for solution/suspension;
injection
Dosage frequency: Infusion 2 and 5 are 9 days (+ 1 day) from 
Infusion 1 and 4, respectively. Infusions 3, 6, 7, 8, 9, 10, 11, and 12 
are 48 hr (+48 hr) from the previous infusion. See Section 20.3 and 
Section 20.4 for additional details.
Mode of Administration: intravenous bolus
SUBJECT SELECTION
Targeted Accrual
Enroll 32 subjects (at least 24 evaluable for the primary PK 
assessment)
Number of Groups/Arms/Cohorts
1 cohort: at least 24 evaluable adult subjects (≥18 to ≤65 years old) 
for PK and safety evaluation
Inclusion Criteria
1. Subject is ≥18 to ≤65 years old at the time of screening
2. Hemophilia A or B of any severity, with a documented history of inhibitors requiring the use of 
bypassing agents (FEIBA or rFVIIa) 
3. Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain reaction (PCR); 
or HCV positive with stable hepatic disease
4. Human immunodeficiency virus (HIV) negative; or HIV positive with stable disease and cluster of 
differentiation 4 (CD4) count ≥200 cell/mm3 at screening
5. Adequate peripheral venous access
6. Subject is willing and able to comply with the requirements of the protocol
7. If a female of childbearing potential, subject must have a negative blood pregnancy test and agrees 
to employ adequate birth control measures for the duration of the study, such as:
a
Abstain from sexual intercourse
b
Use a reliable method of contraception (contraception such as an intrauterine device, barrier 
method [e.g., diaphragm or sponge; female condom not permitted] with spermicide, oral 
contraceptive, injectable progesterone, sub dermal implant), and have their male partner use 
a condom
8. If female of non-childbearing potential, confirmed at screening by fulfilling 1 of the following 
criteria:
a
Postmenopausal, defined as amenorrhea for at least 12 months following cessation of all 
exogenous hormonal treatments and with follicle-stimulating hormone levels within the 
laboratory-defined postmenopausal range or postmenopausal with amenorrhea for at least 
24 months and on hormonal replacement therapy
b
Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, 
bilateral tubal ligation (with no subsequent pregnancy at least 1 year from bilateral tubal 
ligation), or bilateral salpingectomy
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Exclusion Criteria
1. Known hypersensitivity to FEIBA or any of its components
2. Clinically symptomatic liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites)
3. Planned elective surgery during participation in this study (excluding minor procedures that will 
not need preventative bleeding treatments, such as exchanges of peripherally inserted central 
catheters)
4. Platelet count < 100,000/µL
5. Clinical or laboratory evidence of disseminated intravascular coagulation
6. Prior history or evidence of thromboembolic event: acute myocardial infarction, deep vein 
thrombosis, pulmonary embolism, etc.
7. Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that may increase the 
subject’s risk of thromboembolic complications 
8. Subject is taking any immunomodulating drug (e.g., corticosteroid agents at a dose equivalent to 
hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to enrollment except 
antiretroviral chemotherapy
9. 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
10. Subject is a family member or employee of the investigator
11. Clinically significant medical, psychiatric or cognitive illness, or recreational drug/alcohol use 
that, in the opinion of the investigator, would affect subject safety or compliance 
STATISTICAL ANALYSIS
Sample Size Calculation
Part 1 (crossover) of this study will evaluate PK equivalence of FEIBA component FII in FEIBA 
reconstituted in 50% reduced volume versus regular volume of SWFI as measured by AUC0-216 h. The 
sample size was based on the premise of a true ratio of geometric means of test and reference of 1.0 using a 
within-subject coefficient of variation of 22.2%, to yield 90% power when equivalence is declared based on 
the 90% CI for the ratio of geometric means for the 2 treatments being completely contained in the margins 
of equivalence defined as 80% to 125%. In order to obtain the required 24 subjects, Part 1 will randomize 
up to 32 subjects for the crossover design, allowing for a possible 25% dropout rate.
With approximately 100 infusions for each treatment (reduced or regular volume of SWFI) administered 
for the study, the upper limit of the 95% CI of the rate of infusions with a specific AE is less than 3.3%, if 
the specific AE is not observed. The upper limit of the 95% CI of the rate of infusions for a specific AE is 
about 5% if 1 AE is observed.
Planned Statistical Analysis
Primary Analysis
For Part 1, an equivalence test will be made for AUC0-216 h of FII. All other PK parameters will be reported 
using descriptive statistics
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AUC0-216 h for FEIBA component FII of reduced volume and regular volume will be compared calculating 
the 90% two-sided confidence interval for the difference of the mean logarithms of AUC0-216 h between 
reduced volume and regular volume. The error variance used to calculate these CIs will be obtained from 
an analysis of variance model that will consist of fixed effect terms that model the subject effect, the 
sequence effect, the period effect, and the drug effect. The antilogs of the confidence limits will constitute
the 90% CI for the ratio of the geometric means (antilog of the means of the log). To establish equivalence, 
the 90% CI for the ratio of the geometric means of the 2 treatments has to be contained in the margins of 
equivalence defined as 80% to 125%.
For Parts 1 and 2, the safety of treatment infusions will be evaluated primarily by the occurrence of 
thromboembolic events and allergic-type hypersensitivity reactions, by treatment for each study part. These 
will be summarized and a 95% CI will be provided. 
Secondary and Exploratory Analysis
Levels of FEIBA components FII, 
 will be displayed graphically over time for each 
subject and summarized by visit and treatment for each study part. 
The AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, tmax, and IR of FEIBA component FII will be summarized 
descriptively by visit and treatment for each study part.
All safety analyses will be performed for each part separately as well as for the 2 parts together.
The number and proportion of subjects experiencing serious and non-serious AEs up to study completion or 
subject withdrawal will be summarized by treatment. The number of product related serious and non-
serious AEs and number of AEs leading to discontinuation will also be summarized by treatment. A 
subgroup of all AEs occurring within 24 and 72 hours of IP infusion will be summarized by treatment.
Additionally, subjects experiencing infusion-related AEs and infusion site reactions will be summarized by 
treatment.
Thrombotic markers (e.g., D-Dimers, prothrombin fragment F 1.2, TAT, and fibrinopeptide A) will be 
summarized using descriptive statistics by treatment. Mean concentration plots will be presented by 
treatment and visit for each thrombotic marker and study part.
The results of the TSQM and the patient preference questionnaires will be summarized by descriptive 
statistics as appropriate. 
Vital signs and clinical laboratory assessments will be summarized descriptively by treatment for each 
study part at each scheduled assessment and for the corresponding change from baseline. Shift tables will 
also be presented for clinical laboratory assessments by treatment for each study part at each scheduled 
assessment.
Full details of the statistical analysis will be specified in the statistical analysis plan (SAP).
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory)/Responsible Party................................ 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 11
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 19
6.1 Description of Investigational Product and Clinical Condition/Indication..... 19
6.2 Population to Be Studied...................................................................................... 20
6.3 Findings from Nonclinical and Clinical Studies................................................. 21
6.3.1 Finding from Nonclinical Studies................................................................. 21
6.3.2 Findings from Clinical Studies ..................................................................... 21
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 22
6.5 Compliance Statement.......................................................................................... 22
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 23
7.1 Study Purpose ....................................................................................................... 23
7.2 Primary Objectives............................................................................................... 23
7.3 Secondary Objectives ........................................................................................... 23
7.4 Exploratory Objective.......................................................................................... 23
8. STUDY DESIGN......................................................................................................... 24
8.1 Brief Summary...................................................................................................... 24
8.2 Study Design Rationale ........................................................................................ 24
8.3 Overall Study Design............................................................................................ 24
8.4 Duration of Study Period(s) and Subject Participation .................................... 26
8.5 Outcome Measures ............................................................................................... 26
8.5.1 Primary Outcome Measures......................................................................... 26
8.5.2 Secondary Outcome Measures ..................................................................... 26
8.5.2.1 Efficacy/Pharmacokinetics..................................................................... 26
8.5.2.2 Safety........................................................................................................ 27
8.5.3 Exploratory Outcomes Measure .................................................................. 27
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8.6 Randomization and Blinding............................................................................... 27
8.7 Study Stopping Rules............................................................................................ 27
8.8 Investigational Product(s).................................................................................... 28
8.8.1 Packaging, Labeling, and Storage................................................................ 28
8.8.2 Administration ............................................................................................... 28
8.8.3 Description of Treatment.............................................................................. 30
8.8.4 Management and Treatment of Break-Through Bleeding ........................ 33
8.8.5 Investigational Product Accountability ....................................................... 34
8.9 Source Data ........................................................................................................... 35
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 36
9.1 Inclusion Criteria.................................................................................................. 36
9.2 Exclusion Criteria................................................................................................. 37
9.3 Withdrawal and Discontinuation ........................................................................ 37
10. STUDY PROCEDURES .......................................................................................... 39
10.1 Informed Consent and Enrollment ................................................................... 39
10.2 Subject Identification Code................................................................................ 39
10.3 Screening and Study Visits................................................................................. 39
10.3.1 Screening and Baseline Assessments.......................................................... 39
10.3.2 Treatment Visits........................................................................................... 41
10.3.2.1 Infusion Visits ....................................................................................... 41
10.3.3 PK only Visits............................................................................................... 42
10.3.4 Study Completion/Termination Visit......................................................... 42
10.4 Medications and Non-Drug Therapies.............................................................. 42
10.5 Subject Questionnaires....................................................................................... 44
10.6 Subject Completion/Discontinuation ................................................................ 44
10.7 Procedures for Monitoring Subject Compliance............................................. 45
11. ASSESSMENT OF PHARMACOKINETICS....................................................... 46
11.1 Sample Collection and Processing..................................................................... 46
11.2 Pharmacokinetic Evaluation and Pharmacokinetic Parameters ................... 46
12. ASSESSMENT OF SAFETY................................................................................... 48
12.1 Adverse Events.................................................................................................... 48
12.1.1 Definitions..................................................................................................... 48
12.1.1.1 Serious Adverse Event.......................................................................... 48
12.1.1.2 Non-Serious Adverse Event ................................................................. 49
12.1.1.3 Unexpected Adverse Events................................................................. 49
12.1.1.4 Pre-existing Diseases............................................................................. 49
12.1.2 Assessment of Adverse Events.................................................................... 50
12.1.2.1 Severity .................................................................................................. 51
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12.1.2.2 Causality................................................................................................ 51
12.1.2.3 Safety Reporting ................................................................................... 52
12.1.3 Medical Device Safety Reporting ............................................................... 54
12.2 Urgent Safety Measures ..................................................................................... 54
12.3 Untoward Medical Occurrences........................................................................ 54
12.4 Non-Medical Complaints ................................................................................... 55
12.5 Medical, Medication, and Non-Drug Therapy History................................... 55
12.6 Physical Examinations........................................................................................ 56
12.7 Clinical Laboratory Parameters........................................................................ 56
12.7.1 Hematology and Clinical Chemistry.......................................................... 56
12.7.2 Coagulation Testing..................................................................................... 57
12.7.3 Viral Serology............................................................................................... 57
12.7.4 CD4 Levels.................................................................................................... 57
12.7.5 Assessment of Laboratory Values .............................................................. 57
12.7.5.1 Assessment of Abnormal Laboratory Values..................................... 57
12.7.6 Biobanking.................................................................................................... 58
12.8 Vital Signs............................................................................................................ 58
12.9 Karnofsky Performance Test............................................................................. 58
12.10 Infusion Site Evaluations.................................................................................. 59
12.11 Special Treatment Considerations .................................................................. 59
13. STATISTICS............................................................................................................. 61
13.1 Sample Size and Power Calculations ................................................................ 61
13.2 Datasets and Analysis Cohorts .......................................................................... 61
13.3 Handling of Missing, Unused, and Spurious Data........................................... 62
13.4 Methods of Analysis............................................................................................ 62
13.4.1 Primary Outcome Measure......................................................................... 62
13.4.1.1 Analysis of the Primary PK Outcome Measure (Part 1)................... 62
13.4.1.2 Analysis of the Primary Safety Outcome Measure (Parts 1 and 2) . 63
13.4.2 Secondary Outcome Measures ................................................................... 63
13.4.2.1 Analysis of the Pharmacokinetic Outcome Measures....................... 63
13.4.2.2 Analysis of the Safety Outcome Measures ......................................... 63
13.4.3 Exploratory Outcome Measures ................................................................ 64
13.5 Planned Interim Analysis of the Study ............................................................. 64
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 65
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 66
15.1 Investigator’s Responsibility.............................................................................. 66
15.1.1 Final Clinical Study Report........................................................................ 66
15.2 Training ............................................................................................................... 66
15.3 Monitoring........................................................................................................... 66
15.4 Auditing ............................................................................................................... 66
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15.5 Non-Compliance with the Protocol ................................................................... 67
15.6 Laboratory and Reader Standardization ......................................................... 67
16. ETHICS ..................................................................................................................... 68
16.1 Subject Privacy ................................................................................................... 68
16.2 Ethics Committee and Regulatory Authorities................................................ 68
16.3 Informed Consent ............................................................................................... 68
16.4 Internal Safety Monitoring Committee ............................................................ 69
17. DATA HANDLING AND RECORD KEEPING................................................... 70
17.1 Confidentiality Policy ......................................................................................... 70
17.2 Study Documentation and Case Report Forms ............................................... 70
17.3 Document and Data Retention........................................................................... 70
18. FINANCING AND INSURANCE........................................................................... 71
19. PUBLICATION POLICY........................................................................................ 71
20. SUPPLEMENTS....................................................................................................... 72
20.1 Study Flow Chart Part 1 .................................................................................... 72
20.2 Study Flow Chart Part 2 .................................................................................... 73
20.3 Schedule of Study Procedures and Assessments (Part 1)................................ 74
20.4 Schedule of Study Procedures and Assessments (Part 2)................................ 76
20.5 Clinical Laboratory Assessments ...................................................................... 77
20.6 Pharmacokinetic Assessments ........................................................................... 78
21. REFERENCES.......................................................................................................... 79
22. SUMMARY OF CHANGES.................................................................................... 81
INVESTIGATOR ACKNOWLEDGEMENT.............................................................. 92
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Tables
Table 1 FEIBA Product Preparation................................................................................. 29
Table 2 Schedule of Study Procedures and Assessments (Part 1)................................... 74
Table 3 Schedule of Study Procedures and Assessments (Part 2)................................... 76
Table 4 Clinical Laboratory Assessments........................................................................ 77
Table 5 PK Assessments.................................................................................................. 78
Figures
Figure 1 Study Design for Part 1 Baxalta Clinical Study 091501 ................................... 72
Figure 2 Study Design for Part 2 Baxalta Clinical Study 091501 .................................... 73
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AICC
anti-inhibitor coagulant complex
ALT
alanine aminotransferase
APCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC0-216 h
area under the concentration-time curve from time zero (preinfusion) to time 
216 hours
AUC0-last
area under the concentration-time curve from time zero (preinfusion) to the last 
quantifiable concentration
AUC0-∞
area under the concentration-time curve from time zero (preinfusion) extrapolated to 
infinity
BU
Bethesda units
BUN
blood urea nitrogen
BW
body weight
CBC
complete blood count
CD4
cluster of differentiation 4
CI
confidence interval
CL
clearance 
Cmax
maximum plasma concentration
CRF
case report form
EC
ethics committee
EOI
end-of-infusion
eCRF
electronic case report form
EDC
electronic data capture
FEIBA
Factor Eight Inhibitor Bypassing Activity
FEIBA NF
Factor Eight Inhibitor Bypassing Activity Nanofiltered
FEIBA VH
Factor Eight Inhibitor Bypassing Activity Vapor Heated
FII
Factor II
FIX
Factor IX
FVII
Factor VII
FVIII
Factor VIII
FVIII:CAg
Factor VIII C antigen
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Abbreviation
Definition
Continued
FX
Factor X
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GSL
Global Safety Lead
HAV
hepatitis A virus
HBsAg
hepatitis B surface antigen
HBV
hepatitis B
Hct
hematocrit
HCV
hepatitis C virus
Hgb
hemoglobin
HIV
human immunodeficiency virus 
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IgG
immumoglobulin G
IgM
immunoglobulin M
IP
investigational product
IR
incremental recovery
ISMC
Internal Safety Monitoring Committee
Min
minutes
MRT
mean residence time 
NMC 
non-medical complaint
PCR
polymerase chain reaction
PK
Pharmacokinetic(s)
PT
prothrombin time
rFVIIa
recombinant activated clotting factor VII
Rsq
r2
SAE
serious adverse event
SAER
serious adverse event report
SIC
subject identification code
SI
serious injuries
SWFI
sterile water for injection
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Abbreviation
Definition
Continued
t1/2
terminal half-life
TAT
thrombin/anti-thrombin complex
tmax
Time to maximum observed plasma concentration
TSQM
Treatment Satisfaction Questionnaire for Medication
Vss
volume of distribution at steady state
λz
terminal rate constant
%AUCex
percentage of AUC obtained by extrapolation
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product and Clinical Condition/Indication
Note: Labeling has been updated since the Investigator Brochure (IB), and Factor Eight 
Inhibitor Bypassing Activity Nanofiltered (FEIBA NF) referenced in the background 
section is now referenced as FEIBA throughout the rest of the protocol.
The investigational product (IP), FEIBA NFi is a plasma derived, activated prothrombin 
complex concentrate (APCC), generically identified as an anti-inhibitor coagulant 
complex (AICC). FEIBA was developed to treat bleeding episodes and cover surgical 
interventions in hemophilia A and B patients with inhibitors and in non-hemophilia 
patients with acquired inhibitorsii and is also intended for use as a prophylactic treatment 
for hemophilia A and B patients with high responding inhibitors and frequent joint 
bleeding. iii,1,2,3
FEIBA was marketed beginning in 1978 and was superseded in 1985 by a 2-stage vapor 
heat-treated product, FEIBA VH. Nanofiltration was introduced to the manufacturing 
process in 2006 to produce FEIBA NF. FEIBA NF shares the same indications as
FEIBA VH.
Hemophilia is an X-linked, recessive, congenital bleeding disorder caused by deficient or 
defective coagulation due to a deficiency in FVIII (hemophilia A), or FIX (hemophilia 
B). The absence of FVIII or FIX leads to spontaneous bleeding episodes (occurring 
primarily in joints, muscles, and less commonly, in soft tissues) and to excessive bleeding 
following trauma or injury.4,5  Replacement therapy for the treatment of hemophilia A, 
and less frequently hemophilia B, can be complicated by an immune response resulting in 
the production of inhibitory alloantibodies to Factor VIII (FVIII) or Factor IX (FIX), 
especially in patients with moderate to severe hemophilia. The development of such 
inhibitory antibodies currently represents the most serious complication of hemophilia 
treatment. The presence of inhibitors against FVIII generally precludes the efficacious 
use of human FVIII replacement therapy. A substantial portion of patients with FVIII 
inhibitors have high-responding, high-titer inhibitors (> 5 Bethesda units [BU]). These 
patients exhibit an anamnestic response after FVIII exposure, sometimes with a dramatic 
increase in inhibitory antibody titer.6,7 The inability to provide FVIII replacement therapy 
                                                
i
FEIBA NF is a trademark of Baxalta US Inc. and Baxalta Innovations GmbH.
ii
Anti-Inhibitor Coagulant Complex, FEIBA Vapor Heated. Package Insert, Baxalta US Inc., Westlake 
Village, CA.
iii
Protocol 090701. FEIBA NF: A Prospective, Open-label, Randomized, Parallel Study to Evaluate 
Efficacy and Safety of Prophylactic versus On-demand Treatment in Patients with Hemophilia A and B 
and High Titer Inhibitor. 2013 Jan 14, Baxalta US Inc., (Westlake Village, CA).
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predisposes this group of patients to increased morbidity and mortality compared with 
hemophilia patients without inhibitors.6 Several therapeutic approaches are currently 
available in the management of hemorrhagic events in patients who have developed 
FVIII inhibitors. These include neutralization with high doses of human FVIII (low titer 
inhibitor only), and treatment with bypassing agents such as Activated Prothrombin 
Complex Concentrates (APCCs), or activated recombinant factor VII (rFVIIa). Among 
these treatment options, only APCCs and rFVIIa are able to control acute hemorrhages in 
hemophilia patients with high titer inhibitors. These agents control bleeding by promoting 
the conversion of prothrombin to thrombin with subsequent fibrin polymerization and 
clot formation via mechanisms that do not require FVIII or FIX. It has been proposed that 
FEIBA products achieve this goal principally by virtue of the presence of a “partial 
prothrombinase complex” consisting of activated Factor X (FX) and prothrombin.8
The active ingredient of FEIBA is a plasma-derived, freeze-dried APCC with FVIII 
inhibitor bypassing activity. The product FEIBA contains mainly non-activated forms of 
the 3 coagulation factors, Factor II (FII), FIX and FX, as well as activated FVII; and 
Factor III coagulant antigen present in a concentration of up to 0.1 U/1 U FEIBA. A 
solution containing 1 U FEIBA shortens the activated partial thromboplastin time (aPTT) 
of FVIII inhibitor plasma up to 50% of the buffer value. Additional details can be found 
in the FEIBA IB.iv
6.2 Population to Be Studied
Adult subjects (age ≥18 to ≤65 years) with hemophilia A or B of any severity, of all 
races and ethnic groups will be studied. All subjects will have a documented history of 
inhibitors requiring the use of bypassing agents (FEIBA or rFVIIa). Subjects will either 
be hepatitis C virus (HCV) negative or HCV positive with stable hepatic disease. 
Subjects will either be human immunodeficiency virus (HIV) negative or HIV positive 
with stable disease and a cluster of differentiation 4 (CD4) count ≥ 200 cell/mm3. See 
additional details in the Inclusion and Exclusion Criteria in Section 9.1 and Section 9.2, 
respectively.
                                                
iv
Investigator’s brochure. Anti-inhibitor coagulant complex nanofiltered; FEIBA NF. 2013 APR 22. 
Baxalta US Inc., (Westlake Village, CA). 
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6.3 Findings from Nonclinical and Clinical Studies
6.3.1 Finding from Nonclinical Studies
The nonclinical studies performed for FEIBA NF included a virus clearance study, which
was performed to investigate the virus reduction capacity of the nanofiltration step in the 
manufacturing of FEIBA NF. 
Preclinical studies have demonstrated FEIBA NF to have comparable activity and other 
biochemical properties to FEIBA VH.
Data from nonclinical studies can be found in the FEIBA NF IB.iv
6.3.2 Findings from Clinical Studies
The results of Baxalta clinical study 090701iii demonstrated that prophylaxis with 
FEIBA NF significantly reduced the annualized bleeding episode rates for spontaneous
and traumatic, joint/non-joint, bleeding episodes when compared with on-demand 
treatment. A statistically significant reduction in the rate of bleeding episodes in new 
target joints in the prophylaxis arm versus the on-demand arm was also observed. An 
examination of adverse events (AEs), abnormal laboratory parameters for hematology 
and clinical chemistry and vital signs demonstrated that FEIBA NF was safe and well 
tolerated for prophylactic use. Clinically, these data suggest that both on-demand and 
prophylaxis regimens were safe and efficacious in the management of hemophilia 
(congenital and acquired) A or B with persistent high- or low-titer inhibitors refractory to 
FVIII or FIX treatment, and further confirmed the safety and effectiveness of FEIBA NF 
for controlling and preventing bleeding episodes.
Baxalta clinical study 091002 was an open-label, uncontrolled, non-interventional 
observational cohort study of FEIBA NF in hemophiliacs with inhibitors. This study was
designed to document routine usage of FEIBA NF as a bypassing agent for on-demand or 
prophylactic treatment in everyday clinical practice and in surgical intervention. The 
safety results of this postauthorization safety study showed that treatment with 
FEIBA NF, administered in 81 subjects with hemophilia and requiring treatment with 
inhibitor-bypass therapy for bleed resolution or bleed prophylaxis, was generally safe 
and well tolerated. The mean infusion rate of FEIBA under routine clinical practice 
during the study (3.7 U/kg per min, range 0.9 to 23.5) was higher than that 
recommended in the Summary of Product Characteristics of FEIBA (2.0 U/kg per min). 
A manual analysis of safety listings did not disclose any AEs associated with a higher 
infusion rate.9 Treatment-related AEs or serious adverse events (SAEs) were reported 
in 9.9% and in 3.7% of subjects, respectively. A deep venous thrombosis and a 
superficial thrombophlebitis were observed in 1 subject with acquired hemophilia.
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The hemostatic effectiveness was rated by the physicians as excellent or good in more 
than 90% of total subjects, with the highest rates reported in subjects with FEIBA NF 
prescribed as regular prophylaxis. Additional details on this study can be found in the 
clinical study report.v
Additional observational, non-interventional studies were conducted with FEIBA NF. 
Additional details on clinical studies can be found in the FEIBA NF IB.iv
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
The FEIBA NF products can precipitate allergic-type hypersensitivity reactions that have 
included, urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and a 
drop in blood pressure; these reactions can be severe and can be systemic (e.g., 
anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other 
infusion reactions, such as chills, pyrexia, and hypertension have also been reported. The 
most commonly reported adverse drug reactions described for FEIBA NF include
increase in inhibitor titer, somnolence, dizziness, dysgeusia, dyspnea, nausea, chills, 
pyrexia, chest pain, and chest discomfort. 
The possibility of thrombotic events should be considered when systemic 
anti-fibrinolytics such as aminocaproic acid and tranexamic acid are used in combination 
with FEIBA NF. Therefore, anti-fibrinolytics should not be used for approximately 6 to 
12 hours before or after the administration of FEIBA NF.
Animal reproduction studies have not been conducted with FEIBA NF. There are no 
adequate and well-controlled studies in pregnant women. It is also not known whether 
FEIBA NF can cause fetal harm when administered to a pregnant woman or an affect 
reproductive capacity. It is not known whether FEIBA NF is excreted in human milk.10
Subjects within the study should be warned regarding this labeling information.
Additional safety experience for FEIBA is provided in the FEIBA NF IB.iv
6.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations, the EU Directives 2001/20/EC and 
2005/28/EC, and applicable national and local regulatory requirements.
                                                
v
Clinical Study Report. Post-Authorization Safety Study of FEIBA NF (Factor VIII Inhibitor Bypassing 
Activity). An open, uncontrolled, non-interventional observational cohort study of FEIBA NF in 
hemophiliacs with inhibitors. 10 Oct 2014. Baxalta US Inc. and Baxalta Innovations GmbH.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is:
1. To compare the pharmacokinetics (PK) of FEIBA component FII and safety of 
FEIBA reconstituted in a reduced volume of sterile water for injection (SWFI) 
versus regular volume SWFI, administered at the standard infusion rate of 
2 U/min/kg
2. To evaluate the safety of infusing reduced volume FEIBA at increased rates of 
4 and 10 U/min/kg in comparison to the standard rate of 2 U/min/kg
7.2 Primary Objectives
1. Determine PK equivalence of FEIBA component FII reconstituted in 50% 
reduced volume SWFI and regular volume SWFI on area under the 
concentration-time curve from time zero (preinfusion) to time 216 hours 
(AUC0-216 h)
2. Determine the occurrence of thromboembolic events and allergic-type 
hypersensitivity reactions 
7.3 Secondary Objectives
1. Determine the safety and tolerability of 50% reduced volume FEIBA
administered at the standard and escalated infusion rates, based on the occurrence 
of AEs
2. Monitor clinically apparent changes in vital signs, infusion rate-related events, 
and infusion site reactions 
3. Determine the effect of 50% reduced volume FEIBA component FII on 
incremental recovery (IR), area under the concentration-time curve from time 
zero (preinfusion) to extrapolated to infinity (AUC0-∞), area under the 
concentration-time curve from time zero (preinfusion) to time of last quantifiable 
concentration (AUC0-last), terminal half-life (t1/2), clearance (CL), mean residence 
time (MRT), volume of distribution at steady state (Vss), maximum plasma 
concentration (Cmax), and time to maximum observed plasma concentration (tmax)
7.4 Exploratory Objective
 
2. Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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8. STUDY DESIGN
8.1 Brief Summary
This is a 2-part Phase 4, prospective, open-label, multicenter study to be conducted in 
at least 24 evaluable hemophilia A or B subjects with inhibitors (≥0.6 BU in 
hemophilia A and ≥0.6 BU in hemophilia B) for the primary PK assessment, (i.e., 
having the AUC0-216 h of FEIBA component FII estimable from both PK infusions), 
with a planned enrollment of 32 subjects. All subjects will receive 3 infusions of FEIBA 
reconstituted in a regular volume of SWFI, and 3 infusions of FEIBA reconstituted in 
50% reduced volume of SWFI, with all 6 of these infusions being given at a rate of 
2 U/min/kg within Part 1 of the study. In Part 2 of the study, all subjects will receive 
3 infusions of FEIBA reconstituted in 50% reduced volume of SWFI at 4 U/min/kg 
followed by 3 infusions FEIBA reduced volume at a rate of 10 U/min/kg. All subjects 
will undergo PK evaluation in Part 1 of the study.
8.2 Study Design Rationale
This study has been designed as a 2-way crossover study in order to assess for PK 
equivalence analysis. By designing it as a crossover study, subjects serve as their own 
controls, reducing the number of subjects needed for the study by half. This study is
open-label because it is a change in infusion volume and infusion rate, which would be 
difficult to properly blind. The goal of the study is to demonstrate PK equivalence of 
FEIBA in reduced volume SWFI to FEIBA regular volume SWFI, and then to increase 
the rate that this reduced volume can be infused. By being able to reduce the volume and 
speed of the infusion, subjects will be able to spend less time infusing. 
As there are washout periods within the study design in which subjects will not be 
receiving IP, steps have been taken to protect them from bleeding episodes, see 
Section 8.8.4 for details. 
8.3 Overall Study Design 
This is a 2-part Phase 4, prospective, open-label, multicenter study to compare PK and 
safety of FEIBA reconstituted in reduced versus regular volume of SWFI, and to evaluate 
the safety of infusing reduced volume FEIBA at increased rates of 4 and 10 U/min/kg 
in comparison with the standard rate of 2 U/min/kg, in up to 32 subjects (up to
24 evaluable) with hemophilia A or B with inhibitors (≥0.6 BU in hemophilia A and 
≥0.6 BU in hemophilia B), with the AUC0-216 h of FEIBA component FII estimable from 
both PK infusions. The overall study design is illustrated in Figure 1 and Figure 2.
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In Part 1, subjects will be administered 2 different volumes of FEIBA in a randomized, 
crossover manner with a washout period between the treatments. Both volumes will be 
given at the standard infusion rate of 2 U/min/kg. After infusion, subjects should be 
observed for 30 minutes in the clinic. For PK infusions and collections, accommodations 
can be made for convenience or to ensure compliance with PK sampling. See 
Section 10.3.2 for details. 
Treatments regimens during Part 1 of the study are:

Part 1 Sequence A: 
1. FEIBA 2 U/min/kg in regular volume SWFI (Infusions 1, 2, and 3)
2. Washout period
3. FEIBA 2 U/min/kg in 50% reduced volume SWFI (Infusions 4, 5, and 6)

Part 1 Sequence B: 
1. FEIBA 2 U/min/kg in 50% reduced volume SWFI (Infusions 1, 2, and 3) 
2. Washout period
3. FEIBA 2 U/min/kg in regular volume SWFI (Infusions 4, 5, and 6)

Infusion dose:
1. Infusions 1 and 4: 85 U/kg ± 100 U
2. All other infusions: 85 ± 15 U/kg
Prior to the first infusion of FEIBA (Sequence A or B), subjects will undergo a washout 
period of at least 12 days from last treatment with APCC (e.g., FEIBA), or at least 
24 hours after the last treatment with an rFVIIa product (e.g., NovoSeven®).
Part 2 is non-randomized with sequential enrollment of subjects who complete Part 1 to 
evaluate FEIBA reconstituted in 50% reduced volume of SWFI at increased rates of 
4 and 10 U/min/ kg. FEIBA Infusions 7, 8, and 9 will be administered at the 4 U/min/kg 
rate. The infusions will be administered every 48 hours (+48 hours) to allow time to 
monitor safety and tolerability of the higher infusion rate. Subjects will follow with 3 
infusions (Infusions 10, 11, and 12) of FEIBA at 10 U/min/kg rate. The infusions will be 
administered every 48 hours (+48 hours) to allow time to monitor safety and tolerability 
of the higher infusion rate. The treatment phases within Part 2 of the study are as follows:

First treatment phase: 4 U/min/kg (Infusions 7, 8, 9) 

Second treatment phase: 10 U/min/kg Infusions 10, 11, 12)
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All infusions will be administered at the hemophilia care centers/study sites. 
Pharmacokinetic collections may be performed at the hemophilia care centers/study sites 
or appropriate ambulatory centers. Each subject will receive a maximum of 14 IP
infusions total (most subjects will receive 12 IP infusions [6 in Part 1 and 6 in Part 2], the 
additional 2 infusions are for reinfusing PK infusions if a bleeding event occurred during 
the 9 day PK collection). Subjects will receive FEIBA at a dose of 85 U/kg ± 100 U for 
all PK infusions (Infusions 1 and 4) and 85 ± 15 U/kg for all other infusions (Infusions 2, 
3, 5, 6, and all Part 2 infusions), see Section 8.8.2. After each infusion, subjects should be 
observed for 30 minutes in the clinic. Additional details on study design and timing are 
described in Section 8.8.3. For additional details on managing bleeding episodes, see 
Section 8.8.4.
Please see Section 16.4 for additional details on the safety reviews performed by the 
Internal Safety Monitoring Committee (ISMC).
8.4 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 13 to 16 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The 
recruitment period is expected to be approximately 9 to 12 months.
The subject participation period is approximately 60 to 90 days from enrollment to 
subject completion (i.e., last study visit), unless prematurely discontinued.
8.5 Outcome Measures
8.5.1 Primary Outcome Measures
The primary outcome measures are:
1. AUC0-216 h of FEIBA component FII in subjects
2. Occurrence of thromboembolic events
3. Occurrence of allergic-type hypersensitivity reactions 
8.5.2 Secondary Outcome Measures
8.5.2.1 Efficacy/Pharmacokinetics 
1. Incremental recovery of FEIBA component FII in subjects
2. AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, and tmax of FEIBA component FII in 
subjects
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8.5.2.2 Safety
1. Evaluate occurrence of all AEs and SAEs
2. Evaluate occurrence of AEs leading to discontinuation
3. Evaluate occurrence of infusion site reactions
4. Evaluate occurrence of all AEs occurring within 24 to 72 hours of IP infusion
5. Evaluation of thrombotic markers (e.g., D-Dimers, prothrombin fragment F 1.2, 
thrombin/anti-thrombin complex [TAT], and fibrinopeptide A)
6. Evaluate vital signs and clinical laboratory assessments
8.5.3 Exploratory Outcomes Measure
 
 
2. Evaluate responses to the TSQM and the patient preference questionnaires
8.6 Randomization and Blinding
Part 1 of this study is a randomized, crossover, active treatment clinical study. In order to 
minimize/avoid bias, subjects will be randomly assigned to 1 of 2 treatment regimens 
(Sequence A: FEIBA regular volume of SWFI followed by FEIBA reduced volume of 
SWFI or Sequence B: FEIBA reduced volume of SWFI followed by FEIBA regular 
volume SWFI) in equal numbers. Part 2 of this study is an open-label, sequential, active 
treatment clinical study. In Part 2, all subjects will receive FEIBA reduced volume of 
SWFI at 2 varying rates of infusion.
8.7 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1. If 2 or more subjects develop anaphylaxis following exposure to FEIBA 
(enrollment and treatment temporarily stopped pending further review by the 
ISMC)
2. The sponsor or investigator, based on emerging data, considers there to be an 
unfavorable risk benefit
3. The sponsor or investigator considers continuation of the study unjustifiable for 
medical or ethical reasons
4. The ISMC recommends study termination
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8.8 Investigational Product(s)
8.8.1 Packaging, Labeling, and Storage
Note: Labeling has been updated since the IB, and FEIBA NF as previously referenced in 
Section 6 is now referenced as FEIBA.
The active ingredient of FEIBA is a plasma-derived, freeze-dried, APCC with FVIII 
inhibitor bypassing activity. FEIBA will be provided in vials containing 350 to 
650 U/vial (nominal potency 500 U), 700 to 1300 U/vial (nominal potency 1,000 U) or 
1750 to 3250 U/vial (nominal potency 2500 U). FEIBA contains mainly non-activated 
forms of the 3 coagulation factors, FII, FIX, and FX, as well as activated FVII; and 
Factor VIII coagulant antigen (FVIII:CAg) present in a concentration of up to 0.1 U/1 U 
FEIBA. The factors of the kallikrein-kinin system are present only in trace amounts, if at 
all. A solution containing 1 U FEIBA shortens the aPTT of FVIII inhibitor plasma to 
50% of the buffer value. The product is supplied as freeze-dried powder or friable solid 
of white to off-white or pale green color.
FEIBA might be marketed locally with storage at room temperature or 2°C to 8°C. To 
standardize conditions in the study, FEIBA should be stored at 2°C to 8°C only.  FEIBA
should not be allowed to freeze, and should be protected from light. Although the 
chemical and physical stability of the reconstituted product has been demonstrated for 
6 hours at room temperature (up to 25°C), in consideration of sterility, infusion of FEIBA 
should be commenced as promptly as practical, but must be completed within 3 hours 
following reconstitution. Reconstituted product must not be returned to the refrigerator.
FEIBA will be provided in kits including SWFI for reconstitution. SWFI will be provided 
in different volumes for preparation of FEIBA infusions at regular volume or reduced 
volume. For additional information, such as reconstitution instructions, please refer to the 
FEIBA product insert 10 and/or other specific instructions provided by the sponsor or 
sponsor’s representative.
8.8.2 Administration
Following reconstitution, FEIBA should be administered using an intravenous needle and 
syringes provided by the sponsor for this study. The standard infusion rate of FEIBA is a 
slow bolus injection, with an infusion rate of 2 U/kg body weight (BW) per minute, which 
in a 75-kg subject, corresponds to an infusion rate of approximately 2.4 to 7.5 mL/minute 
depending on the potency (see label on vial). In order to standardize administration within 
the study, it is recommended that study drug be administered with an infusion pump. 
Details regarding pump qualification will be provided in the study documents. 
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This rate will be modified depending on which part of the study the subject is in. Subjects 
will receive FEIBA at a dose of 85 U/kg ± 100 U for all PK infusions (Infusions 1 and 4) 
and 85 ± 15 U/kg for all other infusions (Infusions 2, 3, 5, 6, and all Part 2 infusions). For 
additional details, see Table 1 for general information on product preparation, as well as 
the study documents, and the FEIBA IB.iv Additional rates of 4 and 10 U/min/kg are also 
used in this study.
Mixing of FEIBA with other products or substances must be avoided. It is advisable to 
flush venous access lines with isotonic saline prior to and after infusion of FEIBA.
Dose calculation for FEIBA will be based on the stated actual potency on vials in 
respective lots. Information regarding lot used, the actual dose given, date of treatment, 
treatment start and stop times, as well as any infusion interruptions will be recorded in the 
electronic case report form (eCRF).
Table 1
FEIBA Product Preparation
FEIBA
Diluent for Regular Volume FEIBA
Diluent for 50% Reduced Volume FEIBA
500 U
10 mL
5 mL
1000 U
20 mL
10 mL
2500 U
50 mL
25 mL
Abbreviations: FEIBA=Factor Eight Inhibitor Bypassing Activity.
Every effort should be made for subjects to be given the same FEIBA lot for 
Infusion 1 and Infusion 4 in order to ensure comparable PK results. Please note that 
the diluent used for reconstitution might not be the same lot between the 2 infusions.
For PK infusions, every measure should be taken to ensure consistent dosing between 
Infusion 1 and Infusion 4. Partial vials may be used in order to maintain a consistent dose 
in case 85 U/kg ± 100 U can not be achieved by administration of whole vials. For 
infusions that are not PK infusions, different FEIBA lots may be mixed within an 
infusion, and whole vials should be rounded up or down to be as close as possible to the 
accurate dosage, as appropriate. Please refer to study documents for detailed instructions.
Please note that the availability of potencies may vary among countries and regions. Dose 
calculations should be made based on potencies available at site.
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8.8.3 Description of Treatment
Part 1 of the study uses a crossover design to evaluate the PK of FEIBA component FII 
and to evaluate the safety of FEIBA reconstituted in 50% reduced volume SWFI versus 
regular volume of SWFI (administered at the standard infusion rate of 2 U/min/kg). 
Part 2 is a non-randomized study with sequential enrollment of subjects who complete 
Part 1. Part 2 will evaluate the safety of infusing FEIBA reconstituted in 50% reduced 
volume of SWFI at increased rates of 4 and 10 U/min/kg.
All subjects will be screened for eligibility based on the listed inclusion and exclusion 
criteria. The subject’s medical history including hemophilia history, confirmation of 
inhibitors, bleeding episode history, and history of FEIBA or rFVIIa usage for the 
previous year will be collected at screening. Also recorded will be the date of last use of 
FEIBA or rFVIIa treatment. Results of the screening assessments will be used to establish 
a subject’s eligibility for the study.
Part 1
After eligibility is established, the duration of the washout period will be determined. 
The washout period is based on the subject’s last dose of FEIBA or rFVIIa. Due to the 
varying lengths of the half-lives of the components, subjects who have received FEIBA
will need to wait 12 days from their last dose of FEIBA before they can receive
Infusion 1 of the study. Subjects who have previously been treated with rFVIIa (e.g., 
NovoSeven), will need to wait at least 24 hours from the last dose of rFVIIa treatment
before they can begin Infusion 1 of the study (in agreement with the reported half-life of 
2.6 to 3.9 hours of FVII). Additional days beyond the minimum of 1 or 12 days 
(treatment dependent) is permissible since subjects have varying courses of treatments 
prior to their enrollment in the study (as long as screening procedures stay within the 
allotted time frame). Subjects who are on prophylactic therapy before the study, will 
need to have an appropriate washout period once eligibility is determined. For subjects 
who are on an on-demand treatment to control bleeding, the washout begins from the 
last day they used treatment. For management of bleeding episodes during Screening 
Washout see Section 8.8.4.
After the washout period is complete, eligible subjects will be randomly assigned 
(1:1) into Part 1 of the study by interactive web response system to receive 3 infusions 
of FEIBA reconstituted in 50% reduced volume SWFI followed by regular volume
SWFI or vice versa. Subjects will receive the first and fourth infusion for PK and
safety analysis and the second, third, fifth, and sixth infusions for collection of 
additional safety data. The first infusion will be given after randomization, 
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and PK blood draws will be taken at the times described in Table 5. After the 216 hour 
PK draw (9 days after Infusion 1), subjects will receive Infusion 2, and subjects will 
receive Infusion 3 forty-eight (+48) hours after Infusion 2. For management of bleeding 
episodes during PK assessments see Section 8.8.4.
After Infusion 3, subjects will go through a washout period of at least 12 days before 
crossing over to the next treatment group for Infusion 4. The 12 days is based on 
Infusion 3, since all subjects receive FEIBA at Infusion 3. For management of bleeding 
episodes during washouts see Section 8.8.4.
Infusion 4 will be the beginning of the new treatment regimen in the crossover scheme, 
and PK assessment will be completed for this infusion. Infusion 4 must be administered 
using the same lot of IP as Infusion 1. Infusion 4 will be given after the minimum of 
12-day washout period is complete, and PK blood draws will be taken at times described 
in Table 5. After the 216-hour PK draw (9 days after Infusion 4), subjects will receive 
Infusion 5, and subjects will receive Infusion 6 forty-eight (+48) hours after Infusion 5.
Additional details on study visits for Part 1 can be found in Section 10.3 and Table 2.
Part 2
Part 2 is non-randomized and uses sequential enrollment of subjects who complete Part 1 
of the study. Subjects in Part 2 will first be administered 3 infusions (Infusions 7, 8, 
and 9) of FEIBA at the 4 U/min/kg rate, followed by 3 infusions (Infusions 10, 11, 
and 12) of FEIBA at the 10 U/min/kg rate. Infusion 7 will be administered 48 hours after
Infusion 6. The infusions in Part 2 will be administered every 48 hours (+48) to allow 
time to monitor safety and tolerability of the higher infusion rate. Infusion rates for the 
treatment phases in Part 2 are:

First treatment phase: 4 U/min/kg (Infusions 7, 8, and 9) 

Second treatment phase: 10 U/min/kg (Infusions 10, 11, and 12)
Following the last infusion, a study termination visit will be conducted within 7 days but 
no sooner than 72 hours after the last infusion.
Additional details on study visits for Part 2 can be found in Section 10.3 and Table 3.
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Additional Treatment and Visit Information
The Schedule of Study Procedures and Events Procedures listed in Table 2 and Table 3
have the visit windows listed in relation to the subjects’ previous infusions instead of by 
study date. This is due to the variability in each subjects schedule based on previous 
therapy and bleeding events. 
All infusions will be administered at hemophilia care centers/study sites. Each subject 
will receive a maximum of 14 IP infusions (12 scheduled IP infusions, as well as the 
possibility of PK infusions being reinfused if the subject had a bleeding episode during 
PK collection). Subjects will receive FEIBA at a dose of 85 U/kg ± 100 U for all PK 
infusions (Infusions 1 and 4) and 85 ± 15 U/kg for all other infusions (Infusions 2, 3, 5, 6, 
and all Part 2 infusions). For specifications on dosing and administration, see 
Section 8.8.2. For information on break-through bleeding control, see Section 8.8.4.
Study visits will be completed concurrently with study infusions. After subjects have 
completed the 12 study infusions, they will complete a Study Completion/Termination 
Visit within 7 days but no sooner than 72 hours after Infusion 12. In case of early 
withdrawal or discontinuation the Study Completion/Termination Visit will need to be 
completed within 7 days but no sooner than 72 hours after the last IP infusion received.
During each visit, the study staff will inquire with the subject about break-through 
bleeding events, treatments, and AEs throughout the study and washout periods. Subjects 
are encouraged to report AEs to the site during the time spans between visits.
Two subject questionnaires will be administered 4 times during the study, a TSQM 
questionnaire and a patient preference questionnaire to assess the subjects’ satisfaction 
and preferences for treatments, for additional details see Section 10.5.
Detailed study flowcharts are presented in Table 2 and Table 3.
Investigational product may be interrupted or discontinued at any time during the study at 
the discretion of the investigator based on his/her evaluation of the subject’s condition or 
safety. No dose modification is permitted for this study.
Any infusion site reactions, regardless of causality, will be recorded on the AE eCRF. 
Any concomitant medications, including those used to treat AE(s), will be recorded on 
the appropriate eCRF.
For details on the safety review by ISMC see Section 16.4.
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8.8.4 Management and Treatment of Break-Through Bleeding
Bleeding episodes are managed as described below for each section of the study 
(screening, PK assessments, and washout). In all cases, if the bleeding episode, of 
whatever severity, is not resolved within 72 hours after an infusion to control bleeding, 
the subject must contact the study site for further treatment recommendations.
Screening Washout
During screening, subjects will be asked to keep track of any FEIBA or rFVIIa usage, as 
the last dose is used to determine the date of the first infusion of IP. If a subject is on 
prophylaxis before the study, once eligibility is determined, the subject will discontinue 
their routine prophylaxis upon instruction of the investigator for the start of the washout 
period. If a subject experiences a bleeding episode during the washout period, subjects 
will be treated for the bleeding episode per standard of care as determined by the 
investigator, and the washout period will be restarted. If the subject has a second bleeding 
episode during the washout period, the investigator should consider whether it is 
appropriate to include the subject into the study or whether they would be better served to 
remain on their current treatment regimen.
Bleeding during PK Assessments
Subjects who have a bleeding episode during the PK assessment periods will not have 
subsequent PK blood samples collected in that specific PK assessment period and will be 
treated for the bleeding episode per standard of care as determined by the investigator. 
Once the bleeding is resolved, subjects will have the IP infusion and PK assessments 
repeated. However, they should wait at least 12 days after their last dose of FEIBA, or at 
least 24 hours after last treatment with an rFVIIa product before proceeding. If the 
subject bleeds again on the second PK collection attempt, bleeding will be treated per 
standard of care as determined by the investigator, and subjects will move on to the next 
IP infusion after waiting at least 48 hours from their last dose of FEIBA. Subjects will 
have one re-attempt on each PK infusion and collection.
Washout Periods before Infusion 4
After Infusion 3, subjects will go through a washout period of at least 12 days before 
crossing over to the next treatment group for Infusion 4. The 12 days is based on 
Infusion 3, since all subjects receive FEIBA at Infusion 3. If bleeding occurs during the 
washout period, it will be treated per standard of care and the washout period will be 
restarted (at least 12 days after their last dose of FEIBA, or at least 24 hours after last 
treatment with an rFVIIa product). If rFVIIa is administered, a washout period of 
12 days after their last dose of FEIBA (i.e. Infusion 3) should still be observed. 
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If multiple bleeding episodes occur during the washout period, the investigator and 
sponsor should decide if it is appropriate for the subject to be taken off the study or 
continue with the study. 
Bleeding during the study at times other than washout periods and PK collection period
If bleeding occurs during any period other than the washout periods and PK assessment 
periods described above (e.g., between Infusions 5 6), it will be treated per standard of 
care. For bleeding events treated with FEIBA, a time window of 48 hours post treatment 
for bleeding should be observed before resuming study infusions. If rFVIIa was used for 
the bleeding event, a time window of 24 hours post treatment should be observed in 
combination with the 48 hour time window since last study administration of FEIBA 
before resuming study infusions per protocol. The subject will resume their treatment 
regimen and visits after control of the bleeding and following the administration windows 
mentioned above. Depending on the clinical circumstances (e.g., treatment of 
uncontrolled bleeding due to injury and associated complications), the investigator and 
sponsor should decide if it is appropriate for the subject to be taken off the study or 
continue with the study.
8.8.5 Investigational Product Accountability
The investigator will ensure that the IP(s) 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(s) was received, including the date received, 
drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP(s) must be dispensed only at the study site or other suitable location (e.g.,
infusion center; home, as applicable per study design). Records will be maintained that 
include the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) 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(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
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8.9 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 
study that are necessary for the reconstruction and evaluation of the study. 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' 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.
No data will be entered directly onto the eCRF.
For additional information on study documentation and eCRFs, see Section 17.2.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject is ≥18 to ≤65 years old at the time of screening
2. Hemophilia A or B of any severity, with a documented history of inhibitors 
requiring the use of bypassing agents (FEIBA or rFVIIa) 
3. HCV negative, either by antibody testing or polymerase chain reaction (PCR); or 
HCV positive with stable hepatic disease
4. HIV negative; or HIV positive with stable disease and CD4 count ≥ 200 cell/mm3
at screening
5. Adequate peripheral venous access
6. Subject is willing and able to comply with the requirements of the protocol
7.
If a female of childbearing potential, subject must have a negative blood 
pregnancy test and agrees to employ adequate birth control measures for the 
duration of the study, such as:
a. Abstain from sexual intercourse
b. Use a reliable method of contraception (contraception such as an 
intrauterine device, barrier method [e.g., diaphragm or sponge; female 
condom not permitted] with spermicide, oral contraceptive, injectable 
progesterone, sub dermal implant), and have their male partner use a 
condom
8. If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a. Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-
stimulating hormone levels within the laboratory-defined postmenopausal 
range or postmenopausal with amenorrhea for at least 24 months and on 
hormonal replacement therapy
b. Documentation of irreversible surgical sterilization by hysterectomy, 
bilateral oophorectomy, bilateral tubal ligation (with no subsequent 
pregnancy at least 1 year from bilateral tubal ligation), or bilateral 
salpingectomy
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. Known hypersensitivity to FEIBA or any of its components
2. Clinically symptomatic liver disease (e.g., liver biopsy confirmed diagnosis of 
cirrhosis, portal vein hypertension, ascites, prothrombin time [PT] 5 seconds 
above upper limit of normal)
3. Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4. Platelet count < 100,000/µL
5. Clinical or laboratory evidence of disseminated intravascular coagulation
6. Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
7. Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
8. Subject is taking any immunomodulating drug (e.g., corticosteroid agents at a 
dose equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days 
prior to enrollment except anti-retroviral chemotherapy 
9. 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
10. Subject is a family member or employee of the investigator
11. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., 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 eCRF. Assessments to be performed at the
termination visit (including in cases of withdraw or discontinuation) are described in 
Section 10.6 and Section 20.3.
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., 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 ISMC determines a subject should be taken off the study

The subject becomes pregnant. IP exposure will be discontinued. Attempts will 
be made to follow the subject through completion of the pregnancy and up to
1 year postdelivery, if feasible. The investigator will record a narrative 
description of the course of the pregnancy and its outcome

In addition, any pregnancies in the partner of a male subject during the study or 
for 12 weeks after the last dose, should also be recorded following authorization 
from the subject’s partner

AE(s)/SAE(s) that in the investigator or sponsor opinion, poses an unacceptable 
risk for continued dosing in the subject

Participation in another clinical study involving an IP during the course of the 
study
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form [ICF] 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 (e.g., 091501) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the ICF). For example, the third subject who signed an ICF at 
study site 02 will be identified as Subject 091501-020003. All study documents (e.g., 
eCRFs, 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 (e.g., 
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. 
All screening data will be collected and reported in eCRFs, regardless of screening 
outcome. If a subject is re-screened, the End of Study eCRF should be completed, and a 
new ICF, new SIC and new eCRF are required for that subject.
The overall study design is illustrated in Figure 1 and Figure 2. Details on the procedures 
to be performed at each study visit, including screening, can be found in Supplement 20.3
and Supplement 20.4 Schedule of Study Procedures and Assessments (Part 1 and Part 2, 
respectively) and Supplement 20.5 Clinical Laboratory Assessments. Pharmacokinetic 
assessment scheduling can be found in Table 5.
10.3.1 Screening and Baseline Assessments
After ICF has been obtained, subjects will be screened on-site for eligibility based on the 
inclusion and exclusion criteria defined in Section 9.1 and Section 9.2, respectively. 
Screening procedures must be performed within 56 days of Infusion 1.
At screening, subjects will be instructed on the symptoms of thromboembolic events by 
the investigator, and to contact the treatment center/hospital if they experience any 
symptoms of thromboembolism.
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Screening assessments include the following:

Eligibility evaluation (review of inclusion/exclusion criteria)

Medical history, including
Hemophilia history, inhibitor development history, bleeding episodes
history, history of FEIBA or rFVIIAa usage for a year prior to screening
Relevant medical and surgical history and all medications taken 4 weeks 
prior to screening

Review of concomitant medications/non-drug therapies

Complete physical examination (see Section 12.6)

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and
measurement body weight and height (see Section 12.8)

Karnofsky performance test assessment (see Section 12.9)

Clinical laboratory assessments (hematology, clinical chemistry, coagulation 
testing, and serology testing; see Section 12.7)

PK assessments (see Section 11.1)

Serum pregnancy test (female subjects of childbearing potential only)

TSQM and patient preference questionnaires (see Section 10.5)
After screening and eligibility is determined, the duration of the washout period will be 
determined. The washout period is based on the subjects’ last dose of FEIBA or rFVIIa 
(e.g., NovoSeven). Due to the varying lengths of the half-lives of the components, 
subjects who have received FEIBA will need to wait 12 days from the last dose of FEIBA
that they received before they can begin Infusion 1. For subjects who have previously 
been treated with rFVIIa, they will need to wait at least 24 hours from the last dose of 
rFVIIa before they can begin Infusion 1 of the study. Additional days beyond the 
minimum of 1 or 12 days (treatment dependent) is permissible (as long as the screening 
assessments stay within the window to Infusion 1) since subjects have varying courses of 
treatments prior to their enrollment in the study. Subjects who are on prophylactic 
therapy before the study, will need to have an appropriate washout period once eligibility 
is determined. Subjects who are on an on-demand treatment to control bleeding, the 
washout begins from the last day they used treatment, if they have a bleeding episode that 
requires treatment during the washout period, the washout period must be restarted before 
they can proceed with the study. For additional details on bleeding, see Section 8.8.4.
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10.3.2 Treatment Visits
10.3.2.1 Infusion Visits
Randomization will occur at Infusion Visit 1 using interactive web response system.

Randomization of eligible subjects to the following treatment sequences:

Part 1 Sequence A: FEIBA 2 U/min/kg in regular volume SWFI 
(3 infusions), washout period, FEIBA 2 U/min/kg in 50% reduced volume 
(3 infusions)

Part 1 Sequence B: FEIBA 2 U/min/kg in 50% reduced volume 
(3 infusions), washout period, FEIBA 2 U/min/kg in regular volume SWFI 
(3 infusions)
For additional details on the description of treatment, see Section 8.8.3.
During the study (Infusion Visits 1 to 12), subjects will return to the study site according 
to the schedule presented in Table 2 and Table 3. Prior to administration of IP, the 
following assessments will be performed at all visits unless otherwise indicated:

Review of concomitant medications/non-drug therapies

AE monitoring

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and 
measure body weight)

Before administration of IP

30 minutes after administration of IP

Clinical laboratory assessments (coagulation testing)

PK assessments (Infusions 1 and 4): from 30 minutes before start of infusion 
through 8 hours after stop of infusion

At the discretion of the investigator, subjects may be given the option of 
staying overnight at study site facility and/or a hotel for convenience or to 
ensure compliance with the serial PK collections. Voluntary overnight stays 
by subjects in hospital or hospital-affiliated facilities for the 
convenience/compliance with study procedures unrelated to AEs will not be 
considered as hospitalizations for SAE reporting purposes unless the 
hospitalization is prolonged.

IP administration (infusion site should be monitored for 30 minutes [± 10 min] 
after infusion)
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
Break-through bleed monitoring

Subjects will be administered the TSQM and patient preference questionnaires
prior to Infusion 1, Infusion 4, and Infusion 7, and after Infusion 12, prior to or up 
to the completion of the Study Completion/Termination Visit
10.3.3 PK only Visits
Additional PK only visits will be performed between Infusion 1 and 2, and between 
Infusions 4 and 5 according to the schedule presented in Table 2 and Table 5. These 
times include 24 hours, 72 hours, 120 hours, 168 hours and 216 hours after Infusions
1 and 4. Exact time ranges can be found in Table 5. For details on treatment of bleeding 
episodes during PK assessments, see Section 8.8.4.
See also information on administration (Section 8.8.2). 
10.3.4 Study Completion/Termination Visit
The Study Completion/Termination Visit will be performed within 7 days but no sooner 
than 72 hours after Infusion 12, or within 7 days but no sooner than 72 hours after the last 
infusion if the subject is discontinuing early. The following assessments will be 
performed:

Review of concomitant medications/non-drug therapies

AE monitoring

Breakthrough bleeds monitoring

Concomitant medication monitoring

Clinical laboratory assessments (hematology, clinical chemistry, coagulation 
testing, serology testing)

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and 
body weight)
10.4 Medications and Non-Drug Therapies 
Once subject eligibility has been confirmed for the study, subjects will begin a washout 
period as described in Section 8.8.3. The subject will discontinue their routine 
prophylaxis upon instruction of the investigator at the beginning of the washout period. 
See Section 8.8.4 for instructions on bleeding control.
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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 immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) except
anti-retroviral chemotherapy

Any investigational drug or device
A subject who has taken any of these medications or received any of these non-drug 
therapies will be withdrawn from further study participation.
Antifibrinolytics should not be used approximately 6 to 12 hours before or after the 
administration of FEIBA.
The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:

Medications:

Hemostatic agents, such as tranexamic acid, are permitted, as indicated by 
the subject’s treating physician, to treat mucosal bleeding during the study
(these are permitted; however, they should not be taken within 12 hours
before or after administration of FEIBA)

Any medications deemed necessary by the subject’s physician to treat or 
prevent any medical condition (with the exception of those listed as not 
permitted)

Any over-the-counter medication used by the subject to treat symptoms or 
signs of any medical condition

Supplemental vitamins, minerals

Any standard of care to treat breakthrough bleeds

Non-drug therapies:

Any non-drug therapy (e.g., physiotherapy) deemed necessary by the 
subject’s physician to treat or prevent any medical condition
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10.5 Subject Questionnaires
Two questionnaires will be administered to subjects within this study (TSQM 11 and a 
patient preference questionnaire). These questionnaires will be used to assess the 
subject’s preferences on the IP, as well as their satisfaction with the IP, and will be 
collected in the eCRF or on paper. Both questionnaires will be administered:

After screening prior to Infusion 1

After Infusion 3 prior to Infusion 4

After Infusion 6 prior to Infusion 7

After Infusion 12,  prior to or up to the completion of the Study 
Completion/Termination Visit
These questionnaires can be completed between visits but should be completed prior to 
the start of the next infusion. The final questionnaire should be completed prior to or 
during the Study Completion/Termination Visit.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when the subject 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 eCRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems, and severe allergic reaction), ISMC recommends a subject should not continue. 
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 Study Completion/Termination Visit is done as 
an additional, unscheduled visit, the assessment results shall be recorded with the 
Study Completion/Termination Visit. If a subject terminates participation in the 
study and does not return for the Study 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 20.3 Schedule of Study Procedures and 
Assessments and Supplement 20.5 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
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures will be used to monitor subject compliance.
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11. ASSESSMENT OF PHARMACOKINETICS
11.1 Sample Collection and Processing
Blood PK samples for the determination of FEIBA components FII, 
 
will be taken 30 and 15 minutes preinfusion, at end of infusion, and 30 and 
60 minutes, 3, 8, 24, 48, 96, 168, and 216 hours after stop of infusion (see Table 5 for 
sampling time points and allowed sampling time windows) following Infusions 1 and 4. 
The date and time of each sample collections will be documented in the subject’s eCRF.
Blood sample processing and handling details will be presented in a separate laboratory 
manual. Information on accommodations (i.e., hotel stays and hospitalization) for PK 
assessments can be found in Section 10.3.2.1.
11.2 Pharmacokinetic Evaluation and Pharmacokinetic Parameters
For PK assessments (Infusion 1 and 4), subjects will receive an infusion of 
85 U/kg ± 100 U FEIBA reconstituted in 50% reduced volume SWFI followed by regular
volume SWFI or vice versa. There will be a washout period of at least 12 days following 
the Infusion 3 before subjects cross over to the next treatment group. For PK assessments, 
subjects are required to not be actively bleeding at the time of infusion.
Subjects who have a bleeding episode during the PK assessment periods will not have 
subsequent PK blood samples collected in that specific PK assessment period. Bleeding 
and additional washouts will be managed as described in Section 8.8.4. After a washout 
period as described in Section 8.8.4, the IP infusion and PK assessments will be repeated.
Pharmacokinetic parameters will be derived for baseline-corrected FII, 
 
 activity. Baseline-corrected FII, 
 activities will be calculated by 
subtracting the preinfusion value (or average of preinfusion values) from each 
measurement after infusion.
The following PK parameters will be calculated for FII, 
 using 
standard noncompartmental methods after administration with FEIBA reconstituted in 
regular volume of SWFI or FEIBA reconstituted in 50% reduced volume of SWFI:

AUC0-216 h

AUC0-∞

AUC0-last

t1/2

MRT
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
CL

Vss

Cmax

tmax

IR at Cmax; defined as (observed Cmax - Cpreinfusion)/[total dose/body weight]
Additional PK parameters may be calculated at the discretion of the PK scientist and/or 
sponsor.
The following PK parameters will be calculated for diagnostic purposes and listed, but 
will not be summarized:
t1/2, Interval
The time interval of the log-linear regression used to determine the terminal 
rate constant lambda_z (λz)
t1/2, N
Number of data points included in the log-linear regression analysis to 
determine λz
Rsq
Goodness-of-fit statistic for calculation of λz (coefficient of determination). If 
Rsq  < 0.800, then λz and associated parameters will not be reported
%AUCex
Percentage of AUC0-∞obtained by extrapolation. If % AUCex > 20.00%, then 
AUC0-∞and associated parameters will not be reported
All PK analyses will use the actual sampling times, wherever possible. Actual sampling 
times will be defined as time from the start of infusion to the collection time of blood. 
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 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 (e.g., an abnormal laboratory finding), 
symptom (e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP.
12.1.1.1 Serious Adverse Event
A SAE is defined as an untoward medical occurrence that at any dose meets 1 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 (i.e., 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 1 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
Additional events which should be reported the same way as SAEs are as follows:

Reviewed and confirmed seroconversion for HIV, hepatitis A virus, hepatitis B 
virus, HCV, hepatitis E virus, or parvovirus B19
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
Hospitalization for planned port placement or removal is not considered an SAE, 
however, any hospitalization required for an emergency port removal is 
considered an SAE

Any thromboembolic event

Allergic-type hypersensitivity reactions (e.g., analyphylaxis)
Uncomplicated pregnancies, following maternal or paternal 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. Any 
pregnancy occurring during the study should be reported to the sponsor within 24 hours 
of the site learning about the pregnancy. The pregnancy should be followed until
completion of the pregnancy and up to 1 year postdelivery, if feasible. Pregnancies not 
considered an (S)AE as described above will be captured in the eCRF.
Voluntary overnight stays by subjects in hospital or hospital-affiliated facilities for the 
convenience/compliance with study procedures as described in Section 10.3.2 for reasons 
unrelated to AEs will not be considered as hospitalization for SAE reporting purposes
unless the hospitalization is prolonged.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., 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.
12.1.1.4 Pre-existing Diseases
Pre-existing 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 pre-existing disease, the event must be described on 
the AE eCRF.
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12.1.2 Assessment of Adverse Events
Each AE from the first IP exposure until study termination/completion will be described 
on the AE eCRF 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 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
eCRF. Recovering/resolving AEs will be followed until resolution, it is medically 
stabilized, or 30 days after the Study Completion/Termination Visit, whichever comes 
first, and the follow-up information is to be documented in the eCRF. If the severity 
rating for an ongoing AE changes before the event resolves, the original AE report will 
be revised (i.e., 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 (20% higher than the 
highest permitted dose), underdosing (20% lower than the lowest permitted dose), 
treatment errors (including incorrect route of administration, use of an incorrect product, 
and deviations from the protocol-defined dosing schedule), failures of expected 
pharmacological actions, and unexpected therapeutic or clinical benefits will be followed 
with regard to occurrence of AEs, lack of efficacy, and/or other observations because 
these events may be reportable to regulatory authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and 1 year postdelivery, if 
feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion/termination, the SAE must be reported on the provided SAE Report Form 
within 24 hours after awareness; no additional reporting on eCRFs is necessary.
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12.1.2.1 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.
12.1.2.2 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, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., 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 
rechallenge)
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 72 hours after 
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.
12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 3) and Section 12.1.
Adverse Events/SAEs are to be recorded on the AE page of the eCRF. Each event should 
be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported via the EDC system by 
completing the relevant eCRF page(s) in English. Once the SAE has been recorded in the 
electronic data capture (EDC) system, the sponsor and other designated recipients will be 
informed of the event automatically. For instances in which the EDC may become 
unavailable, SAEs must be reported using the back-up paper SAE Report Form to meet 
the 24-hour timeline requirement (contacts and instructions to be provided in separate 
documentation). Once the EDC becomes available, the site must enter all SAE data as 
reported on the back-up paper SAE report form on the applicable eCRF pages.
The initial SAE information reported on the applicable eCRF pages (or back-up SAE 
Report Form, if applicable) must at least include the following:

Protocol Number

Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)

Investigational product exposure

Medical Term for Event (Diagnosis preferably) 

Description of the (S)AE, including:

Date of onset

(S)AE treatment (drug, dose, route of administration)

Causal relationship by the investigator

Measures taken (i.e., action taken regarding IP in direct relationship to the 
AE)

Seriousness criteria (i.e., death, life-threatening, or other criterion)

Cause of death

Autopsy findings (if available)

Name, address, fax number, email, and telephone number of the reporting 
investigator (for paper SAE Report Forms) 
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12.1.3 Medical Device Safety Reporting
The IP kit contains the BaxJect II Hi-Flow needleless transfer device. All Serious Injuries 
(SI) and Unexpected Adverse Device Events (UADE) must be reported to the sponsor as 
an SAE in the same process as described above.
Serious injury is defined as:

Life-threatening injury or illness results in permanent impairment/ damage to 
body function/ structure.

Requires medical or surgical intervention to preclude permanent impairment/ 
damage to body function/ structure.
12.2 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 study 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 study or studies

Any other immediate action taken in order to protect clinical study 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 (EC) and relevant competent authority(s) are
notified of the urgent safety measures taken in such cases according to local regulations.
12.3 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 12.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the AE eCRF (and SAE Report Form if eCRF is not available). These 
events will be considered as SAEs and will not be included in the analysis of SAEs. 
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12.4 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, e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., 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

Medication errors: an error (of commission or omission) at any step along the 
pathway that begins when a clinician prescribes a medication and ends when the 
patient actually receives the medication e.g., administration of incorrect dose
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.
12.5 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 12.1.2.1) 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.
General medical history will be collected for 4 weeks prior to screening. Any information 
on the subjects’ hemophilia history will be collected a year prior to screening including 
documented history of hemophilia, confirmation of inhibitors, bleeding episodes history, 
and history of FEIBA or rFVIIa usage.
All medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies eCRFs.
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12.6 Physical Examinations
At screening (as described in Table 2 and Table 3), 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 eCRF. At study visits, if a new abnormal or 
worsened abnormal pre-existing condition is detected, the condition will be described on 
the AE eCRF. If the abnormal value was not deemed an AE because it was due to an 
error, due to a pre-existing disease (described in Section 12.1.1.4), 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.
12.7 Clinical Laboratory Parameters
Where applicable (see Section 15.6), assessments will be performed at a central 
laboratory, according to the laboratory manual. Blood samples that remain after study 
testing is done may be stored and used for additional testing. Samples will be destroyed 
after a maximum of 2 years from the time the final study report has been completed. 
Details of blood sampling volumes are presented in the laboratory manual and master 
ICF.
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count [hemoglobin, hematocrit, 
erythrocytes (i.e., red blood cell count), and leukocytes (i.e., white blood cell count)] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) mean 
corpuscular volume, mean corpuscular hemoglobin concentration, and platelet counts.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
aspartate aminotransferase (AST), total protein, albumin, alanine aminotransferase
(ALT), total bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, 
glucose, gamma-glutamyl transpeptidase (GGT), and 5’-nucleotidase.
Blood will be obtained for assessment of hematology and clinical chemistry parameters at 
screening and at study completion/termination. Hematology and clinical chemistry 
assessments will be performed on ethylenediaminetetraacetic acid-anticoagulated whole 
blood and serum, respectively, at the central laboratory. 
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In addition, serum samples for pregnancy tests for females of childbearing potential will 
be collected at screening.
12.7.2 Coagulation Testing
Blood will be obtained for the assessment of coagulation testing and consist of aPTT, PT, 
thrombotic markers (D-Dimers, prothrombin fragment F 1.2, TAT, fibrinopeptide A), FII, 
FX, FIX, FVII, and FVIII or FIX inhibitor level (Nijmegen assay). All coagulation 
testing will be performed at screening, during the study (Infusion Visits 1 to 12), and at 
the Study Completion/Termination Visit.
12.7.3 Viral Serology
Viral serology testing will include HIV-1 and HIV-2 antibody, hepatitis A virus (HAV)
antibody, hepatitis B virus (HBV) antibody, hepatitis B surface antigen (HBsAg), HCV 
antibody, parvovirus B19 (immunoglobulin M [IgM] and immunoglobulin G [IgG] 
antibodies), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus 
antibodies (IgM and IgG). The HCV titer will be confirmed by PCR for all subjects 
reported as HCV positive. All viral serology assessments will be performed at screening
and at the Study Completion/Termination Visit.
12.7.4 CD4 Levels
At screening only, CD4 levels will be determined using flow cytometry in the case of a 
subject being HIV positive.
12.7.5 Assessment of Laboratory Values
12.7.5.1 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value will be recorded on the eCRF. 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 12.1, and record 
the sign, symptom, or medical diagnosis on the AE eCRF), is a symptom or related to a
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.4), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e., because it is due to a 
pre-existing 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.
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12.7.6 Biobanking
Backup samples should be taken and stored appropriately for additional analysis, if 
necessary. These samples may be used for re-testing, further evaluation of an AE, or 
follow-up of other test results. The following samples are planned:

Backup samples for FII, 
 will be taken at screening, and at all 
pre and postinfusion timepoints for PK assessments
Backup samples that remain after study testing is done may be stored and used for 
additional testing (e.g., further evaluation of an abnormal test or an AE. 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.
12.8 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) 
measured once at screening and weight (lb or kg) will also be collected.
Vital signs will be measured at screening and within 30 minutes before and after 
administration of IP, at each Infusion study visit, and at study completion/termination. 
Blood pressure will be measured when subjects are in the supine position.
Vital sign values are to be recorded on the eCRF. For each abnormal vital sign value, the 
investigator will determine whether or not to report an AE (see definition in Section 12.1
and record the medical diagnosis (preferably), symptom, or sign on the AE eCRF). 
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.
12.9 Karnofsky Performance Test
The Karnofsky Performance Test is a status scale (0-100) utilized to measure the level of 
activity and medical care requirements in subjects. It is an investigator based assessment 
of subject status which evaluates the subjects’ ability to carry on normal life activities, as 
well as the symptoms of their disease. In this scale, a high number performance status 
represents high functionality, and a lower number represents low functionality and likely 
rapid progression of disease.12 Subjects will be scored using this scale at screening.
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12.10 Infusion Site Evaluations
The current site of IP infusion will be assessed for immediate local reactions 30 minutes 
(±10 min) after infusion. In addition, infusion sites will be monitored by the subject for 
72 hours after infusion, and will be discussed with the site staff during the next study 
visit.
Infusion sites will be monitored for pain, tenderness, erythema, and swelling. Infusion 
site evaluations will be made by clinical staff or by the subject or caregiver. If an infusion 
site reaction is observed, a physician will characterize and document the reaction as an 
AE. Infusion sites will continue to be reviewed at each study visit, and any infusion site 
reactions will be followed until resolution. Each infusion site reaction will be categorized 
using the intensity grading described for AEs in Section 12.1.2.1.
12.11 Special Treatment Considerations
Subjects will be screened for eligibility in the study as described in Section 8.2 and
Section 8.8.3, and will be informed of the study specific restrictions and requirements of 
the study. Subjects who are not willing to comply with the study requirements and 
restrictions of the study will not be eligible for enrollment.
All biological agents carry the risk of systemic allergic/hypersensitivity reactions. 
Clinical manifestations of these reactions may include, but are not limited to:

Skin rash

Pruritus (itching)

Urticaria (hives)

Angioedema (for example, swelling of the lips and/or tongue)

Anaphylactic reaction
Proteins may also cause redness, itching, swelling, or pain locally at the infusion site.  
Thromboembolic events have been observed with bypassing agents including FEIBA. 
Clinical manifestations of these events may include, but not limited to:

myocardial infarction

deep vein thrombosis

pulmonary embolism

stroke and

transitory ischemic attack, etc.
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Sometimes, these reactions can be life-threatening. Therefore, all subjects should be 
closely monitored for signs or symptoms that could result from such reactions, educated 
on the signs or symptoms of these types of reactions, and instructed to contact the study 
site immediately if any of the symptoms are experienced following an injection. If a 
subject experiences an acute allergic/hypersensitivity reaction after an infusion of IP, the 
subject should be managed appropriately and given instruction to receive relevant 
supportive care. Additionally, for an event judged by the investigator to be a potential 
systemic allergic/hypersensitivity reaction, a blood sample should be drawn to test for 
anti-drug antibodies.
Subjects who experience a potentially severe allergic reaction will be discontinued from 
IP. They will complete a Termination/Study Completion Visit, and will be monitored for 
stabilization or resolution of the AE. Premedication to prevent allergic reactions will not 
be permitted, as severe allergic reactions are an outcome measure for this study.
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13. STATISTICS
Data handling will be the responsibility of the contract research organization. The data 
will be inspected for inconsistencies by performing validation checks.
All details regarding the statistical analysis and the preparation of tables, listings, and 
figures will be described in the statistical analysis plan (SAP) prepared by the contract 
research organization and approved by the sponsor before database lock.
13.1 Sample Size and Power Calculations
Part 1 (cross-over) of this study will evaluate PK equivalence of FEIBA component FII in 
FEIBA reconstituted in 50% reduced volume SWFI versus regular volume of SWFI as 
measured by AUC0-216 h. The sample size was based on the premise of a true ratio of 
geometric means of test and reference of 1.0 using a within-subject coefficient of 
variation of 22.2%, to yield 90% power when equivalence is declared based on the 90% 
CI for the ratio of geometric means for the 2 treatments being completely contained in the 
margins of equivalence defined as 80% to 125%. The within-subject variability (0.222) 
was estimated by using the square root of mean square error as in previous studies of 
FVIII. The required sample size was estimated to be 24 evaluable subjects. In order to 
obtain the required 24 subjects, Part 1 will randomize up to 32 subjects for the crossover 
PK study, allowing for a possible 25% dropout rate.
With approximately 100 infusions for each treatment (reduced or regular volume of 
SWFI) administered for the study, the upper limit of the 95% CI of the rate of infusions 
with a specific AE is less than 3.3%, if the specific AE is not observed. The upper limit 
of 95% CI of the rate of infusions for a specific AE is about 5% if 1 AE is observed.
13.2 Datasets and Analysis Cohorts
Classification into the safety analysis sets will be conducted prior to database lock.
Major protocol violations will include, but are not limited to: violation of 
inclusion/exclusion criteria, administration of prohibited medications, and erroneous 
administration of study treatment. Subjects will be assigned to treatment groups based on 
randomization.
Safety: The safety population will include all subjects who received at least 1 dose of IP
(FEIBA). All safety analyses will be performed on the safety population. Subjects will be 
evaluated according to the treatment received. The safety population will be defined 
separately for each part of the study.
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PK: The PK population will include all subjects who received at least 1 dose of IP and 
have at least 1 measured concentration at a scheduled PK time point after start of dosing 
without protocol violations or events with potential to affect PK.
13.3 Handling of Missing, Unused, and Spurious Data
All data will be evaluated as observed. A subject who withdraws prior to the last planned 
observation in a study period will be included in the analyses up to the time of 
withdrawal.
For the calculation of AUC0-216 h, non quantifiable PK results will be extrapolated.
13.4 Methods of Analysis
For qualitative parameters, the population size (N for sample size and n for available 
data) and the percentage (of available data) for each class of parameters will be 
presented. Quantitative parameters will be summarized by the population size (N for 
sample size and n for available data), mean, standard deviation, median, minimum, and 
maximum values. All PK parameters will be summarized by treatment using n, mean, 
standard deviation, geometric mean, % geometric coefficient of variation, minimum, 
median, and maximum, except that tmax will be reported with n, minimum, median, and 
maximum only. 
A listing of PK blood sample collection times by individual, as well as derived sampling 
time deviations, will be provided. Pharmacokinetic concentrations/activities and derived 
PK parameters for FII, 
 will be summarized using descriptive statistics 
by treatment and nominal sampling time point. Plots of individual and mean plasma 
concentration-time profiles will be presented by treatment and visit. Plots of individual
and geometric mean AUC0-216 h will also be presented by treatment.
Details and rules for evaluable data in the PK analysis, and subsequent summary statistics 
and inferential statistics will be defined in the SAP.
13.4.1 Primary Outcome Measure
13.4.1.1 Analysis of the Primary PK Outcome Measure (Part 1)
The primary PK outcome measure is the AUC0-216 h of FEIBA component FII. AUC0-216 h
will be derived using noncompartmental methods as described in Section 11.2 and will be 
summarized by treatment using descriptive statistics. The 216 hour timepoint is critical.
Interpolation or extrapolation of the FII concentration at time = 216 hours will be 
performed. Additional details can be found in the SAP. 
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For subjects who require re-infusion due to bleeding episodes during the PK assessment, 
PK parameters will only be listed for the first, interrupted infusion, while those from the 
repeated infusion (if deemed evaluable) will be listed and used for descriptive and 
statistical analysis.
Statistical analyses of the primary PK endpoint will be based on the PK population.
AUC0-216 h for FEIBA component FII of reduced volume and regular volume will be 
compared calculating the 90% two-sided CI for the difference of the mean logarithms of 
AUC0-216 h between reduced volume and regular volume. The error variance used to 
calculate these CIs will be obtained from an analysis of variance model that will consist 
of fixed effect terms that model the subject effect, the sequence effect, the period effect, 
and the drug effect. The antilogs of the confidence limits will constitute the 90% CI for 
the ratio of the geometric means (antilog of the means of the log). To establish 
equivalence, the 90% CI for the ratio of the geometric means of the 2 treatments has to be 
contained in the margins of equivalence defined as 80% to 125%.
13.4.1.2 Analysis of the Primary Safety Outcome Measure (Parts 1 and 2)
The safety of treatment infusions will be evaluated primarily by the occurrence of 
thromboembolic events and allergic-type hypersensitivity reactions. The number and 
proportion (95% exact CI) of subjects experiencing thromboembolic events and
allergic-type hypersensitivity reactions will be summarized by treatment for each study 
part as well as for the 2 parts together.
13.4.2 Secondary Outcome Measures 
13.4.2.1 Analysis of the Pharmacokinetic Outcome Measures
Secondary efficacy/PK outcome measures consist of the IR of FEIBA component FII in 
subjects as well as PK parameters (AUC0-∞, AUC0-last, t1/2, CL, MRT, Vss, Cmax, and tmax) 
of FEIBA component FII. Pharmacokinetic parameters will be derived using 
noncompartmental methods as described in Section 11.2. The secondary outcome 
measures will be descriptively summarized by treatment.
13.4.2.2 Analysis of the Safety Outcome Measures
Adverse events will be coded using the Medical Dictionary for Regulatory Activities and 
will be summarized by presenting the number and percentage of subjects having any AE, 
having an AE in each system organ class, and having each individual AE as reported by 
preferred term. In the summaries, AEs will be counted only once per subject and 
treatment for each study part. If a subject reports the same AE more than once, it will be 
counted with its worst severity and closest relationship to the IP.
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All safety analyses will be performed for each part separately as well as for the two parts 
together.
The number and proportion of subjects experiencing serious and non-serious AEs up to 
study completion or subject withdrawal will be summarized by treatment for each study 
part. The number of product related serious and non-serious AEs, and number of AEs 
leading to discontinuation will also be summarized by treatment. A subgroup of all AEs 
occurring within 24 and 72 hours of IP infusion will be summarized by treatment.
Additionally, subjects experiencing infusion-related AEs and infusion site reactions will 
be summarized by treatment.
Thrombotic markers (e.g., D-Dimers, prothrombin fragment F 1.2, TAT, and 
fibrinopeptide A) will be summarized using descriptive statistics by treatment. Mean 
concentration plots will be presented by treatment and visit for each thrombotic marker.
Vital signs and clinical laboratory assessments as well as the corresponding changes from 
baseline will be summarized descriptively by treatment at each scheduled assessment for 
each study part. Baseline will be defined as the last value prior to the first infusion for 
each treatment. Laboratory abnormalities will be analyzed by shift tables where each 
subject will be counted only once with the worst grade in the summary tables by 
treatment at each scheduled assessment for each study part. All laboratory data will be 
listed with abnormal values flagged.
Individual listings presenting subjects by treatment will be presented for the safety 
parameters. The listings will be created for both change and absolute values, if 
appropriate.
Full details of the statistical analysis will be specified in the SAP.
13.4.3 Exploratory Outcome Measures 
 
 
 
 
The results of the TSQM and the patient preference questionnaires will be summarized 
by descriptive statistics as appropriate.
13.5 Planned Interim Analysis of the Study
There is no planned interim analysis other than a safety and PK data review by the ISMC.
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14. 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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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 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.
15.1.1 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. 
15.2 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.
15.3 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.
15.4 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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15.5 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 (Baxalta) will also ensure the responsible EC 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.
15.6 Laboratory and Reader Standardization
Not applicable; a central laboratory/reader will be used for all clinical assessments.
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16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, ICF, 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.
16.3 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 must sign an ICF before entering into the study according to applicable 
regulatory requirements and ICH GCP. Before use, the ICF will be reviewed by the 
sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The ICF 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 will be allowed sufficient 
time to consider participation in the study. By signing the ICF, patients 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 will be updated, if necessary. This new information and/or revised ICF, that have 
been approved by the applicable EC and regulatory authorities, where applicable, will be 
provided by the investigator to the subjects who consented to participate in the study (see 
Section 16.3).
16.4 Internal Safety Monitoring Committee
This study will be monitored by an ISMC. The ISMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from an ongoing 
clinical study. For this study, the Baxalta ISMC will be composed by appropriate 
members of clinical, safety, and biostatistics division that are not involved in the active 
execution of the trial. The ISMC can stop a study if it finds toxicities or if treatment is 
proven to be not beneficial.
All SAEs will be reviewed by the Chair of the ISMC. There are 3 planned ISMC 
meetings:
1. At least 48 hours after 6 subjects in Part 1 (3 subjects in each group) have 
completed Infusion 5
2. At least 48 hours after 6 subjects have completed Infusion 8 (Part 2)
3. At least 48 hours after 6 subjects have completed Infusion 11 (Part 2)
ISMC preplanned meetings will be held concurrently with the ongoing study.
Subjects can continue with their scheduled therapy and assessments unless the ISMC 
warrants that the trial needs to be suspended due to safety concerns. Additional ad hoc 
meetings of the ISMC may be convened as appropriate per ongoing safety evaluations.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 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 8.9), records detailing the progress of the study for each subject, signed 
ICFs, correspondence with the EC and the study monitor/sponsor, enrollment and 
screening information, eCRFs, 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 eCRFs are provided by the sponsor, only authorized study site personnel will record or 
change data on the eCRFs. If data is not entered on the eCRFs during the study visit, the 
data will be recorded on paper, and this documentation will be considered source 
documentation. Changes to an eCRF will require documentation of the reason for each 
change. An identical (electronic/paper) version of the complete set of eCRFs for each 
subject will remain in the investigator file at the study site in accordance with the data 
retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., 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.
17.3 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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18. 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.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement.
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20.3 Schedule of Study Procedures and Assessments (Part 1)
Table 2
Schedule of Study Procedures and Assessments (Part 1)
Procedures/
Assessments
Screening 
Assessments
Study Visitsa
Washout Period 1e
Infusion #1 PK Visitsb Infusion #2 Infusion #3
Washout Period 2f
Infusion #4
PK Visitsa
Infusion #5 Infusion #6
Study Visit Windowsc
A maximum 
of -56 days 
to 0
Day 1
Multiple 
Visits Day 
1 through 9
9 (+1) days 
from 
Infusion 1
48 hr (+48) 
from 
Infusion 2
At least 12 
days from 
Infusion 3
Multiple Visits 
up to 9 Days 
from Infusion 4
9 (+1) days 
from 
Infusion 4
48 hr (+48) 
from 
Infusion 5
Informed Consentd
X
Eligibility Criteria
X
Medical History
X
Medication and Non-drug 
Therapies
X
X
X
X
X
X
X
Physical Examination
X
Pregnancy Test
X
Vital Signsg
X
X
X
X
X
X
X
Karnofsky Performance Test
X
Laboratory Assessmentsh
X
X
X
X
X
X
X
PK Assessmentsi
X
X
X
X
X
Adverse Events, breakthrough 
bleeds, and site infusion 
reactions
Xj
X
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesk
X
X
Abbreviations: FEIBA=Factor Eight Inhibitor Bypassing Activity; ICF=informed consent form; IP=investigational product; PK=pharmacokinetic; 
rFVIIa=recombinant activated clotting factor VII; SAE=serious adverse event.
a
A Study Completion/Termination Visit is to be completed in Part 1 only for subjects who withdraw or discontinue prior to the end of the study. If a subject 
withdraws or discontinues, this visit should be done in within 7 days but no sooner than 72 hours from the last infusion that the subject receives. Otherwise, the
Study Completion/Termination Visit will occur at the end of Part 2 (see Table 3).
Continued on next page
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Continued
b
Additional PK visits will occur between Infusions 1 and 2, and between Infusions 4 and 5, at 24, 48, 96, 168, and 216 hours after Infusion 1 or Infusion 4 as 
described in Table 5
c
Study Visit Windows:
1. Infusion 1: Infusion 1 can be scheduled after screening assessments have been completed and the appropriate washout period as defined in washout 
(footnote e) below has occurred. Scheduling will also need to ensure that PK timepoints can be collected as described in footnote a and Table 5. If the subject
has a bleeding episode during the 9-day PK collection period, bleeding will be controlled, and the washout period restarted as described in Section 8.8.4, 
Infusion 1 and PK assessments will have one re-attempt.
2. Infusion 2: Infusion 2 is scheduled for 9 days (+1) after Infusion 1. All PK samples from Infusion 1 must be completed before Infusion 2 can begin, except in 
cases of multiple bleeding episodes, see Section 8.8.4. 
3. Infusion 3: Infusion 3 should be scheduled 48 hours (+48 hours) after Infusion 2.
4. Infusion 4: Infusion 4 should be at least 12 days after Infusion 3 (See footnote f on Washout Period 2 for restrictions). If the subject has a bleeding episode 
during the 9-day PK collection, bleeding will be controlled, and the washout period restarted as described in Section 8.8.4, Infusion 4 and PK assessments 
will have one re-attempt.
5. Infusion 5: Infusion 5 should be 9 days (+1) after Infusion 4. All PK samples from Infusion 4 must be completed before Infusion 5 can begin, except in cases 
of multiple bleeding episodes, see Section 8.8.4. 
6. Infusion 6: Infusion 6 should be scheduled for 48 hours (+48) after Infusion 5.
d
Occurs at enrollment (prior to any study-specific procedure).
e
Washout Period 1: Washout Period 1 is based on the subject’s last dose of FEIBA or rFVIIa (e.g., NovoSeven). Due to the varying lengths of the half-lives of the 
drugs, subjects who have received FEIBA will need to wait 12 days from the last dose of FEIBA that they received before they can begin Infusion 1. For subjects 
who have previously been treated with rFVIIa, they will need to wait at least 24 hours from the last dose of rFVIIa before they can begin Infusion 1 of the study. 
Additional days of washout beyond the minimum of 12 days or 1 day for FEIBA or rFVIIa treatment subjects, respectively, are permissible (as long as the 
screening assessments stay within the window to Infusion 1). Subjects who are on prophylactic therapy before the study, will need to have an appropriate 
washout period once eligibility is determined. For subjects who are on an on-demand treatment to control bleeding, the washout begins from the last day of
treatment. If the subject has a bleeding episode that requires treatment during the washout period, the washout period must be restarted before they can proceed 
with the study.
f
Washout Period 2: Washout Period 2 is a minimum of 12 days from Infusion 3, since all subjects receive FEIBA at Infusion 3. If bleeding occurs during the 
washout period, the subject will be treated per standard of care and the washout period will be restarted (at least 12 days from their last dose of FEIBA, or at least 
24 hours after last treatment with an rFVIIa product. If rFVIIa is administered, a washout period of 12 days after their last dose of FEIBA [i.e., Infusion 3] should 
still be observed).
g
Vital signs will include body temperature, pulse rate, blood pressure, respiratory rate, and weight. Blood will be measured when subjects are in the supine 
position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within 30 minutes after completion of the infusion. 
Height, measured once at Screening, will also be collected.
h
For laboratory assessments, see Table 4.
i
For PK assessments, see Section 11 for details.
j
The infusion site will be monitored for AEs for 30 ±10 minutes after the infusion. See Section 12.10 for details. SAEs will be collected from ICF signing but will 
not be included in the analysis of SAEs. See Section 12.3 for details.
k
Questionnaires (TSQM and patient preference questionnaire) will be administered after Screening prior to the start of Infusion 1, and after Infusion 3 prior to the 
start of Infusion 4
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20.4 Schedule of Study Procedures and Assessments (Part 2)
Table 3
Schedule of Study Procedures and Assessments (Part 2)
Procedures/
Assessments
Study Visits
Infusions 7
Infusion 8
Infusion 9
Infusion 10
Infusion 11
Infusions 12
Study Completion/
Termination
Visita
Rate of Infusion
Rate: 4 U/min/kg
Rate: 10 U/min/kg
Study Visit Windows
48 hours (+48) 
from previous 
infusionb
48 hours (+48) 
from previous 
infusionb
48 hours (+48) 
from previous 
infusionb
48 hours (+48) 
from previous 
infusionb
48 hours (+48) 
from previous 
infusionb
48 hours (+48) 
from previous 
infusionb
3 days (+ 4) from 
Infusion 12 (or last 
infusion)a
Medications and Non-drug Therapies
X
X
X
X
X
X
X
Pregnancy Test
Vital Signsc
X
X
X
X
X
X
X
Laboratory Assessmentsd
X
X
X
X
X
X
X
Adverse Events, breakthrough 
bleeds, and site infusion reactionse
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesf
X
X
Abbreviations: FEIBA=Factor Eight Inhibitor Bypassing Activity; IP=investigational product.
a
The Study Completion/Termination Visit includes cases of withdrawal or discontinuation. This visit should be done within 7 days but no sooner than 72 hours 
after Infusion 12). If a subject withdraws or discontinues, this visit should be done within 7 days but no sooner than 72 hours after the last infusion that the 
subject receives.
b
Infusions 7, through 12: All infusions in Part 2 will be scheduled for 48 hours (+48) after their previous infusion.
c
Vital signs will include body temperature, pulse rate, blood pressure, respiratory rate, and weight. Blood will be measured when subjects are in the supine 
position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within 30 minutes after completion of the infusion. 
Height, measured once at Screening, will also be collected.
d
For laboratory assessments, see Table 4.
e
The infusion site will be monitored for AEs for 30 ±10 minutes after the infusion. See Section 12.10 for details. SAEs will be collected from ICF signing but 
will not be included in the analysis of SAEs. See Section 12.3 for details.
f
Subject questionnaires (TSQM and patient preference questionnaire) will be administered after Infusion 6 prior to the start of Infusion 7, and after Infusion 12
prior to or up to the completion of the Study Termination/Completion Visit.
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20.5 Clinical Laboratory Assessments
Table 4
Clinical Laboratory Assessments
Assessments
Screening Visit
Infusions 1 and 4 
PK Visitsa
(multiple visits 
Day 1 through 9)
Infusions 
2, 3, 5, 6, 7, 8, 9, 10, 
11, and 12
Study Completion/
Termination
Visitb
Hematologyc
X
X
Clinical Chemistryd
X
X
Coagulation Testinge
X
X
X
X
Serology Testingf
X
X
PK Assessmentsg
X
X
X
Pregnancy Testh
X
Abbreviations: ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
CBC=complete blood count; FII=Factor II; FIX=Factor IX; FVII=Factor VII; FVIII=Factor VIII; FX=Factor X; GGT=gamma-glutamyl transpeptidase; 
HAV=hepatitis A virus; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; Hct=hematocrit; HCV=hepatitis C virus; Hgb=hemoglobin; HIV=human 
immunodeficiency virus; IgG=immunoglobulin G; IgM=immunoglobulin M; MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular 
volume; PK=pharmacokinetic; PT=prothrombin time; RBC=red blood cell; TAT=thrombin/anti-thrombin complex; WBC=white blood cell.
a
Additional PK visits will occur between Infusions 1 and 2, and between Infusions 4 and 5, at 24, 48, 96, 168, and 216 hours after Infusion 1 or Infusion 4 as 
described inTable 5 .
b
Includes cases of withdraw or discontinuation.
c
Hematology assessments include:  CBC (Hct, Hgb, RBC count, WBC count) with differential, MCV, MCHC, and platelet count.
d
Clinical chemistry assessments include sodium, chloride, potassium, bicarbonate, AST, ALT, albumin, total protein, alkaline phosphatase, total bilirubin, BUN, 
creatinine, glucose, GGT, 5’-nucleotidase.
e
Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1.2, TAT, fibrinopeptide A), FII, FX, FIX, FVII, and FVIII 
or FIX inhibitor level (Nijmegen assay).
f
Serological testing will include: HIV-1 and HIV-2 antibodies (HIV+, check CD4 count–screening visit only), HAV antibodies, HBV antibody, HBsAg, HCV 
antibody, parvovirus B19 (IgM and IgG), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus antibodies (IgM and IgG).
g
PK assessments will include coagulation activity testing of:  Factors II, 
 as described in Table 5.
h
A serum pregnancy test will be performed for females of childbearing potential.
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20.6 Pharmacokinetic Assessments
Table 5
PK Assessments
Procedures/
Assessments
Screening Visit
Infusion 1
Infusion 4
Day from 
Infusion
PK Assessments:
Factor II
X
X
Preinfusion
30 ± 5 min
30 ± 5 min
Day 0
15 ± 5 min
15 ± 5 min
Postinfusiona
EOI
EOI
Day 0
30 ± 5 minb
30 ± 5 minb
60 ± 5 min
60 ± 5 min
3 h ± 30 min
3 h ± 30 min
8 h ± 30 min
8 h ± 30 min
24 ± 4 hb
24 ± 4 hb
Day 1
48 ± 4 h
48 ±4 h
Day 2
96 ± 6 h
96 ± 6 h
Day 4
168 ± 6 h
168 ± 6 h
Day 7
216 ± 6 h
216 ± 6 h
Day 9
Abbreviations: EOI=end-of-infusion; Factor II=FII; 
 h=hours; 
min=minutes; PK=pharmacokinetic.
Notes: PK assessments will be completed on FII, 
 at screening and all timepoints indicated 
before and after Infusion 1 and Infusion 4.
a
Postinfusion sampling times are relative to the end of infusion.
b 
Blood sample for thrombotic marker analysis will be collected at the 30-minute timepoint.
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21. REFERENCES
1. Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity 
(FEIBA®): 10-year compilation of thrombotic adverse events. Haemophilia. 
2002;8:83-90.
2. Hilgartner M, Aledort L, Andes A, Gill J. Efficacy and safety of vapor-heated anti-
inhibitor coagulant complex in hemophilia patients. FEIBA Study Group. 
Transfusion. 1990;30:626-630.
3. Hilgartner MW, Knatterud GL, FEIBA Study Group. The use of factor eight 
inhibitor by-passing activity (FEIBA immuno) product for treatment of bleeding 
episodes in hemophiliacs with inhibitors. Blood. 1983;61:36-40.
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 BM, Kessler 
CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier 
Saunders; 2007:45-59.
6. Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. 
Haemophilia. 1998;4:558-563.
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7. Ehrenforth S, Kreuz W, Scharrer I et al. Incidence of development of factor VIII 
and factor IX inhibitors in haemophiliacs. Lancet 1992;339:594-598.
8. Turecek PL, Varadi K, Gritsch H et al. Factor Xa and prothrombin: mechanism of 
action of FEIBA. Vox Sang. 1999;77 Suppl 1:72-79.
9. Negrier C, Voisin S, Baghaei F et al.: Global Post-Authorization Safety 
Surveillance Study: real-world data on prophylaxis and on-demand treatment using 
FEIBA (an activated prothrombin complex concentrate). Blood Coagul.Fibrinolysis 
In press.
10. Baxter Healthcare Corporation. FEIBA (Anti-inhibitor coagulant complex) for 
intravenous use, lyophylized powder for solution. 15. 2013. FEIBA. United States. 
11. Bharmal M, Payne K, Atkinson MJ et al. Validation of an abbreviated treatment 
satisfaction questionnaire for medication (TSQM-9) among patients on 
antihypertensive medications. Health Qual.Life Outcomes 2009;7:36.
12. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents 
in cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. New 
York: Columbia University Press; 1949:191-205.
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22. SUMMARY OF CHANGES
Protocol 091501 Amendment 1 (Global) 2016 FEB 09
Replaces: Original: 2015 OCT 08
In this section, changes made in this amendment from the previous version of the
protocol, dated 2015 OCT 08, are described and their rationale is given.
1.
Throughout the document: 
Description of Change: Minor grammatical and/or administrative changes were 
made.
Purpose of Change: To improve clarity in the protocol.
2.
Title page, Investigator Acknowledgement
Description of Change: The EudraCT Number was updated to 2015-005781-39.
Purpose of Change: To correct the EudraCT number.
3.
Synopsis, Section 8.1 Brief Summary, Section 8.3 Overall Study Design:
Description of Change: The criteria for subjects with hemophilia A was changed 
from ≥0.4 to ≥0.6 BU.
Purpose of Change: The change was made based on the availability of validated 
assays and their detection level.
4.
Synopsis, Section 8.2 Study Design Rationale, Section 8.3 Overall Study Design, 
Section 8.8.3 Description of Treatment, Section 8.8.4 Management and Treatment 
of Break-Through Bleeding, Section 10.6 Subject Diary, Section 16.4 Internal 
Safety Monitoring Committee; Section 20.3 Schedule of Study Procedures and 
Assessments (Part 1), Section 20.4 Schedule of Study Procedures and 
Assessments (Part 2)
Description of Change: Text describing the previous 4 DMC reviews, and interim 
breaks was removed. Text was simplified to be described in just the synopsis and 
Section 16.4 Data Monitoring Committee which was updated to Internal Safety 
Monitoring Committee with this change. Text was added to define the 3 safety 
reviews as well as continuous monitoring.
Purpose of Change: An operational decision was made to reduce the formal DMC 
reviews from 4 DMC reviews with treatment breaks, to ongoing continual 
monitoring with 3 ISMCs and no break in treatment. This change is in an effort to 
increase the safety monitoring while reducing the total length of time of the study.
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5.
Throughout the document
Description of Change: All references of DMC were removed and updated to 
ISMC.
Purpose of Change: The change was made to align the text to the updated 
operational design.
6.
Synopsis, Section 8.2 Study Design Rationale, Section 8.3 Overall Study Design, 
Section 11.2 Pharmacokinetic Evaluation and Pharmacokinetic Parameters, 
Section 8.8.3 Description of Treatment, Section 8.8.4 Management and Treatment 
of Break-Through Bleeding
Description of Change: Text specifying washout periods was simplified and 
duplications within the text deleted. References to sponsor providing FEIBA was 
removed and replaced with allowing subjects to be given standard of care 
treatment for bleeding during washout periods.
Purpose of Change: Updates to the washout descriptions were made to align with 
the deletion of the DMC, as well as add clarity and simplify the text. In addition,
with the removal of the DMC there are no long interim breaks, hence the sponsor 
has decided it is unnecessary to provide FEIBA and that allowing the investigator 
to choose the treatment for bleeding control for subjects will increase safety, as 
the investigator can choose which product they know works best for the subject.
7.
Section 8.8.4 Management and Treatment of Break-Through Bleeding
Description of Change: The phrase “during the interim period, subjects who are 
on hold for DMC review” was updated to “During the interim period for DMC 
review, subjects”.
Purpose of Change: This change was made to align the text with the DMC 
changes described in Section 16.4 Data Monitoring Committee.
8.
Synopsis
Description of Change: Inclusion criteria 7 and 8 were added to the synopsis.
Purpose of Change: Inclusion criteria 7 and 8 were in the main body of the text 
but not the synopsis, this change is to update the sections to match.
9.
List of Abbreviations, Section 6.5 Compliance Statement
Description of Change: ICH was updated from International “Conference on” 
Harmonisation to “Council for”.
Purpose of Change: The definition of ICH was recently updated, and this was 
reflected within this protocol amendment.
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10. Section 8.8.1 Packaging, Labeling, and Storage
Description of Change: Text was added to describe how the sites will receive 
FEIBA and SWFI within a kit.
Purpose of Change: To add clarity.
11. Section 8.8.2:Adminstration
Description of Change: More detail, including a table was added to describe how 
the study drug will be prepared and administered.
Purpose of Change: Improve clarity and investigator compliance.
12. Section 8.8.2 Administration
Description of Change: Wording was changed from “must” to “every effort 
should be made” when describing using the same lot numbers for Infusion 1 and 
Infusion 4. Additional details were added to include that the diluent does not need 
to be the same lot.
Purpose of Change: To increase clarity and investigator compliance.
13. Section 8.8.3 Description of Treatment
Description of Change: Redundant text was removed and hyperlinks to the 
information in other sections were added.
Purpose of Change: To simplify and add clarity to the protocol
14. Synopsis, Section 8.4 Duration of Study Period(s) and Subject Participation
Description of Change: The duration of time the subjects will be on study was 
clarified by Part 1 and Part 2. Text referencing extension of time for the DMC 
was deleted.
Purpose of Change: This change was to update and align with the new ISMC text.
15. Section 10.6 Subject Diary, Throughout the protocol
Description of Change: The use of subject diaries was removed from the protocol.
Purpose of Change: The use of diaries is no longer needed due to the removal of 
the DMC breaks. This will simplify the study and make participation easier for 
the subjects.
16. Section 12.10 Infusion Site Evaluations
Description of Change: A statement was added to describe discussions of the 
subject with site staff to capture infusion site reactions.
Purpose of Change: To replace what was previously going to be collected by the 
subject diary.
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17. Section 13.2 Datasets and Analysis Cohorts
Description of Change: The word “safety” was added in relation to the analysis 
sets, and reference to the soft database lock and DMC were deleted.
Purpose of Change: This change was to align with the change from DMC to 
ISMC.
18. Section 20.3 Schedule of Study Procedures and Assessments (Part 1)
Description of Change: Footnote text regarding PK sampling timing was moved 
from footnote 5 to footnote 4.
Purpose of Change: This change was to improve clarity.
19. Title page
Description of Change: The words “activated prothrombin complex concentrate” 
were added.
Purpose of Change: To add clarity for the investigators.
20. Synopsis, Section 7.1 Study Purpose
Description of Change: The text “in Part 1” was deleted from the 2nd study 
purpose “To evaluate the safety of infusing reduced volume FEIBA at increased 
rates of 4 and 10 U/min/kg in comparison to the standard rate of 2 U/min/kg in 
Part 1”.
Purpose of Change: This change was added in order to increase flexibility in 
analysis.
21. Synopsis, Section 7.2 Primary Objectives
Description of Change: The occurrence of thromboembolic events was added to 
the primary objectives, and allergic reactions were renamed to allergic-type 
hypersensitivity reactions.
Purpose of Change: This was a medical and safety decision to more closely 
monitor and study the thromboembolic events based on the known information 
regarding FEIBA, and to capture a broader range of allergic reactions.
22. Synopsis, Section 7.3 Secondary Objectives
Description of Change: Thromboembolic events were deleted from secondary 
objectives.
Purpose of Change: Thromboembolic events were moved to primary objectives, 
in order to more closely assess their incidence.
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23. Synopsis, Section 8.5.1 Primary Outcome Measures
Description of Change: Thromboembolic events were added to the primary 
outcome measures, and it was separated from allergic-type hypersensitivity 
reactions.
Purpose of Change: The purpose of this change was to align it to the updated 
primary objectives, and to make the text more readable.
24. Synopsis, Section 8.5.2 Secondary Outcome Measures
Description of Change: The outcome measure of evaluating product-related AEs 
was updated to all AEs and SAEs, an additional outcome measure of evaluating 
the occurrence of AEs leading to discontinuation was added, and evaluating the 
occurrence of thromboembolic AEs was deleted.
Purpose of Change: The purpose of this change was to better evaluate the AEs 
and SAEs of this study. The deletion of the thromboembolic AEs was to not 
duplicate effort already being done in the primary outcome measures.
25. Synopsis
Description of Change: A more precise description of infusion frequency was 
added.
Purpose of Change: To add clarity and increase compliance.
26. Synopsis, Section 8.4 Duration of Study Period(s) and Subject Participation
Description of Change: Timing of planned duration of subject participation was 
updated.
Purpose of Change: The modification of the DMC to ISMC, and removal of the 
interim breaks shortens the duration of subject participation and time on study.
27. Section 6 Background Information
Description of Change: Background information was rearranged and duplicate 
text was deleted.
Purpose of Change: To add clarity and simplify the protocol text.
28. Section 6.2 Population to Be Studied
Description of Change: Previous Section 6.3 was updated to 6.2 based on updates 
to Section 6.1 and 6.2. A line referring to the Inclusion/Exclusion Criteria was 
added.
Purpose of Change: To increase specificity of the study population.
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29. Section 7.2 Primary Objectives
Description of Change: The section was rearranged into numbered format, and 
text updated to match Synopsis wording exactly.
Purpose of Change: To add clarity and simplify the text.
30. Section 8.8.4 Management and Treatment of Break-Through Bleeding, Section 
20.3 Schedule of Study Procedures and Assessments (Part 1)
Description of Change: Additional text was added to describe the washout period 
depending on whether the subject is treated with FEIBA or rFVIIa, as well as for 
management of bleeding episodes during treatment periods.
Purpose of Change: This update was due to the sponsor no longer requiring the 
use of FEIBA for treatment of bleeding, therefore additional text needed to be
added to specify what would occur depending on which treatment was 
administered.
31. Section 8.8.4 Management and Treatment of Break-Through Bleeding
Description of Change: The following sentence was updated: from “If multiple 
bleeding episodes occur during the washout period, the investigator and sponsor 
should decide if it is beneficial for the subject to be taken off the study” to “If 
multiple bleeding episodes occur during the washout period, the investigator and 
sponsor should decide if it is appropriate for the subject to be taken off the study 
or continue with the study”.
Purpose of Change: To clarify and increase investigator compliance.
32. Section 9.3 Withdrawal and Discontinuation
Description of Change: The following withdrawal criterion was added “The 
ISMC determines a subject should be taken off study”.
Purpose of Change: To align with the text in other sections of the protocol.
33. Section 10.3.1 Screening and Baseline Assessments
Description of Change: The text was updated from “subjects will receive 
instruction and educational materials on the symptoms of thromboembolic 
events” to “subjects will be instructed on the symptoms of thromboembolic events 
by the investigator”.
Purpose of Change: This was an operational decision in case educational 
materials were not available in all languages that the study would need.
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34. Section 8.8.3 Description of Treatment, Section 10.3.2.1 Infusion Visits
Description of Change: The procedure for randomization was updated from 
interactive voice response system to interactive web response system.
Purpose of Change: This was an operational decision.
35. Section 10.3.2.1 Infusion Visits, Section 11.1 Sample Collection and Processing
Description of Change: The following sentence was deleted “Funding or 
reimbursement for hotel facilities may be provided as allowed by the Institutional 
Review Board approved ICF and any applicable laws and regulations”.
Purpose of Change: This was determined to be common knowledge that did not 
need to be specified within the protocol text. 
36. Section 10.3.2.1 Infusion Visits, Section 10.5 Patient Questionnaires, Section 20.3 
Schedule of Study Procedures and Assessments (Part 1), Section 20.4 Schedule of 
Study Procedures and Assessments (Part 2)
Description of Change: Timing for questionnaire administration was updated 
from “between” visits, to “prior to the start of the next infusion”.
Purpose of Change: This was to add clarity on when the questionnaires needed to 
be administered.
37. Section 12.1.1.1 Serious Adverse Event
Description of Change: Wording was changed from “should be reported as SAEs” 
to “should be reported the same way as SAEs” “Additional events which should 
be reported as SAEs”: The following was removed “Thromboembolic events 
(myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke, 
transitory ischemic attack, etc.), and replaced with “Any thromboembolic event, 
allergic-type hypersensitivity reactions (e.g., analyphylaxis)”
Purpose of Change: To add clarity and align with the safety profile of the study 
infusions.
38. Section 12.4 Non-Medical Complaints
Description of Change: Medication errors were added to the list of NMCs.
Purpose of Change: This was a medical decision to include this additional NMC.
39. Section 12.11 Special Treatment Considerations
Description of Change: Thromboembolic events were added as a special treatment 
consideration.
Purpose of Change: For safety purposes and to align with the primary outcome 
measures, thromboembolic events have been upgraded special treatment 
considerations.
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40. Section 20.1 Study Flow Chart Part 1, Section 20.2 Study Flow Chart Part 2, 
Section 20.3 Schedule of Study Procedures and Assessments (Part 1), 
Section 20.4 Schedule of Study Procedures and Assessments (Part 2)
Description of Change: Specific timing was removed from the figure for washout 
periods as this has many different timings and is not exactly 12 days, as well as 
references to the DMC were removed.
Purpose of Change: These figures and tables were updated to align with the 
changes in washout periods and removal of the DMC.
41. Section 6.5 Compliance Statement
Description of Change: Template text was updated from “European Clinical Trial 
Directive” to “EU Directives”.
Purpose of Change: Template language was updated since the drafting of the 
protocol. These updates were included into this amendment.
42. Section 8.9 Source Data
Description of Change: The sentence “No data will be entered directly onto the 
eCRF” was added.
Purpose of Change: Template language was updated since the drafting of the 
protocol. These updates were included into this amendment.
43. Section 12.2 Urgent Safety Measures
Description of Change: Additional language was added to include relevant 
competent authority(s) in addition to responsible EC will be notified of urgent 
safety measures.
Purpose of Change: Template language was updated since the drafting of the 
protocol. These updates were included into this amendment.
44. Section 8.8.3 Description of Treatment
Description of Change: The following sentence was deleted “After each subset of 
subjects have completed Part I, PK equivalence of FEIBA reconstituted in 
reduced and regular volumes of SWFI in terms of AUC0-216 h of FII will be 
evaluated.”
Purpose of Change: This was removed with the removal of the 4 DMCs. 
Additional details were left to Section 13 Statistics.
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45. Section 13.2 Datasets and Analysis Cohorts
Description of Change: A sentence regarding handling of data for noncompliant 
subjects were removed.
Purpose of Change: It was felt that this was overly detailed and unnecessary for 
the protocol, and will instead be updated and included into the SAP as necessary.
46. Section 13.4 Methods of Analysis
Description of Change: An additional sentence was added to refer to the SAP.
Purpose of Change: To add clarity to the protocol.
47. Synopsis, Section 13.2 Datasets and Analysis Cohorts
Description of Change: Clarification was added to which subjects were included 
into the safety analysis set.
Purpose of Change: To add clarity to the protocol.
48. Synopsis, Section 13.4.2.2 Analysis of the Safety Outcome Measures
Description of Change: Text was updated from: “The number of product-related 
serious and non-serious AEs will also be summarized by treatment for each study 
part. Subgroup analysis will also be performed for events categorized as 
thromboembolic AEs.” to “The number of product related serious and non-serious 
AEs and number of AEs leading to discontinuation will also be summarized by 
treatment. A subgroup of all AEs occurring within 24 and 72 hours of IP infusion 
will be summarized by treatment”. An additional line was added earlier in the 
section to apply throughout the section “All safety analyses will be performed for 
each part separately as well as for the 2 parts together.”
Purpose of Change: To align the statistics to the updates in the outcome measures.
49. Section 13.4.1.2 Analysis of the Primary Safety Outcome Measures (Parts 1 
and 2)
Description of Change: Thromboembolic events were added into the primary 
safety outcome measures.
Purpose of Change: To align with the changes in the outcome measures.
50. Synopsis, Section 8.3 Overall Study Design, Section 8.8.3 Description of 
Treatment
Description of Change: Additional text describing study infusions and their timing 
was added.
Purpose of Change: Due to the deletion of the DMC text, additional text had to be 
pulled out and reworded from this section. This change was to keep accurate 
descriptions of the treatments.
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51. Section 8.3 Overall Study Design
Description of Change: Infusion numbers were written out in the treatment phase 
description, and 12 IP infusions was clarified.
Purpose of Change: To add clarity to the protocol.
52. Synopsis, Section 8.8.2 Administration, Section 8.8.3 Description of Treatment
Description of Change: Text was added to allow for the use of partial vials for PK 
infusions and the recommendation to use full vials for non-PK infusions.
Purpose of Change: To simplify the dosing calculations and prevent treatment 
errors.
53. Section 8.8.1 Packaging, Labeling, and Storage
Description of Change: Changes to the storage conditions were added.
Purpose of Change: To standardize the storage conditions across countries.
54. Section 8.8.3 Description of Treatment
Description of Change: The bulleted list of treatment summary was removed.
Purpose of Change: This was redundant text and was removed to simplify the 
protocol.
55. Synopsis, Section 13.4 Methods of Analysis, Section 13.4.1.1 Analysis of the 
Primary PK Outcome Measure (Part 1)
Description of Change: The planned statistical analysis of the primary analysis 
was updated.
Purpose of Change: Unnecessary detail was removed from the protocol, and the 
analysis of the AUC0-216 h was changed from a linear mixed effects model to a 
fixed effect. A reference to additional details in the SAP was added.
56. Section 10.3.4 Study Completion/Termination Visit
Description of Change: Review of subject diary and diary collection was removed 
and replaced with breakthrough bleeds monitoring and concomitant medication 
monitoring.
Purpose of Change: To ensure the data will be captured as necessary without the 
use of a subject diary.
57. Section 10.4 Medications and Non-Drug Therapies
Description of Change: A reference to the sponsor providing FEIBA for bleeding 
episodes was removed. Additionally, standard of care medication for bleeding 
episodes was introduced into the protocol to allow for this change in study design.
Purpose of Change: The study design has changed to allow the use of standard of 
care for bleeding episodes.
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58. Synopsis, Section 13.4.1.2 Analysis of the Primary Safety Outcome Measure (Part 
1 and 2), Section 13.4.2.2 Analysis of the Safety Outcome Measures
Description of Change: Infusion site reactions was moved from the primary 
analysis to the secondary analysis. 
Purpose of Change: To align the statistical text with the objectives of the protocol.
59. Section 8.8.4 Management and Treatment of Break-Through Bleeding
Description of Change: Additional text was added to describe the scenario of 
bleeding during times other than washout periods and PK collection periods.
Purpose of Change: To give guidance to the investigators and add clarity to the 
protocol.
60. Section 10.7 Subject Completion/Discontinuation
Description of Change: Severe allergic reaction was added as a reason for 
completion/discontinuation.
Purpose of Change: This was a decision for subject safety.
61. Section 11.1 Sample Collection and Processing, Section 20.5 Clinical Laboratory 
Assessments, Section 20.6 Pharmacokinetic Assessments
Description of Change: PK timepoints were updated.
Purpose of Change: To allow for easier draw times for subjects while preserving 
the integrity of the data.
62. Section 13.3 Handling of Missing, Unused, and Spurious Data
Description of Change: The phrase “no imputation method for missing values will 
be used” was deleted, and the following sentence was added “For the calculation 
of AUC0-216 h, non quantifiable PK results will be extrapolated”.
Purpose of Change: To clarify the statistical analysis.
63. Synopsis, Section 13.1 Sample Size and Power Calculations
Description of Change: The sample size calculation was reworded and clarified, 
adding in the coefficient of variation and the margins of equivalence.
Purpose of Change: To add clarity to the protocol.
64. Section 20.6 Pharmacokinetic Assessments
Description of Change: Blood sample for thrombotic marker analysis will be 
collected at either the 30-minute or 24-hour timepoint. Was updated to just the 
30 minutes timepoint.
Purpose of Change: This was an operational change designed to make decisions 
on which sample to collect easier.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered, FEIBA
STUDY TITLE: A Two-part, Phase 4, Prospective, Open-label, Randomized, 
Crossover Study of the PK and Safety of FEIBA Reconstituted in Regular or 50% 
Reduced Volume and the Safety of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 4
AMENDMENT 1 (Global): 2016 Mar 03
Replaces: Original: 2015 OCT 08
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered, FEIBA
STUDY TITLE: A Two-part, Phase 4, Prospective, Open-label, Randomized, 
Crossover Study of the PK and Safety of FEIBA Reconstituted in Regular or 50% 
Reduced Volume and the Safety of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 4
AMENDMENT 1 (Global): 2016 Mar 03
Replaces: Original: 2015 OCT 08
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD
, Clinical Development
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CLINICAL STUDY PROTOCOL
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
STUDY SHORT TITLE: FEIBA Reconstitution Volume Reduction and Faster 
Infusion Study (FEIBA STAR)
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 2 (Global): 2017 AUG 04
Replaces: Amendment 1 2016 MAR 03
ALL VERSIONS:
Amendment 2 (Global): 2017 AUG 04
Amendment 1 (Global): 2016 MAR 03
Original: 2015 OCT 08
OTHER ID(s)
NCT Number: 02764489
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA 91362, 
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, 
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory)/Responsible Party
MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g., 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 INCLUDING SUSARs, 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
Drug Safety contact information: see SAE Report From
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:

Adverse Event, Section 12.1

Serious Adverse Event, Section 12.1.1.1

Assessment of Adverse Events, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT (IP)
Name of IP
Anti-inhibitor Coagulant Complex Nanofiltered (activated 
prothrombin complex concentrate [APCC]), FEIBA NF. 
Referred to as FEIBA throughout the protocol.
Name(s) of Active 
Ingredient(s)
Coagulation factors II, X, IX, and VIIa
CLINICAL CONDITION(S)/INDICATION(S)
FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B 
patients with

inhibitors for:
Control and prevention of bleeding episodes
Perioperative management
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

FEIBA is not indicated for the treatment of bleeding episodes resulting from 
coagulation factor deficiencies in the absence of inhibitors to factor VIII or 
factor IX.1
PROTOCOL ID
091501
PROTOCOL TITLE
A Phase 3b/4, Prospective, Multicenter, Open-label, 
Randomized, Crossover Study of Tolerability and Safety 
of FEIBA Reconstituted in Regular or 50% Reduced 
Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
Short Title
FEIBA Reconstitution Volume Reduction and Faster Infusion 
Study (FEIBA STAR)
STUDY PHASE
Phase 3b/4, depending on market authorization status per 
country
PLANNED STUDY PERIOD
Initiation
First Subject In: Q 1 2018
Primary Completion
Last Subject In: Q 4 2018
Study Completion
Last Subject Last Visit: Q 4 2018
Duration
6 to 11 weeks
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STUDY OBJECTIVES AND PURPOSE
Study Purpose
To evaluate the tolerability and safety of infusing reduced volume FEIBA at the standard 
infusion rate of 2 U/kg/min, and at increased rates of 4 and 10 U/kg/min, in comparison 
to the standard rate of 2 U/kg/min at the regular volume
Primary Objectives
To evaluate tolerability and safety of FEIBA reconstituted in a 50% reduced volume of 
sterile water for injection (SWFI) administered at the standard infusion rate of 
2 U/kg/min and at increased rates of 4 and 10 U/kg/min, based on the occurrence of any 
adverse event, in particular of thromboembolic events and hypersensitivity reactions 
Exploratory Objectives
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II  with 50% reduced 
volume of FEIBA and faster infusion rates
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
STUDY DESIGN
Study Type/ 
Classification/ 
Discipline
Tolerability and Safety
Control Type
Active
Study Indication 
Type
Treatment
Intervention model
Part 1:  Crossover
Part 2:  Sequential
Blinding/Masking
Part 1:  Randomized, Open-label
Part 2:  Non-Randomized, Open-label
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Study Design
A 2-part, Phase 3b/4, prospective, open-label, multicenter 
study to be conducted in 24 evaluable hemophilia A or B 
subjects with inhibitors (≥0.6 Bethesda units [BU] for the 
primary tolerability and safety assessments.
Part 1:
In Part 1, subjects will be administered two different volumes 
of FEIBA in a randomized, crossover design every 48 hours 
(-8, +24 hours) intervals. Part 1 will monitor the tolerability, 
safety, pre (within 60 min before the infusion) and post-
infusion (at 30 min, hours 1, 2, 6, 8 and 12) concentration of 
coagulation factor II (FII) reconstituted in 50% reduced 
volume of SWFI and administered at the standard infusion rate 
of 2 U/kg/min compared with FEIBA reconstituted in regular 
volume of SWFI at the standard infusion rate.
All subjects will be screened for eligibility based on the listed 
inclusion and exclusion criteria.
Eligible subjects will be randomly assigned (1:1) to receive 
3 infusions of FEIBA reconstituted in 50% reduced volume 
SWFI or regular volume SWFI (Period 1).
Patients finishing 3 infusions in Period 1 (Sequence A or B), 
will either switch from FEIBA reconstituted in reduced volume 
to 3 infusions of FEIBA in regular volume SWFI or vice versa 
(Sequence A or B) depending on randomization.
All patients completing Part 1 will move to Part 2. Evaluable 
patients from Part 1 are all subjects who receive 4 of the 
6 planned infusions, at least 2 infusions in each sequence.
Tolerability and safety data will be collected before, during and 
after each infusion and between infusions; Clinically apparent 
changes in vital signs, laboratory parameters, infusion site 
reactions and infusion rate-related reactions will be monitored.
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FII concentration will be monitored by analyzing 
concentrations before (within 60 min before the infusion) and 
at 30 min after each infusion and at hours 1, 2, 6, 8 and 12 after 
infusion 1,3,4 and 6 as outlined in Section 20.6.
Part 2: 
Part 2 is non-randomized with sequential treatment of all 
evaluable subjects who complete Part 1, will receive at least 
4 of the 6 infusions. Subjects will receive FEIBA reconstituted 
in 50% reduced volume of SWFI at increased rates of 4 and 
10 U/kg/min in a non-randomized fashion, at 48 hours 
(-8, +24 hours) intervals, to evaluate the tolerability and safety 
of infusing FEIBA reconstituted in 50% reduced volume of 
SWFI at increased rates of 4 and 10 U/kg/min.
FEIBA Infusions 7, 8, and 9 will be administered at the 
4 U/kg/min rate and infusions 10, 11 and 12 will be 
administered at 10 U/kg/min.
Following the last infusion (infusion 12), a study termination 
visit will be conducted within 7 days but no sooner than 
72 hours after the last infusion.
Tolerability and safety data will be collected before, during and 
after each infusion and between the infusions; Clinically 
apparent changes in vital signs, infusion rate-related events, 
and infusion site reactions will be monitored.
Concentration of coagulation factor II will be assessed before 
(within 60 minutes before the infusion) and at 30 min after 
each infusion, and at hours 1, 2, 6, 8 and 12 after infusions 9, 
and 12 as outlined in Section 20.6.
The infusions in both parts will be administered every 48 hours 
(-8 hours /+24 hours) to allow time to monitor tolerability and 
safety of the higher infusion rate. 
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All IP infusions will be administered at the hemophilia care 
centers/study sites. Each subject will receive a maximum of 
12 IP infusions (6 in each part). There is no washout period 
before Part 1, between infusions or parts of the study.
Subjects will receive FEIBA at a dose of 85 U/kg ± 15 U/kg 
for all infusions. For infusions, whole vials should be rounded 
up or down to be as close as possible to the accurate dosage, as 
appropriate. Please refer to study documents for detailed 
instructions.
Safety monitoring for this study  will be conducted 
concurrently by an Internal Safety Monitoring Committee 
(ISMC). All SAEs that occur will be reviewed by the Chair of 
the ISMC with the Medical Director within 24 hours. Planned 
ISMC meetings will be held concurrently with the ongoing 
study.
Planned Duration of 
Subject Participation
It is planned that each subject will spend approximately 6 to 
11 weeks in the study. 
Outcome Measure (s)
Primary
Assess tolerability and safety (local and general) related to the infusion and volume of 
reconstitution: 
1.
Occurrence of any adverse event: all AEs and SAEs, and AEs leading to 
discontinuation 
2.
Thromboembolic events and hypersensitivity reactions
3.
Vital signs and Clinical laboratory data
4.
Infusion site and infusion related reactions
Exploratory Outcome Measure(s) 
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II.
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: kit; powder, lyophilized, for 
solution/suspension; injection
Dosage frequency: IP will be infused every 48 hours
(-8 hours/+24 hours).
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Enroll 24 evaluable subjects for the assessments
Number of 
Groups/Arms/Cohorts
1 cohort: at least 24 evaluable adult subjects (≥18 to 
≤65 years old) for tolerability and safety evaluation
Inclusion Criteria
Subject is/has:
1.
≥18 to ≤65 years old at the time of screening
2.
Hemophilia A or B of any severity, with a documented ≥ 3 months history of 
inhibitors (≥ 0.6 BU) requiring the use of bypassing agents (FEIBA or rFVIIa) 
prior to screening. Inhibitor level will be tested at screening if no documented 
history is available.
3.
Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain 
reaction (PCR); or HCV positive with stable liver disease
4.
Human immune deficiency virus (HIV)  negative; or HIV positive with stable 
disease and CD4 count ≥ 200 cell/mm3 at screening
5.
Adequate peripheral venous access
6.
Willing and able to comply with the requirements of the protocol
7.
If a female of childbearing potential, must have a negative blood pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study, such as:
a.
Abstain from sexual intercourse
b.
Use a reliable method of contraception (contraception such as an intrauterine 
device, barrier method [e.g., diaphragm or sponge; female condom not 
permitted] with spermicide, oral contraceptive, injectable progesterone, sub 
dermal implant), and have their male partner use a condom
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8.
If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a.
Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-stimulating 
hormone levels within the laboratory-defined postmenopausal range or 
postmenopausal with amenorrhea for at least 24 months and on hormonal 
replacement therapy
b.
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation (with no subsequent pregnancy at least 
1 year from bilateral tubal ligation), or bilateral salpingectomy
Exclusion Criteria
Subject is/has:
1.
Known hypersensitivity to FEIBA or any of its components
2.
Advanced liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites, prothrombin time [PT] 5 seconds above upper limit of 
normal)
3.
Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4.
Platelet count < 100,000/µL
5.
Clinical or laboratory evidence of disseminated intravascular coagulation
6.
Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
7.
Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
8.
Taking any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to 
enrollment except anti-retroviral chemotherapy.
9.
Herbal supplements that contain anti-platelet activity
10. 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
11. A family member or employee of the investigator
12. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
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STATISTICAL ANALYSIS
Sample Size Calculation
The projected sample size of 24 evaluable subjects for this tolerability and safety study 
was determined by considering available patients, and is not based on statistical power 
calculations.
Planned Statistical Analysis
Statistical analysis for this study will be descriptive in nature.
Primary Analysis
AEs, SAEs and AEs leading to discontinuation, thromboembolic events and 
hypersensitivity reactions that occur during or after the IP infusion will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be provided for temporally associated adverse events; 
and for potentially related adverse events as assessed by the investigators.
Shift tables and summary statistics will be presented for the results of clinical laboratory 
data. All abnormal lab results will be listed.
Summary statistics of vital signs, infusion site and infusion related reactions will be 
carried out.
Exploratory Analysis
All exploratory outcome measures will be analyzed descriptively.
Full details of the statistical analysis will be specified in the statistical analysis plan 
(SAP).
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory)/Responsible Party................................ 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 12
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 18
6.1 Description of Investigational Product and Clinical Condition/Indication..... 18
6.2 Clinical Condition/Indication .............................................................................. 18
6.3 Population to Be Studied...................................................................................... 19
6.4 Findings from Nonclinical and Clinical Studies................................................. 20
6.4.1 Finding from Nonclinical Studies................................................................. 20
6.4.2 Findings from Clinical Studies ..................................................................... 20
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 22
6.6 Compliance Statement.......................................................................................... 22
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 23
7.1 Study Purpose ....................................................................................................... 23
7.2 Primary Objectives............................................................................................... 23
7.3 Exploratory Objectives......................................................................................... 23
8. STUDY DESIGN......................................................................................................... 24
8.1 Brief Summary and Study Design Rationale ..................................................... 24
8.2 Overall Study Design............................................................................................ 25
8.3 Duration of Study Period(s) and Subject Participation .................................... 26
8.4 Outcome Measures ............................................................................................... 26
8.4.1 Primary Outcome Measures......................................................................... 26
8.4.2 Exploratory Outcomes Measure .................................................................. 27
8.5 Randomization and Blinding............................................................................... 27
8.6 Study Stopping Rules............................................................................................ 27
8.7 Investigational Product(s).................................................................................... 27
8.7.1 Packaging, Labeling, and Storage................................................................ 27
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8.7.2 Administration ............................................................................................... 28
8.7.3 Description of Treatment.............................................................................. 29
8.7.4 Management and Treatment of Break-Through Bleeding ........................ 31
8.7.5 Investigational Product Accountability ....................................................... 32
8.8 Source Data ........................................................................................................... 32
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 33
9.1 Inclusion Criteria.................................................................................................. 33
9.2 Exclusion Criteria................................................................................................. 34
9.3 Withdrawal and Discontinuation ........................................................................ 34
10. STUDY PROCEDURES .......................................................................................... 36
10.1 Informed Consent and Enrollment ................................................................... 36
10.2 Subject Identification Code (SIC) ..................................................................... 36
10.3 Screening and Study Visits................................................................................. 36
10.3.1 Screening and Baseline Assessments.......................................................... 36
10.3.2 Treatment Visits........................................................................................... 37
10.3.2.1 Infusion Visits ....................................................................................... 37
10.3.3 Study Completion/Termination Visit......................................................... 38
10.4 Medications and Non-Drug Therapies.............................................................. 39
10.5 Subject Questionnaires....................................................................................... 40
10.6 Subject Completion/Discontinuation ................................................................ 40
10.7 Procedures for Monitoring Subject Compliance............................................. 41
11. ASSESSMENT OF PHARMACOKINETICS....................................................... 41
12. ASSESSMENT OF SAFETY................................................................................... 42
12.1 Adverse Events.................................................................................................... 42
12.1.1 Definitions..................................................................................................... 42
12.1.1.1 Serious Adverse Event.......................................................................... 42
12.1.1.2 Non-Serious Adverse Event ................................................................. 43
12.1.1.3 Unexpected Adverse Events................................................................. 43
12.1.1.4 Pre-existing Diseases............................................................................. 43
12.1.2 Assessment of Adverse Events.................................................................... 44
12.1.2.1 Severity .................................................................................................. 45
12.1.2.2 Causality................................................................................................ 45
12.1.2.3 Safety Reporting ................................................................................... 46
12.1.3 Medical Device Safety Reporting ............................................................... 47
12.2 Urgent Safety Measures ..................................................................................... 48
12.3 Untoward Medical Occurrences........................................................................ 48
12.4 Non-Medical Complaints ................................................................................... 49
12.5 Medical, Medication, and Non-Drug Therapy History................................... 49
12.6 Physical Examinations........................................................................................ 50
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12.7 Clinical Laboratory Parameters........................................................................ 50
12.7.1 Hematology and Clinical Chemistry.......................................................... 50
12.7.2 Concentration of FII and Coagulation Testing......................................... 51
12.7.3 Viral Serology............................................................................................... 51
12.7.4 CD4 Levels.................................................................................................... 51
12.7.5 Assessment of Laboratory Values .............................................................. 51
12.7.5.1 Assessment of Abnormal Laboratory Values..................................... 51
12.7.6 Biobanking.................................................................................................... 52
12.8 Vital Signs............................................................................................................ 52
12.9 Karnofsky Performance Test............................................................................. 52
12.10 Infusion Site Evaluations.................................................................................. 53
12.11 Special Treatment Considerations .................................................................. 53
13. STATISTICS............................................................................................................. 55
13.1 Sample Size and Power Calculations ................................................................ 55
13.2 Datasets and Analysis Cohorts .......................................................................... 55
13.3 Handling of Missing, Unused, and Spurious Data........................................... 55
13.4 Methods of Analysis............................................................................................ 55
13.4.1 Primary Outcome Measure......................................................................... 55
13.4.1.1 Analysis of the Primary Outcome Measure (Parts 1 and 2)............. 55
13.4.2 Exploratory Outcome Measures ................................................................ 56
13.5 Planned Interim Analysis of the Study ............................................................. 56
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 56
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 57
15.1 Investigator’s Responsibility.............................................................................. 57
15.1.1 Final Clinical Study Report........................................................................ 57
15.2 Training ............................................................................................................... 57
15.3 Monitoring........................................................................................................... 57
15.4 Safety Monitoring ............................................................................................... 57
15.5 Auditing ............................................................................................................... 58
15.6 Non-Compliance with the Protocol ................................................................... 58
15.7 Laboratory and Reader Standardization ......................................................... 59
16. ETHICS ..................................................................................................................... 59
16.1 Subject Privacy ................................................................................................... 59
16.2 Ethics Committee and Regulatory Authorities................................................ 59
16.3 Informed Consent ............................................................................................... 59
17. DATA HANDLING AND RECORD KEEPING................................................... 60
17.1 Confidentiality Policy ......................................................................................... 60
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17.2 Study Documentation and Case Report Forms ............................................... 60
17.3 Document and Data Retention........................................................................... 61
18. FINANCING AND INSURANCE........................................................................... 61
19. PUBLICATION POLICY........................................................................................ 61
20. SUPPLEMENTS....................................................................................................... 62
20.1 Study Flow Chart Part 1 .................................................................................... 62
20.2 Study Flow Chart Part 2 .................................................................................... 63
20.3 Schedule of Study Procedures and Assessments (Part 1)................................ 64
20.4 Schedule of Study Procedures and Assessments (Part 2)................................ 66
20.5 Clinical Laboratory Assessments ...................................................................... 68
20.6 Concentrations of FII and Coagulation testing................................................ 69
21. REFERENCES.......................................................................................................... 70
22. SUMMARY OF CHANGES.................................................................................... 72
INVESTIGATOR ACKNOWLEDGEMENT.............................................................. 78
Tables
Table 1 FEIBA Product Preparation................................................................................ 29
Table 2 Schedule of Study Procedures and Assessments (Part 1)................................... 64
Table 3 Schedule of Study Procedures and Assessments (Part 2)................................... 66
Table 4 Clinical Laboratory Assessments........................................................................ 68
Table 5 FII and Coagulation Testing Time Frame........................................................... 69
Figures
Figure 1 Study Design for Part 1 Baxalta Clinical Study 091501 ................................... 62
Figure 2 Study Design for Part 2 Baxalta Clinical Study 091501 ................................... 63
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AICC
anti-inhibitor coagulant complex
ALT
alanine aminotransferase
APCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BU
Bethesda units
BUN
blood urea nitrogen
BW
body weight
CBC
complete blood count
CD4
cluster of differentiation 4
CI
confidence interval
EC
ethics committee
EOI
end-of-infusion
CRF
case report form
EDC
electronic data capture
FEIBA
Factor Eight Inhibitor Bypassing Activity
FEIBA NF
Factor Eight Inhibitor Bypassing Activity Nanofiltered
FEIBA VH
Factor Eight Inhibitor Bypassing Activity Vapor Heated
FII
Factor II
FIX
Factor IX
FVII
Factor VII
FVIII
Factor VIII
FVIII:CAg
Factor VIII C antigen
FX
Factor X
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GSL
Global Safety Lead
HAV
hepatitis A virus
HBsAg
hepatitis B surface antigen
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Abbreviation
Definition
HBV
hepatitis B
Hct
hematocrit
HCV
hepatitis C virus
Hgb
hemoglobin
HIV
human immunodeficiency virus 
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IgG
Immumoglobulin G
IgM
immunoglobulin M
IP
investigational product
ISMC
Internal Safety Monitoring Committee
Min
minutes
NMC 
non-medical complaint
PCR
polymerase chain reaction
PT
prothrombin time
rFVIIa
recombinant activated clotting factor VII
Rsq
r2
SAE
serious adverse event
SAER
serious adverse event report
SIC
subject identification code
SI
serious injuries
SWFI
sterile water for injection
TAT
thrombin/anti-thrombin complex
TSQM
Treatment Satisfaction Questionnaire for Medication
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product and Clinical Condition/Indication
The investigational product (IP), FEIBAi is a plasma derived, activated prothrombin 
complex concentrate (APCC), generically identified as an anti-inhibitor coagulant 
complex (AICC). FEIBA was developed to treat bleeding episodes and cover surgical 
interventions in hemophilia A and B patients with inhibitors and in non-hemophilia 
patients with acquired inhibitorsii and is also intended for use as a prophylactic treatment 
for hemophilia A and B patients with high responding inhibitors and frequent joint 
bleeding.iii,2,3,4
Baxalta’s first licensed FEIBA product, AICC FEIBA, was marketed beginning in 1975
and was superseded in 1985 by a 2-stage vapor heat-treated product, AICC FEIBA VH.
Nanofiltration was introduced to the manufacturing process in 2006 to produce 
FEIBA NF, now called FEIBA.
6.2 Clinical Condition/Indication 
Hemophilia is an X-linked, recessive, congenital bleeding disorder caused by 
deficient or defective coagulation due to a deficiency in FVIII (hemophilia A), or FIX 
(hemophilia B). The absence of FVIII or FIX leads to spontaneous bleeding episodes 
(occurring primarily in joints, muscles, and less commonly, in soft tissues) and to 
excessive bleeding following trauma or injury.5,6 Replacement therapy for the treatment 
of hemophilia A, and less frequently hemophilia B, can be complicated by an immune 
response resulting in the production of inhibitory alloantibodies to Factor VIII (FVIII) or 
Factor IX (FIX), especially in patients with moderate to severe hemophilia. The 
development of such inhibitory antibodies currently represents the most serious 
complication of hemophilia treatment. The presence of inhibitors against FVIII 
generally precludes the efficacious use of human FVIII replacement therapy. A 
substantial portion of patients with FVIII inhibitors have high-responding, high-titer 
inhibitors (> 5 Bethesda units [BU]). These patients exhibit an anamnestic response 
after FVIII exposure, sometimes with a dramatic increase in inhibitory antibody titer.7,8
The inability to provide FVIII replacement therapy predisposes this group of patients to 
increased morbidity and mortality compared with hemophilia patients without inhibitors.7
                                                
i
FEIBA NF is a trademark of Baxalta Inc. US and Baxalta Innovations GmbH.
ii
Anti-Inhibitor Coagulant Complex, FEIBA Vapor Heated. Package Insert, Baxalta US Inc., Westlake 
Village, CA.
iii
Protocol 090701. FEIBA NF: A Prospective, Open-label, Randomized, Parallel Study to Evaluate 
Efficacy and Safety of Prophylactic versus On-demand Treatment in Patients with Hemophilia A and B 
and High Titer Inhibitor. 2013 Jan 14, Baxalta US Inc.,(Westlake Village, CA).
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Several therapeutic approaches are currently available in the management of hemorrhagic 
events in patients who have developed FVIII inhibitors. These include neutralization with 
high doses of human FVIII (low titer inhibitor only), and treatment with bypassing agents 
such as Activated Prothrombin Complex Concentrate (APCC), or activated recombinant 
factor VII (rFVIIa). Among these treatment options, only APCCs and rFVIIa are able to 
control acute hemorrhages in hemophilia patients with high titer inhibitors. These agents 
control bleeding by promoting the conversion of prothrombin to thrombin with 
subsequent fibrin polymerization and clot formation via mechanisms that do not require 
FVIII or FIX. It has been proposed that FEIBA products achieve this goal principally by 
virtue of the presence of a “partial prothrombinase complex” consisting of activated 
Factor X (FX) and prothrombin.9
The active ingredient of FEIBA is a plasma-derived, freeze-dried APCC with FVIII 
inhibitor bypassing activity. Recent studies have demonstrated that FEIBA is a 
multicomponent therapeutic agents with activities potentially targeting different sites in 
the coagulation system.10 FEIBA contains mainly non-activated forms of the vitamin K -
dependent proteins Factor II (FII), FVII, FIX and FX, as well as small amounts of 
activated prothrombin complex proteins; and Factor VIII coagulant antigen present in a
concentration of up to 0.1 U/1 U FEIBA. From a number of confirmed studies it became 
clear that the FII–FXa complex is one of the key components in this system of different 
proteins.11  A solution containing 1 U FEIBA shortens the activated partial 
thromboplastin time (aPTT) of FVIII inhibitor plasma up to 50% of the buffer value. 
Additional details can be found in the FEIBA IB.iv
6.3 Population to Be Studied
Adult subjects (age ≥18 to ≤65 years) with hemophilia A or B (congenital or acquired) 
of any severity, of all races and ethnic groups will be studied. All subjects will have a 
documented history of inhibitors (≥ 0.6 BU) requiring the use of bypassing agents 
(FEIBA or rFVIIa); subjects with no documented history will require testing of the 
inhibitor level before entering the study. Subjects will either be hepatitis C virus (HCV)
negative or HCV positive with stable hepatic disease. Subjects will either be human 
immunodeficiency virus (HIV) negative or HIV positive with stable disease and a cluster 
of differentiation 4 (CD4) count ≥ 200 cell/mm3. See additional details in the Inclusion 
and Exclusion Criteria in Section 9.1 and Section 9.2, respectively.
                                                
iv
Investigator’s brochure. Anti-inhibitor coagulant complex nanofiltered; FEIBA NF. 2016 FEB 24. 
Baxalta US Inc., (Westlake Village, CA). 
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6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Finding from Nonclinical Studies
The nonclinical studies included a virus clearance study, which was performed to 
investigate the virus reduction capacity of the nanofiltration step in the manufacturing of 
FEIBA NF. 
Data from nonclinical studies can be found in the FEIBA NF IB.iv
6.4.2 Findings from Clinical Studies
The results of Baxalta clinical study 090701iii demonstrated that prophylaxis with 
FEIBA significantly reduced the annualized bleeding rates for all bleed types and for 
spontaneous, traumatic, joint, and non-joint, bleeding episodes when compared with on-
demand treatment. A statistically significant reduction in the rate of bleeding episodes in 
new target joints in the prophylaxis arm versus the on-demand arm was also observed. 
An examination of adverse events (AEs), abnormal laboratory parameters for hematology 
and clinical chemistry and vital signs demonstrated that FEIBA was safe and well 
tolerated for prophylactic use. Clinically, these data suggest that FEIBA is safe and 
efficacious in the management of hemophilia A or B with persistent high-titer inhibitors
or low-titer inhibitors refractory to FVIII or FIX treatment, and further confirmed the 
safety and effectiveness of FEIBA for controlling and preventing bleeding episodes.
Baxalta clinical study 091002 was an open-label, uncontrolled, non-interventional 
observational cohort study of FEIBA NF in hemophiliacs with inhibitors. This study was
designed to document routine usage of FEIBA NF as a bypassing agent for on-demand or 
prophylactic treatment in everyday clinical practice and in surgical intervention. The 
safety results of this postauthorization safety study showed that treatment with 
FEIBA NF, administered in 81 subjects with hemophilia, requiring treatment with 
inhibitor-bypass therapy for bleed resolution or bleed prophylaxis, was generally safe 
and well tolerated. The mean infusion rate of FEIBA under routine clinical practice 
during the study (3.7 U/kg per min, range 0.9 to 23.5) was higher than that recommended 
in the Summary of Product Characteristics of FEIBA (2.0 U/kg per min). A manual 
analysis of safety listings did not disclose any AEs associated with a higher infusion 
rate.12 Treatment-related AEs or serious adverse events (SAEs) were reported in 9.9% 
and in 3.7% of subjects, respectively. A deep venous thrombosis and a superficial 
thrombophlebitis were observed in 1 subject with acquired hemophilia.
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The hemostatic effectiveness was rated by the physicians as excellent or good in more 
than 90% of total subjects, with the highest rates reported in subjects with FEIBA NF 
prescribed as regular prophylaxis. Additional details on this study can be found in the 
clinical study report.v
FEIBA consists of zymogens and traces of activated forms of procoagulant factors II, 
VII, IX, X, anticoagulants protein C and TFPI, and small amounts of cofactors FV, FVIII 
and protein S, in a balanced ratio. As mentioned before, FII-FXa complex plays a key 
role in FEIBA’s mode of action (MoA). A recently published study has shown that 
although the FII-FXa complex are the key components other procoagulant components of 
FEIBA were necessary to achieve an optimal activity. However prothrombin (FII) is the 
lead procoagulant component of FEIBA.1,11
Due to the complex nature of the composition of FEIBA, pharmacokinetic information 
cannot be determined by measurement of a single component. In recent studies where 
FEIBA was used as a comparator product surrogate markers of coagulation were used to 
determine pharmacokinetics. These surrogate markers of coagulation included 
determination of thrombin generation, activated partial thromboplastin time (aPTT), 
prothrombin time (PT), thrombin–antithrombin complex (TAT) and prothrombin 
fragment F1+2 (F1+2), and  aPTT clot waveform analysis, maximum levels of these 
surrogate markers following FEIBA administration were seen after 10 or at 30 min with 
variable results at later time points.10 In another study where thrombin generation was 
measured in patients following infusion of FEIBA peak thrombin levels were seen 
predominantly 30 and 60 minutes after infusion.13 Thus, determination of peak plasma 
concentrations of components of FEIBA seems to be most appropriate performed at 30 or 
60 minutes after infusion.
Additional observational, non-interventional studies were conducted with FEIBA NF. 
Additional details on clinical studies can be found in the FEIBA NF IB.iv
                                                
v
Clinical Study Report. Post-Authorization Safety Study of FEIBA NF (Factor VIII Inhibitor Bypassing 
Activity). An open, uncontrolled, non-interventional observational cohort study of FEIBA NF in 
hemophiliacs with inhibitors. 10 Oct 2014. Baxalta Inc. US and Baxalta Innovations GmbH.
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6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
Uncommon, hypersensitivity reactions observed after infusion of FEIBA have included, 
urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; 
these reactions can be severe and systemic (e.g., anaphylaxis with urticaria and 
angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as 
chills, pyrexia, and hypertension have also been reported. The most commonly reported 
adverse drug reactions described for FEIBA NF include increased inhibitor titer, 
somnolence, dizziness, dysgeusia, dyspnea, nausea, chills, pyrexia, chest pain, and chest 
discomfort.
The possibility of thrombotic events should be considered when FEIBA is used in 
combination with systemic anti-fibrinolytics such as aminocaproic acid and tranexamic 
acid. Therefore, anti-fibrinolytics should not be used for approximately 6 to 12 hours 
before or after the administration of FEIBA.
Animal reproduction studies have not been conducted with FEIBA. There are no 
adequate, well-controlled studies in pregnant women. It is also not known whether 
FEIBA can cause fetal harm when administered to a pregnant woman or an affect on 
reproductive capacity. It is also not known whether FEIBA is excreted in human milk.1
Subjects within the study should be provided with labeling information and a detailed 
discussion of benefit risk profile.
Additional safety experience for FEIBA is provided in the FEIBA NF IB.iv
6.6 Compliance Statement
The study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations, the EU Directives 2001/20/EC and 
2005/28/EC, and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is:
To evaluate the tolerability and safety of infusing 50% reduced volume FEIBA at the 
standard infusion rate of 2 U/kg/min, and at increased rates of 4 and 10 U/kg/min, in 
comparison to the standard rate of 2 U/kg/min at the regular volume 
7.2 Primary Objectives
To evaluate tolerability and safety of FEIBA reconstituted in a 50% reduced volume 
of sterile water for injection (SWFI) administered at the standard infusion rate of 
2 U/kg/min and at increased rates of 4 and 10 U/kg/min, based on the occurrence of 
any adverse event, in particular of thromboembolic events and hypersensitivity 
reactions 
7.3 Exploratory Objectives
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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8. STUDY DESIGN
8.1 Brief Summary and Study Design Rationale
This is a 2-part Phase 3b/4 (depending on market authorization status per country), 
prospective, open-label, multicenter study to be conducted in at least 24 evaluable
hemophilia A or B subjects with inhibitors (≥0.6 BU in hemophilia A and B) to
determine the tolerability and safety of FEIBA component FII with a planned enrollment 
of 24 evaluable subjects. Evaluable subjects are defined as the ones who complete both 
parts of the study (i.e. received at least  8 of the 12 infusions; 4 in each part and 2 in each 
sequence in Part 1).
All subjects will receive 3 infusions of FEIBA reconstituted in a regular volume of 
SWFI, and 3 infusions of FEIBA reconstituted in 50% reduced volume of SWFI, with all 
6 of these infusions being given at a rate of 2 U/kg/min within Part 1 of the study. In 
Part 2 of the study, all subjects will receive 3 infusions of FEIBA reconstituted in 
50% reduced volume of SWFI at 4 U/kg/min followed by 3 infusions FEIBA reduced 
volume at a rate of 10 U/kg/min. 
This study has been designed as a 2-way crossover study in order to assess primarily 
tolerability and safety of FEIBA. By designing it as a crossover study, subjects serve as 
their own controls. In addition, having received 6 infusions at 2U/Kg/min in Part 1, 
patients will be near to or at steady state (post 6 infusion of FEIBA) prior to starting 
Part 2. This study is open-label because it is a change in infusion volume and infusion 
rate, which would not make it feasible to properly blind. The goal of the study is to 
determine tolerability and safety of FEIBA in 50% reduced volume SWFI to FEIBA 
regular volume SWFI, and increase rate of the 50% reduced volume at 4U/kg/min and 
10U/kg/min. By being able to reduce the volume and speed of the infusion, subjects will 
be able to spend less time infusing and reduce infusion burden during the regular use.
The exploratory objectives include  pre (within 60 min before infusion) and post-infusion 
(at 30 min, hours 1, 2, 6, 8 and 12) concentration of coagulation factor II (FII); the effect 
of 50% reduced volume FEIBA  and faster infusion rate on coagulation parameters.
FII (prothrombin) was chosen as a lead marker for FEIBA for several reasons:
1.
In previously published studies it has been demonstrated that FII is a key protein 
component of the active ingredient of FEIBA
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2.
Amongst the vitamin K-dependent proteins, FII has the highest relative plasma 
concentration as it has the lowest specific activity, and therefore the absolute 
amount of FII in FEIBA measured as protein mass is higher than for any other 
vitamin K-dependent protein
3.
The half life of FII is longer than that of any other vitamin K-dependent protein 
contained in FEIBA.
8.2 Overall Study Design 
This is a 2-part Phase 3b/4 (depending on market authorization status per country), 
prospective, open-label, multicenter study to compare tolerability and safety of FEIBA 
reconstituted in 50 % reduced volume versus regular volume of SWFI, and to 
evaluate the safety of infusing reduced volume FEIBA at increased infusion rates of 
4 and 10 U/kg/min in comparison with the standard rate of 2 U/kg/min, in 24 evaluable
with hemophilia A or B with inhibitors (≥0.6 BU in hemophilia A and B). There is no 
washout period prior to Part 1 or between infusions and between the two parts of the 
study. The overall study design is illustrated in Figure 1 and Figure 2.
In Part 1, subjects will be administered 2 different volumes of FEIBA every 48 hours
(-8/+24 hours) in a 1:1 randomized, crossover manner. Both volumes will be given at the 
standard infusion rate of 2 U/kg/min. After infusion, subjects should be observed for at 
least 30 minutes at the study site. See Section 10.3.2 for details. 
Treatments regimens during Part 1 of the study are:

Part 1 Sequence A:
1. FEIBA 2 U/kg/min in regular volume SWFI (Infusions 1, 2, and 3)
2. FEIBA 2 U/kg/min in 50% reduced volume SWFI (Infusions 1, 2, and 3)

Part 1 Sequence B, patients from sequence A cross over to: 
1. FEIBA 2 U/kg/min in 50% reduced volume SWFI (Infusions 4, 5, and 6)
2. FEIBA 2 U/kg/min in regular volume SWFI (Infusions 4, 5, and 6)

Infusion dose:
All infusions: 85 ± 15 U/kg
Part 2 is non-randomized with sequential treatment of subjects who complete Part 1 to 
evaluate FEIBA reconstituted in 50% reduced volume of SWFI at increased rates of 
4 and 10 U/kg/min. FEIBA Infusions 7, 8, and 9 will be administered at the 4 U/kg/min
rate followed by 3 infusions (Infusions 10, 11, and 12) of FEIBA at 10 U/kg/min rate. 
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The infusions will be administered every 48 hours (-8 hours/+24 hours) to allow time to 
monitor safety and tolerability of the higher infusion rate.
The treatment phases within Part 2 of the study are as follows:

First treatment phase: 4 U/kg/min (Infusions 7, 8, 9) 

Second treatment phase: 10 U/kg/min Infusions 10, 11, 12)

Infusion dose:
All infusions: 85 ± 15 U/kg
All infusions will be administered at the hemophilia care centers/study sites. Sample 
collections may be performed at the hemophilia care centers/study sites, appropriate 
ambulatory centers or at home. Each subject will receive a maximum of 12 IP infusions 
total [6 in Part 1 and 6 in Part 2]. Subjects will receive FEIBA at a dose of 85 ± 15 U/kg 
for all  infusions see Section 8.7.2. After each infusion, subjects should be observed for 
30 minutes at the study site. Additional details on study design and timing are described 
in Section 8.7.3. For additional details on managing bleeding episodes, see Section 8.7.4.
See Section 15.4 for additional details on the safety reviews performed by the Internal 
Safety Monitoring Committee (ISMC).
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is expected to be approximately 10 to 13 months from 
study initiation (i.e., first subject enrolled) to study completion (i.e., last subject last 
visit). The recruitment period is expected to be approximately 9 to 11 months.
The subject participation period is approximately 6 to 11 weeks from enrollment to 
subject completion (i.e., last study visit), unless prematurely discontinued.
8.4 Outcome Measures
8.4.1 Primary Outcome Measures
Tolerability and safety (local and general) related to the infusion and volume of 
reconstitution: 
1.
Occurrence of any adverse event: all AEs and SAEs, and AEs leading to 
discontinuation 
2.
Thromboembolic events and hypersensitivity reactions
3.
Vital signs and Clinical laboratory data
4.
Infusion site and infusion related reactions
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8.4.2 Exploratory Outcomes Measure
1.
To monitor pre- (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
8.5 Randomization and Blinding
Part 1 of this study is a randomized, crossover, active treatment clinical study. Subjects 
will be randomly assigned to 1 of 2 treatment sequences at a 1:1 ratio (Sequence A: 
FEIBA regular volume of SWFI followed by FEIBA reduced volume of SWFI or 
Sequence B: FEIBA reduced volume of SWFI followed by FEIBA regular volume 
SWFI). Part 2 of this study is an open-label, sequential, active treatment clinical study. In 
Part 2, all subjects will receive FEIBA reduced volume of SWFI at 2 varying rates of 
infusion.
8.6 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1.
If 2 or more subjects develop anaphylaxis and / or thromboembolic events 
following exposure to FEIBA (enrollment and treatment temporarily stopped 
pending further review by the ISMC)
2.
The sponsor or investigator, based on emerging data, considers there to be an 
unfavorable risk benefit
3.
The sponsor or investigator considers continuation of the study unjustifiable for 
medical or ethical reasons
4.
The ISMC recommends study termination
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
The active ingredient of FEIBA is a plasma-derived, freeze-dried, APCC with FVIII 
inhibitor bypassing activity. FEIBA will be provided in vials with a nominal potency of 
500 U/vial, 1,000 U/vialand 2,500 U/vial). FEIBA contains mainly non-activated forms 
of the 3 coagulation factors, FII, FIX, and FX, as well as activated FVII; and Factor VIII 
coagulant antigen (FVIII:CAg) present in a concentration of up to 0.1 U/1 U FEIBA. 
The factors of the kallikrein-kinin system are present only in trace amounts, if at all. 
A solution containing 1 U FEIBA shortens the aPTT of FVIII inhibitor plasma to 50% of 
the buffer value. The product is supplied as freeze-dried powder or friable solid of white 
to off-white or pale green color.
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To standardize conditions in the study, FEIBA should be stored at 2°C to 8°C only.  
FEIBA should not be allowed to freeze, and should be protected from light. Aseptic 
techniques must be used for reconstituting and administering FEIBA. Although the 
chemical and physical stability of the reconstituted product has been demonstrated for 
3 hours at room temperature (up to 25°C), however, the solution should be used 
immediately as the preparation does not contain preservatives. Reconstituted product 
must not be returned to the refrigerator.
FEIBA will be provided in kits including SWFI for reconstitution. SWFI will be provided 
in different volumes for preparation of FEIBA infusions at regular volume or reduced 
volume. For additional information, such as reconstitution instructions, please refer to the 
FEIBA product insert 1 and/or other specific instructions provided by the sponsor or 
sponsor’s representative.
8.7.2 Administration
Following reconstitution, FEIBA should be administered immediately using an 
intravenous needle and syringes provided by the sponsor for this study. The standard 
infusion rate of FEIBA is 2 U/kg body weight (BW) per minute, which in a 75kg subject, 
corresponds to an infusion rate of approximately 2.4 to 7.5 mL/minute depending on the 
potency (see label on vial). 
In order to standardize administration within the study, it is recommended that study drug 
be administered with an infusion pump. The infusion rate will be modified depending on 
which part of the study the subject is in, rates of 4 and 10 U/kg/min are also used in this 
study.
Subjects will receive FEIBA at a dose of 85 ± 15 U/kg for all infusions every 48 hours 
(-8 hours/+24 hours). Dose calculation for FEIBA will be based on the stated actual 
potency on vials in respective lots.  FEIBA lots may be mixed within an infusion, and 
whole vials should be rounded up or down to be as close as possible to the accurate 
dosage, as appropriate.
For additional details, see Table 1 for general information on product preparation, as well 
as the study documents, and the FEIBA IB.iv
Mixing of FEIBA with other products or substances must be avoided. It is advisable to 
flush venous access lines with isotonic saline prior to and after infusion of FEIBA.
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Dose calculation for FEIBA will be based on the stated actual potency on vials in 
respective lots. Information regarding lot used, the actual dose given, date of treatment, 
treatment start and stop times, as well as any infusion interruptions will be recorded in the
case report form (CRF).
Table 1
FEIBA Product Preparation
FEIBA
Diluent for Regular Volume FEIBA
Diluent for 50% Reduced Volume FEIBA
500 U
10 mL
5 mL
1000 U
20 mL
10 mL
2500 U
50 mL
25 mL
Abbreviations: FEIBA=Factor Eight Inhibitor Bypassing Activity.
Please note that the availability of potencies may vary among countries and regions. Dose 
calculations should be made based on potencies available at site.
8.7.3 Description of Treatment
Part 1 of the study uses a crossover design to evaluate the tolerability and safety of 
FEIBA reconstituted in 50% reduced volume SWFI versus regular volume of SWFI 
(administered at the standard infusion rate of 2 U/kg/min). Part 2 is a non-randomized 
study with sequential enrollment of subjects who complete Part 1. Part 2 will evaluate the 
tolerability and safety of infusing FEIBA reconstituted in 50% reduced volume of SWFI 
at increased infusion rates of 4 and 10 U/kg/min.
All subjects will be screened for eligibility based on the listed inclusion and exclusion 
criteria. The subject’s medical history including hemophilia history, confirmation of 
inhibitors, bleeding episode history, concomitant medications and history of FEIBA or 
rFVIIa usage for the previous year will be collected at screening. Also recorded will be 
the date of last use of FEIBA or rFVIIa treatment. Results of the screening assessments 
will be used to establish a subject’s eligibility for the study.
Part 1
After eligibility is established, the eligible subjects will be randomly assigned (1:1) 
into Part 1 of the study to receive 3 infusions of FEIBA reconstituted in 50% reduced 
volume SWFI followed by regular volume SWFI or vice versa every 48 hours 
(-8 hours/+24 hours).
Additional details on study visits for Part 1 can be found in Section 10.3 and Table 2.
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Part 2
Part 2 is non-randomized and uses sequential enrollment of subjects who complete Part 1 
of the study. Subjects in Part 2 will first be administered 3 infusions (Infusions 7, 8, 
and 9) of FEIBA at the 4 U/kg/min rate, followed by 3 infusions (Infusions 10, 11, 
and 12) of FEIBA at the 10 U/kg/min rate. Infusion 7 will be administered 48 hours 
(-8 hours/+24 hours) after Infusion 6. The infusions in Part 2 will be administered every 
48 hours (-8 hours/+24 hours) to allow time to monitor safety and tolerability of the 
higher infusion rate. Infusion rates for the treatment phases in Part 2 are:

First treatment phase: 4 U/kg/min (Infusions 7, 8, and 9) 

Second treatment phase: 10 U/kg/min (Infusions 10, 11, and 12)
Following the last infusion, a study termination visit will be conducted within 7 days but 
no sooner than 72 hours after the last infusion.
Additional details on study visits for Part 2 can be found in Section 10.3 and Table 3.
Additional Treatment and Visit Information
The Schedule of Study Procedures and Events Procedures listed in Table 2 and Table 3
have the visit windows listed in relation to the subject’s previous infusion. This is due to 
the variability in each subjects schedule based on previous therapy and bleeding events. 
All infusions will be administered at hemophilia care centers/study sites. Each subject 
will receive a maximum of 12 IP infusions. Subjects will receive FEIBA at a dose of 
85 ± 15 U/kg for all infusions. For specifications on dosing and administration, see 
Section 8.7.2. For information on break-through bleeding control, see Section 8.7.4.
Study visits will be completed concurrently with study infusions. After subjects 
have completed the 12 study infusions, they will complete a Study Completion/
Termination Visit within 7 days but no sooner than 72 hours after Infusion 12. 
In case of early withdrawal or discontinuation the Study Completion/Termination Visit 
will need to be completed within 7 days but no sooner than 72 hours after the last IP 
infusion received.
During each visit, the study staff will inquire with the subject about break-through 
bleeding events, treatments, and AEs throughout the study. Subjects are encouraged to 
report AEs to the site during the time spans between visits.
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Two subject questionnaires will be administered 5 times during the study, a TSQM 
questionnaire and a patient preference questionnaire to assess the subjects’ satisfaction 
and preferences for treatments, for additional details see Section 10.5.
Detailed study flowcharts are presented in Table 2 and Table 3.
Investigational product may be interrupted or discontinued at any time during the study at 
the discretion of the investigator based on his/her evaluation of the subject’s condition or 
safety. No dose modification is permitted for this study.
Any infusion site reactions, regardless of causality, will be recorded on the AE CRF. Any 
concomitant medications, including those used to treat AE(s), will be recorded on the 
appropriate CRF.
For details on the safety review by ISMC see Section 15.4.
8.7.4 Management and Treatment of Break-Through Bleeding
Bleeding episodes are managed as described below for each part of the study. In all cases, 
if the bleeding episode, of whatever severity, is not resolved within 48 hours after an 
infusion to control bleeding, the subject must contact the hemophilia treatment 
center/study site for further treatment recommendations.
Screening
During screening, subjects will be asked to keep track of any FEIBA or rFVIIa usage, as 
the last dose may be used to determine the date of the first infusion of IP. If a subject 
experiences a bleeding episode during the screening period, subjects will be treated for 
the bleeding episode per standard of care as determined by the investigator and the 
patient will be randomized after resolution of bleeding episode. 
Bleeding during the study 
If bleeding occurs during the study, it will be treated per standard of care. For bleeding 
events treated with FEIBA or rFVIIa, a time window of 48 hours post treatment for 
bleeding should be observed before resuming study infusions. The subject will resume 
their treatment regimen and visits after control of the bleeding and following the 
administration window mentioned above. Depending on the clinical circumstances (e.g., 
treatment of uncontrolled bleeding due to injury and associated complications), the 
investigator and sponsor should decide if it is appropriate for the subject to continue in 
the study.
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8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) 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(s) was received, including the date received, 
drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP(s) must be dispensed only at the study site or other suitable location (e.g.,
infusion center; home, as applicable per study design). Records will be maintained that 
include the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) 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(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
study that are necessary for the reconstruction and evaluation of the study. 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' 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.
Subject questionnaires may be entered directly onto the CRF.
For additional information on study documentation and CRFs, see Section 17.2.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
≥18 to ≤65 years old at the time of  screening
2.
Hemophilia A or B of any severity, with a documented ≥ 3 months history of 
inhibitors (≥ 0.6 BU) requiring the use of bypassing agents (FEIBA or rFVIIa) 
prior to screening. Inhibitor level will be tested at screening if no documented 
history is available.
3.
Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain 
reaction (PCR); or HCV positive with stable liver disease
4.
Human immune deficiency virus (HIV) negative; or HIV positive with stable 
disease and CD4 count ≥ 200 cell/mm3 at screening
5.
Adequate peripheral venous access
6.
Willing and able to comply with the requirements of the protocol
7.
If a female of childbearing potential, must have a negative blood pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study, such as:
a. Abstain from sexual intercourse
b. Use a reliable method of contraception (contraception such as an intrauterine 
device, barrier method [e.g., diaphragm or sponge; female condom not 
permitted] with spermicide, oral contraceptive, injectable progesterone, sub 
dermal implant), and have their male partner use a condom
8.
If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a. Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-stimulating 
hormone levels within the laboratory-defined postmenopausal range or 
postmenopausal with amenorrhea for at least 24 months and on hormonal 
replacement therapy
b. Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation (with no subsequent pregnancy at least 
1 year from bilateral tubal ligation), or bilateral salpingectomy
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. Known hypersensitivity to FEIBA or any of its components
2.
Advanced liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites, prothrombin time [PT] 5 seconds above upper limit of 
normal)
3.
Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4.
Platelet count < 100,000/µL
5.
Clinical or laboratory evidence of disseminated intravascular coagulation
6.
Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
7.
Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
8.
Taking any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to 
enrollment except anti-retroviral chemotherapy.
9.
Herbal supplements that contain anti-platelet activity
10. 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
11. Family member or employee of the investigator
12. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., 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 withdraw or discontinuation) are described in 
Section 10.6 and Section 20.3.
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., 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 ISMC recommends a subject should be taken off the study

The subject becomes pregnant. IP exposure will be discontinued. Attempts will 
be made to follow the subject through completion of the pregnancy and up to
1 year postdelivery, if feasible. The investigator will record a narrative 
description of the course of the pregnancy and its outcome

AE(s)/SAE(s) that the investigator or sponsor feels poses an unacceptable risk 
for continued dosing in the subject

Participation in another clinical study involving an IP during the course of the 
study
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form [ICF] and assent form, if applicable) is considered enrolled in the study.
10.2 Subject Identification Code (SIC)
The following series of numbers will comprise the SIC: protocol identifier (e.g., 091501) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the ICF). For example, the third subject who signed an ICF at 
study site 02 will be identified as Subject 091501-020003. All study documents (e.g., 
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 (e.g., 
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. 
All screening data will be collected and reported in CRFs, regardless of screening 
outcome. 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 overall study design is illustrated in Figure 1 and Figure 2. Details on the procedures 
to be performed at each study visit, including screening, can be found in Supplement 20.3
and Supplement 20.4 Schedule of Study Procedures and Assessments (Part 1 and Part 2, 
respectively) and Supplement 0 Clinical Laboratory Assessments. FII concentration 
scheduling can be found in Section 20.6.
10.3.1 Screening and Baseline Assessments
After ICF is obtained, subjects will be screened on-site for eligibility based on the 
inclusion and exclusion criteria defined in Section 9.1 and Section 9.2, respectively. 
Screening procedures must be performed within 35 days of Infusion 1.
At screening, subjects will be instructed on the symptoms of thromboembolic and 
systemic hypersensitivity events by the investigator, and to contact the treatment 
center/hospital if they experience any symptoms.
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Screening assessments include the following:

Eligibility evaluation (review of inclusion/exclusion criteria)

Medical history, including
Hemophilia history, inhibitor development history, bleeding episodes
history, history of FEIBA or rFVIIa usage for a year prior to screening
Relevant medical and surgical history and all medications taken 4 weeks 
prior to screening

Review of concomitant medications/non-drug therapies

Complete physical examination (see Section 12.6)

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and
measurement body weight and height (see Section 12.8)

Karnofsky performance test assessment (see Section 12.9)

Clinical laboratory assessments (hematology, clinical chemistry, , serology 
testing and inhibitor level if no documentation is available ≥3 months prior to 
screening; see Section 12.7)

Serum pregnancy test (female subjects of childbearing potential only)

TSQM and patient preference questionnaires (see Section 10.5)
After screening and eligibility sare determined, the subject will be enrolled in the study. 
For additional details on bleeding, see Section 8.7.4.
10.3.2 Treatment Visits
10.3.2.1 Infusion Visits
Randomization will occur after the subject has been confirmed to be eligible and prior to 
the first infusion.

Randomization of eligible subjects to the following treatment sequences:
Part 1 Sequence A: FEIBA 2 U/kg/min in regular volume SWFI 
(3 infusions), FEIBA 2 U/kg/min in 50% reduced volume (3 infusions)
Part 1 Sequence B: FEIBA 2 U/kg/min in 50% reduced volume 
(3 infusions), FEIBA 2 U/kg/min in regular volume SWFI (3 infusions)
For additional details on the description of treatment, see Section 8.7.3.
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During the study (Infusion Visits 1 to 12), subjects will return to the study site according 
to the schedule presented in Table 2 and Table 3. Prior to administration of IP, the 
following assessments will be performed at all visits unless otherwise indicated:

Review of concomitant medications/non-drug therapies

AE monitoring

Vital signs (body temperature, pulse rate, blood pressure and respiratory rate)
Before administration of IP
at 30 minutes after administration of IP

Clinical laboratory assessments Table 4

IP administration (infusion site should be monitored for at 30 minutes [± 10 min] 
after infusion)

Break-through bleed monitoring

Subjects will be administered the TSQM and patient preference questionnaires:
After screening prior to Infusion 1
After Infusion 3 prior to Infusion 4
After Infusion 6 prior to Infusion 7
After Infusion 9,  prior to infusion 10
After infusion 12 or up to the completion of the Study 
Completion/Termination Visit

Prothrombin II levels will be drawn within 60 min before IP administration and at 
30 min, hours 1, 2, 6, 8 and 12 after IP administration, as outlined in Table 5 See 
also information on administration (Section 8.7.2). 
10.3.3 Study Completion/Termination Visit
The Study Completion/Termination Visit including if the subject is discontinuing early 
will be performed within 7 days but no sooner than 72 hours after Infusion 12, or the last 
infusion if discontinued early. The following assessments will be performed:

Review of concomitant medications/non-drug therapies

AE monitoring

Breakthrough bleeds monitoring

Concomitant medication monitoring
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
Clinical laboratory assessments see Table 4

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and 
body weight)
10.4 Medications and Non-Drug Therapies 
Once subject eligibility has been confirmed for the study, the following medications and 
non-drug therapies are not permitted during the course of the study:

Medications:
Any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) except
anti-retroviral chemotherapy
Any investigational drug or device
A subject who receive any of these therapies will be withdrawn from further study 
participation.
Antifibrinolytics should not be used approximately 6 to 12 hours before or after the 
administration of FEIBA.
The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:

Medications:
Hemostatic agents, such as tranexamic acid, are permitted, as indicated by 
the subject’s treating physician, to treat mucosal bleeding during the 
study (these are permitted; however, they should not be taken within 6 to 
12 hours before or after administration of FEIBA)
Any medications deemed necessary by the subject’s physician to treat or 
prevent any medical condition (with the exception of those listed as not 
permitted)
Any over-the-counter medication used by the subject to treat symptoms 
or signs of any medical condition
Supplemental vitamins, minerals
Any standard of care to treat breakthrough bleeds
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
Non-drug therapies:
Any non-drug therapy (e.g., physiotherapy) deemed necessary by the 
subject’s physician to treat or prevent any medical condition
10.5 Subject Questionnaires
Two questionnaires will be administered to subjects within this study (TSQM 14 and a 
patient preference questionnaire). These questionnaires will be used to assess the 
subject’s preferences on the IP, as well as their satisfaction with the IP, and will be 
collected in the CRF or on paper. Both questionnaires will be administered:

After screening prior to Infusion 1

After Infusion 3 prior to Infusion 4

After Infusion 6 prior to Infusion 7

After Infusion 9,  prior to infusion 10

After infusion 12 or up to the completion of the Study Completion/Termination 
Visit
These questionnaires can be completed between visits but should be completed prior to 
the start of the next infusion. The final questionnaire should be completed prior to or 
during the Study Completion/Termination Visit.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when the subject ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according to the protocol.
Reasons for completion/discontinuation will be reported on the Completion /
Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems, and severe hypersensitivity reaction), ISMC recommends a subject should not 
continue. Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
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Every effort will be made to have discontinued subjects complete the Study 
Completion/Termination Visit. If the Study Completion/Termination Visit is done as 
an additional, unscheduled visit, the assessment results shall be recorded with the 
Study Completion/Termination Visit. If a subject terminates participation in the 
study and does not return for the Study Completion/Termination Visit, their last 
recorded assessments shall remain recorded with their last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of 
discontinuation will be used in the analysis and included in the clinical study report. 
If additional assessments are required, the assessments shall be recorded separately.
Assessments to be performed at the termination visit (including in cases of withdraw or 
discontinuation) can be found in Supplement 20.3 Schedule of Study Procedures and 
Assessments and Supplement 0 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
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures will be used to monitor subject compliance.
11. ASSESSMENT OF PHARMACOKINETICS
Pharmacokinetics will not be evaluated in this study.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 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 (e.g., an abnormal laboratory finding), 
symptom (e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that at any dose meets 1 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 (i.e., 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 1 of the other 
outcomes listed in the definitions above. Examples of such events are:
Intensive treatment in an emergency room or at home for bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependence or drug abuse
Additional events which should be reported the same way as SAEs are as follows:

Reviewed and confirmed seroconversion for HIV, hepatitis A virus, hepatitis B 
virus, HCV, hepatitis E virus, or parvovirus B19
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
Hospitalization for planned port placement or removal is not considered an SAE, 
however, any hospitalization required for an emergency port removal is 
considered an SAE

Any thromboembolic event

Hypersensitivity reactions
Uncomplicated pregnancies, following maternal or paternal 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. Any 
pregnancy occurring during the study should be reported to the sponsor within 24 hours 
of the site learning about the pregnancy. The pregnancy should be followed until
completion of the pregnancy and up to 1 year postdelivery, if feasible. Pregnancies not 
considered an (S)AE as described above will be captured in the CRF.
Voluntary overnight stays by subjects in hospital or hospital-affiliated facilities for the 
convenience/compliance with study procedures as described in Section 10.3.2 for reasons 
unrelated to AEs will not be considered as hospitalization for SAE reporting purposes
unless the hospitalization is prolonged.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., 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.
12.1.1.4 Pre-existing Diseases
Pre-existing 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 pre-existing disease, the event must be described on 
the AE CRF.
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12.1.2 Assessment of Adverse Events
Each AE from the first IP exposure until study termination/completion 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 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., 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, it is medically 
stabilized, or 30 days after the Study Completion/Termination Visit, whichever comes 
first, and the follow-up information is to be documented in the CRF. If the severity rating 
for an ongoing AE changes before the event resolves, the original AE report will be 
revised (i.e., 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 (20% higher than the 
highest permitted dose), underdosing (20% lower than the lowest permitted dose), 
treatment errors (including incorrect route of administration, use of an incorrect product, 
and deviations from the protocol-defined dosing schedule), failures of expected 
pharmacological actions, and unexpected therapeutic or clinical benefits will be followed 
with regard to occurrence of AEs, lack of efficacy, and/or other observations because 
these events may be reportable to regulatory authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and 1 year postdelivery, if 
feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion/termination, the SAE must be reported on the provided SAE Report Form 
within 24 hours after awareness; no additional reporting on CRFs is necessary.
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12.1.2.1 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.
12.1.2.2 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, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., 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 
rechallenge)
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 72 hours after 
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.
12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 3) and Section 12.1.
Adverse Events/SAEs are to be recorded on the AE page of the CRF. Each event should 
be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported by completing the relevant CRF 
page(s) in English. Once the SAE has been recorded, SAEs must be reported  to the 
sponsor to meet the 24-hour timeline requirement (contacts and instructions to be 
provided in separate documentation). 
The initial SAE information reported on the applicable CRF pages (must at least include 
the following:

Protocol Number

Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)

Investigational product exposure

Medical Term for Event (Diagnosis preferably) 

Description of the (S)AE, including:
Date of onset
(S)AE treatment (drug, dose, route of administration)
Causal relationship by the investigator
Measures taken (i.e., action taken regarding IP in direct relationship to the 
AE)

Seriousness criteria (i.e., death, life-threatening, or other criterion)

Cause of death

Autopsy findings (if available)

Name, address, fax number, email, and telephone number of the reporting 
investigator (for paper SAE Report Forms) 
12.1.3 Medical Device Safety Reporting
The IP kit contains the BaxJect II Hi-Flow needleless transfer device. All Serious Injuries 
(SI) and Unexpected Adverse Device Events (UADE) must be reported to the sponsor as 
an SAE in the same process as described above.
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Serious injury is defined as:

Life-threatening injury or illness results in permanent impairment/ damage to 
body function/ structure.

Requires medical or surgical intervention to preclude permanent impairment/ 
damage to body function/ structure.
12.2 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 study 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 study or studies

Any other immediate action taken in order to protect clinical study 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 (EC) and relevant competent authority(s) are
notified of the urgent safety measures taken in such cases according to local regulations.
12.3 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 12.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the AE CRF . These events will be considered as SAEs but will not be 
included in the analysis of SAEs. 
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12.4 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, e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., 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

Medication errors: an error (of commission or omission) at any step along the 
pathway that begins when a clinician prescribes a medication and ends when the 
patient actually receives the medication e.g., administration of incorrect dose
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.
12.5 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 12.1.2.1) 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.
General medical history will be collected for 4 weeks prior to screening. Any information 
on the subjects’ hemophilia history will be collected a year prior to screening including 
documented history of hemophilia, confirmation of inhibitors, bleeding episodes history, 
and history of FEIBA or rFVIIa usage.
All medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies CRFs.
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12.6 Physical Examinations
At screening (as described in Table 2 and Table 3), 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 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 pre-existing disease (described in Section 12.1.1.4), 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.
12.7 Clinical Laboratory Parameters
Assessments will be performed at a central laboratory (see Section 15.7), according to the 
laboratory manual. Blood samples that remain after study testing is done may be stored 
and used for any additional testing as needed (see Section 12.7.6). Samples will be 
destroyed after a maximum of 2 years from the time the final study report has been 
completed. 
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count [hemoglobin, hematocrit, 
erythrocytes (i.e., red blood cell count), and leukocytes (i.e., white blood cell count)] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) mean 
corpuscular volume, mean corpuscular hemoglobin concentration, and platelet counts. 
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
aspartate aminotransferase (AST), total protein, albumin, alanine aminotransferase
(ALT), total bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, 
glucose, gamma-glutamyl transpeptidase (GGT), and 5’-nucleotidase.
Blood will be obtained for assessment of hematology and clinical chemistry parameters at 
screening and at study completion/termination. 
In addition, serum samples for pregnancy tests for females of childbearing potential will 
be collected at screening.
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12.7.2 Concentration of FII and Coagulation Testing
Blood samples for the determination of FEIBA components FII will be taken within 
60 (±15) min before and at 30 (±10) min, after completion of each infusion. In addition 
hours 1 (±15min), 2  (±30min), 6 (±1hour), 8 (±2hours) and 12 (±4hours) samples will be 
taken after infusion 1,3,4,6,9 and 12 (see Section 20.6 for sampling time points and 
allowed sampling time windows). The date and time of each sample collections will be 
documented in the subject’s CRF. 
Blood will be obtained for the assessment of coagulation testing and consist of aPTT, PT, 
thrombotic markers (D-Dimers, prothrombin fragment F 1+2, TAT, fibrinopeptide A), 
and FII concentration. Coagulation testing will be performed, during the study and 
samples at hours 1 (±15min), 6 (±1hour) and 12 (±4 hours) will be taken after infusion 
1,3,4,6,9 and 12 (see Section 20.6 for sampling time points and allowed sampling time 
windows). 
12.7.3 Viral Serology
Viral serology testing will include HIV-1 and HIV-2 antibody, hepatitis A virus (HAV)
antibody, hepatitis B virus (HBV) antibody, hepatitis B surface antigen (HBsAg), HCV 
antibody, parvovirus B19 (immunoglobulin M [IgM] and immunoglobulin G [IgG] 
antibodies), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus 
antibodies (IgM and IgG). The HCV titer will be confirmed by PCR for all subjects 
reported as HCV positive. All viral serology assessments will be performed at screening
and at the Study Completion/Termination Visit.
12.7.4 CD4 Levels
At screening only, CD4 levels will be determined using flow cytometry in the case of a 
subject being HIV positive.
12.7.5 Assessment of Laboratory Values
12.7.5.1 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value 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 12.1, 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 12.1.1.4), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e., because it is due to a 
pre-existing disease, due to a lab error, or due to another issue that will be specified. 
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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.
12.7.6 Biobanking
Backup samples should be taken and stored appropriately for additional analysis, if 
necessary. Backup samples that remain after study testing is done may be stored and used 
for additional testing (e.g., further evaluation of an abnormal test or an AE. 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.
12.8 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) 
measured once at screening and weight (lb or kg) measured at screening and 
completion/termination will also be collected.
Vital signs will be measured at screening and within 30 minutes before and after (except 
weight) administration of IP, at each Infusion study visit, and at study 
completion/termination. Blood pressure will be measured when subjects are in the supine 
position.
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 12.1
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.
12.9 Karnofsky Performance Test
The Karnofsky Performance Test is a status scale (0-100) utilized to measure the level of 
activity and medical care requirements in subjects. It is an investigator based assessment 
of subject status which evaluates the subjects’ ability to carry on normal life activities, as 
well as the symptoms of their disease. In this scale, a high number performance status 
represents high functionality, and a lower number represents low functionality and likely 
rapid progression of disease.15 Subjects will be scored using this scale at screening.
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12.10 Infusion Site Evaluations
The current site of IP infusion will be assessed for immediate local reactions at 
30 minutes (±10 min) after infusion. In addition, infusion sites will be monitored by the 
subject for up to 12 hours after infusion, and will be discussed with the site staff during 
the next study visit.
Infusion sites will be monitored for pain, tenderness, erythema, and swelling. Infusion 
site evaluations will be made by clinical staff or by the subject or caregiver. If an infusion 
site reaction is observed, a physician will characterize and document the reaction as an 
AE. Infusion sites will continue to be reviewed at each study visit, and any infusion site 
reactions will be followed until resolution. Each infusion site reaction will be categorized 
using the intensity grading described for AEs in Section 12.1.2.1.
12.11 Special Treatment Considerations
Subjects will be screened for eligibility in the study as described in Section 9.1 and
Section 8.7.3, and will be informed of the study specific restrictions and requirements of 
the study. Subjects who are not willing to comply with the study requirements and 
restrictions of the study will not be eligible for enrollment.
All biological agents carry the risk of hypersensitivity reactions. Clinical manifestations 
of these reactions may include, but are not limited to:

Skin rash

Pruritus (itching)

Urticaria (hives)

Angioedema (for example, swelling of the lips and/or tongue)

Anaphylactic reaction
Proteins may also cause redness, itching, swelling, or pain locally at the infusion site.
Thromboembolic events have been observed with bypassing agents including FEIBA. 
Clinical manifestations of these events may include, but not limited to:

myocardial infarction

deep vein thrombosis

pulmonary embolism

stroke and

transitory ischemic attack
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Sometimes, these reactions can be life-threatening. Therefore, all subjects should be 
closely monitored for signs or symptoms that could result from such reactions, educated 
on the signs or symptoms of these types of reactions, and instructed to contact the study 
site immediately if any of the symptoms are experienced following an injection. If a 
subject experiences an acute hypersensitivity reaction after an infusion of IP, the subject
should be managed appropriately and given instruction to receive relevant supportive 
care. 
Subjects who experience a potentially severe hypersensitivity  reaction will be 
discontinued from IP. They will complete a Termination/Study Completion Visit, and 
will be monitored for stabilization or resolution of the AE. Premedication to prevent 
allergic reactions will not be permitted, as severe hypersensitivity reactions are an 
outcome measure for this study.
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13. STATISTICS
Data handling will be conducted by the contract research organization. The data will be 
inspected for inconsistencies by performing validation checks.
Statistical analysis for this study will be descriptive in nature. All details regarding the 
statistical analysis and the preparation of tables, listings, and figures will be described in 
the statistical analysis plan (SAP) prepared by the contract research organization and 
approved by the sponsor before database lock.
13.1 Sample Size and Power Calculations
The sample size of 24 evaluable subjects for this safety study was determined by 
considering available patients, and is not based on statistical power calculations.
13.2 Datasets and Analysis Cohorts
Safety: The safety analysis set will include all subjects who received at least 1 dose of IP
(FEIBA). All safety analyses will be performed on the safety analysis set. Subjects will 
be evaluated according to the treatment received.
13.3 Handling of Missing, Unused, and Spurious Data
All data will be evaluated as observed. A subject who withdraws prior to the last planned 
observation in a study period will be included in the analyses up to the time of 
withdrawal.
13.4 Methods of Analysis
13.4.1 Primary Outcome Measure
13.4.1.1 Analysis of the Primary Outcome Measure (Parts 1 and 2)
AEs, SAEs and AEs leading to discontinuation, thromboembolic events and 
hypersensitivity reactions that occurred during or after IP infusions will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be carried out for temporally associated adverse 
events; and for temporally associated or potentially related adverse events as assessed by 
the investigators. Temporally associated AEs are defined as AEs that begin during 
infusion or within 24 hours (or 1 day where time of onset is not available) after 
completion of infusion, irrespective of being related or not related to treatment.
In addition, tables will be prepared to list each AE, the number of subjects who 
experienced an AE at least once, and the rate of subjects with AE(s). 
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AEs will be grouped by system organ class. Each event will then be divided into defined 
severity grades (mild, moderate, severe). The tables will also divide the AEs into those 
considered related to the infusion and those considered unrelated. These tables will also 
be carried out for temporally associated adverse events; and for temporally associated or 
causally related adverse events. 
AEs and SAEs for each subject, including the same event on several occasions, will be 
listed separately, giving both MedDRA preferred term and the original term used by the 
investigator, system organ class, severity grade, seriousness, relation to the treatment, 
onset date, and stop date.
AEs that occurred before first IP infusion will be listed separately.
Shift tables and summary statistics will be presented for the results of clinical laboratory 
data. All abnormal lab results will be listed.
Summary statistics of vital signs, infusion site and infusion related reactions will be 
carried out.
13.4.2 Exploratory Outcome Measures 
All exploratory outcome measures will be analyzed descriptively.
Full details of the statistical analysis will be specified in the SAP.
13.5 Planned Interim Analysis of the Study
There is no planned interim analysis other than a safety data review by the ISMC.
14. 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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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 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.
15.1.1 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. 
15.2 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.
15.3 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.
15.4 Safety Monitoring
Primary objective of the study is to monitor safety parameters throughout the study with a 
special emphasis on hypersensitivity and thromboembolic events. Adverse event data will 
be collected at each visit assessed and documented on the CRFs as outlined in 
section 12.1.2.3.
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Serious adverse events are monitored and reported per the safety reporting guidelines as 
outlined in section 12.1.2.3.
This study will be monitored by an ISMC. The ISMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from the ongoing 
clinical study. For this study, the ISMC will be composed by appropriate members of 
clinical, safety, and biostatistics division that are not involved in the active execution of 
the trial. The ISMC can stop a study if it finds toxicities or if treatment is proven to be not 
beneficial. 
All SAEs will be reviewed within 24 hours by the Chair of the ISMC. There are 
3 planned ISMC meetings:
1.
Within 24 hours after 6 subjects in Part 1 (3 subjects in each group) have 
completed Infusion 5
2.
Within 24 hours after 6 subjects have completed Infusion 7 (Part 2)
3.
Within 24 hours after 6 subjects have completed Infusion 10 (Part 2)
ISMC preplanned meetings will be held concurrently with the ongoing study.
Subjects can continue with their scheduled therapy and assessments unless the ISMC 
warrants that the trial needs to be suspended due to safety concerns. Additional ad hoc 
meetings of the ISMC may be convened as appropriate per ongoing safety evaluations.
15.5 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.
15.6 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 (Baxalta) will also ensure the responsible EC is notified of the 
urgent measures taken in such cases according to local regulations.
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If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.7 Laboratory and Reader Standardization
Not applicable; a central laboratory/reader will be used for all clinical assessments.
16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, ICF, any promotional 
material/advertisements, and any other written information to be provided to patients 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.
16.3 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 must sign an ICF before entering into the study according to applicable 
regulatory requirements and ICH GCP. Before use, the ICF will be reviewed by the 
sponsor and approved by the EC and regulatory authority(ies), where applicable, 
(see Section 16.2). The ICF 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.
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Patients will be allowed sufficient time to consider participation in the study. By signing 
the ICF, patients agree that they will complete all evaluations required by the study, 
unless they withdraw voluntarily or are terminated from the study for any reason.
The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised ICF, that have 
been approved by the applicable EC and regulatory authorities, where applicable, will be 
provided by the investigator to the subjects who consented to participate in the study.
17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper/electronic 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 ICFs, 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 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/electronic format, and this documentation will be 
considered source documentation. Changes to an 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 17.3).
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The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., 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.
17.3 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.
18. 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.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement.
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20.3 Schedule of Study Procedures and Assessments (Part 1)
Table 2
Schedule of Study Procedures and Assessments (Part 1)
Procedures/
Assessments
Screening 
Assessments
Study Visitsa
Randomization
Infusion #1
Infusion #2
Infusion #3
Infusion #4
Infusion #5
Infusion #6
Study Visit Windowsb
A maximum 
of -35 days 
to 0
Day 1
within 48 hrs 
(-8/+24) 
from Infusion 1
48 hrs 
(-8/+24) 
from Infusion 2
48 hrs 
(-8/+24) 
from Infusion 3
48 hrs 
(-8/+24) 
from Infusion 4
48 hrs
(-8/+24) 
from Infusion 5
Informed Consentc
X
Eligibility Criteria
X
Medical History
X
Medication and Non-drug Therapies
X
X
X
X
X
X
X
Physical Examination
X
Pregnancy Test
X
Vital Signsd
X
X
X
X
X
X
X
Karnofsky Performance Test
X
Laboratory Assessmentse
X
X
X
X
X
X
X
Inhibitor level if no documentation
X
Factor II levelsf
X
X
X
X
Adverse Events, breakthrough bleeds, 
and infusion site reactionsg
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesh
X
X
Coagulation testingi
X
X
X
X
Abbreviations: ICF=informed consent form; IP=investigational product
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Continued
a A Study Completion/Termination Visit is to be completed in Part 1 only for subjects who withdraw or discontinue prior to the end of the study. If a 
subject withdraws or discontinues, this visit should be completed within 7 days but no sooner than 72 hours from the last infusion that the subject
received. Otherwise, the Study Completion/Termination Visit will occur at the end of Part 2 (see Table 3).
b Study Visit Windows:
Infusion 1 can be scheduled after screening assessments have been completed; all other infusions will occur within 48 hours (-8/+24hours) from the 
previous infusion.
c Occurs at enrollment (prior to any study-specific procedure).
d Vital signs will include body temperature, pulse rate, blood pressure, and respiratory rate,. Blood pressure will be measured when subjects are in the 
supine position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within at 30 minutes after completion of 
the infusion. Height, measured once at Screening, and weight measured at Screening and Completion/Termination will also be collected.
e For laboratory assessments, see Section 0.
f FII levels within 60 minutes (±15min) before and 30 mins (±10min) and all timepoint within 60 min (±15 min) before and at 30 min (±10 min), 
hours 1 (±15 min), 2 (±30 min), 6 (±1 hour), 8 (±2 hour), and 12 (±4hours) after infusions 1, 3, 4 and 6.
g The infusion site will be monitored for AEs for 30 ±10 minutes after each study infusion. See Section 12.10 for details. SAEs will be collected from ICF 
signing but will not be included in the analysis of SAEs. See Section 12.3 for details.
h Questionnaires (TSQM and patient preference questionnaire) will be administered after screening prior to Infusion 1, after Infusion 3 prior to Infusion 4, 
after Infusion 6 prior to Infusion 7, after Infusion 9 prior to infusion 10, and after infusion 12 or up to the completion of the Study 
Completion/Termination Visit. These questionnaires can be completed between visits but should be completed prior to the start of the next infusion. The 
final questionnaire should be completed prior to or during the Study Completion/Termination Visit.. See Section 10.5 for details. 
i Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A) post-infusion at 
1 hr ± 15 min (mentioned in Section 12.7.2).
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20.4 Schedule of Study Procedures and Assessments (Part 2)
Table 3
Schedule of Study Procedures and Assessments (Part 2)
Procedures/
Assessments
Study Visits
Infusions 7
Infusion 8
Infusion 9
Infusion 10
Infusion 11
Infusions 12
Study 
Completion/
Termination 
Visita
Rate of Infusion
Rate: 4 U/kg/min
Rate: 10 U/kg/min
Study Visit Windowsb
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
72 h to 7 days 
from 
Infusion 12 
(or last infusion)
Medications and Non-drug Therapies
X
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
Laboratory Assessmentsd
X
X
X
X
X
X
X
Factor II levelse
X
X
Adverse Events, breakthrough 
bleeds, and infusion site, infusion 
related reactionsf
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesg
X
X
X
Coagulation testingh
X
X
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Continued
a
The Study Completion/Termination Visit includes cases of withdrawal or discontinuation. This visit should be done within 7 days but no sooner than 
72 hours after Infusion 12). If a subject withdraws or discontinues, this visit should be done within 7 days but no sooner than 72 hours after the last 
infusion that the subject receives.
b
Infusions will occur within 48 hours (+-8/+24hours) from the previous infusion.
c
Vital signs will include body temperature, pulse rate, blood pressure, respiratory rate,. Blood pressure will be measured when subjects are in the supine 
position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within at 30 minutes after completion of the 
infusion. Height, measured once at Screening, and weight measured at Screening and Completion/Termination will also be collected.
d
For laboratory assessments, see Section 0.
e
FII levels within 60 minutes (±15min) before and 30 mins (±10min) and all timepoint within 60 min (±15 min) before and at 30 min (±10 min), hours 1 
(±15 min), 2 (±30 min), 6 (±1 hour), 8 (±2 hour), and 12 (±4hours) after infusions 9 and 12.
f
The infusion site will be monitored for AEs for 30 ±10 minutes after the infusion. See Section 12.10 for details. SAEs will be collected from ICF 
signing but will not be included in the analysis of SAEs. See Section 12.3 for details.
g
Questionnaires (TSQM and patient preference questionnaire) will be administered after screening prior to Infusion 1, after Infusion 3 prior to Infusion 4, 
after Infusion 6 prior to Infusion 7, after Infusion 9 prior to infusion 10, and after infusion 12 or up to the completion of the Study 
Completion/Termination Visit. These questionnaires can be completed between visits but should be completed prior to the start of the next infusion. The 
final questionnaire should be completed prior to or during the Study Completion/Termination Visit. See Section 10.5 for details.
h Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A) (mentioned in 
Section 12.7.2).
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20.5 Clinical Laboratory Assessments
Table 4
Clinical Laboratory Assessments
Assessments 
Screening Visit
Infusions 1, 3, 4, 6, 9, 12
Study Completion/ 
TerminationVisita
Hematologyb
X
X
Clinical Chemistryc
X
X
Coagulation Testingd
X
Serological Testinge and CD4f
X
X
Pregnancy Testg
X
a
Includes cases of withdraw or discontinuation.
b
Hematology assessments include:  CBC (Hct, Hgb, RBC count, WBC count) with differential, MCV, MCHC, and platelet count.
c
Clinical chemistry assessments include sodium, chloride, potassium, bicarbonate, AST, ALT, albumin, total protein, alkaline phosphatase, total 
bilirubin, BUN, creatinine, glucose, GGT, 5’-nucleotidase.
d
Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A (mentioned in 
Section 12.7.2).
e
Serological testing will include: HIV-1 and HIV-2 antibodies (HIV+, check CD4 count–screening visit only), HAV antibodies, HBV antibody, HBsAg, 
HCV antibody, parvovirus B19 (IgM and IgG), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus antibodies (IgM and IgG).
f
CD4 at screening in case of positive HIV test results.
g
A serum pregnancy test will be performed for females of childbearing potential.
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20.6 Concentrations of FII and Coagulation testing
Table 5
FII and Coagulation Testing Time Frame
Procedures/Assessments
PART 1
Infusions 1, 3, 4, 6
PART 2
Infusions 9, 12 
Infusions 
2, 5, 7, 8, 10, 11
FII concentration
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
1 hr ± 15 min
2 hr ± 30 min
6 hr ± 1 hr
8 hr ± 2 hr
12 hr ± 4 hr
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
1 hr ± 15 min
2 hr ± 30 min
6 hr ± 1 hr
8 hr ± 2 hr
12 hr ± 4 hr
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
Coagulation testing: 
aPTT, PT, thrombotic markers 
(D-Dimers, Prothrombin 
fragment F 1+2, TAT, 
fibrinopeptide A)
Infusions 1, 3, 4, 6, 9, and 12
Post infusion:
1 hr ± 15 min
6 hr ± 1 hr
12 hr ± 4 hr
Abbreviations: EOI=end-of-infusion; Factor II, h=hours; min=minutes; 
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21. REFERENCES
1.
Baxter Healthcare Corporation. FEIBA (Anti-inhibitor coagulant complex) for 
intravenous use, lyophylized powder for solution. 2013.
https://www.baxter.com/assets/downloads/feiba_us_pi.pdf
2.
Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity 
(FEIBA®): 10-year compilation of thrombotic adverse events. Haemophilia. 
2002;8(2):83-90.
3.
Hilgartner M, Aledort L, Andes A, Gill J. Efficacy and safety of vapor-heated anti-
inhibitor coagulant complex in hemophilia patients. FEIBA Study Group. 
Transfusion. 1990;30(7):626-630.
4.
Hilgartner MW, Knatterud GL, Group FS. The use of factor eight inhibitor by-
passing activity (FEIBA immuno) product for treatment of bleeding episodes in 
hemophiliacs with inhibitors. Blood. 1983;61(1):36-40.
5.
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(3):560-575.
6.
Boggio LN, Kessler CM. Hemophilia A and B. In: Kitchens C, Alving BM, Kessler 
CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier 
Saunders; 2007:45-59.Open Access: 
7.
Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. 
Haemophilia. 1998;4(4):558-563.
8.
Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII 
and factor IX inhibitors in haemophiliacs. Lancet. 1992;339(8793):594-598.
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9.
Turecek PL, Varadi K, Gritsch H, et al. Factor Xa and prothrombin: mechanism of 
action of FEIBA. Vox Sang. 1999;77 Suppl 1:72-79.
10.
Turecek P, Schwarz HP. Factor eight inhibitor bypassing activity. In: Bertolini B, 
Goss N, Curling J, eds. Production of Plasma Proteins for Therapeutic Use. United 
States: John Wiley and Sons; 2013:49-64.Open Access: 
https://books.google.at/books?id=MGL0QOc-
rtsC&printsec=frontcover&source=gbs_ViewAPI&output
11.
Varadi K, Tangada S, Loeschberger M, et al. Pro- and anticoagulant factors 
facilitate thrombin generation and balance the haemostatic response to FEIBA® in 
prophylactic therapy. Haemophilia. 2016;22(4):615-624.
12.
Négrier C, Voisin S, Baghaei F, et al. Global Post-Authorization Safety 
Surveillance Study: real-world data on prophylaxis and on-demand treatment using 
FEIBA (an activated prothrombin complex concentrate). Blood Coagul 
Fibrinolysis. 2016;27(5):551-556.
13.
Himmelspach M, Richter G, Muhr E, et al. A fully recombinant partial prothrombin 
complex effectively bypasses FVIII in vitro and in vivo. Thromb Haemost. 
2002;88(6):1003-1011.
14.
Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. 
Validation of an abbreviated treatment satisfaction questionnaire for medication 
(TSQM-9) among patients on antihypertensive medications. Health Qual Life 
Outcomes. 2009;7:36.
15.
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents 
in cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. New 
York: Columbia University Press; 1949:191-205.Open Access: 
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22. SUMMARY OF CHANGES
Protocol 091501 AMENDMENT 2 (Global): 2017 AUG 04
Replaces: Protocol 091501 Amendment 1 (Global): 2016 MAR 03
In this section, changes made in this amendment from the previous version of the
protocol, dated 2016 MAR 03, are described and their rationale is given.
1.
Throughout the document
Description of Change: Minor grammatical and/or administrative changes were 
made.
Purpose of Change: To improve clarity in the protocol.
2.
Study title and throughout the document
Description of Change: The phase of the study was changed from 3b to 3b/4.
Purpose of Change: To reflect the study phase per registration status in differnet 
countries.
3.
Study title and throughout the document
Description of Change: The words “two-part” and “the safety” were removed 
from the title and PK was changed to Tolerability.
Purpose of Change: To align with the sduty design and provide clarity.
4.
Serious Adverse Event Reporting, Section 2
Description of Change: SAE reporting via eCRF removed.
Purpose of Change: To clarify that only SAER Forms will be used.
5.
Name of IP, Section 2 (Synopsis)
Description of Change: The sentence, Referred to as FEIBA throughout the 
protocol, was added.
Purpose of Change: To provide clarity to reader.
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6.
CLINICAL CONDITION(S)/INDICATION(S), Section 3 (Synopsis)
Description of Change: The following was added to this section and the reference 
was updated to 12: 
1. FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in 
hemophilia A and B patients with inhibitors for:
2. Control and prevention of bleeding episodes
3. Perioperative management
4. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
5. FEIBA is not indicated for the treatment of bleeding episodes resulting from 
coagulation factor deficiencies in the absence of inhibitors to factor VIII or 
factor IX.
Purpose of Change: Provide full range of indications as mentioned in the USPI 
and update the reference to USPI at the end of this document.
7.
Short title, Section 3 (Synopsis) 
Description of Change: Added FEIBA STAR. 
Purpose of Change: Further shortened the title for ease of reading.
8.
STUDY PHASE, Section 3 (Synopsis) 
Description of Change: Added the sentence, “Phase 3b/4, depending on market 
authorization status per country”. 
Purpose of Change: To provide clear understanding of phase of the study 
depending on product registration status per country.
9.
PLANNED STUDY PERIOD, Section 3 (Synopsis) 
Description of Change: Updated timelines for initiation, primary completion, 
study completion and duration. 
Purpose of Change: Provide updated timelines for study.
10.
STUDY OBJECTIVES AND PURPOSE, Section 3 (Synopsis) and throughout 
the document 
Description of Change: Updated study purpose, primary objectives and 
exploratory objectives to include Tolerability and Safety and remove PK and 
secondary objectives. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
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11.
STUDY DESIGN, Section 3 (Synopsis) and throughout the document
Description of Change: Study design changed to Tolerability and Safety from PK 
Comparability, Pharmacokinetic and Safety. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
12.
Planned Duration of Subject Participation, Section 3 (Synopsis) and throughout 
the document 
Description of Change: Each subject will spend approximately 6 to 11 weeks in 
the study. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
13.
Outcome Measure (s), Section 3 (Synopsis) and throughout the document
Description of Change: Changed Primary and Exploratory Outcome Measure(s). 
Removed secondary outcome measure (s).
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
14.
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF 
ADMINISTRATION, Active Product, Section 3 (Synopsis)  
and throughout the document
Description of Change: Dosage frequency updated to IP will be infused every 48 
hours (-8 hours/+24 hours).
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
15.
SUBJECT SELECTION, Targeted Accrual, Section 3 (Synopsis) 
Description of Change: Changed to enroll 24 evaluable subjects for the 
assessments.
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
16.
Primary Objective, Section 3 (Synopsis) 
Description of Change: Anaphylaxis was removed as an example from primary 
objective 2. 
Purpose of Change: Provide the reader with clarity.
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17.
Exclusion Criteria, Section 3 (Synopsis) and throughout the document
Description of Change: From clinically symptomatic liver disease changed to 
Advanced liver disease and prothrombin time [PT] 5 seconds above upper limit of 
normal was included. 
Purpose of Change: The change was made to exclude patients with PT 5 seconds 
and above ULN with advanced liver disease.
18.
Exclusion Criteria and throughout the document
Description of Change: Herbal supplements containing anti-platelet activity has 
been added as an exclusion criteria. 
Purpose of Change: The change was made to align the text to the updated 
operational design.
19.
STATISTICAL ANALYSIS, Sample size calculation, Section 3 (Synopsis)
Description of Change: Updated sample size calculation and Planned Statistical 
Analysis. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
20.
Section 6.2
Description of Change: References 9 and 10 added. Recent studies have 
demonstrated that FEIBA is a multicomponent therapeutic agents with activities 
potentially targeting different sites in the coagulation system and From a number 
of confirmed studies it became clear that the FII–FXa complex is one of the key 
components in this system of different proteins, was added.
Purpose of Change: To provide clarity on FEIBA MOA and importance of FII-
FXa complex.
21.
Section 6, 
Description of Change: Some text was adapted to improve consistency of text 
with current Investigators’ Brochure content.
Purpose of Change: To ensure consistency between this protocol and the current 
Investigator’s Brochure.
22.
Description of Treatment, Section 8.7.3
Description of Change: Updated Part 1 and 2 as per design change from PK to 
tolerability and safety evaluation.
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
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23.
Management and Treatment of Break-Through Bleeding, Section 8.7.4
Description of Change: Updated bleeding episode to be resolved in 48 hours and 
washout period removed during screening.
Purpose of Change: To provide early treatment recommendation to patients and 
not to withdraw therapy from patients during screening washout.
24.
Source Data, Section 8.8
Description of Change: Subject questionnaires may be entered directly onto the 
CRF.
Purpose of Change: To provide clarification.clarify .
25.
Screening and Baseline Assessments, Section 9.3.1
Description of Change: Updated as per change in design to tolerability and safety.
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
26.
Infusion Visits, Section 10.3.2.1 and through out the document
Description of Change: Changed to randomization will occur after the subject has 
been confirmed to be eligible and prior to the first infusion. Added breakthrough 
bleeding monitoring. Added Prothrombin II levels to be drawn at various times 
related to IP administration.
Purpose of Change: Electronic randomization systems will not be used. 
Breakthough bleeding and Prothrombin II levels will be a measure of tolerability 
and safety.
27.
Source Data, Section 12.7.2 and through out the document
Description of Change: Updated as per change in design to tolerability and safety. 
Timelines for blood samples to determination of FEIBA component FII and 
Coagulation testing have been defined. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
28.
Biobanking, Section 12.7.6
Description of Change: Updated to exclude need for samples to be used for re-
testing, further evaluation of an AE, or follow-up of other results. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
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29.
Infusion Site Evaluations, Section 12.10
Description of Change: Updated infusion sites monitoring by subjects from 72 to 
48 hours. 
Purpose of Change: Infusions will be given every 48 hours.
30.
Statistics, Section 13. 
Description of Change: The entire statistics section was revised in line with the 
change in study design from PK to tolerability and safety. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
31.
Study Flow Chart Part 1 and 2, Section 20.1 and 20.2. 
Description of Change: Updated in line with the change in study design from PK 
to tolerability and safety. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
32.
Schedule of Study Procedures and Assessments (Part 1) and (Part 2), 
Section 20.3 and 20.4 . 
Description of Change: Updated in line with the change in study design from PK 
to tolerability and safety. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
33.
Table 4: Clinical Laboratory Assessments, Section 20.5  
Description of Change: Updated in line with the change in study design from PK 
to tolerability and safety. 
Purpose of Change: To align with change in design of study from PK to 
Tolerability and Safety.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 2 (Global): 2017 AUG 04
Replaces
Amendment 1 (Global): 2016 MAR 03
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 2 (Global): 2017 AUG 04
Replaces
Amendment 1 (Global): 2016 MAR 03
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD, 
 
Global Clinical Development Operations
Baxalta Innovations GmbH / Baxalta US Inc.
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CLINICAL STUDY PROTOCOL
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
STUDY SHORT TITLE: FEIBA Reconstitution Volume Reduction and Faster 
Infusion Study (FEIBA STAR)
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 3 (Global): 2017 SEP 14
Replaces:
AMENDMENT 2 (Global): 2017 AUG 04
ALL VERSIONS:
AMENDMENT 3 (Global): 2017 SEP 14
Amendment 2 (Global): 2017 AUG 04
Amendment 1 (Global): 2016 MAR 03
Original: 2015 OCT 08
OTHER ID(s)
NCT Number: 02764489
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA 91362, 
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, 
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory)/Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g., 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 INCLUDING SUSARs, 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
Drug Safety contact information: see SAE Report From
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:

Adverse Event, Section 12.1

Serious Adverse Event, Section 12.1.1.1

Assessment of Adverse Events, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT (IP)
Name of IP
Anti-inhibitor Coagulant Complex Nanofiltered (activated 
prothrombin complex concentrate [APCC]), FEIBA NF. 
Referred to as FEIBA throughout the protocol.
Name(s) of Active 
Ingredient(s)
Coagulation factors II, X, IX, and VIIa
CLINICAL CONDITION(S)/INDICATION(S)
FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B 
patients with

inhibitors for:
Control and prevention of bleeding episodes
Perioperative management
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

FEIBA is not indicated for the treatment of bleeding episodes resulting from 
coagulation factor deficiencies in the absence of inhibitors to factor VIII or 
factor IX.1
PROTOCOL ID
091501
PROTOCOL TITLE
A Phase 3b/4, Prospective, Multicenter, Open-label, 
Randomized, Crossover Study of Tolerability and Safety 
of FEIBA Reconstituted in Regular or 50% Reduced 
Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
Short Title
FEIBA Reconstitution Volume Reduction and Faster Infusion 
Study (FEIBA STAR)
STUDY PHASE
Phase 3b/4, depending on market authorization status per 
country
PLANNED STUDY PERIOD
Initiation
First Subject In: Q 1 2018
Primary Completion
Last Subject In: Q 4 2018
Study Completion
Last Subject Last Visit: Q 4 2018
Duration
6 to 11 weeks
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STUDY OBJECTIVES AND PURPOSE
Study Purpose
To evaluate the tolerability and safety of infusing reduced volume FEIBA at the standard 
infusion rate of 2 U/kg/min, and at increased rates of 4 and 10 U/kg/min, in comparison 
to the standard rate of 2 U/kg/min at the regular volume
Primary Objectives
To evaluate tolerability and safety of FEIBA reconstituted in a 50% reduced volume of 
sterile water for injection (SWFI) administered at the standard infusion rate of 
2 U/kg/min and at increased rates of 4 and 10 U/kg/min, based on the occurrence of any 
adverse event, in particular of thromboembolic events and hypersensitivity reactions 
Exploratory Objectives
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II  with 50% reduced 
volume of FEIBA and faster infusion rates
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
STUDY DESIGN
Study Type/ 
Classification/ 
Discipline
Tolerability and Safety
Control Type
Active
Study Indication 
Type
Treatment
Intervention model
Part 1:  Crossover
Part 2:  Sequential
Blinding/Masking
Part 1:  Randomized, Open-label
Part 2:  Non-Randomized, Open-label
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Study Design
A 2-part, Phase 3b/4, prospective, open-label, multicenter 
study to be conducted in 24 evaluable hemophilia A or B 
subjects with inhibitors (≥0.6 Bethesda units [BU] for the 
primary tolerability and safety assessments.
Part 1:
In Part 1, subjects will be administered two different volumes 
of FEIBA in a randomized, crossover design every 48 hours 
(-8, +24 hours) intervals. Part 1 will monitor the tolerability, 
safety, pre (within 60 min before the infusion) and post-
infusion (at 30 min, hours 1, 2, 6, 8 and 12) concentration of 
coagulation factor II (FII) reconstituted in 50% reduced 
volume of SWFI and administered at the standard infusion rate 
of 2 U/kg/min compared with FEIBA reconstituted in regular 
volume of SWFI at the standard infusion rate.
All subjects will be screened for eligibility based on the listed 
inclusion and exclusion criteria.
Eligible subjects will be randomly assigned (1:1) to receive 
3 infusions of FEIBA reconstituted in 50% reduced volume 
SWFI or regular volume SWFI (Period 1).
Patients finishing 3 infusions in Period 1 (Sequence A or B), 
will either switch from FEIBA reconstituted in reduced volume 
to 3 infusions of FEIBA in regular volume SWFI or vice versa 
(Sequence A or B) depending on randomization.
All patients completing Part 1 will move to Part 2. Evaluable 
patients from Part 1 are all subjects who receive 4 of the 
6 planned infusions, at least 2 infusions in each sequence.
Tolerability and safety data will be collected before, during and 
after each infusion and between infusions; Clinically apparent 
changes in vital signs, laboratory parameters, infusion site 
reactions and infusion rate-related reactions will be monitored.
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FII concentration will be monitored by analyzing 
concentrations before (within 60 min before the infusion) and 
at 30 min after each infusion and at hours 1, 2, 6, 8 and 12 after 
infusion 1,3,4 and 6 as outlined in Section 20.6.
Part 2: 
Part 2 is non-randomized with sequential treatment of all 
evaluable subjects who complete Part 1, will receive at least 
4 of the 6 infusions. Subjects will receive FEIBA reconstituted 
in 50% reduced volume of SWFI at increased rates of 4 and 
10 U/kg/min in a non-randomized fashion, at 48 hours 
(-8, +24 hours) intervals, to evaluate the tolerability and safety 
of infusing FEIBA reconstituted in 50% reduced volume of 
SWFI at increased rates of 4 and 10 U/kg/min.
FEIBA Infusions 7, 8, and 9 will be administered at the 
4 U/kg/min rate and infusions 10, 11 and 12 will be 
administered at 10 U/kg/min.
Following the last infusion (infusion 12), a study termination 
visit will be conducted within 7 days but no sooner than 
72 hours after the last infusion.
Tolerability and safety data will be collected before, during and 
after each infusion and between the infusions; Clinically 
apparent changes in vital signs, infusion rate-related events, 
and infusion site reactions will be monitored.
Concentration of coagulation factor II will be assessed before 
(within 60 minutes before the infusion) and at 30 min after 
each infusion, and at hours 1, 2, 6, 8 and 12 after infusions 9, 
and 12 as outlined in Section 20.6.
The infusions in both parts will be administered every 48 hours 
(-8 hours /+24 hours) to allow time to monitor tolerability and 
safety of the higher infusion rate. 
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All IP infusions will be administered at the hemophilia care 
centers/study sites. Each subject will receive a maximum of 
12 IP infusions (6 in each part). There is no washout period 
before Part 1, between infusions or parts of the study.
Subjects will receive FEIBA at a dose of 85 U/kg ± 15 U/kg 
for all infusions. For infusions, whole vials should be rounded 
up or down to be as close as possible to the accurate dosage, as 
appropriate. Please refer to study documents for detailed 
instructions.
Safety monitoring for this study  will be conducted 
concurrently by an Internal Safety Monitoring Committee 
(ISMC). All SAEs that occur will be reviewed by the Chair of 
the ISMC with the Medical Director within 24 hours. Planned 
ISMC meetings will be held concurrently with the ongoing 
study.
Planned Duration of 
Subject Participation
It is planned that each subject will spend approximately 6 to 
11 weeks in the study. 
Outcome Measure (s)
Primary
Assess tolerability and safety (local and general) related to the infusion and volume of 
reconstitution: 
1.
Occurrence of any adverse event: all AEs and SAEs, and AEs leading to 
discontinuation 
2.
Thromboembolic events and hypersensitivity reactions
3.
Vital signs and Clinical laboratory data
4.
Infusion site and infusion related reactions
Exploratory Outcome Measure(s) 
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II. 
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: kit; powder, lyophilized, for 
solution/suspension; injection
Dosage frequency: IP will be infused every 48 hours
(-8 hours/+24 hours).
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Enroll 24 evaluable subjects for the assessments
Number of 
Groups/Arms/Cohorts
1 cohort: at least 24 evaluable adult subjects (≥18 to 
≤65 years old) for tolerability and safety evaluation
Inclusion Criteria
Subject is/has:
1.
≥18 to ≤65 years old at the time of screening
2.
Hemophilia A or B of any severity, with a documented ≥ 3 months history of 
inhibitors (≥ 0.6 BU) requiring the use of bypassing agents (FEIBA or rFVIIa) 
prior to screening. Inhibitor level will be tested at screening if no documented 
history is available.
3.
Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain 
reaction (PCR); or HCV positive with stable liver disease
4.
Human immune deficiency virus (HIV)  negative; or HIV positive with stable 
disease and CD4 count ≥ 200 cell/mm3 at screening
5.
Adequate peripheral venous access
6.
Willing and able to comply with the requirements of the protocol
7.
If a female of childbearing potential, must have a negative blood pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study, such as:
a.
Abstain from sexual intercourse
b.
Use a reliable method of contraception (contraception such as an intrauterine 
device, barrier method [e.g., diaphragm or sponge; female condom not 
permitted] with spermicide, oral contraceptive, injectable progesterone, sub 
dermal implant), and have their male partner use a condom
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8.
If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a.
Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-stimulating 
hormone levels within the laboratory-defined postmenopausal range or 
postmenopausal with amenorrhea for at least 24 months and on hormonal 
replacement therapy
b.
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation (with no subsequent pregnancy at least 
1 year from bilateral tubal ligation), or bilateral salpingectomy
Exclusion Criteria
Subject is/has:
1.
Known hypersensitivity to FEIBA or any of its components
2.
Advanced liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites, prothrombin time [PT] 5 seconds above upper limit of 
normal)
3.
Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4.
Platelet count < 100,000/µL
5.
Clinical or laboratory evidence of disseminated intravascular coagulation
6.
Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
7.
Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
8.
Taking any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to 
enrollment except anti-retroviral chemotherapy.
9.
Herbal supplements that contain anti-platelet activity
10. 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
11. A family member or employee of the investigator
12. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
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STATISTICAL ANALYSIS
Sample Size Calculation
The projected sample size of 24 evaluable subjects for this tolerability and safety study 
was determined by considering available patients, and is not based on statistical power 
calculations.
Planned Statistical Analysis
Statistical analysis for this study will be descriptive in nature.
Primary Analysis
AEs, SAEs and AEs leading to discontinuation, thromboembolic events and 
hypersensitivity reactions that occur during or after the IP infusion will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be provided for temporally associated adverse events; 
and for potentially related adverse events as assessed by the investigators.
Shift tables and summary statistics will be presented for the results of clinical laboratory 
data. All abnormal lab results will be listed.
Summary statistics of vital signs, infusion site and infusion related reactions will be 
carried out.
Exploratory Analysis
All exploratory outcome measures will be analyzed descriptively.
Full details of the statistical analysis will be specified in the statistical analysis plan 
(SAP).
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory)/Responsible Party ................................ 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 12
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 18
6.1 Description of Investigational Product and Clinical Condition/Indication..... 18
6.2 Clinical Condition/Indication .............................................................................. 18
6.3 Population to Be Studied...................................................................................... 19
6.4 Findings from Nonclinical and Clinical Studies................................................. 20
6.4.1 Finding from Nonclinical Studies................................................................. 20
6.4.2 Findings from Clinical Studies ..................................................................... 20
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 22
6.6 Compliance Statement.......................................................................................... 22
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 23
7.1 Study Purpose ....................................................................................................... 23
7.2 Primary Objectives............................................................................................... 23
7.3 Exploratory Objectives......................................................................................... 23
8. STUDY DESIGN......................................................................................................... 24
8.1 Brief Summary and Study Design Rationale ..................................................... 24
8.2 Overall Study Design............................................................................................ 25
8.3 Duration of Study Period(s) and Subject Participation .................................... 26
8.4 Outcome Measures ............................................................................................... 26
8.4.1 Primary Outcome Measures......................................................................... 26
8.4.2 Exploratory Outcomes Measure .................................................................. 27
8.5 Randomization and Blinding............................................................................... 27
8.6 Study Stopping Rules............................................................................................ 27
8.7 Investigational Product(s).................................................................................... 27
8.7.1 Packaging, Labeling, and Storage................................................................ 27
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8.7.2 Administration ............................................................................................... 28
8.7.3 Description of Treatment.............................................................................. 29
8.7.4 Management and Treatment of Break-Through Bleeding ........................ 31
8.7.5 Investigational Product Accountability ....................................................... 32
8.8 Source Data ........................................................................................................... 32
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 33
9.1 Inclusion Criteria.................................................................................................. 33
9.2 Exclusion Criteria................................................................................................. 34
9.3 Withdrawal and Discontinuation ........................................................................ 34
10. STUDY PROCEDURES .......................................................................................... 36
10.1 Informed Consent and Enrollment ................................................................... 36
10.2 Subject Identification Code (SIC) ..................................................................... 36
10.3 Screening and Study Visits................................................................................. 36
10.3.1 Screening and Baseline Assessments.......................................................... 36
10.3.2 Treatment Visits........................................................................................... 37
10.3.2.1 Infusion Visits ....................................................................................... 37
10.3.3 Study Completion/Termination Visit......................................................... 38
10.4 Medications and Non-Drug Therapies.............................................................. 39
10.5 Subject Questionnaires....................................................................................... 40
10.6 Subject Completion/Discontinuation ................................................................ 40
10.7 Procedures for Monitoring Subject Compliance............................................. 41
11. ASSESSMENT OF PHARMACOKINETICS....................................................... 41
12. ASSESSMENT OF SAFETY................................................................................... 42
12.1 Adverse Events.................................................................................................... 42
12.1.1 Definitions..................................................................................................... 42
12.1.1.1 Serious Adverse Event.......................................................................... 42
12.1.1.2 Non-Serious Adverse Event ................................................................. 43
12.1.1.3 Unexpected Adverse Events................................................................. 43
12.1.1.4 Pre-existing Diseases............................................................................. 44
12.1.2 Assessment of Adverse Events.................................................................... 44
12.1.2.1 Severity .................................................................................................. 45
12.1.2.2 Causality................................................................................................ 45
12.1.2.3 Safety Reporting ................................................................................... 47
12.1.3 Medical Device Safety Reporting ............................................................... 48
12.2 Urgent Safety Measures ..................................................................................... 48
12.3 Untoward Medical Occurrences........................................................................ 48
12.4 Non-Medical Complaints ................................................................................... 49
12.5 Medical, Medication, and Non-Drug Therapy History................................... 49
12.6 Physical Examinations........................................................................................ 50
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12.7 Clinical Laboratory Parameters........................................................................ 50
12.7.1 Hematology and Clinical Chemistry.......................................................... 50
12.7.2 Concentration of FII and Coagulation Testing......................................... 51
12.7.3 Viral Serology............................................................................................... 51
12.7.4 CD4 Levels.................................................................................................... 51
12.7.5 Assessment of Laboratory Values .............................................................. 51
12.7.5.1 Assessment of Abnormal Laboratory Values..................................... 51
12.7.6 Biobanking.................................................................................................... 52
12.8 Vital Signs............................................................................................................ 52
12.9 Karnofsky Performance Test............................................................................. 52
12.10 Infusion Site Evaluations.................................................................................. 53
12.11 Special Treatment Considerations .................................................................. 53
13. STATISTICS............................................................................................................. 55
13.1 Sample Size and Power Calculations ................................................................ 55
13.2 Datasets and Analysis Cohorts .......................................................................... 55
13.3 Handling of Missing, Unused, and Spurious Data........................................... 55
13.4 Methods of Analysis............................................................................................ 55
13.4.1 Primary Outcome Measure......................................................................... 55
13.4.1.1 Analysis of the Primary Outcome Measure (Parts 1 and 2)............. 55
13.4.2 Exploratory Outcome Measures ................................................................ 56
13.5 Planned Interim Analysis of the Study ............................................................. 56
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 56
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 57
15.1 Investigator’s Responsibility.............................................................................. 57
15.1.1 Final Clinical Study Report........................................................................ 57
15.2 Training ............................................................................................................... 57
15.3 Monitoring........................................................................................................... 57
15.4 Safety Monitoring ............................................................................................... 58
15.5 Auditing ............................................................................................................... 58
15.6 Non-Compliance with the Protocol ................................................................... 59
15.7 Laboratory and Reader Standardization ......................................................... 59
16. ETHICS ..................................................................................................................... 60
16.1 Subject Privacy ................................................................................................... 60
16.2 Ethics Committee and Regulatory Authorities................................................ 60
16.3 Informed Consent ............................................................................................... 60
17. DATA HANDLING AND RECORD KEEPING................................................... 61
17.1 Confidentiality Policy ......................................................................................... 61
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17.2 Study Documentation and Case Report Forms ............................................... 61
17.3 Document and Data Retention........................................................................... 61
18. FINANCING AND INSURANCE........................................................................... 62
19. PUBLICATION POLICY........................................................................................ 62
20. SUPPLEMENTS....................................................................................................... 63
20.1 Study Flow Chart Part 1 .................................................................................... 63
20.2 Study Flow Chart Part 2 .................................................................................... 64
20.3 Schedule of Study Procedures and Assessments (Part 1)................................ 65
20.4 Schedule of Study Procedures and Assessments (Part 2)................................ 67
20.5 Clinical Laboratory Assessments ...................................................................... 69
20.6 Concentrations of FII and Coagulation testing................................................ 70
21. REFERENCES.......................................................................................................... 71
22. SUMMARY OF CHANGES.................................................................................... 73
INVESTIGATOR ACKNOWLEDGEMENT.............................................................. 74
Tables
Table 1 FEIBA Product Preparation................................................................................ 29
Table 2 Schedule of Study Procedures and Assessments (Part 1)................................... 65
Table 3 Schedule of Study Procedures and Assessments (Part 2)................................... 67
Table 4 Clinical Laboratory Assessments........................................................................ 69
Table 5 FII and Coagulation Testing Time Frame........................................................... 70
Figures
Figure 1 Study Design for Part 1 Baxalta Clinical Study 091501 ................................... 63
Figure 2 Study Design for Part 2 Baxalta Clinical Study 091501 ................................... 64
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AICC
anti-inhibitor coagulant complex
ALT
alanine aminotransferase
APCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BU
Bethesda units
BUN
blood urea nitrogen
BW
body weight
CBC
complete blood count
CD4
cluster of differentiation 4
CI
confidence interval
EC
ethics committee
EOI
end-of-infusion
CRF
case report form
EDC
electronic data capture
FEIBA
Factor Eight Inhibitor Bypassing Activity
FEIBA NF
Factor Eight Inhibitor Bypassing Activity Nanofiltered
FEIBA VH
Factor Eight Inhibitor Bypassing Activity Vapor Heated
FII
Factor II
FIX
Factor IX
FVII
Factor VII
FVIII
Factor VIII
FVIII:CAg
Factor VIII C antigen
FX
Factor X
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GSL
Global Safety Lead
HAV
hepatitis A virus
HBsAg
hepatitis B surface antigen
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Abbreviation
Definition
HBV
hepatitis B
Hct
hematocrit
HCV
hepatitis C virus
Hgb
hemoglobin
HIV
human immunodeficiency virus 
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IgG
Immumoglobulin G
IgM
immunoglobulin M
IP
investigational product
ISMC
Internal Safety Monitoring Committee
Min
minutes
NMC 
non-medical complaint
PCR
polymerase chain reaction
PT
prothrombin time
rFVIIa
recombinant activated clotting factor VII
Rsq
r2
SAE
serious adverse event
SAER
serious adverse event report
SIC
subject identification code
SI
serious injuries
SWFI
sterile water for injection
TAT
thrombin/anti-thrombin complex
TSQM
Treatment Satisfaction Questionnaire for Medication
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product and Clinical Condition/Indication
The investigational product (IP), FEIBAi is a plasma derived, activated prothrombin 
complex concentrate (APCC), generically identified as an anti-inhibitor coagulant 
complex (AICC). FEIBA was developed to treat bleeding episodes and cover surgical 
interventions in hemophilia A and B patients with inhibitors and in non-hemophilia 
patients with acquired inhibitorsii and is also intended for use as a prophylactic treatment 
for hemophilia A and B patients with high responding inhibitors and frequent joint 
bleeding.iii,2,3,4
Baxalta’s first licensed FEIBA product, AICC FEIBA, was marketed beginning in 1975
and was superseded in 1985 by a 2-stage vapor heat-treated product, AICC FEIBA VH.
Nanofiltration was introduced to the manufacturing process in 2006 to produce 
FEIBA NF, now called FEIBA.
6.2 Clinical Condition/Indication 
Hemophilia is an X-linked, recessive, congenital bleeding disorder caused by 
deficient or defective coagulation due to a deficiency in FVIII (hemophilia A), or FIX 
(hemophilia B). The absence of FVIII or FIX leads to spontaneous bleeding episodes 
(occurring primarily in joints, muscles, and less commonly, in soft tissues) and to 
excessive bleeding following trauma or injury.5,6 Replacement therapy for the treatment 
of hemophilia A, and less frequently hemophilia B, can be complicated by an immune 
response resulting in the production of inhibitory alloantibodies to Factor VIII (FVIII) or 
Factor IX (FIX), especially in patients with moderate to severe hemophilia. The 
development of such inhibitory antibodies currently represents the most serious 
complication of hemophilia treatment. The presence of inhibitors against FVIII 
generally precludes the efficacious use of human FVIII replacement therapy. A 
substantial portion of patients with FVIII inhibitors have high-responding, high-titer 
inhibitors (> 5 Bethesda units [BU]). These patients exhibit an anamnestic response 
after FVIII exposure, sometimes with a dramatic increase in inhibitory antibody titer.7,8
The inability to provide FVIII replacement therapy predisposes this group of patients to 
increased morbidity and mortality compared with hemophilia patients without inhibitors.7
                                                
i
FEIBA NF is a trademark of Baxalta Inc. US and Baxalta Innovations GmbH.
ii
Anti-Inhibitor Coagulant Complex, FEIBA Vapor Heated. Package Insert, Baxalta US Inc., Westlake 
Village, CA.
iii
Protocol 090701. FEIBA NF: A Prospective, Open-label, Randomized, Parallel Study to Evaluate 
Efficacy and Safety of Prophylactic versus On-demand Treatment in Patients with Hemophilia A and B 
and High Titer Inhibitor. 2013 Jan 14, Baxalta US Inc.,(Westlake Village, CA).
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Several therapeutic approaches are currently available in the management of hemorrhagic 
events in patients who have developed FVIII inhibitors. These include neutralization with 
high doses of human FVIII (low titer inhibitor only), and treatment with bypassing agents 
such as Activated Prothrombin Complex Concentrate (APCC), or activated recombinant 
factor VII (rFVIIa). Among these treatment options, only APCCs and rFVIIa are able to 
control acute hemorrhages in hemophilia patients with high titer inhibitors. These agents 
control bleeding by promoting the conversion of prothrombin to thrombin with 
subsequent fibrin polymerization and clot formation via mechanisms that do not require 
FVIII or FIX. It has been proposed that FEIBA products achieve this goal principally by 
virtue of the presence of a “partial prothrombinase complex” consisting of activated 
Factor X (FX) and prothrombin.9
The active ingredient of FEIBA is a plasma-derived, freeze-dried APCC with FVIII 
inhibitor bypassing activity. Recent studies have demonstrated that FEIBA is a 
multicomponent therapeutic agents with activities potentially targeting different sites in 
the coagulation system.10 FEIBA contains mainly non-activated forms of the vitamin K -
dependent proteins Factor II (FII), FVII, FIX and FX, as well as small amounts of 
activated prothrombin complex proteins; and Factor VIII coagulant antigen present in a
concentration of up to 0.1 U/1 U FEIBA. From a number of confirmed studies it became 
clear that the FII–FXa complex is one of the key components in this system of different 
proteins.11  A solution containing 1 U FEIBA shortens the activated partial 
thromboplastin time (aPTT) of FVIII inhibitor plasma up to 50% of the buffer value. 
Additional details can be found in the FEIBA IB.iv
6.3 Population to Be Studied
Adult subjects (age ≥18 to ≤65 years) with hemophilia A or B (congenital or acquired) 
of any severity, of all races and ethnic groups will be studied. All subjects will have a 
documented history of inhibitors (≥ 0.6 BU) requiring the use of bypassing agents 
(FEIBA or rFVIIa); subjects with no documented history will require testing of the 
inhibitor level before entering the study. Subjects will either be hepatitis C virus (HCV)
negative or HCV positive with stable hepatic disease. Subjects will either be human 
immunodeficiency virus (HIV) negative or HIV positive with stable disease and a cluster 
of differentiation 4 (CD4) count ≥ 200 cell/mm3. See additional details in the Inclusion 
and Exclusion Criteria in Section 9.1 and Section 9.2, respectively.
                                                
iv
Investigator’s brochure. Anti-inhibitor coagulant complex nanofiltered; FEIBA NF. 2016 FEB 24. 
Baxalta US Inc., (Westlake Village, CA). 
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6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Finding from Nonclinical Studies
The nonclinical studies included a virus clearance study, which was performed to 
investigate the virus reduction capacity of the nanofiltration step in the manufacturing of 
FEIBA NF. 
Data from nonclinical studies can be found in the FEIBA NF IB.iv
6.4.2 Findings from Clinical Studies
The results of Baxalta clinical study 090701iii demonstrated that prophylaxis with 
FEIBA significantly reduced the annualized bleeding rates for all bleed types and for 
spontaneous, traumatic, joint, and non-joint, bleeding episodes when compared with on-
demand treatment. A statistically significant reduction in the rate of bleeding episodes in 
new target joints in the prophylaxis arm versus the on-demand arm was also observed. 
An examination of adverse events (AEs), abnormal laboratory parameters for hematology 
and clinical chemistry and vital signs demonstrated that FEIBA was safe and well 
tolerated for prophylactic use. Clinically, these data suggest that FEIBA is safe and 
efficacious in the management of hemophilia A or B with persistent high-titer inhibitors
or low-titer inhibitors refractory to FVIII or FIX treatment, and further confirmed the 
safety and effectiveness of FEIBA for controlling and preventing bleeding episodes.
Baxalta clinical study 091002 was an open-label, uncontrolled, non-interventional 
observational cohort study of FEIBA NF in hemophiliacs with inhibitors. This study was
designed to document routine usage of FEIBA NF as a bypassing agent for on-demand or 
prophylactic treatment in everyday clinical practice and in surgical intervention. The 
safety results of this postauthorization safety study showed that treatment with 
FEIBA NF, administered in 81 subjects with hemophilia, requiring treatment with 
inhibitor-bypass therapy for bleed resolution or bleed prophylaxis, was generally safe 
and well tolerated. The mean infusion rate of FEIBA under routine clinical practice 
during the study (3.7 U/kg per min, range 0.9 to 23.5) was higher than that recommended 
in the Summary of Product Characteristics of FEIBA (2.0 U/kg per min). A manual
analysis of safety listings did not disclose any AEs associated with a higher infusion 
rate.12 Treatment-related AEs or serious adverse events (SAEs) were reported in 9.9% 
and in 3.7% of subjects, respectively. A deep venous thrombosis and a superficial 
thrombophlebitis were observed in 1 subject with acquired hemophilia.
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The hemostatic effectiveness was rated by the physicians as excellent or good in more 
than 90% of total subjects, with the highest rates reported in subjects with FEIBA NF 
prescribed as regular prophylaxis. Additional details on this study can be found in the 
clinical study report.v
FEIBA consists of zymogens and traces of activated forms of procoagulant factors II, 
VII, IX, X, anticoagulants protein C and TFPI, and small amounts of cofactors FV, FVIII 
and protein S, in a balanced ratio. As mentioned before, FII-FXa complex plays a key 
role in FEIBA’s mode of action (MoA). A recently published study has shown that 
although the FII-FXa complex are the key components other procoagulant components of 
FEIBA were necessary to achieve an optimal activity. However prothrombin (FII) is the 
lead procoagulant component of FEIBA.1,11
Due to the complex nature of the composition of FEIBA, pharmacokinetic information 
cannot be determined by measurement of a single component. In recent studies where 
FEIBA was used as a comparator product surrogate markers of coagulation were used to 
determine pharmacokinetics. These surrogate markers of coagulation included 
determination of thrombin generation, activated partial thromboplastin time (aPTT), 
prothrombin time (PT), thrombin–antithrombin complex (TAT) and prothrombin 
fragment F1+2 (F1+2), and  aPTT clot waveform analysis, maximum levels of these 
surrogate markers following FEIBA administration were seen after 10 or at 30 min with 
variable results at later time points.10 In another study where thrombin generation was 
measured in patients following infusion of FEIBA peak thrombin levels were seen 
predominantly 30 and 60 minutes after infusion.13 Thus, determination of peak plasma 
concentrations of components of FEIBA seems to be most appropriate performed at 30 or 
60 minutes after infusion.
Additional observational, non-interventional studies were conducted with FEIBA NF. 
Additional details on clinical studies can be found in the FEIBA NF IB.iv
                                                
v
Clinical Study Report. Post-Authorization Safety Study of FEIBA NF (Factor VIII Inhibitor Bypassing 
Activity). An open, uncontrolled, non-interventional observational cohort study of FEIBA NF in 
hemophiliacs with inhibitors. 10 Oct 2014. Baxalta Inc. US and Baxalta Innovations GmbH.
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6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
Uncommon, hypersensitivity reactions observed after infusion of FEIBA have included, 
urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; 
these reactions can be severe and systemic (e.g., anaphylaxis with urticaria and 
angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as 
chills, pyrexia, and hypertension have also been reported. The most commonly reported 
adverse drug reactions described for FEIBA NF include increased inhibitor titer, 
somnolence, dizziness, dysgeusia, dyspnea, nausea, chills, pyrexia, chest pain, and chest 
discomfort. 
The possibility of thrombotic events should be considered when FEIBA is used in 
combination with systemic anti-fibrinolytics such as aminocaproic acid and tranexamic 
acid. Therefore, anti-fibrinolytics should not be used for approximately 6 to 12 hours 
before or after the administration of FEIBA.
Animal reproduction studies have not been conducted with FEIBA. There are no 
adequate, well-controlled studies in pregnant women. It is also not known whether 
FEIBA can cause fetal harm when administered to a pregnant woman or an affect on 
reproductive capacity. It is also not known whether FEIBA is excreted in human milk.1
Subjects within the study should be provided with labeling information and a detailed 
discussion of benefit risk profile.
Additional safety experience for FEIBA is provided in the FEIBA NF IB.iv
6.6 Compliance Statement
The study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations, the EU Directives 2001/20/EC and 
2005/28/EC, and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is:
To evaluate the tolerability and safety of infusing 50% reduced volume FEIBA at the 
standard infusion rate of 2 U/kg/min, and at increased rates of 4 and 10 U/kg/min, in 
comparison to the standard rate of 2 U/kg/min at the regular volume 
7.2 Primary Objectives
To evaluate tolerability and safety of FEIBA reconstituted in a 50% reduced volume 
of sterile water for injection (SWFI) administered at the standard infusion rate of 
2 U/kg/min and at increased rates of 4 and 10 U/kg/min, based on the occurrence of 
any adverse event, in particular of thromboembolic events and hypersensitivity 
reactions 
7.3 Exploratory Objectives
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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8. STUDY DESIGN
8.1 Brief Summary and Study Design Rationale
This is a 2-part Phase 3b/4 (depending on market authorization status per country), 
prospective, open-label, multicenter study to be conducted in at least 24 evaluable
hemophilia A or B subjects with inhibitors (≥0.6 BU in hemophilia A and B) to
determine the tolerability and safety of FEIBA component FII with a planned enrollment 
of 24 evaluable subjects. Evaluable subjects are defined as the ones who complete both 
parts of the study (i.e. received at least  8 of the 12 infusions; 4 in each part and 2 in each 
sequence in Part 1).
All subjects will receive 3 infusions of FEIBA reconstituted in a regular volume of 
SWFI, and 3 infusions of FEIBA reconstituted in 50% reduced volume of SWFI, with all 
6 of these infusions being given at a rate of 2 U/kg/min within Part 1 of the study. In 
Part 2 of the study, all subjects will receive 3 infusions of FEIBA reconstituted in 
50% reduced volume of SWFI at 4 U/kg/min followed by 3 infusions FEIBA reduced 
volume at a rate of 10 U/kg/min. 
This study has been designed as a 2-way crossover study in order to assess primarily 
tolerability and safety of FEIBA. By designing it as a crossover study, subjects serve as 
their own controls. In addition, having received 6 infusions at 2U/Kg/min in Part 1, 
patients will be near to or at steady state (post 6 infusion of FEIBA) prior to starting 
Part 2. This study is open-label because it is a change in infusion volume and infusion 
rate, which would not make it feasible to properly blind. The goal of the study is to 
determine tolerability and safety of FEIBA in 50% reduced volume SWFI to FEIBA 
regular volume SWFI, and increase rate of the 50% reduced volume at 4U/kg/min and 
10U/kg/min. By being able to reduce the volume and speed of the infusion, subjects will 
be able to spend less time infusing and reduce infusion burden during the regular use.
The exploratory objectives include  pre (within 60 min before infusion) and post-infusion 
(at 30 min, hours 1, 2, 6, 8 and 12) concentration of coagulation factor II (FII); the effect 
of 50% reduced volume FEIBA  and faster infusion rate on coagulation parameters.
FII (prothrombin) was chosen as a lead marker for FEIBA for several reasons:
1.
In previously published studies it has been demonstrated that FII is a key protein 
component of the active ingredient of FEIBA
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2.
Amongst the vitamin K-dependent proteins, FII has the highest relative plasma 
concentration as it has the lowest specific activity, and therefore the absolute 
amount of FII in FEIBA measured as protein mass is higher than for any other 
vitamin K-dependent protein
3.
The half life of FII is longer than that of any other vitamin K-dependent protein 
contained in FEIBA.
8.2 Overall Study Design
This is a 2-part Phase 3b/4 (depending on market authorization status per country), 
prospective, open-label, multicenter study to compare tolerability and safety of FEIBA 
reconstituted in 50 % reduced volume versus regular volume of SWFI, and to 
evaluate the safety of infusing reduced volume FEIBA at increased infusion rates of 
4 and 10 U/kg/min in comparison with the standard rate of 2 U/kg/min, in 24 evaluable
with hemophilia A or B with inhibitors (≥0.6 BU in hemophilia A and B). There is no 
washout period prior to Part 1 or between infusions and between the two parts of the 
study. The overall study design is illustrated in Figure 1 and Figure 2.
In Part 1, subjects will be administered 2 different volumes of FEIBA every 48 hours
(-8/+24 hours) in a 1:1 randomized, crossover manner. Both volumes will be given at the 
standard infusion rate of 2 U/kg/min. After infusion, subjects should be observed for at 
least 30 minutes at the study site. See Section 10.3.2 for details. 
Treatments regimens during Part 1 of the study are:

Part 1 Sequence A:
1. FEIBA 2 U/kg/min in regular volume SWFI (Infusions 1, 2, and 3)
2. FEIBA 2 U/kg/min in 50% reduced volume SWFI (Infusions 1, 2, and 3)

Part 1 Sequence B, patients from sequence A cross over to: 
1. FEIBA 2 U/kg/min in 50% reduced volume SWFI (Infusions 4, 5, and 6)
2. FEIBA 2 U/kg/min in regular volume SWFI (Infusions 4, 5, and 6)

Infusion dose:
All infusions: 85 ± 15 U/kg
Part 2 is non-randomized with sequential treatment of subjects who complete Part 1 to 
evaluate FEIBA reconstituted in 50% reduced volume of SWFI at increased rates of 
4 and 10 U/kg/min. FEIBA Infusions 7, 8, and 9 will be administered at the 4 U/kg/min
rate followed by 3 infusions (Infusions 10, 11, and 12) of FEIBA at 10 U/kg/min rate. 
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The infusions will be administered every 48 hours (-8 hours/+24 hours) to allow time to 
monitor safety and tolerability of the higher infusion rate.
The treatment phases within Part 2 of the study are as follows:

First treatment phase: 4 U/kg/min (Infusions 7, 8, 9) 

Second treatment phase: 10 U/kg/min Infusions 10, 11, 12)

Infusion dose:
All infusions: 85 ± 15 U/kg
All infusions will be administered at the hemophilia care centers/study sites. Sample 
collections may be performed at the hemophilia care centers/study sites, appropriate 
ambulatory centers or at home. Each subject will receive a maximum of 12 IP infusions 
total [6 in Part 1 and 6 in Part 2]. Subjects will receive FEIBA at a dose of 85 ± 15 U/kg 
for all  infusions see Section 8.7.2. After each infusion, subjects should be observed for 
30 minutes at the study site. Additional details on study design and timing are described 
in Section 8.7.3. For additional details on managing bleeding episodes, see Section 8.7.4.
See Section 15.4 for additional details on the safety reviews performed by the Internal 
Safety Monitoring Committee (ISMC).
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is expected to be approximately 10 to 13 months from 
study initiation (i.e., first subject enrolled) to study completion (i.e., last subject last 
visit). The recruitment period is expected to be approximately 9 to 11 months.
The subject participation period is approximately 6 to 11 weeks from enrollment to 
subject completion (i.e., last study visit), unless prematurely discontinued.
8.4 Outcome Measures
8.4.1 Primary Outcome Measures
Tolerability and safety (local and general) related to the infusion and volume of 
reconstitution:
1.
Occurrence of any adverse event: all AEs and SAEs, and AEs leading to 
discontinuation 
2.
Thromboembolic events and hypersensitivity reactions
3.
Vital signs and Clinical laboratory data
4.
Infusion site and infusion related reactions
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8.4.2 Exploratory Outcomes Measure
1.
To monitor pre- (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) concentration of coagulation factor II
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
8.5 Randomization and Blinding
Part 1 of this study is a randomized, crossover, active treatment clinical study. Subjects 
will be randomly assigned to 1 of 2 treatment sequences at a 1:1 ratio (Sequence A: 
FEIBA regular volume of SWFI followed by FEIBA reduced volume of SWFI or 
Sequence B: FEIBA reduced volume of SWFI followed by FEIBA regular volume 
SWFI). Part 2 of this study is an open-label, sequential, active treatment clinical study. In 
Part 2, all subjects will receive FEIBA reduced volume of SWFI at 2 varying rates of 
infusion.
8.6 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1.
If 2 or more subjects develop anaphylaxis and / or thromboembolic events 
following exposure to FEIBA (enrollment and treatment temporarily stopped 
pending further review by the ISMC)
2.
The sponsor or investigator, based on emerging data, considers there to be an 
unfavorable risk benefit
3.
The sponsor or investigator considers continuation of the study unjustifiable for 
medical or ethical reasons
4.
The ISMC recommends study termination
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
The active ingredient of FEIBA is a plasma-derived, freeze-dried, APCC with FVIII
inhibitor bypassing activity. FEIBA will be provided in vials with a nominal potency of 
500 U/vial, 1,000 U/vialand 2,500 U/vial). FEIBA contains mainly non-activated forms 
of the 3 coagulation factors, FII, FIX, and FX, as well as activated FVII; and Factor VIII 
coagulant antigen (FVIII:CAg) present in a concentration of up to 0.1 U/1 U FEIBA. 
The factors of the kallikrein-kinin system are present only in trace amounts, if at all. 
A solution containing 1 U FEIBA shortens the aPTT of FVIII inhibitor plasma to 50% of 
the buffer value. The product is supplied as freeze-dried powder or friable solid of white 
to off-white or pale green color.
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To standardize conditions in the study, FEIBA should be stored at 2°C to 8°C only.  
FEIBA should not be allowed to freeze, and should be protected from light. Aseptic 
techniques must be used for reconstituting and administering FEIBA. Although the 
chemical and physical stability of the reconstituted product has been demonstrated for 
3 hours at room temperature (up to 25°C), however, the solution should be used 
immediately as the preparation does not contain preservatives. Reconstituted product 
must not be returned to the refrigerator.
FEIBA will be provided in kits including SWFI for reconstitution. SWFI will be provided 
in different volumes for preparation of FEIBA infusions at regular volume or reduced 
volume. For additional information, such as reconstitution instructions, please refer to the 
Investigator’s Brochure and/or other specific instructions provided by the sponsor or 
sponsor’s representative.
8.7.2 Administration
Following reconstitution, FEIBA should be administered immediately using an 
intravenous needle and syringes provided by the sponsor for this study. The standard 
infusion rate of FEIBA is 2 U/kg body weight (BW) per minute, which in a 75kg subject, 
corresponds to an infusion rate of approximately 2.4 to 7.5 mL/minute depending on the 
potency (see label on vial). 
In order to standardize administration within the study, it is recommended that study drug 
be administered with an infusion pump. The infusion rate will be modified depending on 
which part of the study the subject is in, rates of 4 and 10 U/kg/min are also used in this 
study.
Subjects will receive FEIBA at a dose of 85 ± 15 U/kg for all infusions every 48 hours 
(-8 hours/+24 hours). Dose calculation for FEIBA will be based on the stated actual 
potency on vials in respective lots.  FEIBA lots may be mixed within an infusion, and 
whole vials should be rounded up or down to be as close as possible to the accurate 
dosage, as appropriate.
For additional details, see Table 1 for general information on product preparation, as well 
as the study documents, and the FEIBA IB.iv
Mixing of FEIBA with other products or substances must be avoided. It is advisable to 
flush venous access lines with isotonic saline prior to and after infusion of FEIBA.
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Dose calculation for FEIBA will be based on the stated actual potency on vials in 
respective lots. Information regarding lot used, the actual dose given, date of treatment, 
treatment start and stop times, as well as any infusion interruptions will be recorded in the
case report form (CRF).
Table 1
FEIBA Product Preparation
FEIBA
Diluent for Regular Volume FEIBA
Diluent for 50% Reduced Volume FEIBA
500 U
10 mL
5 mL
1000 U
20 mL
10 mL
2500 U
50 mL
25 mL
Abbreviations: FEIBA=Factor Eight Inhibitor Bypassing Activity.
Please note that the availability of potencies may vary among countries and regions. Dose
calculations should be made based on potencies available at site.
8.7.3 Description of Treatment
Part 1 of the study uses a crossover design to evaluate the tolerability and safety of 
FEIBA reconstituted in 50% reduced volume SWFI versus regular volume of SWFI
(administered at the standard infusion rate of 2 U/kg/min). Part 2 is a non-randomized 
study with sequential enrollment of subjects who complete Part 1. Part 2 will evaluate the 
tolerability and safety of infusing FEIBA reconstituted in 50% reduced volume of SWFI 
at increased infusion rates of 4 and 10 U/kg/min.
All subjects will be screened for eligibility based on the listed inclusion and exclusion 
criteria. The subject’s medical history including hemophilia history, confirmation of 
inhibitors, bleeding episode history, concomitant medications and history of FEIBA or 
rFVIIa usage for the previous year will be collected at screening. Also recorded will be 
the date of last use of FEIBA or rFVIIa treatment. Results of the screening assessments 
will be used to establish a subject’s eligibility for the study.
Part 1
After eligibility is established, the eligible subjects will be randomly assigned (1:1) 
into Part 1 of the study to receive 3 infusions of FEIBA reconstituted in 50% reduced 
volume SWFI followed by regular volume SWFI or vice versa every 48 hours 
(-8 hours/+24 hours).
Additional details on study visits for Part 1 can be found in Section 10.3 and Table 2.
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Part 2
Part 2 is non-randomized and uses sequential enrollment of subjects who complete Part 1 
of the study. Subjects in Part 2 will first be administered 3 infusions (Infusions 7, 8, 
and 9) of FEIBA at the 4 U/kg/min rate, followed by 3 infusions (Infusions 10, 11, 
and 12) of FEIBA at the 10 U/kg/min rate. Infusion 7 will be administered 48 hours 
(-8 hours/+24 hours) after Infusion 6. The infusions in Part 2 will be administered every 
48 hours (-8 hours/+24 hours) to allow time to monitor safety and tolerability of the 
higher infusion rate. Infusion rates for the treatment phases in Part 2 are:

First treatment phase: 4 U/kg/min (Infusions 7, 8, and 9) 

Second treatment phase: 10 U/kg/min (Infusions 10, 11, and 12)
Following the last infusion, a study termination visit will be conducted within 7 days but 
no sooner than 72 hours after the last infusion.
Additional details on study visits for Part 2 can be found in Section 10.3 and Table 3.
Additional Treatment and Visit Information
The Schedule of Study Procedures and Events Procedures listed in Table 2 and Table 3
have the visit windows listed in relation to the subject’s previous infusion. This is due to 
the variability in each subjects schedule based on previous therapy and bleeding events. 
All infusions will be administered at hemophilia care centers/study sites. Each subject 
will receive a maximum of 12 IP infusions. Subjects will receive FEIBA at a dose of 
85 ± 15 U/kg for all infusions. For specifications on dosing and administration, see 
Section 8.7.2. For information on break-through bleeding control, see Section 8.7.4.
Study visits will be completed concurrently with study infusions. After subjects 
have completed the 12 study infusions, they will complete a Study Completion/
Termination Visit within 7 days but no sooner than 72 hours after Infusion 12. 
In case of early withdrawal or discontinuation the Study Completion/Termination Visit 
will need to be completed within 7 days but no sooner than 72 hours after the last IP 
infusion received.
During each visit, the study staff will inquire with the subject about break-through 
bleeding events, treatments, and AEs throughout the study. Subjects are encouraged to 
report AEs to the site during the time spans between visits.
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Two subject questionnaires will be administered 5 times during the study, a TSQM 
questionnaire and a patient preference questionnaire to assess the subjects’ satisfaction 
and preferences for treatments, for additional details see Section 10.5.
Detailed study flowcharts are presented in Table 2 and Table 3.
Investigational product may be interrupted or discontinued at any time during the study at 
the discretion of the investigator based on his/her evaluation of the subject’s condition or 
safety. No dose modification is permitted for this study.
Any infusion site reactions, regardless of causality, will be recorded on the AE CRF. Any 
concomitant medications, including those used to treat AE(s), will be recorded on the 
appropriate CRF.
For details on the safety review by ISMC see Section 15.4.
8.7.4 Management and Treatment of Break-Through Bleeding
Bleeding episodes are managed as described below for each part of the study. In all cases, 
if the bleeding episode, of whatever severity, is not resolved within 48 hours after an 
infusion to control bleeding, the subject must contact the hemophilia treatment 
center/study site for further treatment recommendations.
Screening
During screening, subjects will be asked to keep track of any FEIBA or rFVIIa usage, as 
the last dose may be used to determine the date of the first infusion of IP. If a subject 
experiences a bleeding episode during the screening period, subjects will be treated for 
the bleeding episode per standard of care as determined by the investigator and the 
patient will be randomized after resolution of bleeding episode. 
Bleeding during the study 
If bleeding occurs during the study, it will be treated per standard of care. For bleeding 
events treated with FEIBA or rFVIIa, a time window of 48 hours post treatment for 
bleeding should be observed before resuming study infusions. The subject will resume 
their treatment regimen and visits after control of the bleeding and following the 
administration window mentioned above. Depending on the clinical circumstances (e.g., 
treatment of uncontrolled bleeding due to injury and associated complications), the 
investigator and sponsor should decide if it is appropriate for the subject to continue in 
the study.
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8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) 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(s) was received, including the date received, 
drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP(s) must be dispensed only at the study site or other suitable location (e.g.,
infusion center; home, as applicable per study design). Records will be maintained that 
include the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) 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(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
study that are necessary for the reconstruction and evaluation of the study. 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' 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.
Subject questionnaires may be entered directly onto the CRF.
For additional information on study documentation and CRFs, see Section 17.2.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
≥18 to ≤65 years old at the time of  screening
2.
Hemophilia A or B of any severity, with a documented ≥ 3 months history of 
inhibitors (≥ 0.6 BU) requiring the use of bypassing agents (FEIBA or rFVIIa) 
prior to screening. Inhibitor level will be tested at screening if no documented 
history is available.
3.
Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain 
reaction (PCR); or HCV positive with stable liver disease
4.
Human immune deficiency virus (HIV) negative; or HIV positive with stable 
disease and CD4 count ≥ 200 cell/mm3 at screening
5.
Adequate peripheral venous access
6.
Willing and able to comply with the requirements of the protocol
7.
If a female of childbearing potential, must have a negative blood pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study, such as:
a. Abstain from sexual intercourse
b. Use a reliable method of contraception (contraception such as an intrauterine 
device, barrier method [e.g., diaphragm or sponge; female condom not 
permitted] with spermicide, oral contraceptive, injectable progesterone, sub 
dermal implant), and have their male partner use a condom
8.
If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a. Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-stimulating 
hormone levels within the laboratory-defined postmenopausal range or 
postmenopausal with amenorrhea for at least 24 months and on hormonal 
replacement therapy
b. Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation (with no subsequent pregnancy at least 
1 year from bilateral tubal ligation), or bilateral salpingectomy
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Known hypersensitivity to FEIBA or any of its components
2.
Advanced liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites, prothrombin time [PT] 5 seconds above upper limit of 
normal)
3.
Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4.
Platelet count < 100,000/µL
5.
Clinical or laboratory evidence of disseminated intravascular coagulation
6.
Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
7.
Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
8.
Taking any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to 
enrollment except anti-retroviral chemotherapy.
9.
Herbal supplements that contain anti-platelet activity
10. 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
11. Family member or employee of the investigator
12. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., 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 withdraw or discontinuation) are described in 
Section 10.6 and Section 20.3.
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., 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 ISMC recommends a subject should be taken off the study

The subject becomes pregnant. IP exposure will be discontinued. Attempts will 
be made to follow the subject through completion of the pregnancy and up to
1 year postdelivery, if feasible. The investigator will record a narrative 
description of the course of the pregnancy and its outcome

AE(s)/SAE(s) that the investigator or sponsor feels poses an unacceptable risk 
for continued dosing in the subject

Participation in another clinical study involving an IP during the course of the 
study
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form [ICF] and assent form, if applicable) is considered enrolled in the study.
10.2 Subject Identification Code (SIC)
The following series of numbers will comprise the SIC: protocol identifier (e.g., 091501) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the ICF). For example, the third subject who signed an ICF at 
study site 02 will be identified as Subject 091501-020003. All study documents (e.g., 
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 (e.g., 
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. 
All screening data will be collected and reported in CRFs, regardless of screening 
outcome. 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 overall study design is illustrated in Figure 1 and Figure 2. Details on the procedures 
to be performed at each study visit, including screening, can be found in Supplement 20.3
and Supplement 20.4 Schedule of Study Procedures and Assessments (Part 1 and Part 2, 
respectively) and Supplement 20.5 Clinical Laboratory Assessments. FII concentration 
scheduling can be found in Section 20.6.
10.3.1 Screening and Baseline Assessments
After ICF is obtained, subjects will be screened on-site for eligibility based on the 
inclusion and exclusion criteria defined in Section 9.1 and Section 9.2, respectively. 
Screening procedures must be performed within 35 days of Infusion 1.
At screening, subjects will be instructed on the symptoms of thromboembolic and 
systemic hypersensitivity events by the investigator, and to contact the treatment 
center/hospital if they experience any symptoms.
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Screening assessments include the following:

Eligibility evaluation (review of inclusion/exclusion criteria)

Medical history, including
Hemophilia history, inhibitor development history, bleeding episodes
history, history of FEIBA or rFVIIa usage for a year prior to screening
Relevant medical and surgical history and all medications taken 4 weeks 
prior to screening

Review of concomitant medications/non-drug therapies

Complete physical examination (see Section 12.6)

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and
measurement body weight and height (see Section 12.8)

Karnofsky performance test assessment (see Section 12.9)

Clinical laboratory assessments (hematology, clinical chemistry, , serology 
testing and inhibitor level if no documentation is available ≥3 months prior to 
screening; see Section 12.7)

Serum pregnancy test (female subjects of childbearing potential only)

TSQM and patient preference questionnaires (see Section 10.5)
After screening and eligibility sare determined, the subject will be enrolled in the study. 
For additional details on bleeding, see Section 8.7.4.
10.3.2 Treatment Visits
10.3.2.1 Infusion Visits
Randomization will occur after the subject has been confirmed to be eligible and prior to 
the first infusion.

Randomization of eligible subjects to the following treatment sequences:
Part 1 Sequence A: FEIBA 2 U/kg/min in regular volume SWFI 
(3 infusions), FEIBA 2 U/kg/min in 50% reduced volume (3 infusions)
Part 1 Sequence B: FEIBA 2 U/kg/min in 50% reduced volume 
(3 infusions), FEIBA 2 U/kg/min in regular volume SWFI (3 infusions)
For additional details on the description of treatment, see Section 8.7.3.
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During the study (Infusion Visits 1 to 12), subjects will return to the study site according 
to the schedule presented in Table 2 and Table 3. Prior to administration of IP, the 
following assessments will be performed at all visits unless otherwise indicated:

Review of concomitant medications/non-drug therapies

AE monitoring

Vital signs (body temperature, pulse rate, blood pressure and respiratory rate)
Before administration of IP
at 30 minutes after administration of IP

Clinical laboratory assessments Table 4

IP administration (infusion site should be monitored for at 30 minutes [± 10 min] 
after infusion)

Break-through bleed monitoring

Subjects will be administered the TSQM and patient preference questionnaires:
After screening prior to Infusion 1
After Infusion 3 prior to Infusion 4
After Infusion 6 prior to Infusion 7
After Infusion 9,  prior to infusion 10
After infusion 12 or up to the completion of the Study 
Completion/Termination Visit

Prothrombin II levels will be drawn within 60 min before IP administration and at 
30 min, hours 1, 2, 6, 8 and 12 after IP administration, as outlined in Table 5 See 
also information on administration (Section 8.7.2). 
10.3.3 Study Completion/Termination Visit
The Study Completion/Termination Visit including if the subject is discontinuing early 
will be performed within 7 days but no sooner than 72 hours after Infusion 12, or the last 
infusion if discontinued early. The following assessments will be performed:

Review of concomitant medications/non-drug therapies

AE monitoring

Breakthrough bleeds monitoring

Concomitant medication monitoring
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
Clinical laboratory assessments see Table 4

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and 
body weight)
10.4 Medications and Non-Drug Therapies 
Once subject eligibility has been confirmed for the study, the following medications and 
non-drug therapies are not permitted during the course of the study:

Medications:
Any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) except
anti-retroviral chemotherapy
Any investigational drug or device
A subject who receive any of these therapies will be withdrawn from further study 
participation.
Antifibrinolytics should not be used approximately 6 to 12 hours before or after the 
administration of FEIBA.
The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:

Medications:
Hemostatic agents, such as tranexamic acid, are permitted, as indicated by 
the subject’s treating physician, to treat mucosal bleeding during the 
study (these are permitted; however, they should not be taken within 6 to 
12 hours before or after administration of FEIBA)
Any medications deemed necessary by the subject’s physician to treat or 
prevent any medical condition (with the exception of those listed as not 
permitted)
Any over-the-counter medication used by the subject to treat symptoms 
or signs of any medical condition
Supplemental vitamins, minerals
Any standard of care to treat breakthrough bleeds
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
Non-drug therapies:
Any non-drug therapy (e.g., physiotherapy) deemed necessary by the 
subject’s physician to treat or prevent any medical condition
10.5 Subject Questionnaires
Two questionnaires will be administered to subjects within this study (TSQM 14 and a 
patient preference questionnaire). These questionnaires will be used to assess the 
subject’s preferences on the IP, as well as their satisfaction with the IP, and will be 
collected in the CRF or on paper. Both questionnaires will be administered:

After screening prior to Infusion 1

After Infusion 3 prior to Infusion 4

After Infusion 6 prior to Infusion 7

After Infusion 9,  prior to infusion 10

After infusion 12 or up to the completion of the Study Completion/Termination 
Visit
These questionnaires can be completed between visits but should be completed prior to 
the start of the next infusion. The final questionnaire should be completed prior to or 
during the Study Completion/Termination Visit.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when the subject ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according to the protocol.
Reasons for completion/discontinuation will be reported on the Completion /
Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems, and severe hypersensitivity reaction), ISMC recommends a subject should not 
continue. Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
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Every effort will be made to have discontinued subjects complete the Study 
Completion/Termination Visit. If the Study Completion/Termination Visit is done as 
an additional, unscheduled visit, the assessment results shall be recorded with the 
Study Completion/Termination Visit. If a subject terminates participation in the 
study and does not return for the Study Completion/Termination Visit, their last 
recorded assessments shall remain recorded with their last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of 
discontinuation will be used in the analysis and included in the clinical study report. 
If additional assessments are required, the assessments shall be recorded separately.
Assessments to be performed at the termination visit (including in cases of withdraw or 
discontinuation) can be found in Supplement 20.3 Schedule of Study Procedures and 
Assessments and Supplement 20.5 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
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures will be used to monitor subject compliance.
11. ASSESSMENT OF PHARMACOKINETICS
Pharmacokinetics will not be evaluated in this study.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 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 (e.g., an abnormal laboratory finding), 
symptom (e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that at any dose meets 1 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 (i.e., 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 1 of the other 
outcomes listed in the definitions above. Examples of such events are:
Intensive treatment in an emergency room or at home for bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependence or drug abuse
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Additional events which should be reported the same way as SAEs are as follows:

Reviewed and confirmed seroconversion for HIV, hepatitis A virus, hepatitis B 
virus, HCV, hepatitis E virus, or parvovirus B19

Hospitalization for planned port placement or removal is not considered an SAE, 
however, any hospitalization required for an emergency port removal is 
considered an SAE

Any thromboembolic event

Hypersensitivity reactions
Uncomplicated pregnancies, following maternal or paternal 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. Any 
pregnancy occurring during the study should be reported to the sponsor within 24 hours 
of the site learning about the pregnancy. The pregnancy should be followed until
completion of the pregnancy and up to 1 year postdelivery, if feasible. Pregnancies not 
considered an (S)AE as described above will be captured in the CRF.
Voluntary overnight stays by subjects in hospital or hospital-affiliated facilities for the 
convenience/compliance with study procedures as described in Section 10.3.2 for reasons 
unrelated to AEs will not be considered as hospitalization for SAE reporting purposes
unless the hospitalization is prolonged.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., 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.
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12.1.1.4 Pre-existing Diseases
Pre-existing 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 pre-existing disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
Each AE from the first IP exposure until study termination/completion 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 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., 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, it is medically 
stabilized, or 30 days after the Study Completion/Termination Visit, whichever comes 
first, and the follow-up information is to be documented in the CRF. If the severity rating 
for an ongoing AE changes before the event resolves, the original AE report will be 
revised (i.e., 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 (20% higher than the 
highest permitted dose), underdosing (20% lower than the lowest permitted dose), 
treatment errors (including incorrect route of administration, use of an incorrect product, 
and deviations from the protocol-defined dosing schedule), failures of expected 
pharmacological actions, and unexpected therapeutic or clinical benefits will be followed 
with regard to occurrence of AEs, lack of efficacy, and/or other observations because 
these events may be reportable to regulatory authorities.
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Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and 1 year postdelivery, if 
feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion/termination, the SAE must be reported on the provided SAE Report Form 
within 24 hours after awareness; no additional reporting on CRFs is necessary.
12.1.2.1 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.
12.1.2.2 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, 
e.g., 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.
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For each AE, the investigator will assess the causal relationship between the IP and the 
AE using his/her clinical expertise and judgment according to the following most 
appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (i.e., 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 
rechallenge)
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 72 hours after 
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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12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 3) and Section 12.1.
Adverse Events/SAEs are to be recorded on the AE page of the CRF. Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported by completing the relevant CRF 
page(s) in English. Once the SAE has been recorded, SAEs must be reported  to the 
sponsor to meet the 24-hour timeline requirement (contacts and instructions to be 
provided in separate documentation). 
The initial SAE information reported on the applicable CRF pages (must at least include 
the following:

Protocol Number

Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)

Investigational product exposure

Medical Term for Event (Diagnosis preferably) 

Description of the (S)AE, including:
Date of onset
(S)AE treatment (drug, dose, route of administration)
Causal relationship by the investigator
Measures taken (i.e., action taken regarding IP in direct relationship to the 
AE)

Seriousness criteria (i.e., death, life-threatening, or other criterion)

Cause of death

Autopsy findings (if available)

Name, address, fax number, email, and telephone number of the reporting 
investigator (for paper SAE Report Forms) 
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12.1.3 Medical Device Safety Reporting
The IP kit contains the BaxJect II Hi-Flow needleless transfer device. All Serious Injuries 
(SI) and Unexpected Adverse Device Events (UADE) must be reported to the sponsor as 
an SAE in the same process as described above.
Serious injury is defined as:

Life-threatening injury or illness results in permanent impairment/ damage to 
body function/ structure.

Requires medical or surgical intervention to preclude permanent impairment/ 
damage to body function/ structure.
12.2 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 study 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 study or studies

Any other immediate action taken in order to protect clinical study 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 (EC) and relevant competent authority(s) are
notified of the urgent safety measures taken in such cases according to local regulations.
12.3 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 12.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the AE CRF . These events will be considered as SAEs but will not be 
included in the analysis of SAEs. 
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12.4 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, e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., 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

Medication errors: an error (of commission or omission) at any step along the 
pathway that begins when a clinician prescribes a medication and ends when the 
patient actually receives the medication e.g., administration of incorrect dose
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.
12.5 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 12.1.2.1) 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.
General medical history will be collected for 4 weeks prior to screening. Any information 
on the subjects’ hemophilia history will be collected a year prior to screening including 
documented history of hemophilia, confirmation of inhibitors, bleeding episodes history, 
and history of FEIBA or rFVIIa usage.
All medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies CRFs.
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12.6 Physical Examinations
At screening (as described in Table 2 and Table 3), 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 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 pre-existing disease (described in Section 12.1.1.4), 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.
12.7 Clinical Laboratory Parameters
Assessments will be performed at a central laboratory (see Section 15.7), according to the 
laboratory manual. Blood samples that remain after study testing is done may be stored 
and used for any additional testing as needed (see Section 12.7.6). Samples will be 
destroyed after a maximum of 2 years from the time the final study report has been 
completed.
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count [hemoglobin, hematocrit, 
erythrocytes (i.e., red blood cell count), and leukocytes (i.e., white blood cell count)] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) mean 
corpuscular volume, mean corpuscular hemoglobin concentration, and platelet counts. 
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
aspartate aminotransferase (AST), total protein, albumin, alanine aminotransferase
(ALT), total bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, 
glucose, gamma-glutamyl transpeptidase (GGT), and 5’-nucleotidase.
Blood will be obtained for assessment of hematology and clinical chemistry parameters at 
screening and at study completion/termination. 
In addition, serum samples for pregnancy tests for females of childbearing potential will 
be collected at screening.
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12.7.2 Concentration of FII and Coagulation Testing
Blood samples for the determination of FEIBA components FII will be taken within 
60 (±15) min before and at 30 (±10) min, after completion of each infusion. In addition 
hours 1 (±15min), 2  (±30min), 6 (±1hour), 8 (±2hours) and 12 (±4hours) samples will be 
taken after infusion 1,3,4,6,9 and 12 (see Section 20.6 for sampling time points and 
allowed sampling time windows). The date and time of each sample collections will be 
documented in the subject’s CRF. 
Blood will be obtained for the assessment of coagulation testing and consist of aPTT, PT, 
thrombotic markers (D-Dimers, prothrombin fragment F 1+2, TAT, fibrinopeptide A), 
and FII concentration. Coagulation testing will be performed, during the study and 
samples at hours 1 (±15min), 6 (±1hour) and 12 (±4 hours) will be taken after infusion 
1,3,4,6,9 and 12 (see Section 20.6 for sampling time points and allowed sampling time 
windows). 
12.7.3 Viral Serology
Viral serology testing will include HIV-1 and HIV-2 antibody, hepatitis A virus (HAV)
antibody, hepatitis B virus (HBV) antibody, hepatitis B surface antigen (HBsAg), HCV 
antibody, parvovirus B19 (immunoglobulin M [IgM] and immunoglobulin G [IgG] 
antibodies), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus 
antibodies (IgM and IgG). The HCV titer will be confirmed by PCR for all subjects 
reported as HCV positive. All viral serology assessments will be performed at screening
and at the Study Completion/Termination Visit.
12.7.4 CD4 Levels
At screening only, CD4 levels will be determined using flow cytometry in the case of a 
subject being HIV positive.
12.7.5 Assessment of Laboratory Values
12.7.5.1 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value 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 12.1, 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 12.1.1.4), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e., because it is due to a 
pre-existing disease, due to a lab error, or due to another issue that will be specified. 
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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.
12.7.6 Biobanking
Backup samples should be taken and stored appropriately for additional analysis, if 
necessary. Backup samples that remain after study testing is done may be stored and used 
for additional testing (e.g., further evaluation of an abnormal test or an AE. 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.
12.8 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) 
measured once at screening and weight (lb or kg) measured at screening and 
completion/termination will also be collected.
Vital signs will be measured at screening and within 30 minutes before and after (except 
weight) administration of IP, at each Infusion study visit, and at study 
completion/termination. Blood pressure will be measured when subjects are in the supine 
position.
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 12.1
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.
12.9 Karnofsky Performance Test
The Karnofsky Performance Test is a status scale (0-100) utilized to measure the level of 
activity and medical care requirements in subjects. It is an investigator based assessment 
of subject status which evaluates the subjects’ ability to carry on normal life activities, as 
well as the symptoms of their disease. In this scale, a high number performance status 
represents high functionality, and a lower number represents low functionality and likely 
rapid progression of disease.15 Subjects will be scored using this scale at screening.
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12.10 Infusion Site Evaluations
The current site of IP infusion will be assessed for immediate local reactions at 
30 minutes (±10 min) after infusion. In addition, infusion sites will be monitored by the 
subject for up to 12 hours after infusion, and will be discussed with the site staff during 
the next study visit.
Infusion sites will be monitored for pain, tenderness, erythema, and swelling. Infusion 
site evaluations will be made by clinical staff or by the subject or caregiver. If an infusion 
site reaction is observed, a physician will characterize and document the reaction as an 
AE. Infusion sites will continue to be reviewed at each study visit, and any infusion site 
reactions will be followed until resolution. Each infusion site reaction will be categorized 
using the intensity grading described for AEs in Section 12.1.2.1.
12.11 Special Treatment Considerations
Subjects will be screened for eligibility in the study as described in Section 9.1 and
Section 8.7.3, and will be informed of the study specific restrictions and requirements of 
the study. Subjects who are not willing to comply with the study requirements and 
restrictions of the study will not be eligible for enrollment.
All biological agents carry the risk of hypersensitivity reactions. Clinical manifestations 
of these reactions may include, but are not limited to:

Skin rash

Pruritus (itching)

Urticaria (hives)

Angioedema (for example, swelling of the lips and/or tongue)

Anaphylactic reaction
Proteins may also cause redness, itching, swelling, or pain locally at the infusion site.
Thromboembolic events have been observed with bypassing agents including FEIBA. 
Clinical manifestations of these events may include, but not limited to:

myocardial infarction

deep vein thrombosis

pulmonary embolism

stroke and

transitory ischemic attack
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Sometimes, these reactions can be life-threatening. Therefore, all subjects should be 
closely monitored for signs or symptoms that could result from such reactions, educated 
on the signs or symptoms of these types of reactions, and instructed to contact the study 
site immediately if any of the symptoms are experienced following an injection. If a 
subject experiences an acute hypersensitivity reaction after an infusion of IP, the subject
should be managed appropriately and given instruction to receive relevant supportive 
care. 
Subjects who experience a potentially severe hypersensitivity  reaction will be 
discontinued from IP. They will complete a Termination/Study Completion Visit, and 
will be monitored for stabilization or resolution of the AE. Premedication to prevent 
allergic reactions will not be permitted, as severe hypersensitivity reactions are an 
outcome measure for this study.
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13. STATISTICS
Data handling will be conducted by the contract research organization. The data will be 
inspected for inconsistencies by performing validation checks.
Statistical analysis for this study will be descriptive in nature. All details regarding the 
statistical analysis and the preparation of tables, listings, and figures will be described in 
the statistical analysis plan (SAP) prepared by the contract research organization and 
approved by the sponsor before database lock.
13.1 Sample Size and Power Calculations
The sample size of 24 evaluable subjects for this safety study was determined by 
considering available patients, and is not based on statistical power calculations.
13.2 Datasets and Analysis Cohorts
Safety: The safety analysis set will include all subjects who received at least 1 dose of IP
(FEIBA). All safety analyses will be performed on the safety analysis set. Subjects will 
be evaluated according to the treatment received.
13.3 Handling of Missing, Unused, and Spurious Data
All data will be evaluated as observed. A subject who withdraws prior to the last planned 
observation in a study period will be included in the analyses up to the time of 
withdrawal.
13.4 Methods of Analysis
13.4.1 Primary Outcome Measure
13.4.1.1 Analysis of the Primary Outcome Measure (Parts 1 and 2)
AEs, SAEs and AEs leading to discontinuation, thromboembolic events and 
hypersensitivity reactions that occurred during or after IP infusions will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be carried out for temporally associated adverse 
events; and for temporally associated or potentially related adverse events as assessed by 
the investigators. Temporally associated AEs are defined as AEs that begin during 
infusion or within 24 hours (or 1 day where time of onset is not available) after 
completion of infusion, irrespective of being related or not related to treatment.
In addition, tables will be prepared to list each AE, the number of subjects who 
experienced an AE at least once, and the rate of subjects with AE(s). 
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AEs will be grouped by system organ class. Each event will then be divided into defined 
severity grades (mild, moderate, severe). The tables will also divide the AEs into those 
considered related to the infusion and those considered unrelated. These tables will also 
be carried out for temporally associated adverse events; and for temporally associated or 
causally related adverse events. 
AEs and SAEs for each subject, including the same event on several occasions, will be 
listed separately, giving both MedDRA preferred term and the original term used by the 
investigator, system organ class, severity grade, seriousness, relation to the treatment, 
onset date, and stop date.
AEs that occurred before first IP infusion will be listed separately.
Shift tables and summary statistics will be presented for the results of clinical laboratory 
data. All abnormal lab results will be listed.
Summary statistics of vital signs, infusion site and infusion related reactions will be 
carried out.
13.4.2 Exploratory Outcome Measures 
All exploratory outcome measures will be analyzed descriptively.
Full details of the statistical analysis will be specified in the SAP.
13.5 Planned Interim Analysis of the Study
There is no planned interim analysis other than a safety data review by the ISMC.
14. 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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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 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.
15.1.1 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.
15.2 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.
15.3 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.
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15.4 Safety Monitoring
Primary objective of the study is to monitor safety parameters throughout the study with a 
special emphasis on hypersensitivity and thromboembolic events. Adverse event data will 
be collected at each visit assessed and documented on the CRFs as outlined in
Section 12.1.2.3.
Serious adverse events are monitored and reported per the safety reporting guidelines as 
outlined in Section 12.1.2.3.
This study will be monitored by an ISMC. The ISMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from the ongoing 
clinical study. For this study, the ISMC will be composed by appropriate members of 
clinical, safety, and biostatistics division that are not involved in the active execution of 
the trial. The ISMC can stop a study if it finds toxicities or if treatment is proven to be not 
beneficial. 
All SAEs will be reviewed within 24 hours by the Chair of the ISMC. There are 
3 planned ISMC meetings:
1.
Within 24 hours after 6 subjects in Part 1 (3 subjects in each group) have 
completed Infusion 5
2.
Within 24 hours after 6 subjects have completed Infusion 7 (Part 2)
3.
Within 24 hours after 6 subjects have completed Infusion 10 (Part 2)
ISMC preplanned meetings will be held concurrently with the ongoing study.
Subjects can continue with their scheduled therapy and assessments unless the ISMC
warrants that the trial needs to be suspended due to safety concerns. Additional ad hoc 
meetings of the ISMC may be convened as appropriate per ongoing safety evaluations.
15.5 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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15.6 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 (Baxalta) will also ensure the responsible EC 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.
15.7 Laboratory and Reader Standardization
Not applicable; a central laboratory/reader will be used for all clinical assessments.
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16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, ICF, any promotional 
material/advertisements, and any other written information to be provided to patients 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.
16.3 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 must sign an ICF before entering into the study according to applicable 
regulatory requirements and ICH GCP. Before use, the ICF will be reviewed by the 
sponsor and approved by the EC and regulatory authority(ies), where applicable, (see
Section 16.2). The ICF 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 will be allowed sufficient 
time to consider participation in the study. By signing the ICF, patients agree that they 
will complete all evaluations required by the study, unless they withdraw voluntarily or 
are terminated from the study for any reason.
The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised ICF, that have 
been approved by the applicable EC and regulatory authorities, where applicable, will be 
provided by the investigator to the subjects who consented to participate in the study.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper/electronic 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 ICFs, 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 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/electronic format, and this documentation will be 
considered source documentation. Changes to an 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 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., 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.
17.3 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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18. 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.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement.
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20.3 Schedule of Study Procedures and Assessments (Part 1)
Table 2
Schedule of Study Procedures and Assessments (Part 1)
Procedures/
Assessments
Screening 
Assessments
Study Visitsa
Randomization
Infusion #1
Infusion #2
Infusion #3
Infusion #4
Infusion #5
Infusion #6
Study Visit Windowsb
A maximum 
of -35 days 
to 0
Day 1
within 48 hrs 
(-8/+24) 
from Infusion 1
48 hrs 
(-8/+24) 
from Infusion 2
48 hrs 
(-8/+24) 
from Infusion 3
48 hrs 
(-8/+24) 
from Infusion 4
48 hrs
(-8/+24) 
from Infusion 5
Informed Consentc
X
Eligibility Criteria
X
Medical History
X
Medication and Non-drug Therapies
X
X
X
X
X
X
X
Physical Examination
X
Pregnancy Test
X
Vital Signsd
X
X
X
X
X
X
X
Karnofsky Performance Test
X
Laboratory Assessmentse
X
X
X
X
X
X
X
Inhibitor level if no documentation
X
Factor II levelsf
X
X
X
X
Adverse Events, breakthrough bleeds, 
and infusion site reactionsg
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesh
X
X
Coagulation testingi
X
X
X
X
Abbreviations: ICF=informed consent form; IP=investigational product
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Continued
a A Study Completion/Termination Visit is to be completed in Part 1 only for subjects who withdraw or discontinue prior to the end of the study. If a 
subject withdraws or discontinues, this visit should be completed within 7 days but no sooner than 72 hours from the last infusion that the subject
received. Otherwise, the Study Completion/Termination Visit will occur at the end of Part 2 (see Table 3).
b Study Visit Windows:
Infusion 1 can be scheduled after screening assessments have been completed; all other infusions will occur within 48 hours (-8/+24hours) from the 
previous infusion.
c Occurs at enrollment (prior to any study-specific procedure).
d Vital signs will include body temperature, pulse rate, blood pressure, and respiratory rate,. Blood pressure will be measured when subjects are in the 
supine position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within at 30 minutes after completion of 
the infusion. Height, measured once at Screening, and weight measured at Screening and Completion/Termination will also be collected.
e For laboratory assessments, see Section 20.5.
f FII levels within 60 minutes (±15min) before and 30 mins (±10min) and all timepoint within 60 min (±15 min) before and at 30 min (±10 min), 
hours 1 (±15 min), 2 (±30 min), 6 (±1 hour), 8 (±2 hour), and 12 (±4hours) after infusions 1, 3, 4 and 6.
g The infusion site will be monitored for AEs for 30 ±10 minutes after each study infusion. See Section 12.10 for details. SAEs will be collected from ICF 
signing but will not be included in the analysis of SAEs. See Section 12.3 for details.
h Questionnaires (TSQM and patient preference questionnaire) will be administered after screening prior to Infusion 1, after Infusion 3 prior to Infusion 4, 
after Infusion 6 prior to Infusion 7, after Infusion 9 prior to infusion 10, and after infusion 12 or up to the completion of the Study 
Completion/Termination Visit. These questionnaires can be completed between visits but should be completed prior to the start of the next infusion. The 
final questionnaire should be completed prior to or during the Study Completion/Termination Visit.. See Section 10.5 for details. 
i Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A) post-infusion at 
1 hr ± 15 min (mentioned in Section 12.7.2).
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20.4 Schedule of Study Procedures and Assessments (Part 2)
Table 3
Schedule of Study Procedures and Assessments (Part 2)
Procedures/
Assessments
Study Visits
Infusions 7
Infusion 8
Infusion 9
Infusion 10
Infusion 11
Infusions 12
Study 
Completion/
Termination 
Visita
Rate of Infusion
Rate: 4 U/kg/min
Rate: 10 U/kg/min
Study Visit Windowsb
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
72 h to 7 days 
from Infusion
12 
(or last infusion)
Medications and Non-drug Therapies
X
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
Laboratory Assessmentsd
X
X
X
X
X
X
X
Factor II levelse
X
X
Adverse Events, breakthrough 
bleeds, and infusion site, infusion 
related reactionsf
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesg
X
X
X
Coagulation testingh
X
X
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Continued
a
The Study Completion/Termination Visit includes cases of withdrawal or discontinuation. This visit should be done within 7 days but no sooner than 
72 hours after Infusion 12). If a subject withdraws or discontinues, this visit should be done within 7 days but no sooner than 72 hours after the last 
infusion that the subject receives.
b
Infusions will occur within 48 hours (+-8/+24hours) from the previous infusion.
c
Vital signs will include body temperature, pulse rate, blood pressure, respiratory rate,. Blood pressure will be measured when subjects are in the supine 
position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within at 30 minutes after completion of the 
infusion. Height, measured once at Screening, and weight measured at Screening and Completion/Termination will also be collected.
d
For laboratory assessments, see Section 20.5.
e
FII levels within 60 minutes (±15min) before and 30 mins (±10min) and all timepoint within 60 min (±15 min) before and at 30 min (±10 min), hours 1 
(±15 min), 2 (±30 min), 6 (±1 hour), 8 (±2 hour), and 12 (±4hours) after infusions 9 and 12.
f
The infusion site will be monitored for AEs for 30 ±10 minutes after the infusion. See Section 12.10 for details. SAEs will be collected from ICF 
signing but will not be included in the analysis of SAEs. See Section 12.3 for details.
g
Questionnaires (TSQM and patient preference questionnaire) will be administered after screening prior to Infusion 1, after Infusion 3 prior to Infusion 4, 
after Infusion 6 prior to Infusion 7, after Infusion 9 prior to infusion 10, and after infusion 12 or up to the completion of the Study 
Completion/Termination Visit. These questionnaires can be completed between visits but should be completed prior to the start of the next infusion. The 
final questionnaire should be completed prior to or during the Study Completion/Termination Visit. See Section 10.5 for details.
h Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A) (mentioned in 
Section 12.7.2).
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20.5 Clinical Laboratory Assessments
Table 4
Clinical Laboratory Assessments
Assessments 
Screening Visit
Infusions 1, 3, 4, 6, 9, 12
Study Completion/ 
TerminationVisita
Hematologyb
X
X
Clinical Chemistryc
X
X
Coagulation Testingd
X
Serological Testinge and CD4f
X
X
Pregnancy Testg
X
a
Includes cases of withdraw or discontinuation.
b
Hematology assessments include:  CBC (Hct, Hgb, RBC count, WBC count) with differential, MCV, MCHC, and platelet count.
c
Clinical chemistry assessments include sodium, chloride, potassium, bicarbonate, AST, ALT, albumin, total protein, alkaline phosphatase, total 
bilirubin, BUN, creatinine, glucose, GGT, 5’-nucleotidase.
d
Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A (mentioned in 
Section 12.7.2).
e
Serological testing will include: HIV-1 and HIV-2 antibodies (HIV+, check CD4 count–screening visit only), HAV antibodies, HBV antibody, HBsAg, 
HCV antibody, parvovirus B19 (IgM and IgG), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus antibodies (IgM and IgG).
f
CD4 at screening in case of positive HIV test results.
g
A serum pregnancy test will be performed for females of childbearing potential.
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20.6 Concentrations of FII and Coagulation testing
Table 5
FII and Coagulation Testing Time Frame
Procedures/Assessments
PART 1
Infusions 1, 3, 4, 6
PART 2
Infusions 9, 12 
Infusions 
2, 5, 7, 8, 10, 11
FII concentration
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
1 hr ± 15 min
2 hr ± 30 min
6 hr ± 1 hr
8 hr ± 2 hr
12 hr ± 4 hr
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
1 hr ± 15 min
2 hr ± 30 min
6 hr ± 1 hr
8 hr ± 2 hr
12 hr ± 4 hr
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
Coagulation testing: 
aPTT, PT, thrombotic 
markers (D-Dimers, 
Prothrombin fragment F 1+2, 
TAT, fibrinopeptide A)
Infusions 1, 3, 4, 6, 9, and 12
Post infusion:
1 hr ± 15 min
6 hr ± 1 hr
12 hr ± 4 hr
Abbreviations: EOI=end-of-infusion; Factor II, h=hours; min=minutes
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21. REFERENCES
1.
Baxter Healthcare Corporation. FEIBA (Anti-inhibitor coagulant complex) for 
intravenous use, lyophylized powder for solution. 2013.
https://www.baxter.com/assets/downloads/feiba_us_pi.pdf
2.
Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity 
(FEIBA®): 10-year compilation of thrombotic adverse events. Haemophilia. 
2002;8(2):83-90.
3.
Hilgartner M, Aledort L, Andes A, Gill J. Efficacy and safety of vapor-heated anti-
inhibitor coagulant complex in hemophilia patients. FEIBA Study Group. 
Transfusion. 1990;30(7):626-630.
4.
Hilgartner MW, Knatterud GL, Group FS. The use of factor eight inhibitor by-
passing activity (FEIBA immuno) product for treatment of bleeding episodes in 
hemophiliacs with inhibitors. Blood. 1983;61(1):36-40.
5.
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(3):560-575.
6.
Boggio LN, Kessler CM. Hemophilia A and B. In: Kitchens C, Alving BM, Kessler 
CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier 
Saunders; 2007:45-59.
7.
Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. 
Haemophilia. 1998;4(4):558-563.
8.
Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII 
and factor IX inhibitors in haemophiliacs. Lancet. 1992;339(8793):594-598.
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9.
Turecek PL, Varadi K, Gritsch H, et al. Factor Xa and prothrombin: mechanism of 
action of FEIBA. Vox Sang. 1999;77 Suppl 1:72-79.
10.
Turecek P, Schwarz HP. Factor eight inhibitor bypassing activity. In: Bertolini B, 
Goss N, Curling J, eds. Production of Plasma Proteins for Therapeutic Use. United 
States: John Wiley and Sons; 2013:49-64. Open Access: 
https://books.google.at/books?id=MGL0QOc-
rtsC&printsec=frontcover&source=gbs_ViewAPI&output
11.
Varadi K, Tangada S, Loeschberger M, et al. Pro- and anticoagulant factors 
facilitate thrombin generation and balance the haemostatic response to FEIBA® in 
prophylactic therapy. Haemophilia. 2016;22(4):615-624.
12.
Négrier C, Voisin S, Baghaei F, et al. Global Post-Authorization Safety 
Surveillance Study: real-world data on prophylaxis and on-demand treatment using 
FEIBA (an activated prothrombin complex concentrate). Blood Coagul 
Fibrinolysis. 2016;27(5):551-556.
13.
Himmelspach M, Richter G, Muhr E, et al. A fully recombinant partial prothrombin 
complex effectively bypasses FVIII in vitro and in vivo. Thromb Haemost. 
2002;88(6):1003-1011.
14.
Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. 
Validation of an abbreviated treatment satisfaction questionnaire for medication 
(TSQM-9) among patients on antihypertensive medications. Health Qual Life 
Outcomes. 2009;7:36.
15.
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents 
in cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. New 
York: Columbia University Press; 1949:191-205.
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22. SUMMARY OF CHANGES
Protocol 091501 AMENDMENT 3 (Global): 2017 SEP 14
Replaces: Protocol 091501 AMENDMENT 2 (Global): 2017 AUG 04
In this section, changes made in this amendment from the previous version of the
protocol, dated 2017 AUG 04, are described and their rationale is given.
1.
Packaging, Labeling, and Storage, Section 8.7.1
Description of Change: Product Insert changed to Investigator’s Brochure
Purpose of Change: Reconstitution details of the Investigational Product will be 
provided in the Investigator’s Brochure and not the Product Insert.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 3 (Global): 2017 SEP 14
Replaces
AMENDMENT 2 (Global): 2017 AUG 04
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 3 (Global): 2017 SEP 14
Replaces
AMENDMENT 2 (Global): 2017 AUG 04
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
 MD, 
Global Clinical Development Operations
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CLINICAL STUDY PROTOCOL
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
STUDY SHORT TITLE: FEIBA Reconstitution Volume Reduction and Faster 
Infusion Study (FEIBA STAR)
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 4 (Global): 2018 MAR 07
Replaces:
AMENDMENT 3 (Global): 2017 SEP 14
ALL VERSIONS:
Amendment 4 (Global): 2018 MAR 07
Amendment 3 (Global): 2017 SEP 14
Amendment 2 (Global): 2017 AUG 04
Amendment 1 (Global): 2016 MAR 03
Original: 2015 OCT 08
OTHER ID(s)
NCT Number: 02764489
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
Study Sponsor(s):
Baxalta US Inc.
300 Shire Way,
Lexington, MA 02421,
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, 
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory)/Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g., 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 INCLUDING SUSARs, 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
Drug Safety contact information: see SAE Report From
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:

Adverse Event, Section 12.1

Serious Adverse Event, Section 12.1.1.1

Assessment of Adverse Events, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT (IP)
Name of IP
Anti-inhibitor Coagulant Complex Nanofiltered (activated 
prothrombin complex concentrate [APCC]), FEIBA NF. 
Referred to as FEIBA throughout the protocol.
Name(s) of Active 
Ingredient(s)
Coagulation factors II, Xa, IX, and VIIa
CLINICAL CONDITION(S)/INDICATION(S)
FEIBA is an Anti-Inhibitor Coagulant Complex (AICC) indicated for use in hemophilia 
A and B patients with

inhibitors for:
Control and prevention of bleeding episodes
Perioperative management
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

FEIBA is not indicated for the treatment of bleeding episodes resulting from 
coagulation factor deficiencies in the absence of inhibitors to factor VIII or 
factor IX (FIX).1
PROTOCOL ID
091501
PROTOCOL TITLE
A Phase 3b/4, Prospective, Multicenter, Open-label, 
Randomized, Crossover Study of Tolerability and Safety 
of FEIBA Reconstituted in Regular or 50% Reduced 
Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
Short Title
FEIBA Reconstitution Volume Reduction and Faster Infusion 
Study (FEIBA STAR)
STUDY PHASE
Phase 3b/4, depending on market authorization status per 
country
PLANNED STUDY PERIOD
Initiation
First Subject In: Q 3 2018
Primary Completion
Last Subject In: Q1 2020
Study Completion
Last Subject Last Visit: Q2 2020
Duration
6 to 11 weeks
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STUDY OBJECTIVES AND PURPOSE
Study Purpose
To evaluate the tolerability and safety of infusing reduced volume FEIBA at the standard 
infusion rate of 2 U/kg/min, and at increased rates of 4 and 10 U/kg/min, in comparison 
to the standard rate of 2 U/kg/min at the regular volume
Primary Objectives
To evaluate tolerability and safety of FEIBA reconstituted in a 50% reduced volume of 
sterile water for injection (SWFI) administered at the standard infusion rate of 
2 U/kg/min and at increased rates of 4 and 10 U/kg/min, based on the occurrence of any 
adverse event, in particular of thromboembolic events and hypersensitivity reactions 
Exploratory Objectives
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) activity of coagulation factor II  with 50% reduced volume 
of FEIBA and faster infusion rates
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
STUDY DESIGN
Study Type/ 
Classification/ 
Discipline
Tolerability and Safety
Control Type
Active
Study Indication Type
Treatment
Intervention model
Part 1:  Crossover
Part 2:  Sequential
Blinding/Masking
Part 1:  Randomized, Open-label
Part 2:  Non-Randomized, Open-label
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Study Design
A 2-part, Phase 3b/4, prospective, open-label, multicenter 
study to be conducted in 24 evaluable hemophilia A or B 
subjects with inhibitors (≥0.6 Bethesda units [BU]) for the 
primary tolerability and safety assessments.
Part 1:
In Part 1, subjects will be administered two different volumes 
of FEIBA in a randomized, crossover design every 48 hours 
(-8, +24 hours) intervals. Part 1 will monitor the tolerability, 
safety, pre (within 60 min before the infusion) and post-
infusion (at 30 min, hours 1, 2, 6, 8 and 12) activity of 
coagulation factor II (FII) reconstituted in 50% reduced 
volume of SWFI and administered at the standard infusion rate 
of 2 U/kg/min compared with FEIBA reconstituted in regular 
volume of SWFI at the standard infusion rate.
All subjects will be screened for eligibility based on the listed 
inclusion and exclusion criteria.
Eligible subjects will be randomly assigned (1:1) to receive 
3 infusions of FEIBA reconstituted in 50% reduced volume 
SWFI or regular volume SWFI (Period 1).
Patients finishing 3 infusions in Period 1 (Sequence A or B), 
will either switch from FEIBA reconstituted in reduced volume 
to 3 infusions of FEIBA in regular volume SWFI or vice versa 
(Sequence A or B) depending on randomization.
All patients completing Part 1 will move to Part 2. Evaluable 
patients from Part 1 are all subjects who receive 4 of the 
6 planned infusions, at least 2 infusions in each sequence.
Tolerability and safety data will be collected before, during and 
after each infusion and between infusions; Clinically apparent 
changes in vital signs, laboratory parameters, infusion site 
reactions and infusion rate-related reactions will be monitored.
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FII activity will be monitored by analyzing concentrations 
before (within 60 min before the infusion) and at 30 min after 
each infusion and at hours 1, 2, 6, 8 and 12 after infusion 1,3,4
and 6 as outlined in Section 20.6.
Part 2:
Part 2 is non-randomized with sequential treatment of all 
evaluable subjects who complete Part 1. Subjects will receive 
FEIBA reconstituted in 50% reduced volume of SWFI at 
increased rates of 4 and 10 U/kg/min in a non-randomized 
fashion, at 48 hours (-8, +24 hours) intervals, to evaluate the 
tolerability and safety of infusing FEIBA reconstituted in 50% 
reduced volume of SWFI at increased rates of 4 and 
10 U/kg/min.
FEIBA Infusions 7, 8, and 9 will be administered at the 
4 U/kg/min rate and infusions 10, 11 and 12 will be 
administered at 10 U/kg/min.
Following the last infusion (infusion 12), a study termination 
visit will be conducted within 7 days but no sooner than 
72 hours after the last infusion.
Evaluable patients from Part 2 are all subjects who receive 4 of 
the 6 planned infusions, at least 2 infusions per infusion rate.
Tolerability and safety data will be collected before, during and 
after each infusion and between the infusions; Clinically 
apparent changes in vital signs, infusion rate-related events, 
and infusion site reactions will be monitored.
Activity of coagulation factor II will be assessed before (within 
60 minutes before the infusion) and at 30 min after each 
infusion, and at hours 1, 2, 6, 8 and 12 after infusions 9, and 
12 as outlined in Section 20.6.
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The infusions in both parts will be administered every 48 hours 
(-8 hours /+24 hours) to allow time to monitor tolerability and 
safety of the higher infusion rate. 
All IP infusions will be administered at the hemophilia care 
centers/study sites. Each subject will receive a maximum of 
12 IP infusions (6 in each part). There is no washout period 
before Part 1, between infusions or parts of the study.
Subjects will receive FEIBA at a dose of 85 U/kg ± 15 U/kg 
for all infusions. For infusions, whole vials should be rounded 
up or down to be as close as possible to the accurate dosage, as 
appropriate. Please refer to study documents for detailed 
instructions.
Safety monitoring for this study  will be conducted 
concurrently by an Internal Safety Monitoring Committee 
(ISMC). All serious adverse events (SAEs) that occur will be 
reviewed by the Chair of the ISMC with the Medical Director 
within 24 hours. Planned ISMC meetings will be held 
concurrently with the ongoing study.
Planned Duration of 
Subject Participation
It is planned that each subject will spend approximately 6 to 
11 weeks in the study. 
Outcome Measure (s)
Primary
Tolerability and safety (local and general) related to infusion rate and volume of 
reconstitution will be assessed by the occurrence of all AEs including hypersensitivity, 
thromboembolic events and infusion site reactions, AEs leading to discontinuation, 
changes in vital signs and laboratory parameters which are considered AEs.
Exploratory Outcome Measure(s) 
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) activity of coagulation factor II. 
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: kit; powder, lyophilized, for 
solution/suspension; injection
Dosage frequency: IP will be infused every 48 hours
(-8 hours/+24 hours).
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Enroll 32 subjects to have 24 evaluable subjects for the 
assessments
Number of 
Groups/Arms/Cohorts
1 cohort: at least 24 evaluable adult subjects (≥18 to 
≤65 years old) for tolerability and safety evaluation
Inclusion Criteria
Subject is/has:
1.
≥18 to ≤65 years old at the time of screening
2.
Hemophilia A or B of any severity, with a documented ≥ 3 months history of 
inhibitors (≥ 0.6 BU) requiring the use of bypassing agents (FEIBA or rFVIIa) 
prior to screening. Inhibitor level will be tested at screening if no documented 
history is available.
3.
Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain 
reaction (PCR); or HCV positive with stable liver disease
4.
Human immune deficiency virus (HIV)  negative; or HIV positive with stable 
disease and CD4 count ≥ 200 cell/mm3 at screening
5.
Adequate venous access
6.
Willing and able to comply with the requirements of the protocol
7.
If a female of childbearing potential, must have a negative blood pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study, such as:
a.
Abstain from sexual intercourse
b.
Use a reliable method of contraception (contraception such as an intrauterine 
device, barrier method [e.g., diaphragm or sponge; female condom not 
permitted] with spermicide, oral contraceptive, injectable progesterone, sub 
dermal implant), and have their male partner use a condom
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8.
If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a.
Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-stimulating 
hormone levels within the laboratory-defined postmenopausal range or 
postmenopausal with amenorrhea for at least 24 months and on hormonal 
replacement therapy
b.
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation (with no subsequent pregnancy at least 
1 year from bilateral tubal ligation), or bilateral salpingectomy
Exclusion Criteria
Subject is/has:
1.
Known hypersensitivity to FEIBA or any of its components
2.
Advanced liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites, prothrombin time [PT] 5 seconds above upper limit of 
normal)
3.
Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4.
Platelet count < 100,000/µL
5.
Taking Emicizumab (Hemlibra) for bleed prevention
6.
Clinical or laboratory evidence of disseminated intravascular coagulation based 
on medical history
7.
Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
8.
Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
9.
Taking any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to 
enrollment except anti-retroviral chemotherapy.
10. Herbal supplements that contain anti-platelet activity
11. 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. A family member or employee of the investigator
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13. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
STATISTICAL ANALYSIS
Sample Size Calculation
The projected sample size of 24 evaluable subjects for this tolerability and safety study 
was determined by considering available patients, and is not based on statistical power 
calculations. Evaluable patients are all subjects who receive at least 2 infusions per 
sequence in Part 1 and at least 2 infusions per infusion rate in Part 2.
To allow a non-evaluable rate of 25%, 32 subjects will be enrolled.
Planned Statistical Analysis
Statistical analysis for this study will be descriptive in nature.
Primary Analysis
AEs, SAEs and AEs leading to discontinuation, thromboembolic events, hypersensitivity 
and infusion site reactions that occur during or after the IP infusion will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be provided for temporally associated adverse events; 
and for potentially related adverse events as assessed by the investigators.
Lab results and vital signs which are considered AEs will be listed.
Exploratory Analysis
All exploratory outcome measures will be analyzed for descriptive purposes only.
Due to uncertainty around prior dosing/steady state and the unknown clinical relevance of 
FII as lead marker for FEIBA, FII levels will be analyzed as standardized increase from 
the corresponding pre-dose levels. The minimum, time-averaged up to 48 hours (for the 
48 hour time point, the pre-infusion value of the next infusion will be taken), and 
maximum standardized increase from the pre-dose level will be analyzed for descriptive 
purposes only.
For the purpose of estimating a potential impact of infusion volume (regular and reduced 
volume within Part 1) at an infusion rate of 2 U/kg/min on the minimum, time-averaged 
up to 48 hours and maximum standardized increase, a linear mixed effects model will be 
used that models the sequence, period and volume as fixed effect and subject nested 
within sequence as random effect.
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For the purpose of estimating a potential impact of infusion rates (4 and 10 U/kg/min 
within part 2) with reduced volume on the minimum, time-averaged up to 48 hours and 
maximum standardized increase, a linear mixed effects model that models infusion rate as 
fixed and subject as random effect will be used.
The potential impact of infusion volume as well as the potential impact of infusion rates 
on the minimum, time-averaged up to 48 hours and maximum standardized increase will 
be described using point estimates for infusion volume and rates with corresponding 
two-sided 95% confidence intervals (CI) obtained from the models above. 
Full details of the statistical analysis will be specified in the statistical analysis plan 
(SAP).
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory)/Responsible Party ................................ 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 13
5. LIST OF ABBREVIATIONS .................................................................................... 17
6. BACKGROUND INFORMATION .......................................................................... 19
6.1 Description of Investigational Product and Clinical Condition/Indication..... 19
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 Finding from Nonclinical Studies................................................................. 21
6.4.2 Findings from Clinical Studies ..................................................................... 21
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 23
6.6 Compliance Statement.......................................................................................... 23
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 24
7.1 Study Purpose ....................................................................................................... 24
7.2 Primary Objectives............................................................................................... 24
7.3 Exploratory Objectives......................................................................................... 24
8. STUDY DESIGN......................................................................................................... 25
8.1 Brief Summary and Study Design Rationale ..................................................... 25
8.2 Overall Study Design............................................................................................ 26
8.3 Duration of Study Period(s) and Subject Participation .................................... 27
8.4 Outcome Measures ............................................................................................... 27
8.4.1 Primary Outcome Measures......................................................................... 27
8.4.2 Exploratory Outcomes Measure................................................................... 28
8.5 Randomization and Blinding............................................................................... 28
8.6 Study Stopping Rules............................................................................................ 28
8.7 Investigational Product(s) .................................................................................... 28
8.7.1 Packaging, Labeling, and Storage................................................................ 28
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8.7.2 Administration ............................................................................................... 29
8.7.3 Description of Treatment.............................................................................. 30
8.7.4 Management and Treatment of Break-Through Bleeding ........................ 32
8.7.5 Investigational Product Accountability ....................................................... 33
8.8 Source Data ........................................................................................................... 33
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 34
9.1 Inclusion Criteria.................................................................................................. 34
9.2 Exclusion Criteria................................................................................................. 35
9.3 Withdrawal and Discontinuation ........................................................................ 36
10. STUDY PROCEDURES .......................................................................................... 37
10.1 Informed Consent and Enrollment ................................................................... 37
10.2 Subject Identification Code................................................................................ 37
10.3 Screening and Study Visits................................................................................. 37
10.3.1 Screening and Baseline Assessments.......................................................... 37
10.3.2 Treatment Visits........................................................................................... 38
10.3.2.1 Infusion Visits........................................................................................ 38
10.3.3 Study Completion/Termination Visit......................................................... 39
10.4 Medications and Non-Drug Therapies.............................................................. 40
10.5 Subject Questionnaires....................................................................................... 41
10.6 Subject Completion/Discontinuation ................................................................ 41
10.7 Procedures for Monitoring Subject Compliance ............................................. 42
11. ASSESSMENT OF PHARMACOKINETICS....................................................... 42
12. ASSESSMENT OF SAFETY................................................................................... 43
12.1 Adverse Events.................................................................................................... 43
12.1.1 Definitions..................................................................................................... 43
12.1.1.1 Serious Adverse Event.......................................................................... 43
12.1.1.2 Non-Serious Adverse Event ................................................................. 44
12.1.1.3 Unexpected Adverse Events................................................................. 44
12.1.1.4 Pre-existing Diseases............................................................................. 45
12.1.2 Assessment of Adverse Events.................................................................... 45
12.1.2.1 Severity .................................................................................................. 46
12.1.2.2 Causality................................................................................................ 46
12.1.2.3 Safety Reporting ................................................................................... 48
12.1.3 Medical Device Safety Reporting ............................................................... 49
12.2 Urgent Safety Measures ..................................................................................... 49
12.3 Untoward Medical Occurrences........................................................................ 49
12.4 Non-Medical Complaints ................................................................................... 50
12.5 Medical, Medication, and Non-Drug Therapy History................................... 50
12.6 Physical Examinations........................................................................................ 51
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12.7 Clinical Laboratory Parameters........................................................................ 51
12.7.1 Hematology and Clinical Chemistry.......................................................... 51
12.7.2 Activity of FII and Coagulation Testing.................................................... 52
12.7.3 Viral Serology............................................................................................... 52
12.7.4 CD4 Levels.................................................................................................... 52
12.7.5 Assessment of Laboratory Values .............................................................. 52
12.7.5.1 Assessment of Abnormal Laboratory Values..................................... 52
12.7.6 Biobanking.................................................................................................... 53
12.8 Vital Signs............................................................................................................ 53
12.9 Karnofsky Performance Test............................................................................. 53
12.10 Infusion Site Evaluations.................................................................................. 54
12.11 Special Treatment Considerations .................................................................. 54
13. STATISTICS............................................................................................................. 56
13.1 Sample Size and Power Calculations ................................................................ 56
13.2 Datasets and Analysis Cohorts .......................................................................... 56
13.3 Handling of Missing, Unused, and Spurious Data........................................... 56
13.4 Methods of Analysis............................................................................................ 56
13.4.1 Primary Outcome Measure......................................................................... 56
13.4.1.1 Analysis of the Primary Outcome Measure (Parts 1 and 2)............. 56
13.4.2 Exploratory Outcome Measures................................................................. 57
13.5 Planned Interim Analysis of the Study ............................................................. 58
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 58
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 59
15.1 Investigator’s Responsibility.............................................................................. 59
15.1.1 Final Clinical Study Report ........................................................................ 59
15.2 Training ............................................................................................................... 59
15.3 Monitoring........................................................................................................... 59
15.4 Safety Monitoring ............................................................................................... 60
15.5 Auditing ............................................................................................................... 60
15.6 Non-Compliance with the Protocol ................................................................... 61
15.7 Laboratory and Reader Standardization ......................................................... 61
16. ETHICS ..................................................................................................................... 62
16.1 Subject Privacy ................................................................................................... 62
16.2 Ethics Committee and Regulatory Authorities................................................ 62
16.3 Informed Consent ............................................................................................... 62
17. DATA HANDLING AND RECORD KEEPING................................................... 63
17.1 Confidentiality Policy ......................................................................................... 63
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17.2 Study Documentation and Case Report Forms ............................................... 63
17.3 Document and Data Retention........................................................................... 63
18. FINANCING AND INSURANCE........................................................................... 64
19. PUBLICATION POLICY........................................................................................ 64
20. SUPPLEMENTS....................................................................................................... 65
20.1 Study Flow Chart Part 1 .................................................................................... 65
20.2 Study Flow Chart Part 2 .................................................................................... 66
20.3 Schedule of Study Procedures and Assessments (Part 1)................................ 67
20.4 Schedule of Study Procedures and Assessments (Part 2)................................ 69
20.5 Clinical Laboratory Assessments ...................................................................... 71
20.6 FII activity and Coagulation testing.................................................................. 72
21. REFERENCES.......................................................................................................... 73
22. SUMMARY OF CHANGES.................................................................................... 75
INVESTIGATOR ACKNOWLEDGEMENT.............................................................. 79
Tables
Table 1 FEIBA Product Preparation................................................................................ 30
Table 2 Schedule of Study Procedures and Assessments (Part 1)................................... 67
Table 3 Schedule of Study Procedures and Assessments (Part 2)................................... 69
Table 4 Clinical Laboratory Assessments........................................................................ 71
Table 5 FII and Coagulation Testing Time Frame........................................................... 72
Figures
Figure 1 Study Design for Part 1 Baxalta Clinical Study 091501 ................................... 65
Figure 2 Study Design for Part 2 Baxalta Clinical Study 091501 ................................... 66
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AICC
anti-inhibitor coagulant complex
ALT
alanine aminotransferase
APCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BU
Bethesda units
BUN
blood urea nitrogen
BW
body weight
CBC
complete blood count
CD4
cluster of differentiation 4
CI
confidence interval
EC
ethics committee
CRF
case report form
FEIBA
Factor Eight Inhibitor Bypassing Activity
FEIBA NF
Factor Eight Inhibitor Bypassing Activity Nanofiltered
FEIBA VH
Factor Eight Inhibitor Bypassing Activity Vapor Heated
FII
Factor II
FIX
Factor IX
FVII
Factor VII
FVIII
Factor VIII
FVIII:CAg
Factor VIII C antigen
FX
Factor X
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
HAV
hepatitis A virus
HBsAg
hepatitis B surface antigen
HBV
hepatitis B
Hct
hematocrit
HCV
hepatitis C virus
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Abbreviation
Definition
Hgb
hemoglobin
HIV
human immunodeficiency virus 
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IgG
Immumoglobulin G
IgM
immunoglobulin M
IP
investigational product
ISMC
Internal Safety Monitoring Committee
Min
minutes
NMC 
non-medical complaint
PCR
polymerase chain reaction
PT
prothrombin time
rFVIIa
activated recombinant factor VII
SAE
serious adverse event
SAER
serious adverse event report
SIC
subject identification code
SI
serious injuries
SWFI
sterile water for injection
TAT
thrombin/anti-thrombin complex
TSQM
Treatment Satisfaction Questionnaire for Medication
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product and Clinical Condition/Indication
The investigational product (IP), FEIBAi is a plasma derived, activated prothrombin 
complex concentrate (APCC), generically identified as an anti-inhibitor coagulant 
complex (AICC). FEIBA was developed to treat bleeding episodes and cover surgical 
interventions in hemophilia A and B patients with inhibitors and in non-hemophilia 
patients with acquired inhibitorsii and is also intended for use as a prophylactic treatment 
for hemophilia A and B patients with high responding inhibitors and frequent joint 
bleeding.iii,2,3,4
Baxalta’s first licensed FEIBA product, AICC FEIBA, was marketed beginning in 1975
and was superseded in 1985 by a 2-stage vapor heat-treated product, AICC FEIBA VH.
Nanofiltration was introduced to the manufacturing process in 2006 to produce 
FEIBA NF, now called FEIBA.
6.2 Clinical Condition/Indication 
Hemophilia is an X-linked, recessive, congenital bleeding disorder caused by 
deficient or defective coagulation due to a deficiency in FVIII (hemophilia A), or FIX 
(hemophilia B). The absence of FVIII or FIX leads to spontaneous bleeding episodes 
(occurring primarily in joints, muscles, and less commonly, in soft tissues) and to 
excessive bleeding following trauma or injury.5,6 Replacement therapy for the treatment 
of hemophilia A, and less frequently hemophilia B, can be complicated by an immune 
response resulting in the production of inhibitory alloantibodies to Factor VIII (FVIII) or 
Factor IX (FIX), especially in patients with moderate to severe hemophilia. The 
development of such inhibitory antibodies currently represents the most serious 
complication of hemophilia treatment. The presence of inhibitors against FVIII 
generally precludes the efficacious use of human FVIII replacement therapy. A 
substantial portion of patients with FVIII inhibitors have high-responding, high-titer 
inhibitors (> 5 Bethesda units [BU]). These patients exhibit an anamnestic response 
after FVIII exposure, sometimes with a dramatic increase in inhibitory antibody titer.7,8
The inability to provide FVIII replacement therapy predisposes this group of patients to 
increased morbidity and mortality compared with hemophilia patients without inhibitors.7
                                                
i
FEIBA NF is a trademark of Baxalta Inc. US and Baxalta Innovations GmbH.
ii
Anti-Inhibitor Coagulant Complex, FEIBA Vapor Heated. Package Insert, Baxalta US Inc., Westlake 
Village, CA.
iii
Protocol 090701. FEIBA NF: A Prospective, Open-label, Randomized, Parallel Study to Evaluate 
Efficacy and Safety of Prophylactic versus On-demand Treatment in Patients with Hemophilia A and B 
and High Titer Inhibitor. 2013 Jan 14, Baxalta US Inc.,(Westlake Village, CA).
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Several therapeutic approaches are currently available in the management of hemorrhagic 
events in patients who have developed FVIII inhibitors. These include neutralization with 
high doses of human FVIII (low titer inhibitor only), and treatment with bypassing agents 
such as Activated Prothrombin Complex Concentrate (APCC), or activated recombinant 
factor VII (rFVIIa). Among these treatment options, only APCCs and rFVIIa are able to 
control acute hemorrhages in hemophilia patients with high titer inhibitors. These agents 
control bleeding by promoting the conversion of prothrombin to thrombin with 
subsequent fibrin polymerization and clot formation via mechanisms that do not require 
FVIII or FIX. It has been proposed that FEIBA products achieve this goal principally by 
virtue of the presence of a “partial prothrombinase complex” consisting of activated 
Factor X (FX) and prothrombin.9
The active ingredient of FEIBA is a plasma-derived, freeze-dried APCC with FVIII 
inhibitor bypassing activity. Recent studies have demonstrated that FEIBA is a 
multicomponent therapeutic agents with activities potentially targeting different sites in 
the coagulation system.10 FEIBA contains mainly non-activated forms of the vitamin 
K -dependent proteins Factor II (FII), FVII, FIX and FX, as well as small amounts of 
activated prothrombin complex proteins; and Factor VIII coagulant antigen present in a
concentration of up to 0.1 U/1 U FEIBA. From a number of confirmed studies it became 
clear that the FII–FXa complex is one of the key components in this system of different 
proteins.11 A solution containing 1 U FEIBA shortens the activated partial thromboplastin 
time (aPTT) of FVIII inhibitor plasma up to 50% of the buffer value. Additional details 
can be found in the FEIBA IB.iv
6.3 Population to Be Studied
Adult subjects (age ≥18 to ≤65 years) with hemophilia A or B (congenital or acquired) 
of any severity, of all races and ethnic groups will be studied. All subjects will have a 
documented history of inhibitors (≥ 0.6 BU) requiring the use of bypassing agents 
(FEIBA or rFVIIa); subjects with no documented history will require testing of the 
inhibitor level before entering the study. Subjects will either be hepatitis C virus (HCV)
negative or HCV positive with stable hepatic disease. Subjects will either be human 
immunodeficiency virus (HIV) negative or HIV positive with stable disease and a cluster 
of differentiation 4 (CD4) count ≥ 200 cell/mm3. See additional details in the Inclusion 
and Exclusion Criteria in Section 9.1 and Section 9.2, respectively.
                                                
iv
Investigator’s brochure. Anti-inhibitor coagulant complex nanofiltered; FEIBA NF. 2016 FEB 24. 
Baxalta US Inc., (Westlake Village, CA).
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6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Finding from Nonclinical Studies
The nonclinical studies included a virus clearance study, which was performed to 
investigate the virus reduction capacity of the nanofiltration step in the manufacturing of 
FEIBA NF. 
Data from nonclinical studies can be found in the FEIBA NF IB.iv
6.4.2 Findings from Clinical Studies
The results of Baxalta clinical study 090701iii demonstrated that prophylaxis with 
FEIBA significantly reduced the annualized bleeding rates for all bleed types and for 
spontaneous, traumatic, joint, and non-joint, bleeding episodes when compared with on-
demand treatment. A statistically significant reduction in the rate of bleeding episodes in 
new target joints in the prophylaxis arm versus the on-demand arm was also observed. An 
examination of adverse events (AEs), abnormal laboratory parameters for hematology 
and clinical chemistry and vital signs demonstrated that FEIBA was safe and well 
tolerated for prophylactic use. Clinically, these data suggest that FEIBA is safe and 
efficacious in the management of hemophilia A or B with persistent high-titer inhibitors
or low-titer inhibitors refractory to FVIII or FIX treatment, and further confirmed the 
safety and effectiveness of FEIBA for controlling and preventing bleeding episodes.
Baxalta clinical study 091002 was an open-label, uncontrolled, non-interventional 
observational cohort study of FEIBA NF in hemophiliacs with inhibitors. This study was
designed to document routine usage of FEIBA NF as a bypassing agent for on-demand or 
prophylactic treatment in everyday clinical practice and in surgical intervention. The 
safety results of this post-authorization safety study showed that treatment with 
FEIBA NF, administered in 81 subjects with hemophilia, requiring treatment with 
inhibitor-bypass therapy for bleed resolution or bleed prophylaxis, was generally safe 
and well tolerated. The mean infusion rate of FEIBA under routine clinical practice 
during the study (3.7 U/kg per min, range 0.9 to 23.5) was higher than that recommended 
in the Summary of Product Characteristics of FEIBA (2.0 U/kg per min). A manual 
analysis of safety listings did not disclose any AEs associated with a higher infusion 
rate.12 Treatment-related AEs or serious adverse events (SAEs) were reported in 9.9% 
and in 3.7% of subjects, respectively. A deep venous thrombosis and a superficial 
thrombophlebitis were observed in 1 subject with acquired hemophilia.
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The hemostatic effectiveness was rated by the physicians as excellent or good in more 
than 90% of total subjects, with the highest rates reported in subjects with FEIBA NF 
prescribed as regular prophylaxis. Additional details on this study can be found in the 
clinical study report.v
FEIBA consists of zymogens and traces of activated forms of procoagulant factors II, 
VII, IX, X, anticoagulants protein C and TFPI, and small amounts of cofactors FV, FVIII 
and protein S, in a balanced ratio. As mentioned before, FII-FXa complex plays a key 
role in FEIBA’s mode of action (MoA). A recently published study has shown that 
although the FII-FXa complex are the key components other procoagulant components of 
FEIBA were necessary to achieve an optimal activity. However prothrombin (FII) is the 
lead procoagulant component of FEIBA.1,11
Due to the complex nature of the composition of FEIBA, pharmacokinetic information 
cannot be determined by measurement of a single component. In recent studies where 
FEIBA was used as a comparator product surrogate markers of coagulation were used to 
determine pharmacokinetics. These surrogate markers of coagulation included 
determination of thrombin generation, activated partial thromboplastin time (aPTT), 
prothrombin time (PT), thrombin–antithrombin complex (TAT) and prothrombin 
fragment F1+2 (F1+2), and  aPTT clot waveform analysis, maximum levels of these 
surrogate markers following FEIBA administration were seen after 10 or at 30 min with 
variable results at later time points.10 In another study where thrombin generation was 
measured in patients following infusion of FEIBA peak thrombin levels were seen 
predominantly 30 and 60 minutes after infusion.13 Thus, determination of peak plasma 
levels of components of FEIBA seems to be most appropriate performed at 30 or 
60 minutes after infusion.
Additional observational, non-interventional studies were conducted with FEIBA NF. 
Additional details on clinical studies can be found in the FEIBA NF IB.iv
                                                
v
Clinical Study Report. Post-Authorization Safety Study of FEIBA NF (Factor VIII Inhibitor Bypassing 
Activity). An open, uncontrolled, non-interventional observational cohort study of FEIBA NF in 
hemophiliacs with inhibitors. 10 Oct 2014. Baxalta Inc. US and Baxalta Innovations GmbH.
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6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
Uncommon, hypersensitivity reactions observed after infusion of FEIBA have included, 
urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; 
these reactions can be severe and systemic (e.g., anaphylaxis with urticaria and 
angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as 
chills, pyrexia, and hypertension have also been reported. The most commonly reported 
adverse drug reactions described for FEIBA NF include increased inhibitor titer, 
somnolence, dizziness, dysgeusia, dyspnea, nausea, chills, pyrexia, chest pain, and chest 
discomfort.
The possibility of thrombotic events should be considered when FEIBA is used in 
combination with systemic anti-fibrinolytics such as aminocaproic acid and tranexamic 
acid. Therefore, anti-fibrinolytics should not be used for approximately 6 to 12 hours 
before or after the administration of FEIBA.
Animal reproduction studies have not been conducted with FEIBA. There are no 
adequate, well-controlled studies in pregnant women. It is also not known whether 
FEIBA can cause fetal harm when administered to a pregnant woman or an affect on 
reproductive capacity. It is also not known whether FEIBA is excreted in human milk.1
Subjects within the study should be provided with labeling information and a detailed 
discussion of benefit risk profile.
Additional safety experience for FEIBA is provided in the FEIBA NF IB.iv
6.6 Compliance Statement
The study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP (R2), Nov 2016), 
Title 21 of the US Code of Federal Regulations, the EU Directives 2001/20/EC and 
2005/28/EC, and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is:
To evaluate the tolerability and safety of infusing 50% reduced volume FEIBA at the 
standard infusion rate of 2 U/kg/min, and at increased rates of 4 and 10 U/kg/min, in 
comparison to the standard rate of 2 U/kg/min at the regular volume 
7.2 Primary Objectives
To evaluate tolerability and safety of FEIBA reconstituted in a 50% reduced volume 
of sterile water for injection (SWFI) administered at the standard infusion rate of 
2 U/kg/min and at increased rates of 4 and 10 U/kg/min, based on the occurrence of 
any adverse event, in particular of thromboembolic events and hypersensitivity 
reactions 
7.3 Exploratory Objectives
1.
To monitor pre (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) activity of coagulation factor II
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
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8. STUDY DESIGN
8.1 Brief Summary and Study Design Rationale
This is a 2-part Phase 3b/4 (depending on market authorization status per country), 
prospective, open-label, multicenter study to be conducted in at least 24 evaluable
hemophilia A or B subjects with inhibitors (≥0.6 BU in hemophilia A and B) to
determine the tolerability and safety of FEIBA with a planned enrollment of 24 evaluable
subjects. Evaluable subjects are defined as the ones who complete both parts of the study
(i.e. received at least  8 of the 12 infusions; 4 in each part: 2 in each sequence in Part 1
and 2 in each infusion rate in Part 2).
All subjects will receive 3 infusions of FEIBA reconstituted in a regular volume of SWFI, 
and 3 infusions of FEIBA reconstituted in 50% reduced volume of SWFI, with all 6 of 
these infusions being given at a rate of 2 U/kg/min within Part 1 of the study. In Part 2 of 
the study, all subjects will receive 3 infusions of FEIBA reconstituted in 50% reduced 
volume of SWFI at 4 U/kg/min followed by 3 infusions FEIBA reduced volume at a rate 
of 10 U/kg/min. 
This study has been designed as a 2-way crossover study in order to assess primarily 
tolerability and safety of FEIBA. By designing it as a crossover study, subjects serve as 
their own controls. In addition, having received 6 infusions at 2U/Kg/min in Part 1, 
patients will be near to or at steady state (post 6 infusion of FEIBA) prior to starting 
Part 2. This study is open-label because it is a change in infusion volume and infusion 
rate, which would not make it feasible to properly blind. The goal of the study is to 
determine tolerability and safety of FEIBA in 50% reduced volume SWFI to FEIBA 
regular volume SWFI, and increase rate of the 50% reduced volume at 4U/kg/min and 
10U/kg/min. By being able to reduce the volume and speed of the infusion, subjects will 
be able to spend less time infusing and reduce infusion burden during the regular use.
The exploratory objectives include  pre (within 60 min before infusion) and post-infusion 
(at 30 min, hours 1, 2, 6, 8 and 12) activity of coagulation factor II (FII); the effect of 
50% reduced volume FEIBA  and faster infusion rate on coagulation parameters.
FII (prothrombin) was chosen as a lead marker for FEIBA for several reasons:
1.
In previously published studies it has been demonstrated that FII is a key protein 
component of the active ingredient of FEIBA
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2.
Amongst the vitamin K-dependent proteins, FII has the highest relative plasma 
level as it has the lowest specific activity, and therefore the absolute amount of FII 
in FEIBA measured as protein mass is higher than for any other vitamin K-
dependent protein
3.
The half life of FII is longer than that of any other vitamin K-dependent protein 
contained in FEIBA.
8.2 Overall Study Design
This is a 2-part Phase 3b/4 (depending on market authorization status per country), 
prospective, open-label, multicenter study to compare tolerability and safety of FEIBA 
reconstituted in 50 % reduced volume versus regular volume of SWFI, and to 
evaluate the safety of infusing reduced volume FEIBA at increased infusion rates of 
4 and 10 U/kg/min in comparison with the standard rate of 2 U/kg/min, in 24 evaluable
with hemophilia A or B with inhibitors (≥0.6 BU in hemophilia A and B). There is no 
washout period prior to Part 1 or between infusions and between the two parts of the 
study. The overall study design is illustrated in Figure 1 and Figure 2.
In Part 1, subjects will be administered 2 different volumes of FEIBA every 48 hours
(-8/+24 hours) in a 1:1 randomized, crossover manner. Both volumes will be given at the 
standard infusion rate of 2 U/kg/min. After infusion, subjects should be observed for at 
least 30 minutes at the study site. See Section 10.3.2 for details. 
Treatments regimens during Part 1 of the study are:

Part 1 Sequence A:
1. FEIBA 2 U/kg/min in regular volume SWFI (Infusions 1, 2, and 3)
2. FEIBA 2 U/kg/min in 50% reduced volume SWFI (Infusions 1, 2, and 3)

Part 1 Sequence B, patients from sequence A cross over to: 
1. FEIBA 2 U/kg/min in 50% reduced volume SWFI (Infusions 4, 5, and 6)
2. FEIBA 2 U/kg/min in regular volume SWFI (Infusions 4, 5, and 6)

Infusion dose:
All infusions: 85 ± 15 U/kg
Part 2 is non-randomized with sequential treatment of subjects who complete Part 1 to 
evaluate FEIBA reconstituted in 50% reduced volume of SWFI at increased rates of 
4 and 10 U/kg/min. FEIBA Infusions 7, 8, and 9 will be administered at the 4 U/kg/min
rate followed by 3 infusions (Infusions 10, 11, and 12) of FEIBA at 10 U/kg/min rate. 
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The infusions will be administered every 48 hours (-8 hours/+24 hours) to allow time to 
monitor safety and tolerability of the higher infusion rate.
The treatment phases within Part 2 of the study are as follows:

First treatment phase: 4 U/kg/min (Infusions 7, 8, 9) 

Second treatment phase: 10 U/kg/min Infusions 10, 11, 12)

Infusion dose:
All infusions: 85 ± 15 U/kg
All infusions will be administered at the hemophilia care centers/study sites. Sample 
collections may be performed at the hemophilia care centers/study sites, appropriate 
ambulatory centers and in certain geographies, may also be available at home. Each 
subject will receive a maximum of 12 IP infusions total [6 in Part 1 and 6 in Part 2]. 
Subjects will receive FEIBA at a dose of 85 ± 15 U/kg for all  infusions see 
Section 8.7.2. After each infusion, subjects should be observed for 30 minutes at the 
study site. Additional details on study design and timing are described in Section 8.7.3.
For additional details on managing bleeding episodes, see Section 8.7.4.
See Section 15.4 for additional details on the safety reviews performed by the Internal 
Safety Monitoring Committee (ISMC).
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is expected to be approximately 10 to 13 months from 
study initiation (i.e., first subject enrolled) to study completion (i.e., last subject last 
visit). The recruitment period is expected to be approximately 9 to 11 months.
The subject participation period is approximately 6 to 11 weeks from enrollment to 
subject completion (i.e., last study visit), unless prematurely discontinued.
8.4 Outcome Measures
8.4.1 Primary Outcome Measures
Tolerability and safety (local and general) related to  infusion rate and volume of 
reconstitution will be assessed by the occurrence of all AEs including hypersensitivity, 
thromboembolic events and infusion site reactions, AEs leading to discontinuation, 
changes in vital signs and laboratory parameters which are considered AEs. 
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8.4.2 Exploratory Outcomes Measure
1.
To monitor pre- (within 60 min before the infusion) and post-infusion (at 30 min, 
hours 1, 2, 6, 8 and 12) activity of coagulation factor II
2.
Evaluate subject treatment preference using Treatment Satisfaction Questionnaire 
for Medication (TSQM) and patient preference questionnaire
8.5 Randomization and Blinding
Part 1 of this study is a randomized, crossover, active treatment clinical study. Subjects 
will be randomly assigned to 1 of 2 treatment sequences at a 1:1 ratio (Sequence A:
FEIBA regular volume of SWFI followed by FEIBA reduced volume of SWFI or 
Sequence B: FEIBA reduced volume of SWFI followed by FEIBA regular volume 
SWFI). Part 2 of this study is an open-label, sequential, active treatment clinical study. In 
Part 2, all subjects will receive FEIBA reduced volume of SWFI at 2 varying rates of 
infusion.
8.6 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1.
If 2 or more subjects develop anaphylaxis and / or thromboembolic events 
following exposure to FEIBA (enrollment and treatment temporarily stopped 
pending further review by the ISMC)
2.
The sponsor or investigator, based on emerging data, considers there to be an 
unfavorable risk benefit
3.
The sponsor or investigator considers continuation of the study unjustifiable for 
medical or ethical reasons
4.
The ISMC recommends study termination
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
The active ingredient of FEIBA is a plasma-derived, freeze-dried, APCC with FVIII 
inhibitor bypassing activity. FEIBA will be provided in vials with a nominal potency of 
500 U/vial, 1,000 U/vial and 2,500 U/vial). FEIBA contains mainly non-activated forms 
of the 3 coagulation factors, FII, FIX, and FX, as well as activated FVII; and Factor VIII 
coagulant antigen (FVIII:CAg) present in a concentration of up to 0.1 U/1 U FEIBA. 
The factors of the kallikrein-kinin system are present only in trace amounts, if at all. 
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A solution containing 1 U FEIBA shortens the aPTT of FVIII inhibitor plasma to 50% of 
the buffer value. The product is supplied as freeze-dried powder or friable solid of white 
to off-white or pale green color.
To standardize conditions in the study, FEIBA should be stored at 2°C to 8°C only.  
FEIBA should not be allowed to freeze, and should be protected from light. Aseptic 
techniques must be used for reconstituting and administering FEIBA. Although the 
chemical and physical stability of the reconstituted product has been demonstrated for 
3 hours at room temperature (up to 25°C), however, the solution should be used 
immediately as the preparation does not contain preservatives. Reconstituted product 
must not be returned to the refrigerator.
FEIBA will be provided in kits including SWFI for reconstitution. SWFI will be provided 
in different volumes for preparation of FEIBA infusions at regular volume or reduced 
volume. For additional information, such as reconstitution instructions, please refer to the 
Investigator’s Brochure, the study specific pharmacy manual and/or other specific 
instructions provided by the sponsor or sponsor’s representative.
8.7.2 Administration
Following reconstitution, FEIBA should be administered immediately using an 
intravenous needle and syringes provided by the sponsor for this study. The standard 
infusion rate of FEIBA is 2 U/kg body weight (BW) per minute, which in a 75kg subject, 
corresponds to an infusion rate of approximately 2.4 to 7.5 mL/minute depending on the 
potency (see label on vial). 
In order to standardize administration within the study, it is recommended that study drug 
be administered with an infusion pump. The infusion rate will be modified depending on 
which part of the study the subject is in, rates of 4 and 10 U/kg/min are also used in this 
study.
Subjects will receive FEIBA at a dose of 85 ± 15 U/kg for all infusions every 48 hours 
(-8 hours/+24 hours). Dose calculation for FEIBA will be based on the stated actual 
potency on vials in respective lots.  FEIBA lots may be mixed within an infusion, and 
whole vials should be rounded up or down to be as close as possible to the accurate 
dosage, as appropriate.
For additional details, see Table 1 for general information on product preparation, as well 
as the study documents, and the FEIBA IB.iv
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Mixing of FEIBA with other products or substances must be avoided. It is advisable to 
flush venous access lines with isotonic saline prior to and after infusion of FEIBA.
Dose calculation for FEIBA will be based on the stated actual potency on vials in 
respective lots. Information regarding lot used, the actual dose given, date of treatment, 
treatment start and stop times, as well as any infusion interruptions will be recorded in the
case report form (CRF).
Table 1
FEIBA Product Preparation
FEIBA
Diluent for Regular Volume FEIBA
Diluent for 50% Reduced Volume FEIBA
500 U
10 mL
5 mL
1000 U
20 mL
10 mL
2500 U
50 mL
25 mL
Abbreviations: FEIBA=Factor Eight Inhibitor Bypassing Activity.
Please note that the availability of potencies may vary among countries and regions. Dose 
calculations should be made based on potencies available at site.
8.7.3 Description of Treatment
Part 1 of the study uses a crossover design to evaluate the tolerability and safety of 
FEIBA reconstituted in 50% reduced volume SWFI versus regular volume of SWFI 
(administered at the standard infusion rate of 2 U/kg/min). Part 2 is a non-randomized 
study with sequential enrollment of subjects who complete Part 1. Part 2 will evaluate the 
tolerability and safety of infusing FEIBA reconstituted in 50% reduced volume of SWFI 
at increased infusion rates of 4 and 10 U/kg/min.
All subjects will be screened for eligibility based on the listed inclusion and exclusion 
criteria. The subject’s medical history including hemophilia history, confirmation of 
inhibitors, bleeding episode history, concomitant medications and history of FEIBA or 
rFVIIa (dose and frequency) usage for the previous year will be collected at screening. 
Also recorded will be the use of FEIBA or rFVIIa (dose and frequency) during the 
screening period, date of last use of FEIBA or rFVIIa treatment and any bleeding 
episodes experienced. Results of the screening assessments will be used to establish a 
subject’s eligibility for the study.
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Part 1
After eligibility is established, the eligible subjects will be randomly assigned (1:1) 
into Part 1 of the study to receive 3 infusions of FEIBA reconstituted in 50% reduced 
volume SWFI followed by regular volume SWFI or vice versa every 48 hours 
(-8 hours/+24 hours).
Additional details on study visits for Part 1 can be found in Section 10.3 and Table 2.
Part 2
Part 2 is non-randomized and uses sequential enrollment of subjects who complete Part 1 
of the study. Subjects in Part 2 will first be administered 3 infusions (Infusions 7, 8, 
and 9) of FEIBA at the 4 U/kg/min rate, followed by 3 infusions (Infusions 10, 11, 
and 12) of FEIBA at the 10 U/kg/min rate. Infusion 7 will be administered 48 hours 
(-8 hours/+24 hours) after Infusion 6. The infusions in Part 2 will be administered every 
48 hours (-8 hours/+24 hours) to allow time to monitor safety and tolerability of the 
higher infusion rate. Infusion rates for the treatment phases in Part 2 are:

First treatment phase: 4 U/kg/min (Infusions 7, 8, and 9) 

Second treatment phase: 10 U/kg/min (Infusions 10, 11, and 12)
Following the last infusion, a study termination visit will be conducted within 7 days but 
no sooner than 72 hours after the last infusion.
Additional details on study visits for Part 2 can be found in Section 10.3 and Table 3.
Additional Treatment and Visit Information
The Schedule of Study Procedures and Events Procedures listed in Table 2 and Table 3
have the visit windows listed in relation to the subject’s previous infusion. This is due to 
the variability in each subjects schedule based on previous therapy and bleeding events. 
All infusions will be administered at hemophilia care centers/study sites. Each subject 
will receive a maximum of 12 IP infusions. Subjects will receive FEIBA at a dose of 
85 ± 15 U/kg for all infusions. For specifications on dosing and administration, see 
Section 8.7.2. For information on break-through bleeding control, see Section 8.7.4.
Study visits will be completed concurrently with study infusions. After subjects 
have completed the 12 study infusions, they will complete a Study Completion/
Termination Visit within 7 days but no sooner than 72 hours after Infusion 12. 
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In case of early withdrawal or discontinuation the Study Completion/Termination Visit 
will need to be completed within 7 days but no sooner than 72 hours after the last IP 
infusion received.
During each visit, the study staff will inquire with the subject about break-through 
bleeding events, treatments, and AEs throughout the study. Subjects are encouraged to 
report AEs to the site during the time spans between visits.
Two subject questionnaires will be administered 5 times during the study, a TSQM 
questionnaire and a patient preference questionnaire to assess the subjects’ satisfaction 
and preferences for treatments, for additional details see Section 10.5.
Detailed study flowcharts are presented in Figure 1 and Figure 2.
Investigational product may be interrupted or discontinued at any time during the study at 
the discretion of the investigator based on his/her evaluation of the subject’s condition or 
safety. No dose modification is permitted for this study.
Any infusion site reactions, regardless of causality, will be recorded on the AE CRF. Any 
concomitant medications, including those used to treat AE(s), will be recorded on the 
appropriate CRF.
For details on the safety review by ISMC see Section 15.4.
8.7.4 Management and Treatment of Break-Through Bleeding
Bleeding episodes are managed as described below for each part of the study. In all cases, 
if the bleeding episode, of whatever severity, is not resolved within 48 hours after an 
infusion to control bleeding, the subject must contact the hemophilia treatment 
center/study site for further treatment recommendations.
Screening
During screening, subjects will be asked to keep track of any FEIBA or rFVIIa usage, as 
the last dose may be used to determine the date of the first infusion of IP. If a subject 
experiences a bleeding episode during the screening period, subjects will be treated for 
the bleeding episode per standard of care as determined by the investigator and the 
patient will be randomized after resolution of bleeding episode. 
Bleeding during the study 
If bleeding occurs during the study, it will be treated per standard of care. 
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For bleeding events treated with FEIBA or rFVIIa, a time window of 48 hours post 
treatment for bleeding should be observed before resuming study infusions. The subject 
will resume their treatment regimen and visits after control of the bleeding and following 
the administration window mentioned above. Depending on the clinical circumstances 
(e.g., treatment of uncontrolled bleeding due to injury and associated complications), the 
investigator and sponsor should decide if it is appropriate for the subject to continue in 
the study.
8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) 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(s) was received, including the date received, 
drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP(s) must be dispensed only at the study site or other suitable location (e.g.,
infusion center; home, as applicable per study design). Records will be maintained that 
include the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) 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(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
study that are necessary for the reconstruction and evaluation of the study. 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' 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.
Subject questionnaires may be entered directly onto the CRF.
For additional information on study documentation and CRFs, see Section 17.2.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
≥18 to ≤65 years old at the time of  screening
2.
Hemophilia A or B of any severity, with a documented ≥ 3 months history of 
inhibitors (≥ 0.6 BU) requiring the use of bypassing agents (FEIBA or rFVIIa) 
prior to screening. Inhibitor level will be tested at screening if no documented 
history is available.
3.
Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain 
reaction (PCR); or HCV positive with stable liver disease
4.
Human immune deficiency virus (HIV) negative; or HIV positive with stable 
disease and CD4 count ≥ 200 cell/mm3 at screening
5.
Adequate venous access
6.
Willing and able to comply with the requirements of the protocol
7.
If a female of childbearing potential, must have a negative blood pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study, such as:
a. Abstain from sexual intercourse
b. Use a reliable method of contraception (contraception such as an intrauterine 
device, barrier method [e.g., diaphragm or sponge; female condom not 
permitted] with spermicide, oral contraceptive, injectable progesterone, sub 
dermal implant), and have their male partner use a condom
8.
If female of non-childbearing potential, confirmed at screening by fulfilling 1 of 
the following criteria:
a. Postmenopausal, defined as amenorrhea for at least 12 months following 
cessation of all exogenous hormonal treatments and with follicle-stimulating 
hormone levels within the laboratory-defined postmenopausal range or 
postmenopausal with amenorrhea for at least 24 months and on hormonal 
replacement therapy
b. Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation (with no subsequent pregnancy at least 
1 year from bilateral tubal ligation), or bilateral salpingectomy
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Known hypersensitivity to FEIBA or any of its components
2.
Advanced liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal 
vein hypertension, ascites, prothrombin time [PT] 5 seconds above upper limit of 
normal)
3.
Planned elective surgery during participation in this study (excluding minor 
procedures that will not need preventative bleeding treatments, such as exchanges 
of peripherally inserted central catheters)
4.
Platelet count < 100,000/µL
5.
Taking Emicizumab (Hemlibra) for bleed prevention
6.
Clinical or laboratory evidence of disseminated intravascular coagulation based 
on medical history
7.
Prior history or evidence of thromboembolic event: acute myocardial infarction, 
deep vein thrombosis, pulmonary embolism, etc.
8.
Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that 
may increase the subject’s risk of thromboembolic complications
9.
Taking any immunomodulating drug (e.g., corticosteroid agents at a dose 
equivalent to hydrocortisone > 10 mg/day, or α-interferon) within 30 days prior to 
enrollment except anti-retroviral chemotherapy.
10. Herbal supplements that contain anti-platelet activity
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. Family member or employee of the investigator
13. Clinically significant medical, psychiatric or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject 
safety or compliance
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9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., 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 withdraw or discontinuation) are described in 
Section 10.3.3 and Section 20.3.
Discontinuation (i.e., complete withdrawal from study participation) may be due to drop-
out (i.e., active discontinuation by subject) or loss to follow-up (i.e., 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 ISMC recommends a subject should be taken off the study

The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
postdelivery, if feasible. The investigator will record a narrative description of the 
course of the pregnancy and its outcome

AE(s)/SAE(s) that the investigator or sponsor feels poses an unacceptable risk for 
continued dosing in the subject

Participation in another clinical study involving an IP during the course of the 
study
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form [ICF] 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 (e.g., 091501) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the ICF). For example, the third subject who signed an ICF at 
study site 02 will be identified as Subject 091501-020003. All study documents (e.g., 
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 
(e.g., 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. 
All screening data will be collected and reported in CRFs, regardless of screening 
outcome. 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 overall study design is illustrated in Figure 1 and Figure 2. Details on the procedures 
to be performed at each study visit, including screening, can be found in Supplement 20.3
and Supplement 20.4 Schedule of Study Procedures and Assessments (Part 1 and Part 2, 
respectively) and Supplement 20.5 Clinical Laboratory Assessments. FII activity 
scheduling can be found in Section 20.6.
10.3.1 Screening and Baseline Assessments
After ICF is obtained, subjects will be screened on-site for eligibility based on the 
inclusion and exclusion criteria defined in Section 9.1 and Section 9.2, respectively. 
Screening procedures must be performed within 35 days of Infusion 1.
At screening, subjects will be instructed on the symptoms of thromboembolic and 
systemic hypersensitivity events by the investigator, and to contact the treatment 
center/hospital if they experience any symptoms.
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Screening assessments include the following:

Eligibility evaluation (review of inclusion/exclusion criteria)

Medical history, including
Hemophilia history, inhibitor development history, bleeding episodes history, 
history of FEIBA or rFVIIa usage for a year prior to screening
Relevant medical and surgical history and all medications including bypassing 
agents (dose and frequency) taken 4 weeks prior to screening

Review of concomitant medications/non-drug therapies

Complete physical examination (see Section 12.6)

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and
measurement body weight and height (see Section 12.8)

Karnofsky performance test assessment (see Section 12.9)

Clinical laboratory assessments (hematology, FII activity, clinical chemistry, 
serology testing and inhibitor level if no documentation is available ≥3 months 
prior to screening; see Section 12.7)

Serum pregnancy test (female subjects of childbearing potential only)

TSQM and patient preference questionnaires (only at randomization; see 
Section 10.5)
After screening and eligibility are determined, the subject will be enrolled in the study. 
For additional details on bleeding, see Section 8.7.4.
10.3.2 Treatment Visits
10.3.2.1 Infusion Visits
Randomization will occur after the subject has been confirmed to be eligible and prior to 
the first infusion.

Randomization of eligible subjects to the following treatment sequences:
Part 1 Sequence A: FEIBA 2 U/kg/min in regular volume SWFI (3 infusions), 
FEIBA 2 U/kg/min in 50% reduced volume (3 infusions)
Part 1 Sequence B: FEIBA 2 U/kg/min in 50% reduced volume (3 infusions), 
FEIBA 2 U/kg/min in regular volume SWFI (3 infusions)
For additional details on the description of treatment, see Section 8.7.3.
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During the study (Infusion Visits 1 to 12), subjects will return to the study site according 
to the schedule presented in Table 2 and Table 3. Prior to administration of IP, the 
following assessments will be performed at all visits unless otherwise indicated:

Review of concomitant medications/non-drug therapies

AE monitoring

Vital signs (body temperature, pulse rate, blood pressure and respiratory rate)
Before administration of IP
at 30 minutes after administration of IP

Clinical laboratory assessments Table 4

IP administration (infusion site should be monitored for at 30 minutes [± 10 min] 
after infusion)

Break-through bleed monitoring

Coagulation testing

Infusion site reactions.

Subjects will be administered the TSQM and patient preference questionnaires:
After screening prior to Infusion 1
After Infusion 3 prior to Infusion 4
After Infusion 6 prior to Infusion 7
After Infusion 9,  prior to infusion 10
After infusion 12 or up to the completion of the Study 
Completion/Termination Visit

Factor II levels will be drawn within 60 min before IP administration and at 
30 min, hours 1, 2, 6, 8 and 12 after IP administration, as outlined in Table 5. See 
also information on administration (Section 8.7.2). 
10.3.3 Study Completion/Termination Visit
The Study Completion/Termination Visit including if the subject is discontinuing early 
will be performed within 7 days but no sooner than 72 hours after Infusion 12, or the last 
infusion if discontinued early. The following assessments will be performed:

Review of concomitant medications/non-drug therapies

AE monitoring
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
Breakthrough bleeds monitoring

Clinical laboratory assessments see Table 4

Vital signs (body temperature, pulse rate, blood pressure, respiratory rate, and 
body weight)
10.4 Medications and Non-Drug Therapies 
Once subject eligibility has been confirmed for the study, the following medications and 
non-drug therapies are not permitted during the course of the study:

Medications:
Concomitant use of Emicizumab (Hemlibra)
Any immunomodulating drug (e.g., corticosteroid agents at a dose equivalent 
to hydrocortisone > 10 mg/day, or α-interferon) except anti-retroviral 
chemotherapy
Any investigational drug or device
A subject who receive any of these therapies will be withdrawn from further study 
participation.
Antifibrinolytics should not be used approximately 6 to 12 hours before or after the 
administration of FEIBA.
Avoid concomitant use of rFVIIa, except when used to treat breakthrough bleeds that do 
not respond to FEIBA.
The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:

Medications:
Hemostatic agents, such as tranexamic acid, are permitted, as indicated by the 
subject’s treating physician, to treat mucosal bleeding during the study (these 
are permitted; however, they should not be taken within 6 to 12 hours before 
or after administration of FEIBA)
Any medications deemed necessary by the subject’s physician to treat or 
prevent any medical condition (with the exception of those listed as not 
permitted)
Any over-the-counter medication used by the subject to treat symptoms or 
signs of any medical condition
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Supplemental vitamins, minerals
Any standard of care to treat breakthrough bleeds

Non-drug therapies:
Any non-drug therapy (e.g., physiotherapy) deemed necessary by the subject’s 
physician to treat or prevent any medical condition
10.5 Subject Questionnaires
Two questionnaires will be administered to subjects within this study (TSQM 14 and a 
patient preference questionnaire). These questionnaires will be used to assess the 
subject’s preferences on the IP, as well as their satisfaction with the IP, and will be 
collected in the CRF or on paper. Both questionnaires will be administered:

After screening prior to Infusion 1

After Infusion 3 prior to Infusion 4

After Infusion 6 prior to Infusion 7

After Infusion 9,  prior to infusion 10

After infusion 12 or up to the completion of the Study Completion/Termination 
Visit
These questionnaires can be completed between visits but should be completed prior to 
the start of the next infusion. The final questionnaire should be completed prior to or 
during the Study Completion/Termination Visit.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when the subject ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according to the protocol.
Reasons for completion/discontinuation will be reported on the Completion /
Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems, and severe hypersensitivity reaction), ISMC recommends a subject should not 
continue. Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF.
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Every effort will be made to have discontinued subjects complete the Study 
Completion/Termination Visit. If the Study Completion/Termination Visit is done as 
an additional, unscheduled visit, the assessment results shall be recorded with the 
Study Completion/Termination Visit. If a subject terminates participation in the 
study and does not return for the Study Completion/Termination Visit, their last 
recorded assessments shall remain recorded with their last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of 
discontinuation will be used in the analysis and included in the clinical study report. 
If additional assessments are required, the assessments shall be recorded separately.
Assessments to be performed at the termination visit (including in cases of withdraw or 
discontinuation) can be found in Supplement 20.3 Schedule of Study Procedures and 
Assessments and Supplement 20.5 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. 
The sponsor may complete the study earlier once  24 evaluable patients complete the 
study (i.e., before 32 subjects are enrolled).
10.7 Procedures for Monitoring Subject Compliance
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures will be used to monitor subject compliance.
11. ASSESSMENT OF PHARMACOKINETICS
Pharmacokinetics will not be evaluated in this study.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 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 (e.g., an abnormal laboratory finding), 
symptom (e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that at any dose meets 1 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. Admittance for the purpose of PK blood draws will
not be considered an SAE. 

Results in persistent or significant disability/incapacity (i.e., 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 1 of the other 
outcomes listed in the definitions above. Examples of such events are:
Intensive treatment in an emergency room or at home for bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependence or drug abuse
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Additional events which should be reported the same way as SAEs are as follows:

Reviewed and confirmed seroconversion for HIV, hepatitis A virus, hepatitis B 
virus, HCV, hepatitis E virus, or parvovirus B19 

Hospitalization for planned port placement or removal is not considered an SAE, 
however, any hospitalization required for an emergency port removal is 
considered an SAE

Any thromboembolic event (including thrombotic microangiopathy)

Hypersensitivity reactions
Uncomplicated pregnancies, following maternal or paternal 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. Any 
pregnancy occurring during the study following maternal or paternal exposure should be 
reported to the sponsor within 24 hours of the site learning about the pregnancy. The 
pregnancy should be followed until completion of the pregnancy and up to 1 year 
postdelivery, if feasible. A separate ICF will be used to cover partner consent for data 
collection in the event of a pregnancy. Pregnancies not considered an (S)AE as described
above will be captured in the CRF.
Voluntary overnight stays by subjects in hospital or hospital-affiliated facilities for the 
convenience/compliance with study procedures as described in Section 10.3.2 for reasons 
unrelated to AEs will not be considered as hospitalization for SAE reporting purposes
unless the hospitalization is prolonged.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., 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.
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12.1.1.4 Pre-existing Diseases
Pre-existing 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 pre-existing disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
Each AE from the first IP exposure until study termination/completion 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 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., 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, it is medically 
stabilized, or 30 days after the Study Completion/Termination Visit, whichever comes 
first, and the follow-up information is to be documented in the CRF. If the severity rating 
for an ongoing AE changes before the event resolves, the original AE report will be 
revised (i.e., 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 (20% higher than the 
highest permitted dose), underdosing (20% lower than the lowest permitted dose), 
treatment errors (including incorrect route of administration, use of an incorrect product, 
and deviations from the protocol-defined dosing schedule), failures of expected 
pharmacological actions, and unexpected therapeutic or clinical benefits will be followed 
with regard to occurrence of AEs, lack of efficacy, and/or other observations because 
these events may be reportable to regulatory authorities.
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Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and 1 year postdelivery, if 
feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion/termination, the SAE must be reported on the provided SAE Report Form 
within 24 hours after awareness; no additional reporting on CRFs is necessary.
12.1.2.1 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.
12.1.2.2 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, 
e.g., 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.
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For each AE, the investigator will assess the causal relationship between the IP and the 
AE using his/her clinical expertise and judgment according to the following most 
appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (i.e., 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 
rechallenge)
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 72 hours after 
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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12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 3) and Section 12.1.
Adverse Events/SAEs are to be recorded on the AE page of the CRF. Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported by completing the relevant CRF 
page(s) in English. Once the SAE has been recorded, SAEs must be reported  to the 
sponsor to meet the 24-hour timeline requirement (contacts and instructions to be 
provided in separate documentation). 
The initial SAE information reported on the applicable CRF pages (must at least include 
the following:

Protocol Number

Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)

Investigational product exposure

Medical Term for Event (Diagnosis preferably) 

Description of the (S)AE, including:
Date of onset
(S)AE treatment (drug, dose, route of administration)
Causal relationship by the investigator
Measures taken (i.e., action taken regarding IP in direct relationship to the 
AE)

Seriousness criteria (i.e., death, life-threatening, or other criterion)

Cause of death

Autopsy findings (if available)

Name, address, fax number, email, and telephone number of the reporting 
investigator (for paper SAE Report Forms) 
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12.1.3 Medical Device Safety Reporting
The IP kit contains the BaxJect II Hi-Flow needleless transfer device. All Serious Injuries 
(SI) and Unexpected Adverse Device Events (UADE) must be reported to the sponsor as 
an SAE in the same process as described above.
Serious injury is defined as:

Life-threatening injury or illness results in permanent impairment/ damage to 
body function/ structure.

Requires medical or surgical intervention to preclude permanent impairment/ 
damage to body function/ structure.
12.2 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 study 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 study or studies

Any other immediate action taken in order to protect clinical study 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 (EC) and relevant competent authority(s) are
notified of the urgent safety measures taken in such cases according to local regulations.
12.3 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 12.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the AE CRF . These events will be considered as SAEs but will not be 
included in the analysis of SAEs. 
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12.4 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, e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., 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

Medication errors: an error (of commission or omission) at any step along the 
pathway that begins when a clinician prescribes a medication and ends when the 
patient actually receives the medication e.g., administration of incorrect dose
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor (or sponsor’s representative) within 1 business day. If requested, defective 
product(s) will be returned to the sponsor for inspection and analysis according to 
procedures.
12.5 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 12.1.2.1) 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.
General medical history will be collected for 4 weeks prior to screening. Any information 
on the subjects’ hemophilia history will be collected a year prior to screening including 
documented history of hemophilia, confirmation of inhibitors, bleeding episodes history, 
and history of FEIBA or rFVIIa usage.
All medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies CRFs.
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12.6 Physical Examinations
At screening (as described in Table 2 and Table 3), 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 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 pre-existing disease (described in Section 12.1.1.4), 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.
12.7 Clinical Laboratory Parameters
Assessments will be performed at a central laboratory (see Section 15.7), according to the 
laboratory manual. Blood samples that remain after study testing is done may be stored 
and used for any additional testing as needed (see Section 12.7.6). Samples will be 
destroyed after a maximum of 2 years from the time the final study report has been 
completed. 
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count [hemoglobin, hematocrit, 
erythrocytes (i.e., red blood cell count), and leukocytes (i.e., white blood cell count)] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) mean 
corpuscular volume, mean corpuscular hemoglobin concentration, and platelet counts.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
aspartate aminotransferase (AST), total protein, albumin, alanine aminotransferase
(ALT), total bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, 
glucose, gamma-glutamyl transpeptidase (GGT), and 5’-nucleotidase.
Blood will be obtained for assessment of hematology and clinical chemistry parameters at 
screening and at study completion/termination. 
In addition, serum samples for pregnancy tests for females of childbearing potential will 
be collected at screening.
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12.7.2 Activity of FII and Coagulation Testing
Blood samples for the determination of FEIBA components FII will be taken at 
screening, within 60 (±15) min before and at 30 (±10) min, after completion of each 
infusion. In addition, hours 1 (±15min), 2  (±30min), 6 (±1hour), 8 (±2hours) and 
12 (±4hours) samples will be taken after infusion 1,3,4,6,9 and 12. The preinfusion FII 
can be considered as post infusion 48 hr timepoint sample for the prior infusion; therefore 
no additional blood sample will be required for this timepoint (see Section 20.6 for 
sampling time points and allowed sampling time windows). The date and time of each 
sample collections will be documented in the subject’s CRF. 
Blood will be obtained for the assessment of coagulation testing and consist of aPTT, PT, 
and thrombotic markers (D-Dimers, prothrombin fragment F 1+2, TAT, and 
fibrinopeptide A). Coagulation testing will be performed during the study and samples
will be taken within 60 (±15) min before and at hours 1 (±15min), and 6 (±1) hour  after 
infusion 1,3,4,6,9 and 12 (see Section 20.6 for sampling time points and allowed 
sampling time windows). 
12.7.3 Viral Serology
Viral serology testing will include HIV-1 and HIV-2 antibody, hepatitis A virus (HAV)
antibody, hepatitis B surface antigen (HBsAg), HCV antibody, parvovirus B19 
(immunoglobulin M [IgM] and immunoglobulin G [IgG] antibodies), cytomegalovirus 
antibodies (IgM and IgG), and Epstein-Barr virus antibodies (IgM and IgG). The HCV 
titer will be confirmed by PCR for all subjects reported as HCV positive. All viral 
serology assessments will be performed at screening and at the Study 
Completion/Termination Visit.
12.7.4 CD4 Levels
At screening only, CD4 levels will be determined using flow cytometry in the case of a 
subject being HIV positive.
12.7.5 Assessment of Laboratory Values
12.7.5.1 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value 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 12.1, 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 12.1.1.4), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
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significant, the investigator will indicate the reason, i.e., because it is due to a pre-existing 
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.
12.7.6 Biobanking
Backup samples should be taken and stored appropriately for additional analysis, if 
necessary. Backup samples that remain after study testing is done may be stored and used 
for additional testing (e.g., further evaluation of an abnormal test or an AE. 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.
12.8 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) 
measured once at screening and weight (lb or kg) measured at screening and 
completion/termination will also be collected.
Vital signs will be measured at screening and within 30 minutes before and after (except 
weight) administration of IP, at each Infusion study visit, and at study 
completion/termination. Blood pressure will be measured when subjects are in the supine 
position.
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 12.1
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.
12.9 Karnofsky Performance Test
The Karnofsky Performance Test is a status scale (0-100) utilized to measure the level of 
activity and medical care requirements in subjects. It is an investigator based assessment 
of subject status which evaluates the subjects’ ability to carry on normal life activities, as 
well as the symptoms of their disease. In this scale, a high number performance status 
represents high functionality, and a lower number represents low functionality and likely 
rapid progression of disease.15 Subjects will be scored using this scale at screening.
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12.10 Infusion Site Evaluations
The current site of IP infusion will be assessed for immediate local reactions at 
30 minutes (±10 min) after infusion. In addition, infusion sites will be monitored by the 
subject for up to 12 hours after infusion, and will be discussed with the site staff during 
the next study visit.
Infusion sites will be monitored for pain, tenderness, erythema, and swelling. Infusion 
site evaluations will be made by clinical staff or by the subject or caregiver. If an infusion 
site reaction is observed, a physician will characterize and document the reaction as an 
AE. Infusion sites will continue to be reviewed at each study visit, and any infusion site 
reactions will be followed until resolution. Each infusion site reaction will be categorized 
using the intensity grading described for AEs in Section 12.1.2.1.
12.11 Special Treatment Considerations
Subjects will be screened for eligibility in the study as described in Section 9.1 and
Section 8.7.3, and will be informed of the study specific restrictions and requirements of 
the study. Subjects who are not willing to comply with the study requirements and 
restrictions of the study will not be eligible for enrollment.
All biological agents carry the risk of hypersensitivity reactions. Clinical manifestations 
of these reactions may include, but are not limited to:

Skin rash

Pruritus (itching)

Urticaria (hives)

Angioedema (for example, swelling of the lips and/or tongue)

Anaphylactic reaction
Proteins may also cause redness, itching, swelling, or pain locally at the infusion site.
Thromboembolic events have been observed with bypassing agents including FEIBA. 
Clinical manifestations of these events may include, but not limited to:

myocardial infarction

deep vein thrombosis

pulmonary embolism

stroke and

transitory ischemic attack
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Sometimes, these reactions can be life-threatening. Therefore, all subjects should be 
closely monitored for signs or symptoms that could result from such reactions, educated 
on the signs or symptoms of these types of reactions, and instructed to contact the study 
site immediately if any of the symptoms are experienced following an injection. If a 
subject experiences an acute hypersensitivity reaction after an infusion of IP, the subject
should be managed appropriately and given instruction to receive relevant supportive 
care.
Subjects who experience a potentially severe hypersensitivity  reaction will be 
discontinued from IP. They will complete a Termination/Study Completion Visit, and 
will be monitored for stabilization or resolution of the AE. Premedication to prevent 
allergic reactions will not be permitted, as severe hypersensitivity reactions are an 
outcome measure for this study.
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13. STATISTICS
Data handling will be conducted by the contract research organization. The data will be 
inspected for inconsistencies by performing validation checks.
Statistical analysis for this study will be descriptive in nature. All details regarding the 
statistical analysis and the preparation of tables, listings, and figures will be described in 
the statistical analysis plan (SAP) prepared by the contract research organization and 
approved by the sponsor before database lock.
13.1 Sample Size and Power Calculations
The sample size of 24 evaluable subjects for this safety study was determined by 
considering available patients, and is not based on statistical power calculations.
Evaluable patients are all subjects who receive at least 2 infusions per sequence in Part 1 
and at least 2 infusions per infusion rate in Part 2.
To allow a non-evaluable rate of 25%, 32 subjects will be enrolled.
13.2 Datasets and Analysis Cohorts
Safety: The safety analysis set will include all subjects who received at least 1 dose of IP
(FEIBA). All safety analyses will be performed on the safety analysis set. Subjects will 
be evaluated according to the treatment received.
13.3 Handling of Missing, Unused, and Spurious Data
All data will be evaluated as observed. A subject who withdraws prior to the last planned 
observation in a study period will be included in the analyses up to the time of 
withdrawal.
13.4 Methods of Analysis
13.4.1 Primary Outcome Measure
13.4.1.1 Analysis of the Primary Outcome Measure (Parts 1 and 2)
AEs, SAEs and AEs leading to discontinuation, thromboembolic events, hypersensitivity 
and infusion site reactions that occur during or after the IP infusion will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be carried out for temporally associated adverse 
events; and for temporally associated or potentially related adverse events as assessed by 
the investigators. Temporally associated AEs are defined as AEs that begin during 
infusion or within 24 hours (or 1 day where time of onset is not available) after 
completion of infusion, irrespective of being related or not related to treatment.
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In addition, tables will be prepared to list each AE, the number of subjects who 
experienced an AE at least once, and the rate of subjects with AE(s). 
AEs will be grouped by system organ class. Each event will then be divided into defined 
severity grades (mild, moderate, severe). The tables will also divide the AEs into those 
considered related to the infusion and those considered unrelated. These tables will also 
be carried out for temporally associated adverse events; and for temporally associated or 
causally related adverse events. 
AEs and SAEs for each subject, including the same event on several occasions, will be 
listed separately, giving both MedDRA preferred term and the original term used by the 
investigator, system organ class, severity grade, seriousness, relation to the treatment, 
onset date, and stop date.
AEs that occurred before first IP infusion will be listed separately.
Lab results and vital signs which are considered AEs will be listed.
13.4.2 Exploratory Outcome Measures 
All exploratory outcome measures will be analyzed for descriptive purposes only.
Due to uncertainty around prior dosing/steady state and the unknown clinical relevance of 
FII as lead marker for FEIBA, FII levels will be analyzed as standardized increase from 
the corresponding pre-dose levels. The minimum, time-averaged up to 48 hours (for the 
48 hour time point, the pre-infusion value of the next infusion will be taken), and 
maximum standardized increase from the pre-dose level will be analyzed for descriptive 
purposes only.
The standardized increase from pre-dose levels will be calculated as (Ct – Cpre)/dose 
where Ct refers to the FII level at time point t in U/dL, Cpre is the corresponding pre-
dose level in U/dL, and dose refers to the weight adjusted FEIBA dose administered in 
U/kg which will be summarized per subject and infusion as minimum, time-averaged up 
to 48 hours and maximum over the sampling period. The time-averaged standardized 
increase (TASI) will be calculated as a weighted average of the standardized increases 
with weights corresponding to linear interpolation between sampling time points. 
For the purpose of estimating a potential impact of infusion volume (regular and reduced 
volume within Part 1) at an infusion rate of 2 U/kg/min on the minimum, time-averaged
up to 48 hours and maximum standardized increase, a linear mixed effects model will be 
used that models the sequence, period and volume as fixed effect and subject nested 
within sequence as random effect.
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For the purpose of estimating a potential impact of infusion rates (4 and 10 U/kg/min 
within part 2) with reduced volume on the minimum, time-averaged up to 48 hours and 
maximum standardized increase, a linear mixed effects model that models infusion rate as 
fixed and subject as random effect will be used.
The potential impact of infusion volume as well as the potential impact of infusion rates 
on the minimum, time-averaged up to 48 hours and maximum standardized increase will 
be described using point estimates for infusion volume and rates with corresponding 
two-sided 95% confidence intervals obtained from the models described above. 
Full details of the statistical analysis will be specified in the SAP.
13.5 Planned Interim Analysis of the Study
There is no planned interim analysis other than a safety data review by the ISMC.
14. 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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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP E6 R(2), 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.
15.1.1 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.
15.2 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.
15.3 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.
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15.4 Safety Monitoring
Primary objective of the study is to monitor safety parameters throughout the study with a 
special emphasis on hypersensitivity and thromboembolic events. Adverse event data will 
be collected at each visit assessed and documented on the CRFs as outlined in 
Section 12.1.2.3.
Serious adverse events are monitored and reported per the safety reporting guidelines as 
outlined in Section 12.1.2.3.
This study will be monitored by an ISMC. The ISMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from the ongoing 
clinical study. For this study, the ISMC will be composed by appropriate members of 
clinical, safety, and biostatistics division that are not involved in the active execution of 
the trial. The ISMC can stop a study if it finds toxicities or if treatment is proven to be not 
beneficial. 
All SAEs will be reviewed within 24 hours by the Chair of the ISMC. There are 
3 planned ISMC meetings:
1.
Within 24 hours after 6 subjects in Part 1 (3 subjects in each group) have 
completed Infusion 5
2.
Within 24 hours after 6 subjects have completed Infusion 7 (Part 2)
3.
Within 24 hours after 6 subjects have completed Infusion 10 (Part 2)
ISMC preplanned meetings will be held concurrently with the ongoing study.
Subjects can continue with their scheduled therapy and assessments unless the ISMC 
warrants that the trial needs to be suspended due to safety concerns. Additional ad hoc 
meetings of the ISMC may be convened as appropriate per ongoing safety evaluations.
15.5 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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15.6 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 (Baxalta) will also ensure the responsible EC 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.
15.7 Laboratory and Reader Standardization
Not applicable; a central laboratory/reader will be used for all clinical assessments.
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16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, ICF, any promotional 
material/advertisements, and any other written information to be provided to patients 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.
16.3 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 must sign an ICF before entering into the study according to applicable 
regulatory requirements and ICH GCP. Before use, the ICF will be reviewed by the 
sponsor and approved by the EC and regulatory authority(ies), where applicable, (see
Section 16.2). The ICF 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 will be allowed sufficient 
time to consider participation in the study. By signing the ICF, patients agree that they 
will complete all evaluations required by the study, unless they withdraw voluntarily or 
are terminated from the study for any reason.
The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised ICF, that have 
been approved by the applicable EC and regulatory authorities, where applicable, will be 
provided by the investigator to the subjects who consented to participate in the study.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper/electronic 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 ICFs, 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 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/electronic format, and this documentation will be 
considered source documentation. Changes to an 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 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., 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.
17.3 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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18. 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.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement.
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20.3 Schedule of Study Procedures and Assessments (Part 1)
Table 2
Schedule of Study Procedures and Assessments (Part 1)
Procedures/
Assessments
Screening 
Assessments
Study Visitsa
Randomization
Infusion #1
Infusion #2
Infusion #3
Infusion #4
Infusion #5 
Infusion #6
Study Visit Windowsb
A maximum 
of -35 days 
to 0
Day 1
within 48 hrs 
(-8/+24) 
from Infusion 1
48 hrs 
(-8/+24) 
from Infusion 2
48 hrs 
(-8/+24) 
from Infusion 3
48 hrs 
(-8/+24) 
from Infusion 4
48 hrs
(-8/+24) 
from Infusion 5
Informed Consentc
X
Eligibility Criteria
X
Medical History
X
Medication and Non-drug Therapies
X
X
X
X
X
X
X
Physical Examination
X
Pregnancy Test
X
Vital Signsd
X
X
X
X
X
X
X
Karnofsky Performance Test
X
Laboratory Assessmentse
X
X
X
X
X
X
X
Inhibitor level if no documentation
X
Factor II levelsf, g
X
X
X
X
X
X
X
Adverse Events, breakthrough bleeds, 
and infusion site reactionsh
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesi
X
X
Coagulation testingj
X
X
X
X
Continued on Next Page
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Continued
Abbreviations: ICF=informed consent form; IP=investigational product
a A Study Completion/Termination Visit is to be completed in Part 1 only for subjects who withdraw or discontinue prior to the end of the study. If a subject 
withdraws or discontinues, this visit should be completed within 7 days but no sooner than 72 hours from the last infusion that the subject received. 
Otherwise, the Study Completion/Termination Visit will occur at the end of Part 2 (see Table 3).
b Study Visit Windows:
Infusion 1 can be scheduled after screening assessments have been completed; all other infusions will occur within 48 hours (-8/+24hours) from the 
previous infusion.
c Occurs at enrollment (prior to any study-specific procedure).
d Vital signs will include body temperature, pulse rate, blood pressure, and respiratory rate,. Blood pressure will be measured when subjects are in the 
supine position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within at 30 minutes after completion of 
the infusion. Height, measured once at Screening, and weight measured at Screening and Completion/Termination will also be collected.
e For laboratory assessments, see Section 20.5.
f FII levels within 60 minutes (±15min) before, and 30 mins (±10min) after infusions 2 and 5. 
g FII levels within 60 min (±15 min) before, and at 30 min (±10 min) and hours 1 (±15 min), 2 (±30 min), 6 (±1 hour), 8 (±2 hour) and 12 (±4hours) after 
infusions 1, 3, 4 and 6.
h The infusion site will be monitored for AEs for 30 ±10 minutes after each study infusion. See Section 12.10 for details. SAEs occurring before IP 
exposure. See Section 12.3 for details.
i Questionnaires (TSQM and patient preference questionnaire) will be administered after screening prior to Infusion 1, after Infusion 3 prior to Infusion 4, 
after Infusion 6 prior to Infusion 7, after Infusion 9 prior to infusion 10, and after infusion 12 or up to the completion of the Study Completion/Termination 
Visit. These questionnaires can be completed between visits but should be completed prior to the start of the next infusion. The final questionnaire should 
be completed prior to or during the Study Completion/Termination Visit.. See Section 10.5 for details. 
j Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A) pre-infusion within 
60 min (±15 min), and post-infusion at 1 hr ± 15 min and 6 hr ± 1 hr (mentioned in Section 12.7.2).
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20.4 Schedule of Study Procedures and Assessments (Part 2)
Table 3
Schedule of Study Procedures and Assessments (Part 2)
Procedures/
Assessments
Study Visits
Infusions 7
Infusion 8
Infusion 9
Infusion 10
Infusion 11
Infusions 12
Study 
Completion/
Termination 
Visita
Rate of Infusion
Rate: 4 U/kg/min
Rate: 10 U/kg/min
Study Visit Windowsb
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) 
from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) from 
previous 
infusion
48 hours 
(-8/+24) 
from 
previous 
infusion
72 h to 7 days 
from Infusion
12 
(or last infusion)
Medications and Non-drug Therapies
X
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
Laboratory Assessmentsd
X
X
X
X
X
X
X
Factor II levelse, f
X
X
X
X
X
X
Adverse Events, breakthrough 
bleeds, and infusion site, infusion 
related reactionsg
X
X
X
X
X
X
X
IP Treatment
X
X
X
X
X
X
TSQM and patient preference 
questionnairesh
X
X
X
Coagulation testingi
X
X
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Continued
a
The Study Completion/Termination Visit includes cases of withdrawal or discontinuation. This visit should be done within 7 days but no sooner than 
72 hours after Infusion 12). If a subject withdraws or discontinues, this visit should be done within 7 days but no sooner than 72 hours after the last 
infusion that the subject receives.
b
Infusions will occur within 48 hours (-8/+24hours) from the previous infusion.
c
Vital signs will include body temperature, pulse rate, blood pressure, respiratory rate,. Blood pressure will be measured when subjects are in the supine 
position. On the day of IP administration, vital signs will be taken within 30 minutes prior to infusion and within at 30 minutes after completion of the 
infusion. Height, measured once at Screening, and weight measured at Screening and Completion/Termination will also be collected.
d
For laboratory assessments, see Section 20.5.
e
FII levels within 60 minutes (±15min) before, and 30 mins (±10min) after infusions 7, 8, 10 and 11.
f
FII levels within 60 min (±15 min) before, and at 30 min (±10 min) and hours 1 (±15 min), 2 (±30 min), 6 (±1 hour), 8 (±2 hour) and 12 (±4hours) after 
infusions 9 and 12.
g
The infusion site will be monitored for AEs for 30 ±10 minutes after the infusion. See Section 12.10 for details. SAEs occurring before IP exposure
will not be included in the analysis of SAEs. See Section 12.3 for details.
h
Questionnaires (TSQM and patient preference questionnaire) will be administered after screening prior to Infusion 1, after Infusion 3 prior to Infusion 4, 
after Infusion 6 prior to Infusion 7, after Infusion 9 prior to infusion 10, and after infusion 12 or up to the completion of the Study 
Completion/Termination Visit. These questionnaires can be completed between visits but should be completed prior to the start of the next infusion. The 
final questionnaire should be completed prior to or during the Study Completion/Termination Visit. See Section 10.5 for details.
i
Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A) pre-infusion within 
60 min (±15 min), and post-infusion at 1 hr ± 15 min and 6 hr ± 1 hr (mentioned in Section 12.7.2).
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20.5 Clinical Laboratory Assessments
Table 4
Clinical Laboratory Assessments
Assessments 
Screening Visit
Infusions 1, 3, 4, 6, 9, 12 
Study Completion/ 
TerminationVisita
Hematologyb
X
X
Clinical Chemistryc
X
X
Coagulation Testingd
X
Serological Testinge and CD4f
X
X
Pregnancy Testg
X
a
Includes cases of withdraw or discontinuation.
b
Hematology assessments include:  CBC (Hct, Hgb, RBC count, WBC count) with differential, MCV, MCHC, and platelet count.
c
Clinical chemistry assessments include sodium, chloride, potassium, bicarbonate, AST, ALT, albumin, total protein, alkaline phosphatase, total 
bilirubin, BUN, creatinine, glucose, GGT, 5’-nucleotidase.
d
Coagulation testing will include: aPTT, PT, thrombotic markers (D-Dimers, Prothrombin fragment F 1+2, TAT, fibrinopeptide A (mentioned in 
Section 12.7.2).
e
Serological testing will include: HIV-1 and HIV-2 antibodies (HIV+, check CD4 count–screening visit only), HAV antibodies, , HBsAg, HCV antibody, 
parvovirus B19 (IgM and IgG), cytomegalovirus antibodies (IgM and IgG), and Epstein-Barr virus antibodies (IgM and IgG).
f
CD4 at screening in case of positive HIV test results.
g
A serum pregnancy test will be performed for females of childbearing potential.
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20.6 FII activity and Coagulation testing
Table 5
FII and Coagulation Testing Time Frame
Procedures/Assessments
PART 1
Infusions 1, 3, 4, 6
PART 2
Infusions 9, 12 
Infusions 
2, 5, 7, 8, 10, 11
FII activity
At screening
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
1 hr ± 15 min
2 hr ± 30 min
6 hr ± 1 hr
8 hr ± 2 hr
12 hr ± 4 hr
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
1 hr ± 15 min
2 hr ± 30 min
6 hr ± 1 hr
8 hr ± 2 hr
12 hr ± 4 hr
Preinfusion:
within 60 min (±15 min)
Post infusion:
30 ± 10 min
Coagulation testing: 
aPTT, PT, thrombotic 
markers (D-Dimers, 
Prothrombin fragment F 1+2, 
TAT, fibrinopeptide A)
Infusions 1, 3, 4, 6, 9, and 12
Preinfusion:
within 60 min (±15 min)
Post infusion:
1 hr ± 15 min
6 hr ± 1 hr
Abbreviations: FII=Factor II, h=hours; min=minutes
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21. REFERENCES
1.
Baxter Healthcare Corporation. FEIBA (Anti-inhibitor coagulant complex) for 
intravenous use, lyophylized powder for solution:2013. Web Link: 
https://www.baxter.com/assets/downloads/feiba_us_pi.pdf
2.
Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity 
(FEIBA®): 10-year compilation of thrombotic adverse events. Haemophilia. 
2002;8(2):83-90.
3.
Hilgartner M, Aledort L, Andes A, Gill J. Efficacy and safety of vapor-heated anti-
inhibitor coagulant complex in hemophilia patients. FEIBA Study Group. 
Transfusion. 1990;30(7):626-630.
4.
Hilgartner MW, Knatterud GL, Group FS. The use of factor eight inhibitor by-
passing activity (FEIBA immuno) product for treatment of bleeding episodes in 
hemophiliacs with inhibitors. Blood. 1983;61(1):36-40.
5.
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(3):560-575.
6.
Boggio LN, Kessler CM. Hemophilia A and B. In: Kitchens C, Alving BM, Kessler 
CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier 
Saunders; 2007:45-59.
7.
Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. 
Haemophilia. 1998;4(4):558-563.
8.
Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII 
and factor IX inhibitors in haemophiliacs. Lancet. 1992;339(8793):594-598.
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9.
Turecek PL, Varadi K, Gritsch H, et al. Factor Xa and prothrombin: mechanism of 
action of FEIBA. Vox Sang. 1999;77 Suppl 1:72-79.
10.
Turecek P, Schwarz HP. Factor eight inhibitor bypassing activity. In: Bertolini B, 
Goss N, Curling J, eds. Production of Plasma Proteins for Therapeutic Use. United 
States: John Wiley and Sons; 2013:49-64.
11.
Varadi K, Tangada S, Loeschberger M, et al. Pro- and anticoagulant factors 
facilitate thrombin generation and balance the haemostatic response to FEIBA® in 
prophylactic therapy. Haemophilia. 2016;22(4):615-624.
12.
Négrier C, Voisin S, Baghaei F, et al. Global Post-Authorization Safety 
Surveillance Study: real-world data on prophylaxis and on-demand treatment using 
FEIBA (an activated prothrombin complex concentrate). Blood Coagul 
Fibrinolysis. 2016;27(5):551-556.
13.
Himmelspach M, Richter G, Muhr E, et al. A fully recombinant partial prothrombin 
complex effectively bypasses FVIII in vitro and in vivo. Thromb Haemost. 
2002;88(6):1003-1011.
14.
Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. 
Validation of an abbreviated treatment satisfaction questionnaire for medication 
(TSQM-9) among patients on antihypertensive medications. Health Qual Life 
Outcomes. 2009;7:36.
15.
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents 
in cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. New 
York: Columbia University Press; 1949:191-205.
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22. SUMMARY OF CHANGES
Protocol 091501 AMENDMENT 4 (Global): 2018 MAR 07
Replaces: Protocol 091501 AMENDMENT 3 (Global): 2017 SEP 14
In this section, changes made in this amendment from the previous version of the
protocol, dated 2017 SEP 14, are described and their rationale is given.
1.
Throughout the document
Description of change:  “concentration” of Factor II was changed to “activity” of 
Factor II throughout.
Purpose of change: To provide clarification as the assay measures activity.
2.
Synopsis and Outcome Measures, Section 8.4.1
Description of Change: Primary outcome measure rephrased.
Purpose of Change: To clarify facilitation of statistical analysis of the primary 
outcome measure after study completion.
3.
Synopsis, Targeted Accrual
Description of change:  added “enroll 32 patients” to have 24 evaluable.
Purpose of change: To provide clarity for study recruitment, that enrolling 
32 subjects will provide the required 24 evaluable subjects by allowing a non-
evaluable rate of 25%.
4.
Synopsis and Statistics, Section 13
Description of change: Added and rephrased: Evaluable patients are all subjects 
who receive at least 2 infusions per sequence in Part 1 and at least 2 infusions per 
infusion rate in Part 2. To allow a non-evaluable rate of 25%, 32 subjects will be 
enrolled.
Purpose of change: Rephrased to clarify criteria for evaluable subjects. Added the 
non-evaluable rate to specify number of subjects to be enrolled, to achieve the 
required evaluable subjects.
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5.
Synopsis and Exclusion Criteria, Section 9.2
Description of Change: Exclusion criterion added: taking Emicizumab (Hemlibra) 
added as an exclusion criterion.
Purpose of Change: As Emicizumab was recently licensed, there is a need to 
mention that administration of it concurrently with FEIBA during this study 
constitutes an exclusion criterion.
6.
Synopsis and Analysis of the Primary Outcome Measure (Parts 1 and 2), 
Section 13.4.1
Description of Change: Clarification that vital signs and lab results considered AEs 
will be listed in summary tables.
Purpose of Change: To facilitate statistical analysis of the primary outcome 
measure after study completion.
7.
Synopsis and Analysis of the Exploratory Outcome Measure 1
Description of Change: Text added: Due to uncertainty around prior dosing/steady 
state and the unknown clinical relevance of FII as lead marker for FEIBA, FII
levels will be analyzed as standardized increase from the corresponding pre-dose 
levels.  The minimum, time-averaged up to 48 hours (for the 48 hour time point, the 
pre-infusion value of the next infusion will be taken), and maximum standardized 
increase from the pre-dose level will be analyzed for descriptive purposes only. 
For the purpose of estimating a potential impact of infusion volume (regular and 
reduced volume within Part 1) at an infusion rate of 2 U/kg/min on the minimum, 
time-averaged up to 48 hours and maximum standardized increase, a linear mixed 
effects model will be used that models the sequence, period and volume as fixed 
effect and subject nested within sequence as random effect. 
For the purpose of estimating a potential impact of infusion rates (4 and 
10 U/kg/min within part 2) with reduced volume on the minimum, time-averaged 
up to 48 hours and maximum standardized increase, a linear mixed effects model 
that models infusion rate as fixed and subject as random effect will be used.
The potential impact of infusion volume as well as the potential impact of infusion 
rates on the minimum, time-averaged up to 48 hours and maximum standardized 
increase will be described using point estimates for infusion volume and rates with  
corresponding two-sided 95% confidence intervals obtained from the models 
above.
Purpose of Change: To facilitate statistical analysis of the exploratory outcome 
measure after study completion.
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8.
Synopsis and Study Design, Section 8.2
Description of change:  The following text was added:  Evaluable patients from 
Part 2 are all subjects who receive 4 of the 6 planned infusions, at least 2 infusions 
per infusion rate.
Purpose of change: Rephrased to clarify criteria for evaluable subjects in part 2 of 
the study. 
9.
Medications and Non-Drug Therapies, Section 10.4
Description of Change: Addition of Emicuzimab as a product not permitted as a 
concomitant therapy. Also, addition of rFVIIa as a product not permitted for 
concomitant/sequential therapy that should not be used unless FEIBA does not 
work to treat breakthrough bleeding.
Purpose of Change: To provide clarity in terms of permissible study medication .
10. Definitions, Section 12.1.1
Description of Change: Addition of the following text in italics: “Any pregnancy 
occurring during the study following maternal or paternal exposure should be 
reported to the sponsor within 24 hours.”
Purpose of Change: To provide clarity in terms of permissible study conduct.
11. Activity of FII and Coagulation Testing , Section 12.7.2
Description of Change: Slight changes to timing of blood draws, specifically 
addition of a pre-infusion blood draw for coagulation parameters to add a control to 
compare to post-infusion blood draw findings, and removal of a blood draw at 
12 hours to make the study less strenuous for the patient. Also added a blood draw 
for FII at screening.
Purpose of Change: To provide clarity and include blood draws that are required for 
proper data analysis. 
12. Viral Serology, Section 12.7.3
Description of Change: Removal of hepatitis B virus antibody  from testing.
Purpose of Change: For HBV, antigen testing is included in the protocol so 
antibody testing is not needed.
13. Schedule of Study Procedures and Assessments, Section 20.3 and Section 20.4
Description of Change: Addition of Xs to clarify when blood would be drawn to 
monitor FII levels, and to clarify that pre-infusion blood draws will be considered 
as 48 hour post-infusion time point for prior infusion.
Purpose of Change: Clarification of study procedure.
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14. Clinical Laboratory Assessments, Section 20.5
Description of Change: Removal of HBVantibody from the testing schedule.
Purpose of Change: HBV antigen testing is included in the protocol so antibody 
testing is not needed.
15. Activity of FII and Coagulation Testing, Section 20.6
Description of Change: Clarification of the FII blood draw schedule in Table 5 .
Purpose of Change: Clarification of study procedures.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 4 (Global): 2018 MAR 07
Replaces
AMENDMENT 3 (Global): 2017 SEP 14
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: Anti-inhibitor Coagulant Complex Nanofiltered 
(activated prothrombin complex concentrate [APCC]) FEIBA NF
STUDY TITLE: A Phase 3b/4, Prospective, Multicenter, Open-label, Randomized, 
Crossover Study of Tolerability and Safety of FEIBA Reconstituted in Regular or 
50% Reduced Volume and of Faster Infusion Rates in Patients with 
Hemophilia A or B with Inhibitors
PROTOCOL IDENTIFIER: 091501
CLINICAL TRIAL PHASE 3b/4
AMENDMENT 4 (Global): 2018 MAR 07
Replaces
AMENDMENT 3 (Global): 2017 SEP 14
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2015-005781-39
IND NUMBER: 13715
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
 MD, 
Global Clinical Development Operations
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