A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional Study of Plasma-Derived Factor VIII/VWF (Alphanate®) in Immune Tolerance Induction Therapy in Subjects With Congenital Hemophilia A
Phase: PHASE2
Conditions: Hemophilia A, Congenital
Sponsor: Grifols Therapeutics LLC

 
Official Title: 
A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional 
Study of Plasma-Derived Factor Vlll/VWF (Alphanate®) in Immune Tolerance 
Induction Therapy in Subjects with Congenital Hemophilia A 
NCT Number: 
NCT03095287 
 
Document Date: 
 
Protocol Version 4.0: 21 March 2019 
 
 
 
 
 
 
 
 

Protocol GBI1406 – Amendment 3 
 
21 Mar 2019 
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Summary of Changes for Amendment 3 
Protocol Version 
Date of Approval 
4.0 
Amendment 3 + Integrated Protocol 
21 Mar 2019 
3.0 
Amendment 2 + Integrated Protocol 
20 Dec 2016 
2.0 
Amendment 1 + Integrated Protocol 
10 Feb 2016 
1.0 
Original 
13 Nov 2015 
 
Amendment 3/21 Mar 2019 
A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional Study of 
Plasma-Derived Factor VIII/VWF (Alphanate®) in Immune Tolerance Induction Therapy in 
Subjects with Congenital Hemophilia A  
The protocol for GBI1406 (Version 3.0, dated 20 Dec 2016) has been amended and reissued 
as Protocol Amendment 3, Version 4.0, dated 21 Mar 2019. See Appendix 2 for a summary 
of changes for Amendment 3. 

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Investigator Signature Page 
The undersigned confirms that he/she agrees to conduct the study under the conditions 
described in this protocol and comply with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice (ICH 
GCP) and all applicable regulatory requirements: 
 
___________________________________  
______________________ 
INVESTIGATOR NAME (Please Print)  
 
LOCATION 
 
___________________________________  
______________________ 
INVESTIGATOR SIGNATURE  
 
 
 
DATE 
 

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PROTOCOL SYNOPSIS 
Title of Study: A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional 
Study of Plasma-Derived Factor VIII/VWF (Alphanate®) in Immune Tolerance Induction 
Therapy in Subjects with Congenital Hemophilia A  
Study Number: GBI1406 
Phase: 2 
Study Objectives: 
Primary Efficacy Objectives 
• To assess the proportion of subjects who achieve complete immune tolerance within 
33 months of initiating Alphanate for immune tolerance induction (ITI) 
Secondary Efficacy Objective(s) (if applicable) 
• To assess the proportion of subjects who achieve either complete or partial immune 
tolerance within 33 months of initiating Alphanate for ITI 
• To assess the maintenance of complete or partial immune tolerance without relapse for 
12 months 
• To assess the annualized frequency of bleeding events  
Safety Objective 
• To assess the safety of Alphanate treatment for ITI  
Overall Study Design and Description: This is a multicenter, multinational, prospective, 
single-arm, nonrandomized, open-label study of approximately 25 male subjects with 
congenital hemophilia A who will receive their first (primary) ITI treatment with Alphanate. 
The study will be conducted at approximately 30 study centers. 
The study consists of 2 phases: 
• A 33-month ITI Treatment Phase in which all eligible subjects will receive ITI treatment 
with Alphanate for a period of up to 33 months. Upon confirmation of complete immune 
tolerization, subjects will then enter a 12-month Prophylactic Phase (that includes the 
protocol-defined dose tapering). If, after 33 months of ITI, a subject has achieved partial 
immune tolerance, the subject will enter a 12-month Prophylactic Phase (that includes the 
protocol-defined dose tapering). 
• A 12-month Prophylactic Phase for all subjects who meet the criteria for complete or 
partial success to continue on a prophylactic dosing regimen of Alphanate. 
Number of Subjects Planned: 25 

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Diagnosis and Main Criteria for Inclusion: 
Note that any criterion number containing vX, was modified in the indicated protocol 
version X (eg, 2v4 indicates that the original criterion #2 was last modified in Protocol 
Version 4). 
Inclusion Criteria: 
A subject must meet all of the following inclusion criteria at the time of the 
Screening/Baseline Visit (as specified below) to be eligible for participation in the study.  
1. The subject has a documented diagnosis of severe congenital hemophilia A with factor 
VIII activity (FVIII:C) <1% of normal. 
2v4. The subject is a male <12 years of age at the Baseline Visit. 
3v4. The subject’s documented historical peak inhibitor titer is ≥5 Bethesda units (BU) and 
≤200 BU. 
4. The subject has an inhibitor titer >0.6 BU and <10 BU at Screening. 
5. The subject has had a delay ≤24 months from the date of diagnosis of the inhibitor to the 
start of the subject’s ITI treatment.  
6. The subject has a caregiver willing to participate and comply with requirements of the 
protocol, including home infusions, blood sampling, and daily diary for the duration of 
the trial. 
7. The subject has provided signed assent, if applicable (per Institutional Review Board or 
Ethics Committee requirements), and a parent or legal guardian has provided signed 
informed consent.  
Exclusion Criteria:  
A subject meeting any of the following exclusion criteria is not eligible for participation in 
the study: 
1. The subject has acquired factor VIII (FVIII) deficiency. 
2. The subject has previously received ITI treatment. 
3. The subject has a recent (within 1 month) history of central line infection at the time of 
Screening. 
4. The subject has a high risk of cardiovascular, cerebrovascular, or thromboembolic event 
as judged by the investigator. 
5.  The subject is currently undergoing treatment with immunosuppressive drugs (eg, 
systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin, 
interferon, or the use of a protein A column or plasmapheresis and is unwilling to 
discontinue these treatments starting at the screening visit. 
6. The subject has a known infection with human immunodeficiency virus (HIV) or has 
clinical signs and symptoms consistent with current HIV infection.  
7. The subject has a known previous infection with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) or has clinical signs and symptoms consistent with current HBV or HCV 
infection. 

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8. The subject has significant proteinuria, has a history of acute renal failure or severe renal 
impairment (blood urea nitrogen or creatinine >2 times the upper limit of normal), or is 
receiving dialysis at Screening. 
9. The subject has a value of aspartate transaminase or alanine aminotransferase >2 times 
the upper limit of normal at Screening. 
10. The subject has clinical evidence of any significant acute or chronic disease that, in the 
opinion of the investigator, may interfere with successful completion of the trial or place 
the subject at undue medical risk. 
11. The subject has a history of anaphylaxis or severe systemic reaction to any 
plasma-derived or other blood products.  
12. The subject has participated in another clinical trial of an investigational product within 
30 days prior to Screening—imaging studies without investigative treatments are 
permitted—or has received any investigational blood product within the previous 
3 months. 
13. In the opinion of the investigator, the subject or caregiver may have compliance problems 
with the protocol or the procedures of the protocol.  
Investigational Product, Dose and Mode of Administration: 
Alphanate is a sterile, lyophilized powder for intravenous injection after reconstitution. 
Alphanate is to be reconstituted with Sterile Water for Injection (SWFI), United States 
Pharmacopeia, European Pharmacopeia, or comparable SWFI. The diluent is supplied in a 
separate vial or prefilled syringe. Instructions for the reconstitution of Alphanate are 
provided in the Pharmacy Manual/Study Manual. 
Subjects will start treatment with Alphanate 100 IU/kg/day with a one-time option to 
increase to a dosing regimen of 200 IU/kg/day at any time after 90 days of ITI treatment if 
inhibitor titer has decreased <20% of the level from the initiation of Alphanate ITI treatment 
or if there has been an increase in the rate of bleeding events relative to the rate of bleeding 
events experienced during the first 90 days of treatment or if the inhibitor titer increases to 
>500 BU following the initiation of Alphanate ITI treatment. Increased bleeding may be 
treated with bypass agents; however, the dose of Alphanate may not be increased until after 
90 days of ITI treatment. Following this 90-day treatment/observation period, a possible 
increase in rate of bleeding events relative to the rate during the 90-day observation period 
will be assessed at each clinic visit, which at any given time will allow for the dosage 
increase to 200 IU/kg. 
The drug is administered by bolus intravenous injection daily until complete immune 
tolerance is achieved or for 33 months if complete immune tolerance is not achieved.  
Complete immune tolerance is defined as the subject achieving all of the following: 
• Undetectable inhibitor titer (<0.6 BU); must be confirmed by 2 consecutive assessments 
performed within approximately 2 weeks of each other 
• FVIII:C plasma recovery ≥66% of the predicted normal value  

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• FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period 
Partial immune tolerance is defined as the subject achieving all of the following: 
• Reduction of inhibitor titer to <5 BU; must be confirmed by 2 consecutive assessments 
performed within approximately 2 weeks of each other 
• FVIII:C plasma recovery of <66% of the predicted normal value or FVIII:C half-life of 
<6 hours after a 72-hour FVIII treatment-free period  
• Clinical response to FVIII therapy  
Treatment failure is defined as: 
• Failure to fulfill the criteria for complete or partial immune tolerance within 33 months 
Subjects achieving complete immune tolerance will enter a 12-month Prophylactic Phase. 
Subjects achieving partial immune tolerance after 33 months will also enter the Prophylactic 
Phase. Treatment failure subjects will be discontinued.  
When subjects being treated at 100 IU/kg/day enter the Prophylactic Phase, the dose will be 
tapered down in a step-wise manner over an 8-week period to reach a final prophylactic dose 
of 50 IU/kg every other day or 3 times per week, at the investigator’s discretion.  
When subjects being treated at 200 IU/kg/day enter the Prophylactic Phase, the dose will be 
tapered down in a step-wise manner over a 12-week period to reach a final prophylactic dose 
of 50 IU/kg every other day or 3 times per week, at the investigator’s discretion. 
After completing the taper period, the subject will receive the prophylactic dose regimen of 
50 IU/kg every other day or 3 times per week, at the investigator’s discretion, for the 
remainder of the 12-month Prophylactic Phase. Subjects completing the 12-month 
Prophylactic Phase will have completed the study. 
Duration of Treatment: 
The duration of a subject’s participation could be as long as 46 months for those subjects 
who achieve partial immune tolerance at the end of the 33-month ITI Treatment Phase and 
also successfully complete the 12-month Prophylactic Phase. Subjects who attain complete 
success before the Month 33 Visit may have a shorter study duration.  
Reference Therapy, Dose and Mode of Administration: None 

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Key Study Variables: 
Primary Efficacy: 
The primary efficacy endpoint is the proportion of subjects achieving complete immune 
tolerance within 33 months of initiation of ITI treatment. 
Secondary Efficacy (if applicable): 
• The proportion of subjects who achieve either complete or partial immune tolerance 
within 33 months of receiving Alphanate for ITI 
• The proportion of subjects who maintain complete immune tolerance or partial immune 
tolerance without relapse for 12 months  
• The annualized frequencies of bleeding events during the ITI Treatment Phase and the 
Prophylactic Phase 
Safety: 
• Adverse events (AEs), including suspected adverse drug reactions (ADRs), adverse 
reactions (ARs), serious adverse events (SAEs), and discontinuations due to AEs and 
SAEs 
• Physical examination results 
• Vital signs (temperature, respiratory rate, pulse rate, systolic blood pressure, and diastolic 
blood pressure) 
• Clinical laboratory parameters: hematology panel, clinical chemistry panel, and urinalysis 
• Bleeding events by severity  
Study Assessments and Procedures: 
ITI Treatment Phase 
Subjects will have study center visits to measure FVIII inhibitor titers at Weeks 2, 4, 6, 8, 
and monthly thereafter during the ITI Treatment Phase to assess the subject’s response to the 
ITI treatments. Additional unscheduled visits for inhibitor titer measurements may occur 
during the first 3 months of ITI treatment and throughout the trial as deemed necessary by the 
investigator. After 2 consecutive undetectable FVIII inhibitor titer measurements have been 
obtained that are required to qualify the subject as a complete success, the sequential 
assessment of the FVIII:C in vivo recovery followed by FVIII:C half-life assessment will be 
performed to confirm that the subject has normal FVIII:C pharmacokinetic parameters.  
FVIII inhibitor titer will be measured by the central laboratory using the Nijmegen 
modification of the Bethesda method for FVIII inhibitor measurements. A negative result 
will be a value of <0.6 BU. The scheduled inhibitor titer sampling should occur ≥24 hours 
after the last Alphanate dosing or at the maximum possible interval from the last dose of 
Alphanate. Upon receipt of a negative inhibitor titer result from the central laboratory, the 
study center will request the subject/caregiver to return to the study center within 
approximately 2 weeks after the last assessment for the confirmatory inhibitor titer 
assessment, along with a simultaneous assessment of FVIII:C in vivo recovery.  

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For subjects with negative titer levels, if in vivo recovery is <66% of the predicted normal 
value, the subject will continue ITI treatment, and the site is to assess in vivo recovery 
monthly until recovery is ≥66% of the predicted normal value. For subjects with negative 
titer levels, if in vivo recovery is ≥66% of the predicted normal value, the site is to schedule 
the visit for FVIII:C half-life assessment to occur within approximately 2 weeks, with 
instructions to caregivers to adhere to a 72-hour FVIII treatment-free period immediately 
prior to the half-life assessment visit. FVIII:C half-life will be assessed from blood samples 
collected immediately before a 50 IU/kg dose of Alphanate is administered in the study 
center, followed by samples at 15 to 30 minutes after Alphanate administration and at 1, 3, 6, 
12 (±2), 24 (±4), and 48 (±4) hours after Alphanate administration. 
Partial Success Subjects: For subjects with 2 consecutive inhibitor titers <5 BU who are 
approaching the end of the ITI Treatment Phase (at the Month 33 Visit), the assessment of 
FVIII:C in vivo recovery and FVIII:C half-life will be performed to obtain FVIII:C 
pharmacokinetic data.  
Prophylactic Phase 
The inhibitor titer will be assessed every month for the first 4 months during the Prophylactic 
Phase and then every 2 months for the remaining 8 months of the Prophylactic Phase to 
measure FVIII inhibitor titer for relapse and to assess sustainability of immune tolerance. 
Additional unscheduled visits for inhibitor titer measurements may occur throughout the trial 
as deemed necessary by the investigator. 
Subjects achieving complete immune tolerance and subjects achieving partial immune 
tolerance at the completion of 33 months of ITI treatment will be monitored for relapse 
during the 12-month Prophylactic Phase. Inhibitor titer and FVIII:C in vivo recovery will be 
assayed by the central laboratory at Months 1, 2, 3, 4, 6, 8, 10, and 12 during the 
Prophylactic Phase. If the inhibitor titer or in vivo recovery indicate the possibility of a 
recurrence of an inhibitor in a subject with complete immune tolerance, the inhibitor titer 
assessment and FVIII:C in vivo recovery assessment must be repeated by the central 
laboratory within approximately 2 weeks to confirm relapse. In a subject with partial immune 
tolerance, if there is a rise of an inhibitor to ≥5 BU, the inhibitor titer assessment must be 
repeated along with a FVIII:C in vivo recovery assessment within approximately 2 weeks to 
confirm relapse by the central laboratory. 
Safety assessments: physical examination, hematology, and urinalysis will be assessed at 
Screening and Baseline, at Months 6, 12, 18, 24, 30, and 33 during the ITI Treatment Phase, 
at Months 3 (except for physical examination), 6, and 12 during the Prophylactic Phase, and 
at the Early Withdrawal Visit. Clinical chemistry will be assessed at all of the 
aforementioned visits except for Baseline. Vital signs will be assessed at all scheduled visits. 
Samples for viral safety testing will be collected at Screening, Baseline, Week 8, Month 6, 
Month 15, Month 30, and Month 33 of the ITI Treatment Phase, as well as at the end of the 
Prophylactic Phase (Month 12) or at the Early Withdrawal Visit. Adverse events and 
concomitant medications will be assessed at all scheduled visits. 

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Statistical Methods: 
Primary Efficacy Analyses 
The proportion of subjects achieving complete immune tolerance receiving Alphanate during 
the ITI Treatment Phase will be calculated along with the 95% confidence interval (CI). The 
exact (Clopper-Pearson) method for the binomial proportion will be used to calculate the 
95% CI. If the lower bound of the 95% CI is greater than 10%, then it is statistically 
significant that the proportion of subjects achieving complete immune tolerance receiving 
Alphanate is greater than the historical spontaneous remission rate of 10%. 
Secondary Efficacy Analyses 
The proportion of subjects achieving either complete or partial immune tolerance within 
33 months of ITI treatment will be summarized with the number, percentage, and 95% CI for 
the percentage. 
Time to achieving inhibitor titer <0.6 BU, time to complete immune tolerance, and time to 
partial immune tolerance will be summarized using the Kaplan-Meier method. 
FVIII inhibitor titer, FVIII:C recovery, and FVIII:C half-life will be summarized with mean, 
standard deviation, median, and minimum/maximum values by visit. 
Frequency of bleeding events will be summarized by severity and annualized for the duration 
of each phase of the clinical trial. For subjects who achieved complete or partial immune 
tolerance, a similar analysis will also be performed for the annualized Prophylactic Phase. 
Safety Analysis 
Physical examination findings will be summarized. 
The incidence of AEs, AEs by causality, and AEs by severity will be summarized. Subjects 
with deaths, SAEs, and AEs leading to premature discontinuation from the study will be 
listed. 
The following AEs of special interest must be reported as related to study drug and will be 
summarized: central venous access and catheter-related complications for which the device 
was placed or was used for FVIII administration within the trial, infusion-site reactions, 
thromboembolic events, and hypersensitivity reactions. 
The severity of bleeding events will be summarized. 
For all laboratory tests, the Screening and/or Baseline value and the change from Baseline 
will be summarized for numeric results, and frequency/percentage will be summarized for 
qualitative results. For those tests with normal ranges, shift tables will be provided. For virus 
safety test results, a data listing will be provided. 
Summary statistics will be provided for the original value and change from baseline values 
for vital sign parameters. 
Determination of Sample Size 
The study by Caram et al (22) indicated that among patients with very high maximum 
inhibitor titers (≥10 BU), the spontaneous remission rate was 3.4% (1 of 29), with the upper 
limit of the 95% CI being 10%. Considering the various factors in estimating the true 

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spontaneous remission rate for this population, a 10% spontaneous remission rate is 
considered a historical control. The Kurth et al publication (3) summarized the retrospective 
review of Alphanate when used for primary ITI treatment and reported complete success in 
3 of 8 primary ITI patients. Using the same criteria for defining “complete success” as those 
in the current study and an intent-to-treat (ITT) analysis approach, the complete success rate 
reported in the International Immune Tolerance Study (1) and in the North American 
Immune Tolerance Registry (14) was in the range of approximately 25 to 40%. Assuming 
that the rate for achieving immune tolerance is 35% with Alphanate treatment based on these 
publications, 25 subjects would provide 80% power to demonstrate a statistically significant 
improvement with a one-sided test at alpha level of 0.025 in an ITT analysis.  

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..........................................................................................................4 
GLOSSARY AND ABBREVIATIONS..................................................................................16 
1 
INTRODUCTION ...........................................................................................................18 
1.1 
Background ............................................................................................................18 
1.2 
Clinical Experience with Grifols FVIII/VWF Products and ITI ...........................19 
1.3 
Study Rationale ......................................................................................................20 
2 
STUDY OBJECTIVES ....................................................................................................21 
2.1 
Primary Objectives.................................................................................................21 
2.2 
Secondary Objectives.............................................................................................21 
2.3 
 ..........................................................................................21 
3 
INVESTIGATIONAL PLAN ..........................................................................................21 
3.1 
Study Design and Plan ...........................................................................................21 
3.2 
Selection of Study Population ................................................................................24 
3.2.1 
Screening and Baseline Entry Criteria .........................................................24 
3.2.1.1 
Inclusion Criteria ...............................................................................24 
3.2.1.2 
Exclusion Criteria ..............................................................................25 
3.3 
Treatments..............................................................................................................26 
3.3.1 
Treatments to be Administered ....................................................................26 
3.3.1.1 
Alphanate, Powder for Injection ........................................................27 
3.3.1.2 
Labeling of Investigational Product ...................................................27 
3.3.1.3 
Storage of Investigational Product .....................................................27 
3.3.1.4 
Accountability for Investigational Product ........................................27 
3.3.2 
Rationale for Selection of Doses/Timing of Investigational Products in 
the Study ......................................................................................................28 
3.3.2.1 
Selection of Doses and Timing of Doses in the Study.......................28 
3.3.2.2 
Subject Numbering ............................................................................28 
3.3.2.3 
Randomization ...................................................................................29 
3.3.2.4 
Blinding..............................................................................................29 
3.3.2.5 
Treatment Compliance .......................................................................29 
3.4 
Prior and Concomitant Therapy .............................................................................29 
3.4.1 
Prohibited Concomitant Medications During the Study ..............................29 
3.5 
Study Endpoints .....................................................................................................30 
3.5.1 
Efficacy Endpoints .......................................................................................30 
3.5.1.1 
Primary Efficacy Endpoint ................................................................30 
3.5.1.2 
Definition of Complete/Partial Immune Tolerance or Failure ...........30 
3.5.1.3 
Secondary Efficacy Endpoints ...........................................................30 
3.5.1.4 
Definition of Relapse .........................................................................31 
3.5.1.5 
 .......................................................................31 
3.5.2 
Safety Endpoints ..........................................................................................31 
3.6 
Assessments ...........................................................................................................32 

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3.6.1 
Assessment Periods ......................................................................................32 
3.6.2 
Observations and Measurements .................................................................32 
3.6.2.1 
Demography, Baseline Characteristics, and Medical History ...........32 
3.6.2.2 
Physical Examination.........................................................................33 
3.6.2.3 
Factor VIII Inhibitor Titer ..................................................................33 
3.6.2.4 
Factor VIII:C Pharmacokinetics ........................................................34 
3.6.2.5 
Monitoring for Relapse ......................................................................35 
3.6.2.6 
Bleeding Events .................................................................................36 
3.6.2.7 
Subject Diary .....................................................................................36 
3.6.3 
Description of Laboratory Tests and Procedures .........................................36 
3.6.3.1 
Virus Safety Testing ..........................................................................38 
3.6.4 
Procedures by Visit ......................................................................................38 
3.6.4.1 
Screening Visit (21 to 30 Days Prior to Baseline Visit) ....................38 
3.6.4.2 
Baseline Visit .....................................................................................39 
3.6.4.3 
Week 2, Week 4, Week 6, Week 8, and Subsequent Monthly 
Visits During ITI Treatment Phase ....................................................40 
3.6.4.4 
Additional Assessments at Months 6, 12, 18, 24, and 30 During 
ITI Treatment Phase ...........................................................................40 
3.6.4.5 
Factor VIII:C Pharmacokinetic Assessment Visits............................41 
3.6.4.6 
Month 33 During ITI Treatment Phase ..............................................42 
3.6.4.7 
Prophylactic Phase Visits ...................................................................43 
3.6.4.8 
Early Termination Visit .....................................................................46 
3.6.4.9 
Unscheduled Visits ............................................................................46 
3.7 
Screen Failures .......................................................................................................47 
3.8 
Interruption of ITI Treatment.................................................................................47 
3.9 
Removal of Subjects ..............................................................................................47 
3.10 
Premature Termination of Study/Closure of Center ..............................................47 
4 
ADVERSE EVENTS .......................................................................................................48 
4.1 
Warnings and Precautions......................................................................................48 
4.2 
Adverse Event Monitoring .....................................................................................48 
4.3 
Adverse Event Definitions .....................................................................................48 
4.3.1 
Adverse Events ............................................................................................48 
4.3.2 
Suspected Adverse Drug Reactions/Adverse Reactions ..............................48 
4.3.3 
Causality of Adverse Event .........................................................................49 
4.3.4 
Severity of Adverse Event or Suspected Adverse Drug Reaction ...............50 
4.3.5 
Expectedness of Adverse Event or Suspected Adverse Drug Reaction ......50 
4.3.6 
Seriousness of Adverse Event or Suspected Adverse Drug Reaction; 
Serious Adverse Event .................................................................................50 
4.3.7 
Adverse Event Documentation ....................................................................51 
4.3.8 
Events of Special Interest.............................................................................52 
4.3.9 
Type and Duration of the Follow-Up of Subjects After Adverse Events ....52 
4.4 
Reporting of Serious Adverse Events ....................................................................53 

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4.4.1 
Reporting Serious Adverse Event ................................................................53 
5 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................53 
5.1 
Statistical and Analytical Plans ..............................................................................53 
5.1.1 
Subject Populations for Analysis .................................................................53 
5.1.2 
Demographic and Baseline Characteristics .................................................54 
5.1.3 
Efficacy Analyses ........................................................................................54 
5.1.3.1 
Analysis of Primary Efficacy Endpoint .............................................54 
5.1.3.2 
Analysis of Secondary Efficacy Endpoints........................................54 
5.1.3.3 
..........................................................55 
5.1.4 
Safety Analyses ............................................................................................55 
5.2 
Determination of Sample Size ...............................................................................55 
6 
ADMINISTRATIVE .......................................................................................................56 
6.1 
Investigators, Other Study Personnel, and External Committees ..........................56 
6.2 
Data Quality ...........................................................................................................56 
6.3 
Documentation .......................................................................................................56 
6.3.1 
Record Retention .........................................................................................57 
6.3.2 
Access to Information for Monitoring .........................................................57 
6.3.3 
Access to Information for Audits or Inspections .........................................57 
7 
ETHICAL AND LEGAL ASPECTS...............................................................................57 
7.1 
Institutional Review Board/Ethics Committee ......................................................57 
7.2 
Ethical Conduct of the Study .................................................................................58 
7.3 
Regulatory Authority Approvals/Authorizations ...................................................58 
7.4 
Subject Information and Consent...........................................................................58 
7.5 
Insurance ................................................................................................................58 
7.6 
Confidentiality .......................................................................................................59 
8 
USE OF DATA AND PUBLICATION ..........................................................................59 
9 
REFERENCES ................................................................................................................60 
10 APPENDICES .................................................................................................................62 
 
LIST OF IN-TEXT TABLES 
Table 3-1 Name, Description, and Location of Laboratory Tests and Procedures ............37 
 
LIST OF IN-TEXT FIGURES 
Figure 3-1 Study Design ....................................................................................................24 
 

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LIST OF APPENDICES 
Appendix 1 
Schedule of Procedures ......................................................................62 
Appendix 2 
Amendment 3 – Summary of Changes ..............................................65 
 

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GLOSSARY AND ABBREVIATIONS 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AR 
adverse reaction 
AST 
aspartate transaminase 
B19V 
parvovirus B19 
BU 
Bethesda units 
BUN 
blood urea nitrogen 
CI 
confidence interval 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EP 
European Pharmacopeia 
FDA 
Food and Drug Administration 
FVIII 
factor VIII 
FVIII:C 
factor VIII activity 
HAV 
hepatitis A virus 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH GCP 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use Good Clinical Practice 
IP 
investigational product 
IRB 
Institutional Review Board 
ITI 
immune tolerance induction 
ITT 
intent-to-treat 
LDH 
lactate dehydrogenase 
NAT 
nucleic acid amplification technology 
SAE 
serious adverse event 
SWFI 
Sterile Water for Injection 

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US 
United States 
USP 
United States Pharmacopeia 
VWD 
von Willebrand disease 
VWF 
von Willebrand factor 
 

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1 
INTRODUCTION 
1.1 
Background 
Alphanate® is an antihemophilic factor/von Willebrand factor (VWF) complex (human) 
indicated for the control and prevention of bleeding in patients with hemophilia A. 
Development of an inhibitor, an endogenously produced neutralizing, alloantibody that reacts 
with and inactivates infused factor VIII (FVIII), represents the most serious complication of 
treatment for patients with hemophilia A (1-3). Patients more likely to develop an inhibitor 
are those with null FVIII mutations, large deletions, nonsense mutations, and intron 
22 inversions (2). The goal of immune tolerance induction (ITI) is to gradually eliminate the 
immune response and the production of anti-FVIII antibodies. 
VWF is a crucial component of hemostasis and plays a key role in FVIII function, 
production, and stabilization. Moreover, there are data indicating that VWF competes with 
the FVIII binding of anti-FVIII antibodies directed against the A3 and C2 domains, which 
are key binding sites for VWF located in the light chain of FVIII (4,5).  
Criteria for a clinically meaningful response to ITI vary among reported studies, but 
complete ITI success (also referred to as complete immune tolerance) is typically defined as 
achieving undetectable inhibitor titers and normal pharmacokinetics of infused FVIII.  
The available published ITI studies have served to identify which variables influence ITI 
success, but direct comparison between studies (or registries) is difficult because of the 
marked differences in products and dosing regimens. These studies also differ widely in 
patient demographics, data collection methods, and endpoint definitions. Existing clinical 
data have been primarily observational but deemed sufficient for various independent expert 
panels to issue ITI management guidelines. These include the European Consensus Panel (6), 
the International Consensus Panel (7), the United Kingdom Hemophilia Centre Doctors 
Organization Guidelines (8), and United States (US) Guidelines (9). Although differences 
exist among panels concerning FVIII dose, supportive care, and treatment 
duration/discontinuation, considerable consensus has been reached regarding the definition of 
complete immune tolerance. Additionally, studies have shown that there are various risk 
factors that increase the risk of failing ITI. These include the initiation of treatment at an age 
≥8 years, a historical peak inhibitor titer >200 Bethesda units (BU), a titer at ITI treatment 
start ≥10 BU, and time between inhibitor detection and ITI ≥2 years (7). Patients who have 
3 or more of these factors are considered at high-risk for ITI failure (10). Beginning therapy 
early after inhibitor diagnosis, preferably when the titer is <10 BU, significantly improves the 
likelihood of successful development of immune tolerance. However, patients with multiple 
risk factors have been shown to successfully achieve immune tolerance, albeit at somewhat 
lower rates (10). 
The definition of complete immune tolerance includes achieving nondetectable inhibitors, 
≥66% in vivo recovery of FVIII activity (FVIII:C) after FVIII infusion, and ≥6 hours 
FVIII:C half-life (7). The definition of a partial, clinically meaningful response to ITI 
typically includes the reduction of inhibitor titer to <5 BU, often with a subnormal in vivo 
recovery of FVIII:C following FVIII infusion (<66% of the predicted normal value based on 

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body mass and amount of FVIII infused) and a subnormal FVIII:C half-life (<6 hours). 
Subjects achieving complete or partial immune tolerance show improved clinical response to 
FVIII replacement.  
In addition, all consensus panels agree that immune tolerance by ITI can be achieved 
successfully with both recombinant and plasma-derived FVIII concentrates and that the 
superiority of product type has not yet been established. The switch to a FVIII/VWF product 
can be considered an option if the response to initial ITI fails with a monoclonal or 
recombinant FVIII product (6,11). The epitope specificity of the inhibitor and the patient’s 
genetic mutation may also impact whether a VWF-containing product will be more 
successful in inducing immune tolerance than a recombinant or highly purified product (12). 
The International Immune Tolerance Study Group registry (13) and the North American 
Immune Tolerance Study registry (14) agreed that patients with poor prognostic factors were 
better tolerized with a high-dose regimen (100 to 200 IU/kg/day); the same unanimity was 
not reached with respect to low-risk patients. Further, a meta-analysis of both retrospective 
registries determined that ITI success was not influenced by dose in low-risk patients, 
defined as patients presenting inhibitor titers <10 BU at the start of ITI and a historical peak 
titer ≤200 BU (15).  
The International Immune Tolerance Study was a randomized clinical trial designed to help 
determine the appropriate dose in low-risk subjects (1). Severe high-titer inhibitor hemophilia 
A subjects were randomly assigned to receive either a high-dose FVIII regimen 
(200 IU/kg/day) or a low-dose FVIII regimen (50 IU/kg 3 times per week). The success rate 
did not differ between treatment arms; however, low-dose subjects bled more often than did 
high-dose subjects, and the study was stopped early for futility and safety considerations.  
1.2 
Clinical Experience with Grifols FVIII/VWF Products and ITI 
The first version of this FVIII/VWF concentrate was licensed in the US in 1978. The first 
formulation to be designated as Alphanate was licensed by the Food and Drug 
Administration (FDA) in 1994, and the current formulation was approved by the FDA in 
1997. Alphanate is approved for the control and prevention of bleeding in patients with 
congenital hemophilia A (and for the treatment of von Willebrand disease [VWD]). 
Alphanate was approved in Italy in 1997 for the treatment and prophylaxis of bleeding in 
patients with hemophilia A and the prevention and treatment of hemorrhage or surgical 
bleeding in patients with VWD, followed by the Netherlands in 2001 for the treatment and 
prophylaxis of bleeding in patients with hemophilia A, and the United Kingdom in 2003 for 
the treatment and prophylaxis of bleeding in patients with hemophilia A and the prevention 
and treatment of hemorrhage or surgical bleeding in patients with VWD. 
A second Grifols product, Fanhdi®, has been approved in the European Union since 1994 for 
the treatment of hemophilia A. Both Alphanate and Fanhdi are manufactured by Grifols 
using very similar processes that include viral inactivation by solvent detergent and heat 
treatment (80ºC for 72 hours). They contain similar amounts of VWF and have comparable 
product release specifications. Alphanate and Fanhdi may be considered comparable 

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products. In addition, in Europe the Summaries of Product Characteristics include 
information on the use of Alphanate and Fanhdi for ITI. 
One retrospective study was performed at 11 US institutions where patients had received 
Alphanate for ITI (3). Data collection started in 2007 from patients who received ITI 
between 1997 and 2010. Primary ITI treatment was carried out in 8 patients, and rescue ITI 
was completed in 25 patients. The dosing regimen was 100 to 200 IU/kg/day for 7 of the 
primary ITI patients, while one of them received 50 IU/kg/day. All of the primary ITI 
patients were <16 years of age at the time of inhibitor diagnosis, and the median age at the 
time of initiation of primary ITI treatment was 41 months. This retrospective study provides 
the basis for adding prospective, clinical trial data to the existing knowledge base. Similarly, 
retrospective data were collected in an international (Spain, Italy, and Germany), multicenter, 
observational study to assess outcomes in patients with moderate to severe hemophilia A 
who developed inhibitors and were subsequently treated with Fanhdi for primary or rescue 
ITI (9,16). Adults and children (age <18 years) with moderate to severe congenital 
hemophilia A (FVIII:C <2%) with inhibitors treated with Fanhdi for primary or rescue ITI 
were included in the study. Treatment regimens varied widely (38 IU/kg 3 times per week to 
300 IU/kg twice a day), although most patients received ≥100 IU/kg/day. All study data were 
collected via retrospective chart review of patients with known ITI outcomes. A total of 
41 patients received primary ITI and 19 patients received rescue ITI. Of the primary ITI 
patients, 88% achieved complete or partial success, generally following the International 
Consensus Guidelines definitions for complete and partial success (7). Of the rescue ITI 
patients, 73% achieved complete or partial success. Median time to complete success was 
19 months; median time to partial success was 22 months. 
Prospective data for ITI with Fanhdi were obtained in the Rits-Fitnhes study. This study was 
a prospective, observational, multicenter design conducted in Italy and Spain with financial 
support from Grifols (17). Subjects were consecutively enrolled from 1999 to 2005. The 
primary outcome parameters of the Rits-Fitnhes study were success (complete or partial) or 
failure to induce immune tolerance and time to ITI success. Seventeen subjects (13 primary 
ITI; 4 rescue ITI) were prospectively enrolled in the study and included adults and children 
(<18 years) with moderate to severe congenital hemophilia A (FVIII <2%), with 
high-responding inhibitors and at least one predictive factor of a poor ITI response. Fanhdi 
was the only FVIII/VWF complex concentrate administered for ITI during the study. Nine 
subjects (53%) had complete success, 7 (41%) had a partial response, and 1 subject (6%) 
discontinued early. 
Overall, the published retrospective data on Alphanate and the supportive published Fanhdi 
(retrospective and prospective) data support the current proposed trial to formally evaluate 
the use of Alphanate in primary ITI subjects.  
1.3 
Study Rationale 
To date, only one randomized, controlled trial in ITI, the International Immune Tolerance 
Study (1), has been completed. Currently, most supporting data for ITI have come from small 
cohort studies and international and national ITI registries. Due to the lack of randomized 
prospective clinical trial data supporting the superiority of any one FVIII product, current 

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The study consists of 2 phases: 
•
A 33-month ITI Treatment Phase in which all eligible subjects will receive ITI treatment
with Alphanate for a period of up to 33 months. Upon confirmation of complete immune
tolerization, subjects will then enter a 12-month Prophylactic Phase (that includes the
protocol-defined dose tapering). If, after 33 months of ITI, a subject has achieved partial
immune tolerance, the subject will enter a 12-month Prophylactic Phase (that includes the
protocol-defined dose tapering).
•
A 12-month Prophylactic Phase for all subjects who meet the criteria for complete or
partial success to continue on a prophylactic dosing regimen of Alphanate (with a
protocol-defined dose tapering).
ITI Treatment Phase up to 33 months: Subjects presenting with an inhibitor titer <10 BU 
should proceed to the Screening Visit.  
The Screening Visit should occur 21 to 30 days before the planned start of ITI treatment to 
ensure availability of all inclusionary/exclusionary laboratory results prior to the initiation of 
ITI dosing. Subjects continuing to meet the entrance criteria will enter the ITI Treatment 
Phase and receive daily doses of Alphanate 100 IU/kg/day for up to 33 months. There is a 
one-time option to increase the dosing regimen to 200 IU/kg/day. This change in the 
subject’s ITI dosing regimen during the ITI Treatment Phase can occur at any time after 
90 days of ITI treatment if there has been less than a 20% decrease in inhibitor titer since the 
initiation of Alphanate ITI treatment or if there has been an increase in the rate of bleeding 
events relative to the rate of bleeding events experienced during the first 90 days of treatment 
or if the inhibitor increases to >500 BU following initiation of Alphanate ITI treatment.  
To accurately capture the peak inhibitor titer on ITI treatment, subjects will have study center 
visits at Weeks 2, 4, 6, 8, and monthly thereafter. Additional unscheduled visits for inhibitor 
titer measurements may occur during the first 3 months of ITI treatment and throughout the 
trial as deemed necessary by the investigator. Weight will be measured at every study center 
visit, and dosing will be based on the subject’s current weight. Between study center visits 
when Alphanate will be administered at home by the subject’s caregiver, the Alphanate dose 
will be the same as the dose calculated at the most recent study center visit where weight was 
measured. Training of caregivers at home may be provided within the first few weeks of 
initiation of ITI treatment for initial port access and newly implanted devices, upon sponsor 
approval. Ongoing home health care for IP infusions will be assessed on a case-by-case basis. 
Subjects will continue to receive their daily Alphanate dose until the inhibitor assay titer is 
negative (<0.6 BU) on 2 consecutive assessments and treatment success is confirmed by 
FVIII:C pharmacokinetic assessments (Section 3.5.1.2), at which time they will enter the 
12-month Prophylactic Phase.  
All subjects will receive ITI treatment for up to 33 months until they achieve complete 
immune tolerance (Section 3.5.1.2). Subjects who have achieved partial immune tolerance 
at the completion of 33 months of ITI treatment will enter the 12-month Prophylactic Phase 
(that includes the protocol-defined dose tapering). Subjects who do not achieve partial 

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immune tolerance at the completion of 33 months of ITI treatment will be discontinued as 
treatment failures.  
Prophylactic Phase up to 12 months: Upon confirmation of achieving complete immune 
tolerance, subjects will enter the 12-month Prophylactic Phase (that includes the 
protocol-defined dose tapering). Subjects achieving partial immune tolerance at the 
completion of the 33-month ITI Treatment Phase will enter the 12-month Prophylactic Phase 
(that includes the protocol-defined dose tapering).  
The Prophylactic Phase begins with an 8-week taper period for subjects tolerized with 
100 IU/kg/day or with a 12-week taper period for subjects tolerized with 200 IU/kg/day to 
bring the dose down in a step-wise manner to a prophylactic dose of Alphanate 50 IU/kg 
every other day or 3 times per week, at the investigator’s discretion. During the Prophylactic 
Phase, subjects will be monitored monthly for the first 4 months and then every 2 months for 
the remaining 8 months to measure FVIII inhibitor titer and FVIII:C in vivo recovery for 
relapse. No other immunotherapy will be permitted during this phase. Additional 
unscheduled visits for inhibitor titer measurements may occur throughout the trial as deemed 
necessary by the investigator. 
For subjects who have attained complete tolerization, relapse in the Prophylactic Phase is 
defined as:  
•
A return of FVIII inhibitor titer to detectable levels (ie, ≥0.6 BU), FVIII:C recovery
<66% of the predicted normal value, or FVIII:C half-life <6 hours, confirmed by repeat
assessment within approximately 2 weeks in the Prophylactic Phase
For subjects who have attained partial tolerization, relapse is defined as: 
•
An increase of FVIII inhibitor titer to ≥5 BU, confirmed by repeat assessment within
approximately 2 weeks in the Prophylactic Phase
In the event of a confirmed relapse during the Prophylactic Phase in which there is a 
concomitant loss of clinical response to FVIII therapy, the subject will be withdrawn from 
the study. 
The duration of a subject’s participation could be as long as 46 months for those subjects 
who achieve partial immune tolerance at the end of the 33-month ITI Treatment Phase and 
also successfully complete the 12-month Prophylactic Phase. Subjects who attain complete 
success before the Month 33 Visit may have a shorter study duration. The overall study 
schema is outlined in Figure 3-1, and the schedule of study procedures is provided in 
Appendix 1. 

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7. The subject has provided signed assent, if applicable (per Institutional Review Board
[IRB] or Ethics Committee [EC] requirements), and a parent or legal guardian has
provided signed informed consent.
3.2.1.2 
Exclusion Criteria 
A subject meeting any of the following exclusion criteria is not eligible for participation in 
the study: 
1. The subject has acquired FVIII deficiency.
2. The subject has previously received ITI treatment.
3. The subject has a recent (within 1 month) history of central line infection at the time of
Screening.
4. The subject has a high risk of cardiovascular, cerebrovascular, or thromboembolic event
as judged by the investigator.
5. The subject is currently undergoing treatment with immunosuppressive drugs (eg,
systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin,
interferon, or the use of a protein A column or plasmapheresis and is unwilling to
discontinue these treatments starting at the screening visit.
6. The subject has a known infection with human immunodeficiency virus (HIV) or has
clinical signs and symptoms consistent with current HIV infection.
7. The subject has a known previous infection with hepatitis B virus (HBV) or hepatitis C
virus (HCV) or has clinical signs and symptoms consistent with current HBV or HCV
infection.
8. The subject has significant proteinuria, has a history of acute renal failure or severe renal
impairment (blood urea nitrogen [BUN] or creatinine >2 times the upper limit of normal),
or is receiving dialysis at Screening.
9. The subject has a value of aspartate transaminase (AST) or alanine aminotransferase
(ALT) >2 times the upper limit of normal at Screening.
10. The subject has clinical evidence of any significant acute or chronic disease that, in the
opinion of the investigator, may interfere with successful completion of the trial or place
the subject at undue medical risk.
11. The subject has a history of anaphylaxis or severe systemic reaction to any
plasma-derived or other blood products.
12. The subject has participated in another clinical trial of an Investigational Product (IP)
within 30 days prior to Screening—imaging studies without investigative treatments are
permitted—or has received any investigational blood product within the previous
3 months.
13. In the opinion of the investigator, the subject or caregiver may have compliance problems
with the protocol or the procedures of the protocol.

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3.3 
Treatments 
3.3.1 
Treatments to be Administered 
Subjects will start treatment with Alphanate 100 IU/kg/day with a one-time option to 
increase to a dosing regimen of 200 IU/kg/day at any time after 90 days of ITI treatment if 
inhibitor titer has decreased <20% of the level from the initiation of Alphanate ITI treatment 
or if there has been an increase in the rate of bleeding events relative to the rate of bleeding 
events experienced during the first 90 days of treatment or if the inhibitor titer increases to 
>500 BU following the initiation of Alphanate ITI treatment. Increased bleeding may be 
treated with bypass agents (Section 3.4); however, the dose of Alphanate may not be 
increased until after 90 days of ITI treatment. Following this 90-day treatment/ observation 
period, a possible increase in the rate of bleeding events relative to the rate during the 90-day 
observation period will be assessed at each clinic visit, which at any given time will allow for 
the dosage increase to 200 IU/kg. 
The drug is administered by bolus intravenous injection daily until complete immune 
tolerance is achieved (Section 3.5.1.2) or for 33 months if complete immune tolerance is not 
achieved. 
When subjects being treated at 100 IU/kg/day enter the Prophylactic Phase, the dose will be 
tapered down in a step-wise manner over an 8-week period to reach a final prophylactic dose 
of 50 IU/kg every other day or 3 times per week, at the investigator’s discretion. During this 
taper period, the subject will receive: 
•
Alphanate 50 IU/kg/day for the first 4-week period
•
Alphanate 50 IU/kg every other day for the second 4-week period
When subjects being treated at 200 IU/kg/day enter the Prophylactic Phase, the dose will be 
tapered down in a step-wise manner over a 12-week period to reach a final prophylactic dose 
of 50 IU/kg every other day or 3 times per week, at the investigator’s discretion. During this 
taper period, the subject will receive: 
•
Alphanate 100 IU/kg/day for the first 4-week period
•
Alphanate 50 IU/kg/day for the second 4-week period
•
Alphanate 50 IU/kg every other day for the third 4-week period
After completing the taper period, the subject will receive the prophylactic dose regimen of 
50 IU/kg every other day or 3 times per week, at the investigator’s discretion, for the 
remainder of the 12-month Prophylactic Phase. Subjects completing the 12-month 
Prophylactic Phase will have completed the study. 
In the event of a confirmed relapse during the Prophylactic Phase in which there is a 
concomitant loss of clinical response to FVIII therapy, the subject will be withdrawn from 
the study. 

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3.3.1.1 
Alphanate, Powder for Injection 
Alphanate is a sterile, lyophilized powder for intravenous injection after reconstitution. 
Alphanate is to be reconstituted with Sterile Water for Injection (SWFI), United States 
Pharmacopeia (USP), European Pharmacopeia (EP), or comparable SWFI. The diluent is 
supplied in a separate vial or prefilled syringe. Instructions for the reconstitution of 
Alphanate are provided in the Pharmacy Manual/Study Manual. 
3.3.1.2 
Labeling of Investigational Product 
Grifols Alphanate IP will be labeled according to the requirements of local law and 
legislation. Label text will be approved according to agreed Grifols procedures, and copies of 
the labels will be made available to the study center upon request. Alphanate batch numbers 
will be included on the labels and in the study files.  
This open-label study design does not require blinding of study participants or investigative 
study center personnel to treatment information. 
3.3.1.3 
Storage of Investigational Product 
Alphanate must be stored in a secure area accessible only by study personnel authorized by 
the investigator, such as the study staff responsible for the preparation and dispensing of IP. 
Depending upon the regional location of the investigator, Alphanate will be supplied with 
diluent either contained in a separate diluent vial or with diluent in a prefilled syringe. 
Alphanate supplied with a separate diluent vial is stable for 3 years, up to the expiration date 
printed on its label, provided that the storage temperature does not exceed 25°C (77°F). Do 
not freeze.  
Alphanate supplied with diluent in a prefilled syringe is stable for 3 years, up to the 
expiration date printed on its label, provided that the storage temperature does not exceed 
30°C (86°F). Do not freeze the diluent. 
Investigators, or designees, are responsible for maintaining storage temperature records and 
for immediately reporting deviations in temperature to the study monitor. 
Details for the storage are located in the Pharmacy Manual provided to each study center, and 
instructions will also be provided to participating subjects. 
3.3.1.4 
Accountability for Investigational Product 
The IP, Alphanate, is to be used only for the study in accordance with the directions given in 
this protocol. The investigator, or designee such as the study center pharmacist, is responsible 
for the distribution of the IP in accordance with directions given in the protocol and 
Pharmacy Manual. 
The investigator is responsible for maintaining accurate records of the IP for his/her study 
center. The IP inventory/dispensing documentation verifying the receipt, dispensing, 

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destruction, or return must be maintained and kept current by the investigator or designee. 
The inventory must be made available for inspection by the monitor. The IP supplies must be 
accounted for by the monitor, and inventory/dispensing logs must be verified by the monitor 
prior to IP return or destruction. Written documentation of all unused inventory is required. 
At the end of the study, a copy of the inventory/dispensing log(s) will be retrieved by the 
monitor and returned to Grifols. 
3.3.2 
Rationale for Selection of Doses/Timing of Investigational Products in the 
Study 
3.3.2.1 
Selection of Doses and Timing of Doses in the Study 
Differences continue to exist between national and international panels (European Consensus 
Panel [6], the International Consensus Panel [7], the United Kingdom Hemophilia Centre 
Doctors Organization Guidelines [8], and the US Guidelines [9]) concerning FVIII ITI dose 
and treatment duration/discontinuation. While the International Immune Tolerance Study 
Group registry and the North America Immune Tolerance Study registry agreed that patients 
with poor prognostic factors were better tolerized with a high-dose regimen 
(100 to 200 IU/kg/day), the same unanimity was not reached with respect to low-risk 
patients. Further, a meta-analysis of both registries determined that ITI success was not 
influenced by dose in low-risk patients, defined as patients presenting inhibitor titers <10 BU 
at the start of ITI and a historical peak titer ≤200 BU (15).  
The selection of the Alphanate ITI dose and frequency of dosing in this trial is based on a 
review of reports of previous ITI studies, the dosing regimens evaluated, and the type of 
patients enrolled (high-risk versus low-risk patients). The International Immune Tolerance 
Study (1) enrolled subjects with low risk. Complete immune tolerance was achieved in 
69.7% of subjects with a dosing regimen of either a high dose (200 IU/kg/day) or a low dose 
(50 IU/kg 3 times per week) and allowed either recombinant or plasma-derived FVIII. An 
important outcome of the International Immune Tolerance Study was that the time to achieve 
a negative inhibitor titer and normal FVIII:C recovery was shorter in the high-dose group 
than in the low-dose group. Additionally, statistically significantly lower bleeding rates 
during ITI were observed in the high-dose group. This observation led to the early 
termination of the study.  
A FVIII dose as low as 50 IU/kg 3 times per week was effective in the International Immune 
Tolerance Study but with higher bleeding rates than with the 200 IU/kg/day regimen, which 
suggests a dose higher than 50 IU/kg 3 times per week may be more appropriate. For this 
reason, the dose of 100 IU/kg/day Alphanate has been chosen as the initial primary ITI 
treatment regimen, with the option to increase the dose to 200 IU/kg/day if the lower dose is 
not effective or to better control bleeding events. For those subjects entering the Prophylactic 
Phase, the Alphanate dose will be reduced in a step-wise manner to 50 IU/kg every other day 
or 3 times per week, at the investigator’s discretion.  
3.3.2.2 
Subject Numbering 
Within each study center, subjects in the study will receive a consecutive 7-digit subject 
number. Subject numbers are assigned beginning with the study center number (3 digits, 

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assigned by the sponsor) followed consecutively with a unique number for each subject 
(4 digits, including leading zeros). For example, if the investigator’s center number is 301, 
subject numbers will be 3010001, 3010002, 3010003, etc., in consecutive order. Subject 
numbers, once assigned, will not be reused at any study center. 
3.3.2.3 
Randomization 
This is a single-arm study with no randomization. 
3.3.2.4 
Blinding 
This is an open-label, single-arm study with no blinding. 
3.3.2.5 
Treatment Compliance 
Subjects/caregivers will be issued a diary to record each dose of Alphanate administered 
during the study (Section 3.6.2.7). Treatment compliance will be assessed based upon records 
from the subject’s diary. Reasons for a deviation from the administration of less than 100% 
of the IP dose (see Sections 3.8 and 3.9) must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records. 
3.4 
Prior and Concomitant Therapy 
Concomitant medications received by the subject during the ITI Treatment Phase and 
Prophylactic Phase must be recorded in the eCRF, including the trade or generic name of the 
medication, the dose, the route of administration, the frequency of the dosing, and the date 
the medication was discontinued. Medications received within 30 days prior to Screening 
will also be recorded in the eCRF. Vaccinations are to be recorded in the concomitant 
medication eCRF.  
Recombinant factor VIIa, prothrombin complex concentrates, activated prothrombin complex 
concentrates, emicizumab, and human FVIII (Alphanate) are allowed to be used 
prophylactically or to treat active bleeding during the ITI Treatment and Prophylactic Phases 
of the study as directed by the investigator. Alphanate will be the only human FVIII allowed 
during this study. Use of these types of medications for prophylaxis or to treat a bleeding 
event should be recorded in the eCRF as concomitant medications for the indication bleeding 
prophylaxis or for the specific bleeding event. This information will be collected from the 
time of study entry onwards. 
3.4.1 
Prohibited Concomitant Medications During the Study 
The following medications and treatments are prohibited during the entire study: 
•
Azathioprine
•
Immunosuppressive drugs (ie, cyclophosphamide, rituximab)
•
Immunoglobulin
•
Treatment with a protein A column or plasmapheresis

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•
Drugs with immunosuppressive side effects (eg, systemic corticosteroids)
3.5 
Study Endpoints 
3.5.1 
Efficacy Endpoints 
3.5.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects achieving complete immune 
tolerance (Section 3.5.1.2) within 33 months of initiation of ITI treatment. 
3.5.1.2 
Definition of Complete/Partial Immune Tolerance or Failure 
Successful achievement of immune tolerance (complete or partial) and failure of ITI are 
defined per International Consensus Panel recommendations (7) and are detailed below. 
Complete immune tolerance is defined as the subject achieving all of the following: 
•
Undetectable inhibitor titer (<0.6 BU); must be confirmed by 2 consecutive assessments
performed within approximately 2 weeks of each other
•
FVIII:C plasma recovery ≥66% of the predicted normal value
•
FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period
Partial immune tolerance is defined as the subject achieving all of the following: 
•
Reduction of inhibitor titer to <5 BU; must be confirmed by 2 consecutive assessments
performed within approximately 2 weeks of each other
•
FVIII:C plasma recovery of <66% of the predicted normal value or FVIII:C half-life of
<6 hours after a 72-hour FVIII treatment-free period
•
Clinical response to FVIII therapy
Treatment failure is defined as: 
•
Failure to fulfill the criteria for complete or partial immune tolerance within 33 months
3.5.1.3 
Secondary Efficacy Endpoints 
The following are secondary efficacy endpoints: 
•
The proportion of subjects who achieve either complete or partial immune tolerance
within 33 months of receiving Alphanate for ITI
•
The proportion of subjects who maintain complete immune tolerance or partial immune
tolerance without relapse (Section 3.5.1.4) for 12 months
•
The annualized frequencies of bleeding events during the ITI Treatment Phase and the
Prophylactic Phase

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• Hypersensitivity reactions, including anaphylaxis and anaphylactic reactions 
3.6 
Assessments 
3.6.1 
Assessment Periods 
The study consists of 2 phases:  
• A 33-month ITI Treatment Phase in which all eligible subjects will receive ITI treatment 
with Alphanate for a period of up to 33 months. The ITI Treatment Phase begins with a 
Screening Visit occurring up to 30 days before start of ITI treatment. Upon confirmation 
of successful immune tolerization, subjects will then enter the Prophylactic Phase 
(immediately for complete success subjects; after 33 months of ITI for partial success 
subjects). 
• A 12-month Prophylactic Phase for all subjects who meet the criteria for complete or 
partial success to continue on a prophylactic dosing regimen of Alphanate. 
3.6.2 
Observations and Measurements 
The following is a description of the procedures or assessments to be performed during the 
study. Refer to the Schedule of Procedures in Appendix 1 and to Section 3.6.4 for the study 
center visits at which the assessments are performed. During the ITI Treatment Phase, the 
study center visits occurring after the Baseline Visit should be scheduled at the 
protocol-specified time relative to the date of the Baseline Visit. During the Prophylactic 
Phase, the study center visits are to be scheduled relative to the beginning of the Prophylactic 
Phase. A ±4-day window around each scheduled visit is allowed. Unscheduled visits may be 
conducted if deemed necessary for the purpose of subject safety. 
3.6.2.1 
Demography, Baseline Characteristics, and Medical History 
Demographic and baseline characteristics of the subject will be collected at the Screening 
Visit and updated at the Baseline Visit. Baseline data will include date of birth, date of FVIII 
inhibitor diagnosis, FVIII genotype information, FVIII treatment at the time of inhibitor 
diagnosis, FVIII products used prior to ITI start, immunosuppressive treatment initiated 
subsequent to inhibitor diagnosis, bleeding events prior to ITI start (collected from medical 
records for a period of up to 12 months prior to Screening), peak FVIII inhibitor titer before 
start of Alphanate ITI (from medical records) and the date of this assessment, and FVIII 
inhibitor titer at the last measurement prior to start of Alphanate ITI.  
For subjects who do not have a documented FVIII genotype, a blood sample should be 
obtained at the Baseline Visit (or at a later clinic visit if blood volumes at the Baseline Visit 
are restrictive) and sent to the central laboratory for genotyping analysis. 
Medical history will be collected at Screening to determine the subject’s eligibility.  

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3.6.2.2 
Physical Examination 
A physical examination will be performed at the Screening Visit to determine the subject’s 
eligibility, every 6 months during the ITI Treatment Phase, every 6 months during the 
Prophylactic Phase, and at the Early Termination Visit. The physical examination will not 
include a genitourinary examination. Findings will be recorded as normal or abnormal 
according to the investigator’s judgment.  
Vital signs (temperature, respiratory rate, pulse rate, and systolic and diastolic blood 
pressures) will be assessed at all scheduled visits (prior to Alphanate dosing if Alphanate is 
administered during the visit).  
Height will be measured at Screening. Weight will be measured at all scheduled visits. 
3.6.2.3 
Factor VIII Inhibitor Titer 
Factor VIII inhibitor titer will be measured by the central laboratory using the Nijmegen 
modification of the Bethesda method for FVIII inhibitor measurements. A negative result 
will be a value of <0.6 BU. The scheduled inhibitor titer sampling should occur ≥24 hours 
after the last Alphanate dosing or at the maximum possible interval from the last dose of 
Alphanate. The study center may need to call the subject/caregiver to remind them about this 
requirement prior to coming in for their regularly scheduled study center visit. Upon receipt 
of a negative inhibitor titer result from the central laboratory, the study center will request the 
subject/caregiver to return to the study center within approximately 2 weeks after the last 
assessment for the confirmatory inhibitor titer assessment, along with a simultaneous 
assessment of FVIII:C in vivo recovery.  
The absence of inhibitor will be confirmed by 2 consecutive negative inhibitor values 
measured within approximately 2 weeks of each other and normalization of FVIII:C 
pharmacokinetic parameters. 
ITI TREATMENT PHASE 
To accurately capture the peak inhibitor titer on ITI treatment, subjects will have study center 
visits at Weeks 2, 4, 6, 8, and monthly thereafter. Additional unscheduled visits for inhibitor 
titer measurements may occur during the first 3 months of ITI treatment and throughout the 
trial as deemed necessary by the investigator.  
Complete Success Subjects: 
During the ITI Treatment Phase, after 2 consecutive undetectable FVIII inhibitor titer 
measurements have been obtained that are required to qualify the subject as a complete 
success, the sequential assessment of the FVIII:C in vivo recovery (which can be obtained at 
the visit to confirm the negative inhibitor titer) followed by FVIII:C half-life assessment will 
be performed to confirm that the subject has normal FVIII:C pharmacokinetic parameters.  

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Partial Success Subjects: 
For subjects with 2 consecutive inhibitor titers <5 BU who are approaching the end of the ITI 
Treatment Phase (at the Month 33 Visit), the assessment of FVIII:C in vivo recovery and 
FVIII:C half-life will be performed to obtain FVIII:C pharmacokinetic data.  
PROPHYLACTIC PHASE 
The inhibitor titer will be assessed every month for the first 4 months during the Prophylactic 
Phase and then every 2 months for the remaining 8 months of the Prophylactic Phase to 
measure FVIII inhibitor titer for relapse and to assess sustainability of immune tolerance. 
Additional unscheduled visits for inhibitor titer measurements may occur throughout the trial 
as deemed necessary by the investigator. 
3.6.2.4 
Factor VIII:C Pharmacokinetics 
Assessment of FVIII:C pharmacokinetics involves an assessment of in vivo recovery and a 
half-life assessment in order to confirm disappearance of the inhibitor. When the first 
inhibitor titer result has been received indicating the subject may have attained complete 
immune tolerance, a second confirmatory inhibitor measurement is to be performed within 
approximately 2 weeks after the last assessment; at this next visit, a sample will also be 
collected for measuring FVIII:C in vivo recovery. Upon confirmation of FVIII:C in vivo 
recovery ≥66% of the predicted normal value, a FVIII:C half-life assessment visit is to be 
scheduled within the following 2 weeks to occur 72 hours after the last Alphanate dose. 
All partial success subjects will also undergo an assessment of FVIII:C pharmacokinetics 
(assessments of FVIII:C in vivo recovery and a half-life) to begin within approximately 
2 weeks of or at their scheduled Month 33 ITI Treatment Phase visit. 
GENERAL PROCEDURES  
Factor VIII:C in vivo recovery 
Factor VIII activity in vivo recovery sampling may occur without a 72-hour FVIII treatment-
free period but ≥24 hours after the last FVIII treatment. Sampling for in vivo recovery is 
performed immediately before in-center dosing with 50 IU/kg Alphanate and is followed by 
a sample collected 15 to 30 minutes after the Alphanate dosing.  
The predicted normal value of FVIII:C in vivo recovery is 2 IU/dL per IU/kg dosed. 
For subjects with negative inhibitor titer levels, if in vivo recovery is <66% of the predicted 
normal value, the subject will continue ITI treatment, and the site is to assess in vivo 
recovery monthly until recovery is ≥66% of the predicted normal value. 
For subjects with negative inhibitor titer levels, if FVIII in vivo recovery is ≥66% of the 
predicted normal value, the site is to schedule the visit for FVIII:C half-life assessment to 
occur within approximately 2 weeks, with instructions to caregivers to adhere to a 72-hour 
FVIII treatment-free period immediately prior to the half-life assessment visit. 

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Factor VIII:C half-life assessments 
A visit to the study center will be scheduled to assess FVIII:C half-life, and the 
subject/caregiver will be informed to discontinue the daily dose of Alphanate for 72 hours 
prior to the visit. A reminder telephone call is to be made by the study center staff 4 days 
prior to the half-life visit date. The staff are also to remind the caregiver regarding the 
2 additional study center visits needed (ie, at 24 hours and 48 hours after in-center dosing, 
respectively) in order to collect the final half-life samples.  
Factor VIII activity half-life will be assessed from blood samples collected immediately 
before a 50 IU/kg dose of Alphanate is administered in the study center, followed by samples 
at 15 to 30 minutes after Alphanate administration and at 1, 3, 6, 12 (±2), 24 (±4), and 
48 (±4) hours after Alphanate administration. Note that 2 additional visits to the study center 
are required to collect the 24-hour and the 48-hour samples. The subject should not receive 
additional Alphanate until the final blood samples for FVIII:C half-life have been taken 
unless treatment is required for a bleeding event. All of the pharmacokinetic samples are to 
be shipped to the central laboratory. 
Subjects should receive their daily dose of Alphanate after all pharmacokinetic blood 
samples have been taken and will continue to receive their daily dose until it is determined 
that complete immune tolerance has been achieved. The subject’s weight, number of units of 
FVIII infused, sampling times, and FVIII:C assay results are necessary for FVIII:C half-life 
calculations. 
For subjects with a negative inhibitor titer level and in vivo recovery ≥66% but with FVIII:C 
half-life <6 hours, the half-life assessment should be repeated approximately every 12 weeks, 
at the investigator’s discretion, until the half-life is ≥6 hours; until then, the subject should 
continue their ITI dosing regimen.  
If the subject’s FVIII:C half-life is ≥6 hours (in conjunction with a negative inhibitor titer 
and in vivo recovery ≥66%), the subject will be considered a complete success and will enter 
the Prophylactic Phase and begin dose tapering as described in Section 3.3.1. 
General procedures pertaining to assessment of FVIII:C pharmacokinetic assessments to 
monitor for relapse are detailed in Section 3.6.2.5.  
3.6.2.5 
Monitoring for Relapse 
Prophylactic Phase: Subjects achieving complete immune tolerance and subjects achieving 
partial immune tolerance at the completion of 33 months of ITI treatment will be monitored 
for relapse during the 12-month Prophylactic Phase. Inhibitor titer and FVIII:C in vivo 
recovery will be assayed by the central laboratory at Months 1, 2, 3, 4, 6, 8, 10, and 12 during 
the Prophylactic Phase. If the inhibitor titer or in vivo recovery indicate the possibility of a 
recurrence of an inhibitor in a subject with complete immune tolerance, the inhibitor titer 
assessment and FVIII:C in vivo recovery assessment must be repeated by the central 
laboratory within approximately 2 weeks to confirm relapse. In a subject with partial immune 
tolerance, if there is a rise of an inhibitor to ≥5 BU, the inhibitor titer assessment must be 

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repeated along with a FVIII:C in vivo recovery assessment within approximately 2 weeks to 
confirm relapse by the central laboratory.  
Two consecutive tests indicating a return of inhibitor titer, reduced FVIII:C in vivo recovery, 
or reduced FVIII:C half-life, are required to define a relapse in subjects achieving complete 
immune tolerance. Two consecutive tests indicating a rise of inhibitor titer to ≥5 BU are 
required to define a relapse in subjects achieving partial immune tolerance.  
In addition, FVIII:C in vivo recovery and half-life will be measured at the completion of the 
12-month Prophylactic Phase to confirm that relapse has not occurred in complete success 
subjects and to obtain pharmacokinetic data in partial success subjects.  
3.6.2.6 
Bleeding Events 
Bleeding events experienced by subjects will be recorded in the eCRF. 
• Central nervous system hemorrhage/head trauma, throat and neck hemorrhage, 
compartment syndrome, and acute gastrointestinal/abdominal hemorrhage will be 
classified as major bleeding events. Hemoglobin should be monitored along with 
hemodynamic stability (ie, pulse rate and blood pressure).  
• Other bleeding events will be classified as minor bleeding events unless otherwise 
specified by the investigator or if their treatment requires hospitalization. 
TREATMENT OF BLEEDING  
Bleeding in patients with hemophilia can occur at different sites, each of which requires 
specific management.  
Recombinant factor VIIa, prothrombin complex concentrates, activated prothrombin complex 
concentrates, and human FVIII (Alphanate) are allowed to be used to treat active bleeding or 
prophylactically as directed by the investigator during the entire study. Alphanate will be the 
only human FVIII allowed during this study. All treatment for bleeding or for bleeding 
prophylaxis during the study will be recorded in the eCRF.  
3.6.2.7 
Subject Diary 
A diary will be provided to each subject/caregiver at the Baseline Visit. The diary will be 
used to record details of Alphanate drug administration (date/clock time of start and end of 
infusion, dose/volume, rate, and treatment interruptions) or other items. The diary may also 
be used to record days of missed work/school/daily activities due to infections and other 
complications. 
3.6.3 
Description of Laboratory Tests and Procedures 
Detailed descriptions of laboratory test procedures are located in the study Laboratory 
Manual. Table 3-1 provides a summary of the laboratory tests conducted for this study. 

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• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Height and weight 
• Physical examination, excluding genitourinary examination 
• Blood and urine samples for clinical laboratory assessments at central laboratory 
- 
Hematology: Hemoglobin, hematocrit, platelets, red blood cell count including red 
blood cell morphology, white blood cell count with differential, absolute reticulocyte 
count 
- 
Virus safety retain samples  
- 
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, lactate dehydrogenase (LDH), AST, ALT, alkaline phosphatase 
(ALP), glucose, total bilirubin, indirect bilirubin 
- 
FVIII inhibitor titer blood sample  
- 
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal) 
Subjects are permitted to be rescreened once. Subjects who fail to meet eligibility criteria 
upon rescreening are screen failures and will not be eligible to participate in the study. 
3.6.4.2 
Baseline Visit 
The following procedures and assessments will be performed at the Baseline Visit: 
• Entrance criteria (Section 3.2.1) to confirm subject eligibility (eg, Screening inhibitor 
titer is <10 BU) 
• Update medical history 
• Adverse events 
• Prior and concomitant medications 
• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• Physical examination, excluding genitourinary examination 
• Blood and urine samples for clinical laboratory assessments at central laboratory 
- 
Hematology: hemoglobin, hematocrit, platelets, red blood cell count including red 
blood cell morphology, white blood cell count with differential, absolute reticulocyte 
count 
- 
Virus safety testing blood samples  
◦ 
If necessary, in order to minimize total blood volume drawn per day, virus safety 
samples may be drawn the day prior to the Baseline Visit instead of combining 
with other baseline blood draws on a single day. However, these samples must be 
obtained prior to first dose of Alphanate. 
- 
FVIII inhibitor titer blood sample 
- 
Genotyping sample: only for subjects with no documented FVIII genotyping results 
available in their medical charts 

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◦ 
The genotyping sample may be obtained at the next scheduled clinic visit, if 
needed. 
- 
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal) 
• Train and document training of subject/caregiver on Alphanate storage requirements, 
preparation instructions, and self/caregiver-administration of Alphanate. 
• Issue diary and train subject/caregiver on its use. 
• Administer first Alphanate treatment based on subject’s current weight measured in the 
study center. 
• Dispense Alphanate IP sufficient until next scheduled visit. 
3.6.4.3 
Week 2, Week 4, Week 6, Week 8, and Subsequent Monthly Visits During ITI 
Treatment Phase 
The following procedures and assessments will be performed at scheduled visits at Weeks 2, 
4, 6, 8, and monthly thereafter during the ITI Treatment Phase: 
• Adverse events 
• Concomitant medications 
• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• FVIII inhibitor titer blood sample (assayed by central laboratory) 
• Virus safety retain samples (Week 8 and Month 15 only) 
• Review subject diary, assess treatment compliance, and retrain subject or caregiver as 
needed. 
• Dispense Alphanate IP sufficient until next scheduled visit. 
3.6.4.4 
Additional Assessments at Months 6, 12, 18, 24, and 30 During ITI Treatment 
Phase 
In addition to the procedures and assessments to be performed during the scheduled 
semimonthly and monthly visits during the ITI Treatment Phase, the following procedures 
and assessments will be performed at Months 6, 12, 18, 24, and 30 during the ITI Treatment 
Phase: 
• Physical examination, excluding genitourinary examination 
• Blood and urine samples for clinical central laboratory assessments 
- 
Hematology: hemoglobin, hematocrit, platelets, red blood cell count including red 
blood cell morphology, white blood cell count with differential, absolute reticulocyte 
count 
- 
Virus safety retain samples (Months 6 and 30 only) 

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- 
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, ALP, glucose, total bilirubin, indirect 
bilirubin 
- 
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal) 
3.6.4.5 
Factor VIII:C Pharmacokinetic Assessment Visits  
When the first inhibitor titer result has been received indicating the subject may have attained 
complete immune tolerance, a second confirmatory inhibitor measurement is to be performed 
within approximately 2 weeks after the last assessment; at this next visit, a sample is also 
collected for measuring FVIII:C in vivo recovery.  
At FVIII:C in vivo recovery visit, the following assessments will be performed: 
• Adverse events 
• Concomitant medications 
• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• Review subject diary, assess treatment compliance, and retrain subject or caregiver as 
needed.  
• FVIII inhibitor titer blood sample (assayed by central laboratory) 
• FVIII:C in vivo recovery blood samples (assayed by central laboratory) as detailed 
below: 
- 
Immediately prior to Alphanate infusion  
◦ 
Administer Alphanate 50 IU/kg.  
- 
15 to 30 minutes after the completion of the Alphanate infusion 
Upon confirmation that FVIII:C in vivo recovery is ≥66% of the predicted normal value, an 
additional visit will be scheduled to occur within approximately the following 2 weeks to 
determine FVIII:C half-life (Section 3.6.2.4).  
Prior to the FVIII:C half-life assessment visit: 
• Call the subject/caregiver to schedule the pharmacokinetic assessment visit and instruct 
subject/caregiver to stop Alphanate treatments for 72 hours prior to the FVIII:C half-life 
assessment visit. Also remind the caregiver of the need for 2 additional visits to obtain 
the 24-hour and the 48-hour pharmacokinetic samples. 
At the FVIII:C half-life visit, the following procedures and assessments will be 
performed: 
• Adverse events 
• Concomitant medications 

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• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• Review subject diary, assess treatment compliance, and retrain subject or caregiver as 
needed.  
• FVIII inhibitor titer blood sample immediately before Alphanate infusion (assayed by 
central laboratory) 
• FVIII:C in vivo recovery and half-life blood samples (assayed by central laboratory) as 
detailed below: 
- 
Immediately prior to Alphanate infusion  
◦ 
Administer Alphanate 50 IU/kg.  
- 
15 to 30 minutes after the completion of Alphanate infusion 
- 
1 hour after completion of Alphanate infusion  
- 
3 hours after completion of Alphanate infusion  
- 
6 hours after completion of Alphanate infusion 
- 
12 hours (±2 hours) after completion of Alphanate infusion 
- 
24 hours (±4 hours) after completion of Alphanate infusion 
- 
48 hours (±4 hours) after completion of Alphanate infusion 
Note: Two additional visits to the study center are required to collect the 24-hour sample 
and the 48-hour sample, and the subject is not to receive additional Alphanate until the 
48-hour blood sample has been taken unless treatment is required for a bleeding event.  
Subjects should receive their daily dose of Alphanate after all pharmacokinetic blood 
samples have been taken, and subjects will continue to receive their daily dose until it is 
determined that complete immune tolerance has been achieved. 
Upon receipt of the result of the FVIII:C half-life assessment: 
The results of FVIII inhibitor titer, FVIII:C in vivo recovery, and FVIII:C half-life will be 
provided to the investigator. If the subject’s FVIII:C half-life is ≥6 hours (in conjunction with 
negative inhibitor titers and FVIII:C in vivo recovery ≥66%), the subject is considered a 
complete success and is to enter the Prophylactic Phase and begin dose tapering as described 
in Section 3.3.1. If the subject has not met the criteria for complete immune tolerance, the 
subject will continue ITI treatments up to 33 months until complete immune tolerance is 
achieved.  
In addition, all subjects achieving partial immune tolerance at the completion of 33 months 
of ITI will have FVIII:C in vivo recovery and half-life assessments. These assessments can 
begin at the Month 33 Visit or begin at a separate visit scheduled within approximately 
2 weeks of the scheduled Month 33 Visit (following a 72-hour FVIII treatment-free period).  
3.6.4.6 
Month 33 During ITI Treatment Phase 
Subjects who are treatment failures at Month 33 should be scheduled for the Early 
Termination Visit (Section 3.6.4.8) instead of the Month 33 Visit.  

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For subjects who have achieved partial immune tolerance, the subject will undergo FVIII:C 
pharmacokinetic assessments at the Month 33 Visit. Alternatively, the pharmacokinetic 
assessments can be scheduled to begin at a separate visit following the Month 33 Visit. If 
FVIII:C pharmacokinetic assessments are to begin at the Month 33 Visit, a telephone call is 
to be made by the study center staff 4 days prior to the visit to instruct the partial success 
subject/caregiver to stop Alphanate treatments for 72 hours prior to the visit.  
The following procedures and assessments will be performed at Month 33 during the ITI 
Treatment Phase for subjects who have achieved partial immune tolerance: 
• Adverse events 
• Concomitant medications 
• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• Physical examination, excluding genitourinary examination 
• Blood and urine samples for clinical central laboratory assessments 
- 
Hematology: hemoglobin, hematocrit, platelets, red blood cell count including red 
blood cell morphology, white blood cell count with differential, absolute reticulocyte 
count 
- 
Virus safety retain samples 
- 
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, ALP, glucose, total bilirubin, indirect 
bilirubin 
- 
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if 
abnormal)FVIII inhibitor titer blood sample (assayed by central laboratory) 
• Review subject diary, assess treatment compliance, and retrain subject or caregiver as 
needed. 
• Perform FVIII inhibitor titer assessment and begin FVIII:C pharmacokinetic assessments 
(Section 3.6.4.5) or schedule a separate visit for the FVIII:C pharmacokinetic 
assessments. 
• Remind subject to not receive Alphanate until completion of the pharmacokinetic 
assessments at 24 hours and 48 hours after in-clinic Alphanate administration. 
3.6.4.7 
Prophylactic Phase Visits 
All subjects who have confirmed complete tolerization and have had FVIII:C 
pharmacokinetic assessments at the completion of the ITI Treatment Phase will enter the 
12-month Prophylactic Phase and continue in this phase through completion. Subjects who 
have confirmed partial tolerization at the completion of 33 months of ITI treatment and have 
had FVIII:C pharmacokinetic assessments at the completion of the ITI Treatment Phase will 
enter the Prophylactic Phase (that includes dose tapering) and continue in this phase through 
completion. If relapse during the Prophylactic Phase is suspected based on FVIII inhibitor 
titer or FVIII:C recovery results, confirmatory assessments of FVIII inhibitor titer and 

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FVIII:C recovery must be performed (assayed by central laboratory) within approximately 
2 weeks to confirm relapse (Section 3.6.2.4).  
The following procedures and assessments will be performed as detailed below during the 
Prophylactic Phase: 
MONTHS 1, 2, 4, 8, AND 10 VISITS DURING PROPHYLACTIC PHASE 
• Adverse events 
• Concomitant medications 
• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• Review subject diary, assess treatment compliance, and retrain subject or caregiver as 
needed 
• FVIII inhibitor titer blood sample (assayed by central laboratory) 
• FVIII:C in vivo recovery blood samples (assayed by central laboratory) as detailed 
below: 
- 
Immediately prior to Alphanate infusion  
◦ 
Administer Alphanate 50 IU/kg.  
- 
15 to 30 minutes after the completion of Alphanate infusion 
• Instruct subject and caregiver on tapering the dose regimen (during the taper period only) 
(Section 3.3.1). 
• Dispense Alphanate sufficient until the next scheduled visit. 
MONTHS 3 AND 6 VISITS DURING PROPHYLACTIC PHASE 
• Adverse events 
• Concomitant medications 
• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• Physical examination at Month 6 visit only, excluding genitourinary examination 
• Review subject diary, assess treatment compliance, and retrain subject or caregiver as 
needed 
• FVIII inhibitor titer prior to in-center Alphanate dosing (assayed by central laboratory) 
• FVIII:C in vivo recovery blood samples (assayed by central laboratory) as detailed 
below: 
- 
Immediately prior to Alphanate infusion  
◦ 
Administer Alphanate 50 IU/kg.  
- 
15 to 30 minutes after the completion of Alphanate infusion 
• Blood and urine samples for clinical central laboratory assessments 

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- 
Hematology: hemoglobin, hematocrit, platelets, red blood cell count including red 
blood cell morphology, white blood cell count with differential, absolute reticulocyte 
count 
- 
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, ALP, glucose, total bilirubin, indirect 
bilirubin 
- 
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal) 
• Dispense Alphanate sufficient until next scheduled visit. 
MONTH 12 VISIT DURING PROPHYLACTIC PHASE 
For subjects who have maintained complete or partial immune tolerance, this visit will 
include the pharmacokinetic assessment of FVIII:C recovery and half-life (analyses 
performed at central laboratory) to confirm absence of relapse and to obtain final FVIII:C 
pharmacokinetic data. Therefore, all subjects must be instructed to not receive Alphanate for 
72 hours prior to the visit. 
• Adverse events 
• Concomitant medications 
• Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) 
• Weight 
• Physical examination, excluding genitourinary examination 
• Review subject diary and assess compliance.  
• Virus safety blood samples and retains 
• Blood and urine samples for clinical central laboratory assessments 
- 
Hematology: hemoglobin, hematocrit, platelets, red blood cell count including red 
blood cell morphology, white blood cell count with differential, absolute reticulocyte 
count 
- 
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, ALP, glucose, total bilirubin, indirect 
bilirubin 
- 
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal 
• FVIII inhibitor titer blood sample immediately before Alphanate infusion (assayed by 
central laboratory) 
• FVIII:C in vivo recovery and half-life blood samples (assayed by central laboratory) as 
detailed below: 
- 
Immediately prior to Alphanate infusion  
◦ 
Administer Alphanate 50 IU/kg  
- 
15 to 30 minutes after the completion of Alphanate infusion 
- 
1 hour after completion of Alphanate infusion  

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- 
3 hours after completion of Alphanate infusion  
- 
6 hours after completion of Alphanate infusion 
- 
12 hours (±2 hours) after completion of Alphanate infusion 
- 
24 hours (±4 hours) after completion of Alphanate infusion 
- 
48 hours (±4 hours) after completion of Alphanate infusion 
Note: Two additional visits to the study center are required to collect the 24-hour sample 
and the 48-hour sample, and the subject is not to receive additional Alphanate until the 
48-hour blood sample has been taken unless treatment is required for a bleeding event.  
• Collect unused Alphanate before sending subject home after in-clinic Alphanate dosing. 
3.6.4.8 
Early Termination Visit 
The following assessments and procedures will be performed for subjects who are withdrawn 
from the study for treatment failure or subjects who discontinue the study prematurely for 
any reason: 
• Adverse events 
• Concomitant medications  
• Vital signs 
• Weight 
• Physical examination, excluding genitourinary examination 
• Blood and urine samples for clinical laboratory assessments to be sent to the central 
laboratory 
- 
Hematology: hemoglobin, hematocrit, platelets, red blood cell count including red 
blood cell morphology, white blood cell count with differential, absolute reticulocyte 
count 
- 
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, ALP, glucose, total bilirubin, indirect 
bilirubin  
- 
FVIII inhibitor titer  
- 
FVIII:C in vivo recovery (Note: If FVIII:C in vivo recovery is ≥66%, separate visits 
must be scheduled at which time the assessment of FVIII:C half-life will be 
performed.) 
- 
Virus safety retain samples 
- 
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal) 
• Collect unused Alphanate 
3.6.4.9 
Unscheduled Visits 
Monitoring the safety of the subject by the investigator may require additional unscheduled 
visits. The sponsor should be consulted prior to performing assessments or procedures 

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outside the scope of the types of assessments that are performed at scheduled visits (ie, for 
assessments or procedures other than repeat physical examination, hematology, clinical 
chemistry, urinalysis, FVIII inhibitor titer, and FVIII:C recovery). 
3.7 
Screen Failures  
Screening evaluations will be used to determine the eligibility of each subject for enrollment. 
Subjects who fail to meet eligibility criteria at Screening may be rescreened once. Subjects 
who fail to meet eligibility criteria upon rescreening will be considered screen failures and 
will not be eligible to participate in the study. 
3.8 
Interruption of ITI Treatment  
Interruptions of ITI treatments should be avoided whenever possible because they could have 
an adverse effect on the outcome of the ITI. If central venous access is temporarily lost 
because of line infection, ITI should continue through peripheral veins as long as possible 
until central venous access can be restored. 
3.9 
Removal of Subjects 
Subjects may withdraw or be withdrawn from the study for the following reasons: 
• At their own request or at the request of their legally acceptable representative 
• If, in the investigator’s opinion, continuation in the study would be detrimental to the 
subject’s well-being 
• At the specific request of the sponsor 
Also subjects must be withdrawn for the following reasons:  
• Subject is determined to be a treatment failure at the completion of 33 months of ITI 
treatment (Section 3.5.1.2). 
• Subject has as a confirmed relapse in the Prophylactic Phase in which there is a 
concomitant loss of clinical response to FVIII therapy. 
• Subject develops an infection with HAV, HBV, HCV, or HIV during the study. 
• Subject develops a concomitant disease which, either because of its severity or duration 
or because it requires a change in treatment, contravenes the condition of the study. 
• Subject is noncompliant with the protocol per the investigator’s discretion. 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject’s 
records.  
3.10 Premature Termination of Study/Closure of Center 
The sponsor, IRB/EC, and regulatory authorities have the right to close this study or a study 
center, and the investigator/sponsor has the right to close a center at any time, although this 
should occur only after consultation among involved parties. The IRB/EC must be informed. 

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Should the study or study center be closed prematurely, all study materials (except 
documentation that has to remain stored at the study center) must be returned to the sponsor. 
The investigator will retain all other documents until notification is given by the sponsor for 
destruction. 
A study center can be closed for the following reasons: 
• Lack of enrollment  
• Noncompliance with the requirements of the study protocol 
• Noncompliance with ICH GCP 
4 
ADVERSE EVENTS  
4.1 
Warnings and Precautions 
For complete information on Alphanate, refer to the Investigator’s Brochure. 
4.2 
Adverse Event Monitoring 
Subjects must be carefully monitored for AEs. This monitoring includes clinical and 
laboratory tests and physical signs. Adverse events should be assessed in terms of their 
seriousness, severity, and relationship to Alphanate. 
4.3 
Adverse Event Definitions 
4.3.1 
Adverse Events  
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 
have a causal relationship with this administration. An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Any AE that occurs at any time between the time of the signature of the informed consent 
form (ICF) and the last day of the subject’s participation in the clinical trial must be reported 
and recorded on the AE eCRF entry. 
All local infusion-site reactions will be recorded in the eCRF. The subset of local 
infusion-site reactions where the symptoms/signs lead to infusion interruption or 
discontinuation, require concomitant medication, or have an impact on the general condition 
of the subject as judged by the investigator will be considered as AEs.  
4.3.2 
Suspected Adverse Drug Reactions/Adverse Reactions 
All noxious and unintended responses to a medicinal product or study treatment related to 
any dose should be considered suspected ADRs. The phrase “responses to a medicinal 

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product” means that a causal relationship between a medicinal product or study treatment and 
an AE is at least a reasonable possibility, that is, the relationship cannot be ruled out. An AR 
is defined as a suspected ADR with a causal relationship of “definite.” 
4.3.3 
Causality of Adverse Event 
The investigator is required to provide a causality assessment for each AE reported to the 
sponsor. The sponsor will consider the investigator’s causality assessment and also provide 
its own assessment. Assessment of the causal relationship to the study drug will be made 
according to the following classifications based on Karch et al (18): 
• Definite: an event that follows a reasonable temporal sequence from administration of the 
treatment or in which the treatment level has been established in body fluids or tissues, 
that follows a known response pattern to the suspected treatment, and that is confirmed 
by improvement on stopping the treatment (dechallenge) and reappearance of the event 
on repeated exposure (rechallenge) 
• Probable: an event that follows a reasonable temporal sequence from administration of 
the treatment, that follows a known response pattern to the suspected treatment, that is 
confirmed by dechallenge, and that could not be reasonably explained by the known 
characteristics of the subject’s clinical state 
• Possible: an event that follows a reasonable temporal sequence from administration of 
the treatment, that follows a known response pattern to the suspected treatment, but that 
could have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject 
• Doubtful/Unlikely: an event that follows a reasonable temporal sequence from 
administration of the treatment, that does not follow a known response pattern to the 
suspected treatment, but that could not be reasonably explained by the known 
characteristics of the subject’s clinical state 
• Unrelated: any event that does not meet the criteria above 
The operational tool to decide the AE causal relationship is based on algorithms by Karch et 
al (19) and Naranjo et al (20). 
When an AE is classified assessing causal relationship by the investigator, as “definitive,” 
“probable,” “possible,” or “doubtful/unlikely,” the event will be defined as a suspected ADR. 
When the causal relationship is labeled “unrelated,” then it will be considered that the AE is 
not imputable to the study treatment and it is not a suspected ADR. 
In addition, when a causal relationship between the study treatment and the AE cannot be 
ruled out by the investigator and/or sponsor, it means that the AE cannot be labeled 
“unrelated.” 
For any subject, all AEs that occur at any time from the beginning of Alphanate 
administration until the final visit of the clinical trial will be considered as 
treatment-emergent AEs. 

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4.3.4 
Severity of Adverse Event or Suspected Adverse Drug Reaction 
Adverse events and suspected ADRs will be classified depending on their severity according 
to the following definitions: 
• Mild: an AE which is well tolerated by the subject, causing minimum degree of malaise 
and without affecting normal activities 
• Moderate: an AE that interferes with the subject’s normal activities 
• Severe: an AE that prevents the subject from performing their normal activities 
Adverse event and suspected ADR severity gradation must be distinguished from AE and 
suspected ADR seriousness gradation, which is defined according to event consequence. For 
example, headache can be mild, moderate, or severe but not necessarily serious in all these 
cases. 
The investigator will be responsible for assessing the AE and suspected ADR intensity 
during the clinical trial, taking into account current criteria included in this section.  
4.3.5 
Expectedness of Adverse Event or Suspected Adverse Drug Reaction 
An AE or suspected ADR is considered “unexpected” if the nature, seriousness, severity, or 
outcome of the reaction(s) is not consistent with the reference information. The expectedness 
shall be determined by the sponsor according to the reference document (ie, the 
Investigator’s Brochure) for any serious ADRs (potentially related SAEs) for expedited 
safety reporting purposes.  
4.3.6 
Seriousness of Adverse Event or Suspected Adverse Drug Reaction; 
Serious Adverse Event 
An AE or suspected ADR is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
• Death 
• Life-threatening AE  
(Life-threatening in the definition of “serious” refers to an event in which the subject was 
at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe.) 
• In-patient hospitalization (when a patient stays more than 24 hours in hospital) or 
prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• A congenital anomaly/birth defect 
• An important medical event  
(Important medical event in the definition of “serious” refers to those events which may 
not be immediately life-threatening or result in death or hospitalization but from medical 

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and scientific judgment may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed above.) 
Only hospital stays of at least 24 hours in duration are to be considered hospitalizations in the 
definition of an SAE. The following hospitalizations do not qualify an AE as an SAE: 
• Hospitalization or prolongation of hospitalization needed for procedures required by the 
clinical trial protocol. 
• Hospitalization or prolongation of hospitalization as part of a routine procedure followed 
by the center. 
• Hospitalization for a survey visit, annual physicals, or social reasons. 
• Elective or preplanned hospitalizations for a pre-existing condition that had not worsened 
from Baseline (eg, elective or scheduled surgery arranged prior to start of the study). 
• Admissions not associated with an AE (eg, social hospitalization for purposes of respite 
care). 
This definition permits either the sponsor or the investigator to decide whether an event is 
“serious.” If either the sponsor or the investigator believes that the event is serious, the event 
must be considered “serious” and evaluated by the sponsor for expedited reporting.  
A distinction should be drawn between serious and severe AEs. The term “severe” is used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of 
relative minor medical significance (such as severe headache). This is not the same as 
“serious,” which is defined on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject’s life or functioning. Seriousness (not severity) is a 
medical term while severity is a subjective term. 
4.3.7 
Adverse Event Documentation 
All AEs and SAEs occurring after the subject has signed the ICF through the final visit (ie, 
end of study) must be fully recorded in the subject’s eCRF and SAE form (if serious) as well 
as in the medical record. If no AE has occurred during the study period, this should also be 
indicated in the eCRF.  
It is the responsibility of the investigator to ensure that AEs are appropriately recorded. 
At each visit, AEs will be elicited by asking the individual a nonleading question such as, 
“Do you feel different in any way since the last visit?” Moreover, AEs will also be collected 
through directly observed events or spontaneously volunteered by the subject. Clearly related 
signs, symptoms, and abnormal diagnostic procedures should preferably be grouped together 
and recorded as a single diagnosis or syndrome wherever possible. 
The following variables must be recorded on the AE eCRF entry: 
• The verbatim term (a diagnosis is preferred) 
• Date/time of onset 

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• Date/time of resolution 
• Severity (mild, moderate, severe) 
• Causality (unrelated, doubtful/unlikely, possible, probable, definite) 
- 
Causality assessment will be made only when the AE occurs after the subject has 
initiated at least one administration of Alphanate. An AE occurring before the 
subject’s exposure to Alphanate will be always labeled as “unrelated.” 
• Seriousness (yes, no) 
• Action taken (with regard to Alphanate) 
• Other action (to treat the event) 
• Outcome and sequelae (follow-up on AE) 
For AEs that occur during Alphanate administration, the infusion rate in effect at the time of 
onset of the AE, the time of onset of the AE, and the time of AE change materially in 
intensity and/or resolve will be captured in the eCRF entry. 
In addition to the investigator’s own description of the AEs, each AE will be coded according 
to the Medical Dictionary for Regulatory Activities (MedDRA). 
For example, a laboratory test abnormality considered clinically relevant, eg, causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the investigator, should be reported as an AE. Each 
event must be adequately supported by documentation as it appears in the subject’s medical 
or case file. 
4.3.8 
Events of Special Interest 
The following AEs during ITI with Alphanate are of special interest, will be intentionally 
solicited from the subject or subject’s caregiver, and will be reported as related to study drug: 
• Central venous access and catheter-related complications for which the device was placed 
or was used for FVIII administration within the trial (eg, line infections, line thrombosis) 
• Infusion-site reactions  
• Thromboembolic events 
• Hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions 
4.3.9 
Type and Duration of the Follow-Up of Subjects After Adverse Events  
Insofar as is possible, all individuals will be followed up until the AE or suspected ADR has 
been resolved. If an AE/suspected ADR/SAE is present when the subject has completed the 
study, the course of the event must be followed until the final outcome is known or the event 
has been stabilized, no further change is expected, and the investigator decides that no further 
follow-up is necessary. 

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4.4 
Reporting of Serious Adverse Events  
4.4.1 
Reporting Serious Adverse Event  
Any SAE (see Section 4.3.6) that occurs after signing the study ICF through the final visit 
(ie, end of study) must be expeditiously reported whether or not considered attributable to the 
study drug. Each SAE must be fully recorded in the subject’s eCRF and SAE Report Form. 
Serious adverse events will be reported using the designated SAE Report Form. When the 
investigator becomes aware of an SAE, she/he must submit a completed, signed, and dated 
SAE Report Form (in English) within 24 hours to the sponsor by email/fax. The date of this 
SAE discovery by the site staff should be documented in the source documents (ie, medical 
records). 
Each SAE must be followed up until resolution or stabilization. After the initial report, all 
relevant information for SAE follow up, and for the outcome, must also be supplied to the 
sponsor in a timely manner (within 3 days from its identification or within 24 hours for 
relevant new information) by means of the SAE Report Form. In addition, the sponsor or 
contract research organization may request additional information and/or reports. 
All SAE Report Forms must be reported by email to: 
Grifols Global Pharmacovigilance for Reporting SAEs  
Email: 
 
FAX (back-up only): 
(US) 
 
(International) 
 
5 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE 
5.1 
Statistical and Analytical Plans 
Data handling and evaluation procedures will be described in the Statistical Analysis Plan. 
5.1.1 
Subject Populations for Analysis 
The subject populations for analysis include the following: 
• The Safety Population includes all subjects who receive any amount of Alphanate. 
• The Treated Population includes all subjects who are enrolled and treated for ITI with at 
least 1 dose of Alphanate. In this study, the Treated Population is the same as the Safety 
Population; however, for efficacy analyses, the term “Treated Population” will be used. 
• The Efficacy Evaluable Population includes all subjects who were determined to have 
achieved complete immune tolerance, to have achieved partial immune tolerance, or to be 

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treatment failures based on meeting the protocol-specified definitions of these categories 
of response. 
5.1.2 
Demographic and Baseline Characteristics 
The demographic and baseline characteristics will be summarized based on the Safety 
Population. For quantitative variables, mean, standard deviation, median, and 
minimum/maximum values will be provided. For qualitative variables, the frequency and 
percentage will be provided. 
5.1.3 
Efficacy Analyses 
Efficacy data and analyses will be performed on the Treated Population. As a sensitivity 
analysis, the analysis of the primary efficacy endpoint will also be performed on the Efficacy 
Evaluable Population. 
5.1.3.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects achieving complete immune 
tolerance during the ITI Treatment Phase and will be compared to the historical spontaneous 
remission rate of 10%.  
The proportion of subjects achieving complete immune tolerance receiving Alphanate during 
the ITI Treatment Phase will be calculated along with the 95% confidence interval (CI). The 
exact (Clopper-Pearson) method for the binomial proportion will be used to calculate the 
95% CI (21). If the lower bound of the 95% CI is greater than 10%, then it is statistically 
significant that the proportion of subjects achieving complete immune tolerance receiving 
Alphanate is greater than the historical spontaneous remission rate of 10%. 
5.1.3.2 
Analysis of Secondary Efficacy Endpoints 
The proportion of subjects achieving either complete or partial immune tolerance within 
33 months of ITI treatment will be summarized with the number, percentage, and 95% CI for 
the percentage.  
Duration of maintenance of complete and partial immune tolerance will be summarized with 
mean, standard deviation, median, and minimum/maximum values. 
Time to achieving inhibitor titer <0.6 BU, time to complete immune tolerance, and time to 
partial immune tolerance will be summarized using the Kaplan-Meier method. 
Factor VIII inhibitor titer, FVIII:C recovery, and FVIII:C half-life will be summarized with 
mean, standard deviation, median, and minimum/maximum values by visit. 
Frequency of bleeding events will be summarized by severity and annualized for the duration 
of each phase of the clinical trial. For subjects who achieved complete or partial immune 
tolerance, a similar analysis will also be performed for the annualized Prophylactic Phase.  

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review of Alphanate when used for primary ITI treatment and reported complete success in 3 
of 8 primary ITI patients. Using the same criteria for defining “complete success” as those in 
the current study and a Treated Population analysis approach, the complete success rate 
reported in the International Immune Tolerance Study (1) and in the North American 
Immune Tolerance Registry (14) was in the range of approximately 25 to 40%. Assuming 
that the rate for achieving immune tolerance is 35% with Alphanate treatment based on these 
publications, 25 subjects would provide 80% power to demonstrate a statistically significant 
improvement with a one-sided test at alpha level of 0.025 in a Treated Population analysis.  
6 
 ADMINISTRATIVE 
6.1 
Investigators, Other Study Personnel, and External Committees 
Information regarding additional key personnel involved in the conduct of the study, 
including names and contact details of participating investigators, monitors, clinical 
laboratories, technical departments and/or institutions, as well as information on members of 
additional study committees, will be found in the study files of the sponsor and at the 
investigator study center within the study reference manual/file.  
Investigators and staff will receive training via an investigators’ meeting, study center 
initiation visit or other appropriate individual study center training session(s). 
6.2 
Data Quality 
Monitoring and auditing procedures defined/agreed by the sponsor will be followed to 
comply with ICH GCP guidelines. Each study center will be visited at regular intervals by a 
monitor to ensure compliance with the study protocol, ICH GCP and legal aspects. The 
on-site verification of the eCRF for completeness and clarity will include cross checking with 
source documents and clarification of administrative matters. Query verification of data will 
be described in the Data Management Plan. 
6.3 
Documentation 
The study data will be recorded and kept current in the eCRF by the study center personnel 
directly responsible for the information. Entries made in the eCRF must be verifiable against 
source documents or have been directly entered into the eCRF, in which case the entry in the 
eCRF will be considered the source data.  
The data in the eCRF will be monitored at the study center by Grifols representatives at 
regular intervals, reviewed for completeness, and compared with the source documents. 
Examples of source documents include individual subject medical records, which are 
separate from the eCRFs.  
All AEs and SAEs must be recorded. All SAEs must be recorded on the SAE form. The SAE 
form must be kept in study center records with a copy provided to the designated person as 
detailed in the study file.  

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6.3.1 
Record Retention 
At study completion, all study data will be transferred to Grifols according to ICH GCP 
guidelines, local laws, regulations, and Grifols requirements. The study file and all source 
data should be retained until notification is given by the sponsor for destruction. 
An investigator is required by ICH GCP guidelines to retain the study files. If an investigator 
moves, withdraws from an investigation, or retires, the responsibility for maintaining the 
records may be transferred to another person (eg, other investigator). Grifols must be notified 
in writing of the person responsible for record retention and the notification will be retained 
in the sponsor study file and the investigator study center file. 
6.3.2 
Access to Information for Monitoring 
The data will be recorded and kept current in the eCRFs by the center personnel directly 
responsible for the information and reviewed for completeness by the monitor. Grifols 
personnel or designee can review the records. 
In accordance with ICH GCP guidelines, the monitor must have direct access to the 
investigator’s source documentation to verify the data recorded in the eCRFs for 
completeness, consistency, and accuracy and to verify adherence to the protocol. “Source 
documentation” includes individual subject files, separate from the eCRFs. Source 
documentation should be maintained and include visit dates, laboratory results, concomitant 
treatments, vital signs, medical history, examinations, AEs, IP dispensing logs, and other 
notes as appropriate. The investigator agrees to cooperate with the monitor to ensure that any 
problems noted during the course of these monitoring visits are resolved. 
6.3.3 
Access to Information for Audits or Inspections 
Representatives of regulatory authorities or of Grifols may conduct audits or inspections or 
audits of the investigator’s study center. If the investigator is notified of an audit or 
inspection by a regulatory authority, the investigator agrees to notify the Grifols Medical 
Monitor immediately. The investigator agrees to provide to representatives of a regulatory 
agency or Grifols access to records, facilities, and personnel for the effective conduct of an 
audit or inspection. 
7 
ETHICAL AND LEGAL ASPECTS 
7.1 
Institutional Review Board/Ethics Committee  
Documented approval from the appropriate IRB/EC will be obtained for each participating 
center/country prior to study start at that center or in that country, according to ICH GCP 
guidelines, local laws, regulations, and organizations. When necessary, an extension, 
amendment or renewal of the IRB/EC approval must be obtained and also forwarded to the 
sponsor. The IRB/EC must supply to the sponsor, upon request, a list of the IRB/EC 
members involved in the vote and a statement to confirm that the IRB/EC is organized and 
operates according to ICH GCP guidelines and applicable laws and regulations. 

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7.2 
Ethical Conduct of the Study 
The procedures set out in this protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the sponsor and investigator abide by 
ICH GCP guidelines. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). This may include an audit by the sponsor representatives and/or an 
inspection by regulatory authority representatives at any time. The investigator must agree to 
the audit or inspection of study-related records by the sponsor representatives and/or 
regulatory authority representatives and must allow direct access to source documents to the 
sponsor and/or regulatory authority representatives.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard(s) to the study 
subjects without prior IRB/EC/sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it, and, if appropriate, the proposed 
protocol amendment should be submitted to the IRB/EC/sponsor. Any deviations from the 
protocol must be fully explained and documented by the investigator. 
7.3 
Regulatory Authority Approvals/Authorizations 
Regulatory authority approvals/authorizations/notifications, where required, must be in place 
and fully documented prior to study start. Study information including contact information 
for investigator study centers responsible for conducting the study will be posted on a 
publicly accessible clinical registry(ies) as required by local law. 
7.4 
Subject Information and Consent 
Subject information/ICF will be provided to investigator study centers. Prior to the beginning 
of the study, the investigator must have the IRB/EC written approval/favorable opinion of the 
written ICF and any other written information to be provided to subjects. The written 
approval of the IRB/EC, together with the approved subject information/ICF, must be filed in 
the study files, and a copy of the documents must also be provided to the sponsor by the 
investigator study center.  
Written informed consent must be obtained before any study specific procedure takes place. 
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. A signed copy of the subject ICF will be 
provided to the subject or subject’s authorized representative. 
7.5 
Insurance 
All subjects participating in the study will have insurance coverage by the sponsor, which is 
in line with applicable laws and/or regulations. 

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7.6 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor. Only the subject number will be recorded 
in the eCRF, and if the subject’s name appears on any other document (eg, pathologist 
report), it must be obliterated before a copy of the document is supplied to the sponsor. Study 
findings stored on a computer will be stored in accordance with local data protection laws. 
Subjects will be informed in writing that representatives of the sponsor, IRB/EC, or 
regulatory authorities may inspect their medical records to verify the information collected 
and that all personal information made available for an audit or inspection will be handled in 
strictest confidence and in accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential.  
The investigator will maintain a list to enable subjects’ records to be identified. 
8 
USE OF DATA AND PUBLICATION 
The sponsor is committed to honoring the principles of academic freedom while, at the same 
time, protecting its confidential information, the subjects, the integrity of the study, and the 
study documentation in compliance with applicable law. The institution and/or the 
investigator recognize that, with respect to any study that is part of a multicenter study, there 
is a need for a coordinated approach to any publication or presentation of results from the 
study centers. Accordingly, the institution/investigator shall not publish or present any results 
from this study to any third parties until: (1) the sponsor publishes the results, (2) the 
institution and/or the investigator receives written notification from the sponsor that 
publication of the results is no longer planned, or (3) 12 months following the close of study, 
whichever occurs first.  
The institution and/or the investigator shall submit to the sponsor for its review a copy of any 
proposed publication at least 30 calendar days prior to the planned date of submission for 
publication or presentation. The institution and the investigator shall consider in good faith 
all comments received from the sponsor during the review period and shall delete the 
sponsor’s confidential information (other than study results).  
If the sponsor determines that the publication contains patentable subject matter which 
requires protection, the sponsor may require the delay of submission for publication or 
presentation for an additional period of time for the purpose of filing patent applications or 
otherwise take measures to protect such information.  
The institution and/or the investigator shall acknowledge the sponsor’s support in all 
publications and presentations.  

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9 
REFERENCES 
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Study: a randomized dose comparison. Blood. 2012 Feb;119(6);1335-44. 
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inhibitor. Blood. 2009 Jan;113(1):11-7. 
3. Kurth M, Puetz J, Kouides P, Sanders J, Sexauer C, Bernstein J, et al. The use of a single 
von Willebrand factor-containing, plasma-derived FVIII product in hemophilia A 
immune tolerance induction: the US experience. J Thromb Haemost. 2011 Nov; 
9(11):2229-34. 
4. Berntorp E, Ekman M, Gunnarsson M, Nilsson IM. Variation in factor VIII inhibitor 
reactivity with different commercial factor VIII preparations. Haemophilia. 
1996;2(2):95-9. 
5. Suzuki T, Arai M, Amano K, Kagawa K, Fukutake K. Factor VIII inhibitor antibodies 
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6. Astermark J, Morado M, Rocino A, van den Berg HM, von Depka M, Gringeri A, et al. 
Current European practice in immune tolerance induction therapy in patients with 
hemophilia and inhibitors. Hemophilia. 2006 Jul;12(4):363-71. 
7. DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International 
workshop on immune tolerance induction: consensus recommendations. Haemophilia. 
2007 Jul;13 Suppl 1:1-22.  
8. Collins P, Chalmers E, Hart D, Jennings I, Liesner R, Rangarajan S, et al. Diagnosis and 
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Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. 
Haemophilia. 2015 Jun 2 [Epub ahead of print, Internet]. Available from: 
http://onlinelibrary.wiley.com/doi/10.1111/hae.12730/epdf 
10. Oldenburg J, Jiménez-Yuste V, Peiródán R, Aledort LM, Santagostino E. Primary and 
rescue immune tolerance induction in children and adults: a multicentre international 
study with a VWF-containing plasma-derived FVIII concentrate. Haemophilia. 2014 
Jan;20(1):83-91. 
11. Gringeri A. VWF/FVIII concentrates in high-risk immunotolerance: the RESIST study. 
Haemophilia. 2007 Dec;13 Suppl 5:73-7. 
12. DiMichele DM. Immune tolerance in haemophilia: the long journey to the fork in the 
road. Br J Haematol. 2012 Oct;159(2):123-34. 

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13. Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia-principal results
from the International Registry. Report of the factor VIII and IX Subcommittee. Thromb
Haemost. 1994 Jul;72(1):155-8.
14. DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices,
outcomes, outcome predictors. Thromb Haemost. 2002 Jan;87(1):52-7.
15. Kroner BL. Comparison of the International Immune Tolerance Registry and the North
American Immune Tolerance Registry. Vox Sang. 1999;77 Suppl 1:33-7.
16. Rangarajan S, Jiménez-Yuste V, Santagostino E. Adult haemophilia A patients with
inhibitors: successful immune tolerance induction with a single FVIII/VWF product.
Haemophilia. 2014 Nov;20(6):3414-7.
17. Gringeri A, Musso R, Mazzucconi MG, Piseddu G, Schiavoni M, Pignoloni P, et al.
Immune tolerance induction with a high purity von Willebrand factor/VIII complex
concentrate in hemophilia A patients with inhibitors at high risk of a poor response.
Hemophilia. 2007 Jul;13(4):373-9.
18. Karch FE, Lasagna L. Adverse drug reactions. a critical review. JAMA. 1975; 234:
1236-41.
19. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions.
Clin Pharmacol Ther. 1977; 21: 247-54.
20. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of
adverse drug reactions. Clin Pharmacol Ther. 1981; 30: 239-45.
21. Clopper CJ, Pearson ES.The use of confidence or fiducial limits illustrated in the case of
the binomial. Biometrika 1934;26(4): 404-13.
22. Caram C, de Souza RG, de Sousa JC, Araújo Pereira T, do Amaral Cerqueira AM, van
der Bom JG, et al. The long-term course of factor VIII inhibitors in patients with
congenital haemophilia A without immune tolerance induction. Thromb Haemost. 2011
Jan;105(1):59-65.

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10 APPENDICES 
Appendix 1 
Schedule of Procedures 
Screening 
Visit 
ITI Treatment Phase 
Prophylactic Phase 
Early 
Withdrawal 
Baseline 
Visit 
Weeks 2, 
4, 6, 8, 
and Then 
Monthly 
After ITI 
Start 
Months 6, 
12, 18, 24, 
and 30 
After ITI 
Start 
Pharmacokinetic 
Assessment Visits 
Month 33 After 
ITI Start 
Pharmacokinetic 
Visit a 
Months 
1, 2, 4, 
8, and 
10 
Months 
3 and 6 
Month 
12 
Procedures/Assessments 
Day 
–30 to –21
From ITI 
Start 
Day of 
ITI 
Start 
FVIII:C 
in vivo 
Recovery 
Visit 
FVIII:C 
Half-life 
Visit a 
Informed consent 
X 
Entrance criteria 
X 
X 
Medical history/demography 
b
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior c/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X d 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
FVIII genotype sample 
X e 
FVIII inhibitor titer sample f 
X 
X 
X g 
X 
X 
X 
X 
X 
X 
X 
X 
Virus safety testing samples 
X h 
X h,i 
X h 
X h 
X h 
X h 
X h 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Issue/review diary and 
retrain as needed j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer Alphanate in the 
study center 
X 
X 
X 
X 
X 
X 
X 
FVIII:C in vivo recovery k 
X 
X 
X 
X l 
X l 
X 
X 
FVIII:C half-life m 
X 
X 
X 
Xn 
Collect unused Alphanate 
X 
X 
Dispense Alphanate 
X 
X 
X 
X 
X o 
X o 

Protocol GBI1406 – Amendment 3 
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a 
This visit will be scheduled within approximately 2 weeks following the confirmation of FVIII:C in vivo recovery ≥66% of the predicted normal value. A 
reminder telephone call is to be made by the study center staff 4 days prior to the half-life visit date. The staff are also to remind the caregiver regarding the 
2 additional study center visits needed (ie, at 24 hours and 48 hours, respectively) in order to collect half-life samples. 
b 
Up to last 12 months of bleeding history will be captured. 
c 
Up to last 12 months of treatments for bleeding events will be captured. 
d 
Physical examination is only performed at Month 6 of the Prophylactic Phase. 
e 
For subjects who do not have a documented FVIII genotype, a blood sample should be obtained at the Baseline Visit, or later clinic visit (if blood volumes at 
the Baseline visit are restrictive), and sent to the central laboratory for genotyping analysis. 
f 
The scheduled inhibitor titer sample should occur ≥24 hours after the last Alphanate dosing or at the maximum possible interval from the last dose of 
Alphanate. 
g 
To accurately capture the peak inhibitor titer on ITI treatment, additional unscheduled visits for inhibitor titer measurements may occur during the first 
3 months of ITI treatment. 
h 
Samples for hepatitis A, hepatitis B, hepatitis C, HIV, and parvovirus B19 viral NAT and serology will be collected at Baseline, prior to Alphanate 
administration, and analyzed for information only. Virus safety retain samples will be collected at Screening, Week 8, Month 6, Month 15, Month 30, and 
Month 33 of the ITI Treatment Phase, as well as at the last visit of the Prophylactic Phase, or at the Early Termination Visit for virus testing in the event that 
a subject exhibits clinical signs and/or symptoms of viral infection; additional samples for viral NAT and serology testing may be collected only if there are 
clinical signs and symptoms of viral infection during the study. For subjects who achieve complete immune tolerance before Month 33, a viral retain sample 
will be collected at their last visit during the ITI Treatment Phase, before entering the Prophylactic Phase. 
i 
If necessary, in order to minimize total blood volume drawn per day, virus safety samples may be drawn the day prior to the Baseline Visit instead of 
combining with other baseline blood draws on a single day. 
j 
Issue and train subject/caregiver on diary and importance of ongoing collection of Alphanate drug administration (date/clock time of start and end of 
infusion, dose/volume, rate, and treatment interruption) or other items. 
k 
When the first inhibitor titer result has been received indicating the subject may have attained complete or partial immune tolerance, a second confirmatory 
inhibitor measurement is to be performed within approximately 2 weeks after the last assessment; at this next visit, a sample is also collected for measuring 
FVIII:C in vivo recovery. FVIII:C in vivo recovery is determined from blood samples collected before dosing and at 15 to 30 minutes after completion of 
dosing of 50 IU/kg Alphanate.  
l 
FVIII:C in vivo recovery is determined by the central laboratory during the Prophylactic Phase for subjects who achieved complete immune tolerance. 
Suspected relapse must be confirmed by a complete pharmacokinetic assessment (FVIII:C in vivo recovery and half-life) at a separate scheduled visit within 
approximately 2 weeks. 
m 
FVIII:C half-life will be performed after a 72-hour FVIII treatment-free period at the following times during the study: 
•
During the ITI Treatment Phase within approximately 2 weeks after the second consecutive inhibitor titer of <0.6 BU is achieved and FVIII:C in vivo
recovery is confirmed to be ≥66% of the predicted normal value
•
At the end of the ITI Treatment Phase in subjects who have achieved partial immune tolerance
•
At the completion of the Prophylactic Phase at the Month 12 visit

Protocol GBI1406 – Amendment 3 
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•
At separately scheduled visits after the Early Termination Visit, but only for subjects who have a FVIII:C in vivo recovery ≥66% of the predicted
normal value
FVIII:C half-life is determined from blood samples collected before dosing and at 15 to 30 minutes and 1, 3, 6, 12, 24 (±4), and 48 (±4) hours after 
completion of dosing of 50 IU/kg Alphanate. 
For subjects with a negative inhibitor titer level and FVIII:C in vivo recovery ≥66% but with FVIII:C half-life <6 hours, the half-life assessment should be 
repeated approximately every 12 weeks, at the investigator’s discretion, until the half-life is ≥6 hours. 
n 
FVIII:C half-life is to be performed at separately scheduled visits after the Early Termination Visit, but only for subjects who have a FVIII:C in vivo 
recovery ≥66% of the predicted normal value. 
o
For complete and partial success subjects, the ITI dose will be tapered down in a step-wise manner over an 8- to 12-week period to reach a final prophylactic
dose of 50 IU/kg every other day or 3 times per week.

Protocol GBI1406 – Amendment 3 
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Appendix 2 
Amendment 3 – Summary of Changes 
Sections 
Change From:  
(Strikethrough is added to highlight deleted text) 
Change To: 
(Underline is added to highlight new text) 
Rationale 
Protocol 
Synopsis; 
Section 3.1, Study 
Design and Plan 
Overall Study Design and Description: This is a 
multicenter, multinational, prospective, single-arm, 
nonrandomized, open-label study of approximately 25 
male subjects with congenital hemophilia A who will 
receive their first (primary) ITI treatment with 
Alphanate. The study will be conducted at 
approximately 20 study centers. 
Overall Study Design and Description: This is a 
multicenter, multinational, prospective, single-arm, 
nonrandomized, open-label study of approximately 25 
male subjects with congenital hemophilia A who will 
receive their first (primary) ITI treatment with 
Alphanate. The study will be conducted at 
approximately 30 study centers. 
The number of 
participating sites has 
increased. 
Protocol 
Synopsis; 
Section 3.2.1, 
Screening and 
Baseline Entry 
Criteria 
Section 3.2.1 
No previous text. 
Section 3.2.1.1 
2. The subject is a male <8 years of age at the
Baseline Visit. 
3. The subject’s documented historical peak inhibitor
titer is ≥10 BU and ≤200 BU. 
Section 3.2.1 
Note that any criterion number containing vX, was 
modified in the indicated protocol version X (eg, 2v4 
indicates that the original criterion #2 was last modified 
in Protocol Version 4). 
Section 3.2.1.1 
2v4. The subject is a male <12 years of age at the 
Baseline Visit.  
3v4. The subject’s documented historical peak inhibitor 
titer is ≥5 BU and ≤200 BU.  
Increasing the 
maximum age of 
study participants as 
well as decreasing the 
threshold of historical 
peak inhibitor titer 
should increase the 
population of eligible 
subjects that can 
enroll in the study. 
Protocol Synopsis 
Safety assessments: physical examination, clinical 
chemistry, hematology, and urinalysis will be 
assessed at Baseline, at Months 6, 12, 18, 30, and 33 
during the ITI Treatment Phase, at Months 3, 6, and 
12 during the Prophylactic Phase, and at the Early 
Withdrawal Visit. Vital signs will be assessed at all 
scheduled visits. Samples for viral safety testing will 
be collected at Baseline and at the end of the 
Prophylactic Phase (Month 12) or at the Early 
Withdrawal Visit. Adverse events and concomitant 
medications will be assessed at all scheduled visits. 
Safety assessments: physical examination, hematology, 
and urinalysis will be assessed at Screening and 
Baseline, at Months 6, 12, 18, 24, 30, and 33 during the 
ITI Treatment Phase, at Months 3 (except for physical 
examination), 6, and 12 during the Prophylactic Phase, 
and at the Early Withdrawal Visit. Clinical chemistry 
will be assessed at all of the aforementioned visits 
except for Baseline. Vital signs will be assessed at all 
scheduled visits. Samples for viral safety testing will be 
collected at Screening, Baseline, Week 8, Month 6, 
Month 15, Month 30, and Month 33 of the ITI 
Treatment Phase, as well as at the end of the 
Prophylactic Phase (Month 12) or at the Early 
Withdrawal Visit. Adverse events and concomitant 
medications will be assessed at all scheduled visits. 
Edited to fix an error 
stating that clinical 
chemistry is collected 
at baseline. 
Clarified that virus 
safety retain samples 
will also be included 
at additional time 
points. 

Protocol GBI1406 – Amendment 3 
21 Mar 2019 
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Sections 
Change From:  
(Strikethrough is added to highlight deleted text) 
Change To: 
(Underline is added to highlight new text) 
Rationale 
Section 1.2, 
Clinical 
Experience with 
Grifols 
FVIII/VWF 
Products and ITI 
The first version of this FVIII/VWF concentrate was 
licensed in the US in 1978. The first formulation to be 
designated as Alphanate was licensed in 1994, and the 
current formulation was approved by the FDA in 
1997. Alphanate is approved for the control and 
prevention of of bleeding in patients with congenital 
hemophilia A (and for the treatment of von 
Willebrand disease). 
Alphanate was also approved in Italy in 1997, 
followed by the Netherlands in 2001 and the United 
Kingdom in 2003 for the control and prevention of 
bleeding in patients with congenital hemophilia A. 
The first version of this FVIII/VWF concentrate was 
licensed in the US in 1978. The first formulation to be 
designated as Alphanate was licensed by the Food and 
Drug Administration (FDA) in 1994, and the current 
formulation was approved by the FDA in 1997. 
Alphanate is approved for the control and prevention of 
bleeding in patients with congenital hemophilia A (and 
for the treatment of von Willebrand disease [VWD]). 
Alphanate was approved in Italy in 1997 for the 
treatment and prophylaxis of bleeding in patients with 
hemophilia A and the prevention and treatment of 
hemorrhage or surgical bleeding in patients with VWD, 
followed by the Netherlands in 2001 for the treatment 
and prophylaxis of bleeding in patients with hemophilia 
A, and the United Kingdom in 2003 for the treatment 
and prophylaxis of bleeding in patients with hemophilia 
A and the prevention and treatment of hemorrhage or 
surgical bleeding in patients with VWD. 
Edits added to clarify 
in which countries 
Alphanate was 
approved. 
Section 3.1, Study 
Design and Plan 
Male subjects <8 years of age at the time of the 
Baseline Visit with severe congenital hemophilia A 
(FVIII:C levels <1%) who are candidates for ITI and 
who meet all inclusion criteria (Section 3.2.1.1) and 
do not meet any exclusion criteria (Section 3.2.1.2) 
are eligible to participate. 
Male subjects <12 years of age at the time of the 
Baseline Visit with severe congenital hemophilia A 
(FVIII:C levels <1%) who are candidates for ITI and 
who meet all inclusion criteria (Section 3.2.1.1) and do 
not meet any exclusion criteria (Section 3.2.1.2) are 
eligible to participate. 
Updated text based 
on changes to 
inclusion criteria. 
Section 3.1, Study 
Design and Plan 
Between study center visits when Alphanate will be 
administered at home by the subject’s caregiver, the 
Alphanate dose will be the same as the dose 
calculated at the most recent study center visit where 
weight was measured. Training of caregivers at home 
may be provided within the first few weeks of 
initiation of ITI treatment for initial port access and 
newly implanted devices, upon sponsor approval. 
Between study center visits when Alphanate will be 
administered at home by the subject’s caregiver, the 
Alphanate dose will be the same as the dose calculated 
at the most recent study center visit where weight was 
measured. Training of caregivers at home may be 
provided within the first few weeks of initiation of ITI 
treatment for initial port access and newly implanted 
devices, upon sponsor approval. Ongoing home health 
care for IP infusions will be assessed on a case-by-case 
basis. 
Home health care has 
been deemed 
necessary and 
approved for select 
subjects on a case-by-
case basis. 

Protocol GBI1406 – Amendment 3 
21 Mar 2019 
CONFIDENTIAL 
Page 70 of 70 
Sections 
Change From:  
(Strikethrough is added to highlight deleted text) 
Change To: 
(Underline is added to highlight new text) 
Rationale 
Appendix 1, 
Schedule of 
Procedures 
h   Samples for hepatitis A, hepatitis B, hepatitis C, 
HIV, and parvovirus B19 viral NAT and serology will 
be collected at Baseline, prior to Alphanate 
administration, and analyzed for information only. 
Virus safety retain samples will be collected at the last 
visit of the Prophylactic Phase or at the Early 
Termination Visit; additional samples for viral NAT 
and serology testing may be collected only if there are 
clinical signs and symptoms of viral infection during 
the study. 
h   Samples for hepatitis A, hepatitis B, hepatitis C, HIV, 
and parvovirus B19 viral NAT and serology will be 
collected at Baseline, prior to Alphanate administration, 
and analyzed for information only. Virus safety retain 
samples will be collected at Screening, Week 8, 
Month 6, Month 15, Month 30, and Month 33 of the ITI 
Treatment Phase, as well as at the last visit of the 
Prophylactic Phase, or at the Early Termination Visit for 
virus testing in the event that a subject exhibits clinical 
signs and/or symptoms of viral infection; additional 
samples for viral NAT and serology testing may be 
collected only if there are clinical signs and symptoms 
of viral infection during the study. For subjects who 
achieve complete immune tolerance before Month 33, a 
viral retain sample will be collected at their last visit 
during the ITI Treatment Phase, before entering the 
Prophylactic Phase. 
Virus safety retain 
samples will also be 
included at additional 
time points.